acute!lower!gastrointestinal!bleeding!in!the! …

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!ACUTE!LOWER!GASTROINTESTINAL!BLEEDING!IN!THE!

UNITED!KINGDOM!!

!!

Candidate:!Miss!Kathryn!Oakland!MBBS!BSc!MRCS!!!!!

Imperial!College!London,!National!Heart!and!Lung!Institute!!

AND!!

NHS!Blood!and!Transplant,!Oxford!!!!!!

Submitted!for!MD(Res)!!!!

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Declaration!of!originality!!!!

The!work! contained! in! this! thesis,! unless! otherwise! referenced,! is! entirely!my!

own.! Statistical! advice! for! chapters! 3O5!was! provided! by! Frances! Seeney! (NHS!

Blood! and! Transplant)! although! I! performed! the! associated! analyses.! Where!

specialist! statistical! analysis!was! required,! this!was! conducted! by! Gary! Collins!

(Professor! of! Statistics,! Centre! for! Statistics! in!Medicine,! University! of! Oxford)!

and!Paul!Bassett!(independent!statistical!consultant)!and!this!is!referenced!in!the!

methods!sections!of!chapters!6!and!7,!respectively.!

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!Copyright!declaration!!!!The!copyright!of!this!thesis!rests!with!the!author!and!is!made!available!under!a!

Creative! Commons! Attribution! NonOCommercial! No! Derivatives! license.!

Researchers!are! free! to!copy,!distribute!or! transmit! the! thesis!on! the!condition!

that! they!attribute! it,! that! they!do!not!use! it! for! commercial!purposes!and! that!

they! do! not! alter,! transform! or! build! upon! it.! For! any! reuse! or! redistribution,!

researchers!must!make!clear!to!others!the!license!terms!of!this!work.!

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Abstract!!

Introduction!

Lower!gastrointestinal!bleeding!(LGIB)!is!a!common!medical!emergency.!Despite!

this,! there! are! few! data! on! presentations,! interventions! and! patient! outcomes.!

The!aim!of! this! research! is! to!describe! the! epidemiology!of! LGIB! in! the!United!

Kingdom,! appraise! clinical! interventions! and! develop! a! risk! score! to! optimise!

patient!triage.!

!

Methods!

A!systematic!review!(SR)!of!common!interventions!for!LGIB!was!undertaken.!A!

prospective!national!observational! study!of!LGIB!presentations! to!UK!hospitals!

during!two!months!in!2015!was!conducted,!collecting!data!on!demographics!and!

outcomes! (reObleeding,! death,! reOadmission).! Frequency! of! intervention! was!

compared!to!that!identified!in!the!SR.!Multivariable!logistic!regression!was!used!

to! develop! a! risk! score! to! predict! need! for! hospitalisation,! and! independently!

validated! using! cases! collected! by! two! additional! acute! hospitals! using! CO

statistics.!

!

Results!

The! SR! identified! that! colonoscopy! within! 24! hours! of! presentation! was!

associated!with!a!higher!diagnostic!yield!and!a!reduced!length!of!hospitalisation.!

In! total! 143/174! (82.2%)! acute! hospitals! in! the! UK! participated! in! the!

observational! study,!providing!data!on!2528!cases!of!LGIB.!Most!patients!were!

elderly!(median!age!74!years)!with!major!coOmorbidities,!including!29.4%!taking!

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antiplatelets!drugs.!Only!52%!patients!underwent! inpatient! investigation,!3.9%!

receiving! colonoscopy.!Median! length! of! stay!was! 3! days! and! 85/2528! (3.4%)!

died!during!admission.!Data!from!2336!acute!admissions!were!used!to!develop!

the! risk! score,! identifying! that! >60%! patients! could! avoid! hospital! admission.!

Age,! gender,! previous!LGIB!admission,! blood!on! rectal! examination,! heart! rate,!

systolic!blood!pressure!and!haemoglobin!strongly!discriminated!safe!discharge!

(cOstatistic!0·84,!95%!confidence!interval!0·82!to!0·86).!!

!

Conclusion!

Few! patients! admitted! with! LGIB! require! treatment! for! bleeding,! or! come! to!

harm.! Many! could! safely! be! managed! as! an! outpatient.! We! developed! and!

validated!a!clinical! risk!score!with!good!discriminative!performance! to! identify!

these!patients.!!

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Acknowledgements!

The!idea!for!a!national!study!of!lower!gastrointestinal!bleeding!was!conceived!by!

Prof.!Mike!Murphy! and!Dr! Vipul! Jairath!without!whom! this! project!would! not!

have! been! possible.! Mike! offered! continuous! support,! encouragement! and!

moderation!when!needed.!No!one!replies!faster!to!emails!(even!whilst!abroad),!

meaning!that!I!always!had!direction,!and!was!the!envy!of!the!other!postOgraduate!

students.!!Vip!was!a!great!mentor!and!role!model.!He!was!full!of!inspiration!and!

encouragement! to! aim! high.! The! reputation! of! NHSBT! opened! doors! for! this!

project!that!would!have!remained!shut!for!simpler!studies,!and!even!kindled!the!

interest! of! busy! general! surgical! teams,! who!would!much! rather! be! operating!

than! trawling! the! wards! for! ‘PR! bleeders’.! I! was! able! to! make! full! use! of! the!

logistical! support! offered! by! the! NHSBT! team,! notably! John! GrantOCasey,! who!

offered!unending!patience.!!Mike!Schachter!provided!a!welcome!external!opinion!

and!Mike!Desborough!was! the! invaluable!sounding!board! I!was!able! to!bounce!

ideas! off! throughout! this!work.! Lastly! I!must! thank!my!partner!Bill!Hemstock.!

Never!has!a!professional!golfer!known!so!much!about!endoscopy,!metaOanalysis!

and!diverticular!disease.!!

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Contents!!!List!of!publications!and!presentations!arising!from!this!thesis………………………..8!List!of!abbreviations……………………………………………………………………………………10!List!of!tables………………………………………………………………………………………………..11!List!of!figures………………………………………………………………………………………………13!

1. Introduction!i. What!is!known!about!acute!lower!gastrointestinal!bleeding?......14!ii. Aims!of!the!thesis..…………………………………………………………………32!iii. Outline!of!thesis…………………………………………………………………….32!

2. Systematic!review!i. Introduction………………………………………………………………………….33!ii. Methods………………………………………………………………………………..34!iii. Characteristics!of!reviewed!studies………………………………………..41!iv. Choice!of!investigation…………………………………………………………..48!v. Timing!of!first!line!investigation…………………………………………….51!vi. Choice!of!treatment!………………………………………………………………57!vii. Assessment!of!methodological!quality……………………………………59!viii. Implications!for!practice!in!the!United!Kingdom…………………….63!

3. National!observational!study!methods!i. Recruitment!of!sites………………………………………………………………68!ii. Case!identification!and!Pilot!Study!1………………………………………69!iii. Data!collection………………………………………………………………………72!iv. Pilot!Study!2………………………………………………………………………….74!v. Data!analysis…………………………………………………………………………76!vi. Definitions…………………………………………………………………………….79!vii. Ethical!considerations……………………………………………………………80!

4. National!observational!study:!patient!results!i. Introduction,!aims!and!objectives…………………………………………..81!ii. Sample!size…………………………………………………………………………...82!iii. Patient!characteristics……………………………………………………………84!iv. Use!of!blood!components……………………………………………………….87!v. Endoscopy!and!endoscopic!haemostasis…………………………………90!vi. Radiology………………………………………………………………………………92!vii. Surgery…………………………………………………………………………………93!viii. Clinically!significant!bleeding…………………………………………………95!ix. Patients!undergoing!no!inpatient!investigations……………………..95!x. Outcomes……………………………………………………………………………...96!xi. Discussion…………………………………………………………………………..104!

5. National!observational!study:!organisation!of!services!i. Endoscopy………………………………………………………………………….110!ii. Interventional!radiology……………………………………………………..112!iii. Specialist!elderly!care…………………………………………………………113!iv. Guidelines…………………………………………………………………………..114!v. Discussion………………………………………………………………………….115!

6. Risk!score!i. Introduction……………………………………………………………………….120!ii. Additional!methods…………………………………………………………….121!

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i. Study!design!and!participants…………………………………121!ii. Study!outcomes………………………………………………………122!iii. Statistical!analysis…………………………………………………..122!iv. Comparative!assessment!with!previously!described!

scores…………………………………………………………………….124!iii. Results!

i. Demographics!and!presenting!features……………………126!ii. Predicting!safe!discharge…………………………………………129!iii. Comparison!of!the!new!score!with!previously!published!

scores…………………………………………………………………….135!iv. Discussion……………………………………………………………………………136!

7. Antiplatelet!and!anticoagulant!agents!!i. Introduction…………………………………………………………………………144!ii. Additional!methods………………………………………………………………146!iii. Management!of!antiplatelets!and!anticoagulants……………………152!iv. Antiplatelets!and!cardiovascular!outcomes……………………………159!v. Discussion……………………………………………………………………………163!

8. Conclusions…………………………………………………………………………………….169!i. Suggestions!for!future!work………………………………………………….175!

References……………………………………………………………………………………………..…178!Appendices……………………………………………………………………………………………….190!Publisher!permissions……………………………………………………………………………….197!!!!!!

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Publications!and!presentations!arising!from!this!thesis!!!Chapter!2:!Oakland!K,!Isherwood!J,!Lahiff!C,!Goldsmith!P,!Desborough!M,!Colman!KS,!Guy!R,!Uberoi!R,!Murphy!MF,!East!JE,!Hopewell!S,!Jairath!V.!Diagnostic!and!therapeutic!treatment!modalities!for!acute!lower!gastrointestinal!bleeding:!a!systematic!review.!Accepted!for!publication,!Endoscopy)International)Open.)!Chapter!3:!Oakland!K,!Guy!R,!Uberoi!R,!Seeney!F,!Collins!G,!GrantOCasey!J,!Mortensen!N,!Murphy!M,!Jairath!V!on!behalf!of!the!National!Comparative!Audit!in!Blood!Transfusion!Lower!Gastrointestinal!Bleeding!Working!Group.!Study!Protocol:!First!nationwide!comparative!audit!of!acute!lower!gastrointestinal!bleeding!in!the!United!Kingdom.!BMJ)Open.!2016!Aug!4;6(8):e011752.!doi:!10.1136/bmjopenO2016O011752.!!Chapter!4:!Oakland!K,!Guy!R,!Uberoi!R,!Hogg!R,!Mortensen!N,!Murphy!MF,!Jairath!V!on!behalf!of!the!UK!Lower!GI!Bleeding!Collaborative.!Acute!lower!gastrointestinal!bleeding!in!the!UK:!patient!characteristics,!interventions!and!outcomes!in!the!first!nationwide!audit.!Gut.!2017!Feb!1.!doi:!10.1136/gutjnlO2016O313428.!!Chapter!6:!Oakland!K!and!Jairath!V,!Uberoi!R,!Guy!R,!Ayaru!L,!Mortensen!N,!Murphy!MF,!!Collins!GS.!Safe!discharge!after!acute!lower!gastrointestinal!bleeding:!derivation!and!validation!of!a!novel!risk!score.!Lancet)Gastroenterology)and)Hepatology,!2017!Jun!23!doi:!10.1016/S2468O1253(17)30150O4! )Plenary)Lectures))Achieving!clinical!excellence!with!PR!bleeding!patients.!2nd!Emergency!Surgery!Conference,!Oxford,!16th!September!2016!!Lessions! Learned! from! the! National! Lower! Gastrointestinal! Bleeding! Audit.!Research! and! audit! in! the! emergency! setting! session,! Association! of!Coloproctology! of! Great! Britain! and! Ireland! Annual! Meeting,! Edinburgh,! July!2016!!!Oral)Presentations))Oakland!K,!Babra!P,!GrantOCasey!J,! Jairath!V,!Guy!R,!Mortensen!N,!Murphy!MF,!Uberoi!R.!The!use!of!radiology!for!haemorrhage!control!in!lower!gastrointestinal!bleeding:! results! from! a! national! comparative! audit.! British! Society! of!Interventional!Radiology,!Manchester,!15O17th!November!2016!)

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)Poster)Presentations)!Oakland!K,!GrantOCasey!J,!Jairath!V,!Guy!R,!Mortensen!N,!Murphy!MF,!Uberoi!R.!The! provision! of! interventional! radiology! for! the! treatment! of! lower!gastrointestinal! bleeding:! results! from! a! nationwide! audit.! British! Society! of!Interventional!Radiology,!Manchester,!15O17th!November!2016!!Oakland!K,!Guy!R,!Uberoi!R,!GrantOCasey!J,!Mortensen!N,!Jairath!V,!Murphy!MF!on! behalf! of! the! National! Comparative! Audit! in! Blood! Transfusion! Lower!Gastrointestinal! Bleeding! Working! Group.! Blood! Transfusion! in! Lower!Gastrointestinal!Bleeding:!Results!From!a!National!Study!in!the!United!Kingdom.!AABB!International!meeting,!Orlando,!October!2016!!Oakland!K,!Guy!R,!Uberoi!R,!GrantOCasey!J,!Mortensen!N,!Murphy!MF,!Jairath!V.!Outcomes!of!acute!lower!gastrointestinal!bleeding:!data!from!a!large!nationwide!audit.!United!European!Gastroenterology!Week,!Vienna,!October!2016!

!Oakland!K,!Uberoi!R,!GrantOCasey!J,!Murphy!MF,!Jairath!V,!Mortensen!N,!Guy!R.!The!use!of!surgery!in!the!management!of!acute!lower!gastrointestinal!bleeding:!results! from! a! large! national! audit.! European! Society! of! Coloproctology,!Milan,!30th!September!2016!!Oakland! K,! GrantOCasey! J,! Jairath!V,! Guy!R,! Mortensen!N,! Murphy!M,! Uberoi!R.!Provision! of! interventional! radiology,! endoscopy! and! surgery! for! acute! lower!gastrointestinal! bleeding! in! the! United! Kingdom:! preliminary! results! of! a!national! comparative! audit.! Cardiovascular! and! Interventional! Radiological!Society!of!Europe!(CIRSE),!Barcelona,!September!2016!!!

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List!of!abbreviations!!!CI!–!confidence!interval!CTA!–!computerised!tomographic!angiography!DAPT!–!dual!antiplatelet!drug!therapy!DOAC!–!direct!oral!anticoagulant!DRE!–!digital!rectal!examination!EUA!–!examination!under!anaesthesia!EBL!–!endoscopic!band!ligation!FFP!–!fresh!frozen!plasma!Hb!O!haemoglobin!HctO!haematocrit!HES!–!hospital!episode!statistics!HRO!heart!rate!ICD!–!International!Classification!of!Diseases!ICU!–!intensive!care!unit!INR!–!international!normalised!ratio!IQR!–!interquartile!range!IR!–!interventional!radiology!LGIB!–lower!gastrointestinal!bleeding!LOS!–!length!of!stay!MA!–!mesenteric!angiography!NCEPOD!–!National!Confidential!Enquiry!into!Patient!Outcomes!and!Death!MD!–!mean!difference!MI!–!myocardial!infarction!NHS!–!national!health!service!NICEO!National!Institute!of!Health!and!Care!Excellence!NRSI!–!nonOrandomised!studies!of!intervention!NSAID!–!nonOsteroidal!antiOinflammatory!drug!OGDO!oesophagogastroduodenoscopy!OR!–!odds!ratio!PCC!–!prothrombin!complex!concentrate!PH!–!proportional!hazards!RBC!–!red!blood!cell!RCT!–!randomised!controlled!trials!RR!–!risk!ratio!SBP!–!systolic!blood!pressure!SD!–!standard!deviation!UGIB!–upper!gastrointestinal!bleeding!UK!–!United!Kingdom!!!!!!!!!

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List!of!tables!!!Table!1:!! Summary!of!evidence!by!comparison!investigated!and!study!

methodology!!Table!2:! !Study!characteristics!!Table!3:!! InterOstudy!variability!of!the!definition!of!reObleeding!

Table!4:!! Assessment! of! methodological! quality;! Cochrane! risk! of! bias! for!RCTS,!NewcastleOOttawa!for!NRSI!

!Table!5:! !Pilot!case!identification!tool!!Table!6:!! Study!definitions!!Table!7:!! Presenting!features!and!demographics!of!patients!admitted!with!or!

who!developed!LGIB!whilst!an!established!inpatient!!Table!8:!! Inpatient!Interventions!for!LGIB!!Table!9:!! The!frequency!of!shock!and!transfusion!by!admitting!Hb!!Table!10:! !Patients!who!required!emergency!laparotomy!for!LGIB!!Table!11:!! Discharge!diagnoses!by!age!!Table!12:!! Outcomes! and! cause! of! death! in! patients! admitted! with! or! who!

developed!LGIB!whilst!an!established!inpatient!!Table!13:!! The!availability!of! in!and!out!of!hours! lower!GI!endoscopy! in! the!

UK!!Table!14:!! The!availability!of! in!and!out!of!hours! interventional!radiology! in!

the!UK!!Table!15:!! Demographic!data!for!candidate!variables!in!the!development!and!

validation!cohort!!Table!16:!! Sources!of!bleeding!!Table!17:!! Diagnostic!and!therapeutic!interventions!!Table!18:!! Final!prediction!model!for!safe!discharge!!Table!19:!! A!score!to!predict!the!safe!discharge!of!patients!presenting!with!a! ! cute!LGIB!!

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Table!20:!! Probability!of!safe!discharge!by!total!score!!Table!21:!! Number!of!patients!safely!discharged!by!score!!Table!22:! !COstatistics!for!the!new!model!against!existing!models!for!safe!

discharge!and!adverse!clinical!outcomes.!!POvalues!are!from!the!DeLong!test,!with!reference!to!the!new!model.!

!Table!23:!! Patient!characteristics!by!drug!group!!Table!24:!! Interventions!for!LGIB!by!antiplatelet!and!anticoagulant!exposure!!Table!25:!! Sources!of!LGIB!by!drug!exposure!!Table!26:!! Unadjusted!patient!outcomes!!Table!27:!! Univariate!and!multivariate!regression!models!for!reObleeding,!reO

admission!with!bleeding,!mortality!and!adverse!cardiovascular!outcomes!

!Table!28:!! Unadjusted!patient!outcomes!in!patients!who!were!receiving!a!

single!antiplatelet!and!had!it!continued!and!those!that!had!it!interrupted!

!Table!29:! Univariate!and!multivariate!regression!models!for!reObleeding,!reO

admission!with!bleeding,!mortality!and!adverse!cardiovascular!outcomes!in!patients!receiving!a!single!antiplatelet!drug!

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List!of!figures!!!Figure!1:!! PRISMA!flowOchart!of!eligible!studies!

Figure!2:!! Forest!plot!of!comparison!of!NRSI!a)!presumptive!diagnoses,!b)!definite!diagnoses.!95%!CI,!95%!confidence!interval!

!Figure!3:!! Forest!of!plot!of!comparison!of!NRSI!a)!therapeutic!yield,!b)!length!

of!stay.!95%!CI,!95%!confidence!interval!!Figure!4:!! Flow!chart!of!excluded!and!included!cases!!Figure!5:!! The!relationship!between!Charlson!CoOmorbidity!Index!and!death!

and!reObleeding!!Figure!6:!! Calibration!plot!of!the!final!prediction!model!for!safe!discharge!in!

the!validation!cohort.!95%!CI!around!the!observed!predictions!(triangle)!at!tenths!of!predicted!risk.!

!Figure!7:!! The!distribution!of!scores!and!associated!proportion!of!safe!

discharges!!!Figure!8:!! FlowOchart!of!cases!! !Figure!9:!! KaplanOMeier!graph!of!time!to!inOhospital!reObleeding!!

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CHAPTER!ONE:!INTRODUCTION!!!1.1!What!is!known!about!acute!lower!gastrointestinal!bleeding?!!!

Acute! lower! gastrointestinal! bleeding! (LGIB)! is! a! common! acute! medical! and!

surgical!emergency.!In!contrast!to!upper!gastrointestinal!bleeding!(UGIB),!which!

has!several!published!guidelines,1!is!well!researched!and!has!seen!improvements!

in! clinical! outcomes,2! LGIB! has! not! been! a! focus! for! clinical! or! scientific!

investigation.!In!the!United!Kingdom!(UK)!LGIB!is!a!leading!indication!for!red!cell!

(RBC)! transfusion,3! but! unlike!UGIB,!most! cases! are! considered! to! resolve! and!

stop!bleeding!without!intervention.4!5!In!2015!the!National!Confidential!Enquiry!

in! Patient! Outcomes! and! Death! (NCEPOD)! published! a! report! on! severe!

gastrointestinal!bleeds!that!found!that!only!44%!of!patients!received!good!care.6!

This! is! at! least! partly! the! result! of! the! lack! of! high! quality! research! into! the!

management!of!patients!that!present!with!LGIB,!a!problem!that!this!thesis!aims!

to!address.!

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Definition)

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Traditionally!UGIB!and!LGIB!have!been!distinguished!by!the!origin!of!bleeding!in!

relation! to! the! ligament! of! Treitz.! UGIB! corresponds! to! bleeding! in! the!

oesophagus,!stomach!and!duodenum,!whereas!LGIB!encompasses!bleeding!in!the!

small! bowel,! colon! and! anorectum.! Developments! in! options! for! investigating!

bleeding! in! the! small! bowel!have! lead! to! the! emergence!of! a! the! term! ‘midOGI’!

bleeding,7! corresponding! to! bleeding! originating! in! the! jejunum! and! ileum.! At!

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presentation! LGIB! can! cause! bright! rectal! bleeding,! clots,! blood!mixed! in!with!

stool! as!well! as!melaena,! although! the! latter!may! indicate! an!upperO!or!midOGI!

source.!!

)

Global)Incidence)

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Although!LGIB! is! common!condition,! there! are! limited! studies!documenting! its!

incidence.!A!population!based!study!in!ten!hospitals!in!Spain!compared!patients!

discharged!with!hospital!codes!consistent!with!GI!complications!over!ten!years.!

It!was! found! that! in! comparison! to! the! upper! GI! tract,!where! the! incidence! of!

complications!fell!from!87/100,000!to!47/100,000!over!ten!years,!the!incidence!

of! complications! in! the! lower! GI! tract! increased! from! 20/100,000! to!

33/100,000.2!The!results!of!the!aforementioned!study!are!limited!by!its!sample!

size;! results! were! extrapolated! from! ten! hospitals! to! calculate! a! national!

incidence.!Additionally!cases!were!captured!using!discharge!codes!that!included!

GI! complications! not! related! to! bleeding.! A! group! in! Iceland! calculated! an!

incidence! of! 87/100,000! for! LGIB! by! multiplying! the! number! of! endoscopy!

referrals!for!the!investigation!of!rectal!bleeding!or!melaena!to!a!single!hospital!in!

2010.8! This! method! also! comprised! a! small! number! of! patients! and! may! be!

inaccurate!as!endoscopy!is!not!the!sole!mode!of!investigation!of!LGIB.!Historical!

studies!estimate!the!incidence!of!LGIB!as!20.5/100,000!but!again!this!is!based!on!

data!from!a!single!centre.9!

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There!are!no!data!on!the!incidence!of!LGIB!in!the!UK.!A!systematic!review!of!the!

literature!and!hospital!episode!data!was!unable!to!quantify!the!incidence!of!LGIB!

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but! did! report! that! it! accounts! for! 20%!of! all! GI! bleeding.10! In! the!UK,! LGIB! is!

typically!managed!by!surgeons!and!represents!3%!of!surgical!referrals.11!

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Patient)Demographics,)CoCmorbidity)and)Pharmacotherapy)

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Studies!of!hospital!registries!have!shown!that!patients!that!develop!LGIB!tend!to!

be! elderly,! with! a!mean! age! of! 63O69! years.11!12! CoOmorbid! illness! is! common,!

78%!admitted!patients!have!>1!coOmorbid!conditions,13!33%!have!≥2.12!Aspirin!

for!secondary!prevention!is!used!in!20O33%,13!clopidogrel!in!3.2%!and!warfarin!

in! 6%! patients.14! There! are! no! published! data! on! the! number! of! patients!

admitted!with!LGIB!who!are!receiving!a!direct!oral!anticoagulant!(DOAC).!!

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PopulationObased!database!studies!suggest!an!increased!risk!of!developing!LGIB!

with! aspirin8! or! longOterm! oral! nonOsteroidal! antiOinflammatory! drug! (NSAID)!

use.15!16!Inhibition!of!cycloOoxygenase!1!by!NSAIDs!and!aspirin!is!associated!with!

reduced! levels! of! protective!mucosal! prostaglandins17!which! induces! intestinal!

ulceration.18!Unlike!the!upper!GI!tract!where!this!effect!may!be!mitigated!by!the!

concomitant!use!of!proton!pump!inhibitors,!in!the!lower!GI!tract!these!drugs!may!

lead! to! an! increase! in! bleeding.19! 20! In! the! colon,! animal! studies! suggest! that!

NSAIDs! and! aspirin! are! additionally! associated! with! derangements! in! the!

microbiome!leading!to!mucosal!inflammation!and!a!propensity!for!bleeding.21!

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Vitamin!K!antagonists!are!also!associated!with!developing!of!LGIB,16!22!increased!

severity!of!bleeding!when!it!occurs,8!and!are!a!risk!factor!for!mortality.12!Unlike!

NSAIDs!and!aspirin,! the!effects!of!oral!anticoagulants!are!most! likely! limited!to!

! 17!

disruption!of!coagulation!as!opposed!to!local!effects!on!the!intestine.!DOACs!are!

increasingly! used! as! alternatives! to! warfarin! due! to! their! more! predictable!

pharmacodynamics!and!improved!side!effect!profiles.!However,!pooled!analyses!

from! randomised! controlled! trials! indicate! that! in! comparison! to! warfarin,!

patients!receiving!DOACs!have!an!increased!risk!of!GIB.23!24!There!are!currently!

no! published! data! on! the! outcomes! of! DOAC! patients! who! develop! LGIB,! and!

guideline! recommendations! on! the! management! of! DOAC! associated! LGIB! are!

based!on!preclinical!information!and!expert!opinion.25!

!

Retrospective! database! studies! have! also! suggested! links! between!

bisphosphonates!and! selective! serotonin! reOuptake! inhibitors!and!an! increased!

risk!of!LGIB,26!27!but!whether!this!risk!is!clinically!significant!remains!unclear.!!

!

Transfusion)

!

RBC! transfusion! is!employed! in!21O40%!patients!admitted!with!LGIB.8!12! In! the!

UK,! GIB! is! the! second! most! common! indication! for! RBC! transfusion! after!

haematological!malignancy,!LGIB!accounting!for!half!of!all!transfusions!for!GIB.3!!

!

In! certain! settings! such!as! critical! care!and!cardiac! surgery,! there! is! increasing!

evidence! that! liberal! RBC! transfusion!may! have! no! advantage! over! restrictive!

transfusion,28! and! that! in! some! patients! it! may! be! harmful,! reducing! 30Oday!

survival.29!In!its!2015!transfusion!guideline,!the!National!Institute!for!Health!and!

Care! Excellence! (NICE)! recommended! using! restrictive! RBC! transfusion! in! all!

! 18!

patients! who! require! transfusion! without! major! bleeding,! acute! coronary!

syndrome!or!chronic!anaemia!requiring!regular!transfusions.30!!

!

In!the!GIB!setting,!evidence!for!liberal!transfusion!is!less!clear.!In!UGIB!there!are!

three! major! trials! of! restrictive! and! liberal! RBC! transfusion.! Villarejo! et) al!

randomised! 60! stable! UGIB! patients! to! receive! RBC! transfusion! once! their!

haematocrit!(Hct)!reached!<28%!(liberal!arm)!or!<21%!(restrictive!arm).31!The!

authors!reported!no!difference!between!the!groups!in!terms!of!length!of!stay!or!

‘organ! failure’,! although! 33! patients! were! lost! to! followOup.! Villanueva! et) al)

conducted! a!much! larger! trial,! randomising! 889! patients! to! receive! single! unit!

transfusions! at! a! haemoglobin! (Hb)! threshold! of! <70g/L,! with! further!

transfusions! to! maintain! a! target! of! 70O90g/L! (restrictive! arm),! or! to! receive!

single!unit!transfusions!at!a!Hb!threshold!of!<90g/L,!with!a!target!of!90O100!g/L!

(liberal!arm).32!Patients!were!enrolled!from!a!single!centre!after!being!admitted!

with! UGIB! of! any! aetiology.! Exclusions! included! massive! exsanguinating!

haemorrhage,!mild!bleeding!(signified!by!a!Blatchford!score!of!0)!and!a!history!of!

ischaemic!cardiovascular!disease.!Overall!mortality!data!demonstrated!improved!

45Oday! survival! with! a! restrictive! strategy.! The! effect! was! most! marked! in!

patients!with!chronic!liver!disease!(ChildOPugh!class!A!or!B)!with!a!hazard!ratio!

of!0.30!(95%!confidence!interval,!CI,!0.11!to!0.85).!In!patients!with!peptic!ulcer!

bleeding,! which! is! more! akin! to! aetiologies! seen! in! LGIB,! there! was! no! effect!

(hazard!ratio!0.70,!95%!CI!0.26!to!1.25).!Similar!results!were!seen!in!reObleeding,!

with!an!overall!reduction!in!further!bleeding!in!the!restrictive!arm!(hazard!ratio!

0.62,!95%!CI!0.43!to!0.91),!which!was!most!marked!in!cirrhotic!patients!(hazard!

ratio! 0.49,! 95%! CI! 0.27! to! 0.90)! and! not! seen! in! patients! with! peptic! ulcer!

! 19!

bleeding! (hazard! ratio! 0.63,! 95%!CI! 0.37! to! 1.07).! There! are! limitations! to! the!

generalisability!of!this!trial.!All!patients!received!oesophagogastroduodenoscopy!

(OGD)!within!six!hours,!which!is!not!feasible!in!many!hospitals.!Variceal!bleeds!

represented!24%!of!the!study!population,!which!is!not!representative!of!the!UK,!

where! they! represent! 11%.33! Jairath!et)al)attempted! to! reproduce! this! in! a!UK!

population! in! a! cluster! randomised,! feasibility! trial.34! Across! six! hospitals! 941!

patients!with!UGIB!of!any!aetiology!were!randomised!to!receive!RBC!at!a!Hb<80!

g/L!with!a!target!of!81O100g/L!(restrictive)!or!Hb<100g/L!with!a!target!of!101O

120g/L! (liberal).! Exclusions! included! only! exsanguinating! haemorrhage.! There!

was! no! significant! difference! between! treatment! arms! in! terms! of! further!

bleeding,! allOcause! mortality,! frequency! of! intervention! or! length! of! stay.! This!

trial!also!has!limitations.!This!was!a!pilot!feasibility!trial!so!was!not!adequately!

powered!to!assess!clinical!outcomes.!There!were!many!protocol!violations,!up!to!

17%!in!the!liberal!arm,!suggesting!a!reluctance!of!clinicians!to!commit!to!a!liberal!

transfusion!strategy.!!

!

Restrictive! transfusion! may! not! be! suitable! for! all! patients.! Murphy! et) al)

randomised!2003!patients!undergoing!elective!cardiac!surgery! to!restrictive!or!

liberal! transfusion! and! found! that! there!were! significantly!more! deaths! in! the!

restrictive!arm.35!The!question!of!whether!patients!with!cardiovascular!disease!

are! suitable! for! restrictive! transfusion! has! been! investigated! in! a! recent!

systematic! review.36! This! review! included! randomised! controlled! trials! in!

patients!with!cardiovascular!disease!in!a!nonOcardiac!surgery!setting,!identifying!

11! trials! of! 3033! participants.! Clinical! settings! included! orthopaedics,! UGIB,!

cardiology,! critical! care! and! vascular! surgery.! Pooled! estimates! suggested! no!

! 20!

effect! on! 30Oday! mortality! (risk! ratio,! RR,! 1.15! 95%! CI! 0.88! to! 1.50)! but! an!

increased!risk!of!myocardial!infarction!and!cardiac!arrest!(RR!1.78,!95%!CI!1.18!

to!2.70)!with!restrictive!transfusion.36!

!

There!are!no!randomised!controlled!trials!on!restrictive!RBC!transfusion!in!LGIB.!

Although!it!is!known!how!many!RBC!transfusions!are!used!in!LGIB,3!there!are!no!

published!data!on!the!transfusion!thresholds!or!targets!that!are!being!employed!

by! clinicians.!Given! the! findings! that! restrictive! transfusion!may!not! be! safe! in!

patients! with! acute! coronary! syndrome! and! other! types! of! cardiovascular!

disease,!whether!it!should!be!adopted!in!LGIB!patients,!who!are!known!to!have!a!

high!burden!of!cardiovascular!coOmorbidity,12!is!not!known.!!

!

Investigation)and)Treatment)

!

Interventions! may! include! upper! and! lower! GI! endoscopy,! diagnostic! or!

therapeutic!radiological!studies,!nuclear!medicine!studies!and!surgery.!In!the!UK!

there! are! no! contemporary! published! data! on! the! most! common! modes! of!

investigation,! although! a! report! by! the! NCEPOD! report! on! GIB! patients! with!

severe! bleeding! (≥4! units! RBC! transfusion)! reported! that! the! most! common!

investigation!of!rectal!bleeding!was!flexible!sigmoidoscopy,!although!it!was!only!

undertaken! in! 23%! cases.6! This! is! in! contrast! to! the!United! States! (US)!where!

colonoscopy! is! the! most! common! investigation! (46%),! flexible! sigmoidoscopy!

being! performed! in! only! 4%.12! Colonoscopy! enables! visualisation! of! the! large!

bowel!in!its!entirety,!but!requires!bowel!preparation!and!may!not!be!tolerated!by!

elderly! patients.37! Flexible! sigmoidoscopy! allows! only! visualisation! of! the! left!

! 21!

sided! of! the! colon,! but! can! be! performed! following! less! invasive! bowel!

preparations.!The!diagnostic!yields!for!each!modality!in!LGIB!are!not!known.!!!

!

As! well! as! identifying! the! cause! of! bleeding,! colonoscopy! and! flexible!

sigmoidoscopy!can!be!used! to!deliver!endoscopic! therapy.!Therapeutic!options!

include! adrenaline! injection,! thermocoagulation,! clipping! and! banding.! Case!

series! have! suggested! efficacy! of! clips! or! bands! in! diverticular! bleeding,38! 39!

argon!laser!in!angiodysplasia40!and!combination!therapies!for!postOpolypectomy!

bleeding.41! There! are! no! randomised! controlled! trials! comparing! these!

modalities,!nor!are!there!data!on!their!longOterm!efficacy.!This!is!reflected!in!the!

low!utilisation!of!endoscopic!therapy!as!a!treatment!option,!used!in!only!2O4.6%!

acute!LGIB!in!the!US!and!Australia.5!12!42!

!

A! bleeding! source! may! also! be! identified! using! computerised! tomographic!

angiography! (CTA)! or!mesenteric! angiography! (MA).! If! active! extravasation! of!

contrast! is! visualised! on! angiography,! mesenteric! embolisation! offers! a!

minimally! invasive! method! to! control! haemorrhage! avoiding! the! need! for!

surgery.!Embolic!agents!include!coils,!gelfoam!and!polyvinyl!particles.!Although!

there! is! potential! risk! of! developing! associated! colonic! ischaemia! after!

embolisation,! the! development! of! superOselective! embolisation! may! to! reduce!

this.43!44!Embolisation!is!reportedly!used!in!only!1O6%!LGIB!cases,5!6!but!whether!

its! uptake! has! resulted! in! a! reduction! in! requirements! for! major! abdominal!

surgery!and!its!associated!complications!is!not!known.!!

!

! 22!

Historically,! nuclear! bleeding! scanning! has! been! used! when! the! origin! of!

bleeding! is! beyond! the! reach! of! the! endoscope.! Its! use! is! limited! by! its!

requirement!for!specialised!staff!and!radioOlabelled!tracers!and!in!the!US,!nuclear!

scans!are!generally!being!replaced!by!CTA.45!However,!it!continues!to!have!a!role!

in! the! investigation! of! small! bowel! bleeding,! such! as! that! associated! with! a!

Meckel’s! diverticulum.! Additional! modalities! for! examining! the! small! bowel!

include! capsule! endoscopy! and! push! enteroscopy.! Capsule! endoscopy! is! well!

tolerated! by! patients! but! is! not! therapeutic! and! biopsy! is! not! possible.! Push!

enteroscopy! is! reported! to! have! a! superior! diagnostic! yield! to! that! of! capsule!

endoscopy46!but!is!limited!by!the!need!for!deep!sedation!or!anaesthesia.!!

!

Surgery!for!acute!haemorrhage!control!in!LGIB!is!now!usually!reserved!for!cases!

where! endoscopic! or! radiological! therapies! fail.47! There! are! limited! reports! on!

the!number!of!cases!that!require!emergency!surgery,!case!series!reporting!its!use!

in! 4.8%! LGIB! admissions.5! Indications! include! diverticular! disease,! bleeding!

colorectal! cancers! and! angiodysplasia.48! Complications! and! mortality! are!

reported! in! 60.3%! and! 15.9%! cases,! respectively.48! This! warrants! further!

concern!considering! that! those! that! survive!an!emergency! laparotomy!(for!any!

pathology)!face!a!1Oyear!mortality!of!25%.49!

!

Diagnoses)

)

Multicentre! database! studies! in! the! US! and! Europe! suggest! that! the! most!

common! sources! of! bleeding! are! diverticular! disease! (32.0O33.1%),!

haemorrhoids! (10.0O20.0%),! colonic! polyps! (13.1%)! and! colitis! (11.7%).12! 50!

! 23!

There!are!no!equivalent! studies! in! the!UK,! although!a! single! centre! case! series!

suggested!similar!findings,!with!diverticular!disease!and!haemorrhoids!being!the!

most!common!diagnoses.11!

!

Although! diverticular! disease! is! the! most! common! cause! of! LGIB,! two!

longitudinal! studies! in! the! US! suggest! that! between! the! years! 2000! and! 2010!

overall!hospitalisations!due!to!diverticular!bleeding!decreased.51!52!In!contrast,!a!

multicentre!study!in!Spain!suggested!that!the!frequency!of!diverticular!bleeding!

increased!between!1996!and!2005.52!The!authors! from!the!US!based!study!did!

not! provide! a! hypothesis! for! this! reduction! in! incidence,52! although! they! did!

suggest! that! the! difference! in! findings! compared! to! the! Spanish! study!was! the!

use! of! different!methods! for! classifying! unspecified! cases! of! GIB.52! Lanas! et)al)

suggested!that!an!increase!in!diverticular!bleeding!may!be!due!to!the!increased!

use! of! anticoagulants,! antiplatelets! and! NSAIDs,! as! seen! in! an! ageing!

population.53!

!

Haemorrhoids! are! a! common! problem! globally,! with! reported! international!

frequencies!of!4.4O14.4%!of!the!adult!population.54!55!There!are!no!contemporary!

data!on!the!incidence!of!haemorrhoids!in!the!UK,!but!estimates!of!the!size!of!the!

problem! can! be! drawn! from! the! number! of! patients! undergoing! elective!

haemorrhoidal! surgery;! 23,000! in! England! in! 2004O2005.56! Haemorrhoids! are!

dilatations!of!the!vascular!cushions!that!surround!the!anus!and!most!commonly!

result! from! constipation.! In! the! US,! presentations! to! Emergency! Departments!

due!to!constipation!increased!by!46%!between!2006!and!2011.57!The!authors!of!

this! study! suggested! that! the! reasons! for! this! were! multifactorial,! related! to!

! 24!

health! service! utilisation! by! elderly! patients,! the! cost! of! over! the! counter!

laxatives!and!increasing!use!of!constipating!medications!such!as!opiates.57!

!

Longitudinal! studies! also! suggest! the! incidence! of! angiodysplasia,53! colonic!

polyps58! and! colorectal! cancer! is! increasing.59! This! trend! is! likely! due! to! the!

introduction!of!bowel!screening!and!adenoma!surveillance!programmes!leading!

to!increased!rates!of!diagnosis.60!Any!effect!on!polyp!and!cancer!related!LGIB!is!

unknown.!!

!

Determining!the!source!of!bleeding!can!be!difficult!and!20.8O50%5!12!patients!are!

discharged! without! a! diagnosis.! This! reduces! to! 9.2%! in! cohorts! where! all!

patients!receive!colonoscopy.8!Often!patients!are!discharged!with!a!diagnosis!of!

‘nonOspecific! gastrointestinal! haemorrhage’! or! ‘acute! haemorrhagic! anaemia’.12!

This! variability! in! the! coding! of! diagnoses! has! implications! for! the!

epidemiological!study!of!LGIB,!particularly!comparison!of!trends!over!time.!!

!

Outcomes)

!

In!comparison!to!UGIB,!LGIB!is!thought!to!have!a!more!benign!course.!Database!

studies!estimate!inOhospital!mortality!of!3.9O8.8%,2!12!but!most!deaths!are!due!to!

medical!morbidity,!such!as!sepsis!and!cardiac!events.5!11!13!Deaths!due!to!severe!

haemorrhage!occur!in!as!little!as!1%!cases.8!11!!

!

Single!centre!case!series!suggest!that!reObleeding!occurs!in!4.3O8.0%!cases!during!

admission,13!61!12.4%!at!3!months62!and!9%!at!one!year.9!The!highest!rates!of!reO

! 25!

bleeding! are! reported! in! patients! diagnosed! with! diverticular! bleeding! and!

angiodysplasia,!found!in!19.2%50!and!16.7%!patients!respectively.63!There!are!no!

large! multicentre! studies! detailing! the! frequency! of! reObleeding! in! the! UK,! or!

comparing!rates!of!reObleeding!across!a!standardised!population.!!

!

In!the!UK!there!no!contemporary!reports!of! the!average! length!of!hospital!stay!

for! patients! admitted! with! LGIB! and! there! are! widely! varying! reports! in! the!

literature!of!averages!between!3O10!days.12!64!Single!centre!retrospective!studies!

report!reOadmission!rates!of!4O7.5%.11!61!65!!

!

Risk)Assessment)

!

Unlike! UGIB,! there! are! no! widely! accepted! risk! assessment! tools! for! LGIB.! In!

UGIB! the! Rockall66! and! Blatchford67! scores! were! both! developed! in! UK!

populations,! and! have! been! extensively! validated! across! many! healthcare!

settings.!!Rockall!and!Blatchford!scores!are!used!to!predict!death,!reObleeding!or!

need!for!intervention.!There!have!been!attempts!to!do!this!in!LGIB!with!varying!

results.12! 68O70! One! database! study! of! 9,391! cases! of! LGIB! identified! that! age,!

intestinal! ischaemia,! coOmorbidity,! inpatient! bleeding,! coagulopathy,!

hypovolaemia,! RBC! transfusion! and! male! sex! were! predictive! of! inOhospital!

mortality.12! A! different! database! study! of! 4044! cases! agreed! that! age! and! coO

morbidity!were!predictive,!but!not!inpatient!bleeding,!transfusion!or!male!sex.70!!

!

The!usual!approach!of!modelling!risk!factors! is!hindered!by!the!paucity!of!data!

captured!about!LGIB.!There!are!several! reasons! for! this.!Research! into!GIB!has!

! 26!

typically! focussed!on!UGIB,! as! it! the!more! severe! type!of!GIB.6!To!develop!and!

validate! risk! assessment! tools! requires! at! least! two! sufficiently! large! and!

complete!sets!of!patient!data,!which!simply!do!not!exist!in!LGIB.!Database!studies!

often!use!hospital!codes!to! identify!patients,!but!as!described!previously,!many!

patients! are! discharged!with! a! nonOspecific! bleeding! or! anaemia! code.12! There!

are! often! geographical! differences! in! the! approach! to! hospital! coding,! for!

example! the! most! frequent! diagnosis! of! exclusion! in! the! US! is! diverticular!

bleeding,! whereas! in! Spain! it! is! anorectal! sources.52! This! means! that! risk!

profiling!based!on!data!from!coding!national!databases!may!not!be!applicable!to!

other! healthcare! settings! where! coding! is! applied! differently.! Additionally,!

treatment!strategies!may!differ!between!healthcare!settings,!which!may!reduce!

the!ability!of!a!risk!score!to!predict!need!for!intervention!in!other!geographical!

areas.! Critically,! a! prediction! tool! that! has! been! developed! in! an! American!

dataset!may! not! be! translatable! to! UK! practice,! where!management! strategies!

differ.!!

!

An!additional!limitation!is!the!focus!on!adverse!outcomes.!The!UGIB!risk!scores!

were! able! to! predict! adverse! outcomes! from! smaller! databases! as! these!

outcomes!are!more!common!in!UGIB!than!LGIB;!mortality!10%!versus!3.9%!and!

reObleeding! 13%! versus! 8%.12!13!33! To! adequately! power! a! statistical!model! to!

accurately! predict! these! outcomes! in! LGIB! would! require! a! larger! number! of!

cases.! The! Blatchford! score! uses! features! that! can! be! identified! at! initial!

assessment!to!predict!reObleeding,! including!features!of!hypovolaemic!shock.!In!

LGIB!these!features!are!much!less!common,!retrospective!studies!demonstrating!

a!frequency!of!shock!of!8%,11!13!making!this!approach!more!difficult.!

! 27!

!

The! lack! of! risk! scoring! has! important! implications! in! LGIB.! Other! than! using!

clinical! experience,! clinicians! have! no! standardised! approach! when! assessing!

LGIB!patients.!This!clinical!ambiguity!means!that!modifiable!risk!factors!may!not!

be!identified!and!in!a!climate!where!uncertainty!is! less!well!tolerated,!this!may!

lead! to! unnecessary! hospital! admissions.! This! has! financial,! social! and!

organisational!consequences.!!

!

Organisational)Requirements)and)Resource)Utilisation)

!

The! investigation! and! treatment! of! LGIB! may! involve! endoscopy,! radiology,!

interventional! radiology! and! surgery.! These! options! are! provided! by! different!

clinical!teams!and!departments!within!a!hospital!and!may!not!be!available!in!all!

hospitals.!!

!

The!2015!NCEPOD!report!into!GIB!found!that!only!55%!hospitals!could!provide!

24/7!onOsite!colonoscopy!and!70%!could!provide!24/7!access!to!interventional!

radiology.6!The!availability!of!endoscopists!who!are!able!to!provide!endoscopic!

haemostasis! in!the! lower!GI!tract! is!unknown.!Additionally,! the!NCEPOD!report!

did! not! collect! detail! on! how! hospitals! without! 24/7! access! to! these! services!

managed! their! patients.! In! response! to! findings! in! their! report,! the! NCEPOD!

made!several!organisational!recommendations.!!

• ‘Patients! with! any! acute! GI! bleed! should! only! be! admitted! to! hospitals!

with!24/7!access! to!onOsite!endoscopy,! interventional! radiology! (onOsite!

! 28!

or! covered! by! a! formal! network),! onOsite! GI! bleed! surgery! and! onOsite!

critical!care!and!anaesthesia.’6!

• ‘The!traditional!separation!of!care!for!UGIB!and!LGIB!in!hospitals!should!

stop.!All! acute!hospitals! should!have! a! lead! clinician!who! is! responsible!

for! local! integrated! care! pathways! for! both! UGIB! and! LGIB! and! their!

clinical! governance,! including! identifying! named! consultants,! ideally!

gastroenterologists,!who!would!be!responsible!for!the!emergency!and!onO

going!care!of!all!major!bleeds.’6!

!

Implementing!these!recommendations!would!require!significant!changes!to!the!

way! the!National!Health!Service! (NHS)! cares! for!GIB.!The!UK! is!unusual! in! the!

ownership!of!LGIB!patients!by!surgeons,!not!gastroenterologists.!Investing!in!the!

provision!of!comprehensive!endoscopy!and!interventional!radiology!would!have!

important! financial! consequences! and! other! than! sensible! expert! opinion,! this!

recommendation!has! little! evidence! supporting! it.! In! the!UK! it! is! currently! not!

known! how! many! LGIB! patients! require! endoscopy.! In! the! literature,! studies!

investigating!benefits!of!performing!all!colonoscopies!for!LGIB!on!an!urgent!basis!

have!had!conflicting!results.!One!cohort! study!demonstrated! increased!rates!of!

diagnosis!if!colonoscopy!was!performed!within!24!hours!of!admission,61!whereas!

a! randomised! controlled! trial! demonstrated! no! benefit.71! Evidence! supporting!

widespread!access!to!intervention!radiology!is!lacking,!but!reports!suggest!that!it!

is! only! used! in! a! minority! of! cases.5! 6! There! are! questions! on! the! use! and!

outcomes! of! both! endoscopy! and! interventional! radiology! that! should! be!

investigated!before!widespread!changes!to!hospital!services.!

!

! 29!

Health)Economics))

!

The!economic!burden!of!LGIB!in!the!UK!is!unknown.!In!the!US,!median!admission!

costs! are! estimated! at! $7,890.72! The! median! cost! of! an! UGIB! admission! is!

estimated!at!$9,548!in!the!US72!and!£2458!in!the!UK.73!A!retrospective!analysis!in!

the!US!found!that!40%!costs!related!to!GIB!were!incurred!following!discharge,74!

suggesting!significant!onOgoing!resource!utilisation!beyond!the!hospital!stay.! In!

the!current!climate!of!close!scrutiny!of!NHS!finances!and!a!drive!towards!proven!

efficiency! and! value! for!money,! any! new! strategy! in! the!management! of! LGIB!

requires! sound! economic! modelling! as! well! as! appraisal! of! its! safety! and!

effectiveness.!

!

Limitations)to)studying)LGIB)in)the)UK)

!

The! NHS! is! in! a! unique! position! where! hospitals! can! collaborate! on! research.!

Numerous! research! collaboratives! and! audit! programmes! have! enabled! the!

collection!data!on!clinical!across!many!different!NHS!Trusts,!providing!a!wealth!

of! observational! data! about! a! range! of! diseases.75! This! is! in! contrast! to!many!

other! countries!where!healthcare! is! fragmented,!hospitals! compete! for! funding!

and!consumers,!which!is!likely!to!limit!coOoperation!between!hospitals.!!

!

Studying!LGIB!does!have!limitations.!Previous!multicentre!studies!of!LGIB!from!

Europe! and! the! US2! 12! rely! on! hospital! codes! to! identify! patients.! The! same!

clinical!codes!are!used!in!the!Hospital!Episode!Statistics!(HES)!data!collected!by!

hospitals!in!the!UK,!but!their!use!has!many!drawbacks.!As!described!previously,!

! 30!

many!codes!are!nonOspecific,!allowing!a!patient!to!be!discharged!with!codes!such!

as!‘nonOspecific!gastrointestinal!haemorrhage.’!This!problem!is!more!of!a!burden!

for! LGIB! than!UGIB.! For! example,! in! the! International! Classification! of! Disease!

(ICD,! version! 10)! there! are!multiple! codes! that! can! be! used! for! UGIB,! such! as!

‘haematemesis’!and!‘melaena’.76!The!sole!equivalent!for!LGIB!is!‘haemorrhage!of!

the! anus! or! rectum’,! which! by! definition! excludes! diverticular! disease,! which!

studies! have! suggested! is! the! most! common! cause! of! LGIB.12! 50! Diverticular!

disease! is! included! in! several! ICD! codes,! but! is! limited! to! perforation! or!

abscess;76!there!is!no!code!for!diverticular!bleeding!per!se.!Similarly!there!is!no!

code!for!haemorrhoidal!bleeding.!!

)The!lack!of!investigation!or!inconclusive!investigations!as!often!found!in!LGIB,5!12!

also! causes! problems! when! attempts! at! validating! hospital! codes! are! made.!

Researchers!have!attempted!to!improve!the!identification!of!LGIB!patients!from!

coded!databases!by!using!classification!trees!and!machine!learning!algorithms,77!

but!these!are!cumbersome!and!have!limited!applicability!in!clinical!research.!To!

start!addressing!the!many!questions!relating!to!LGIB,!a!different!approach!will!be!

required!to!provide!the!level!of!detail!required!to!provide!meaningful!answers.!

!

Discussion:)outstanding)questions)in)LGIB)

!

There!are!several!key!areas!in!LGIB!that!require!research.!There!are!a!global!lack!

of! high! quality! epidemiological! data! that! can! be! used! to! track! trends! in!

diagnoses,! management! and! outcomes.! This! has! implications! for! the! critical!

! 31!

appraisal! of! new! interventions,! as! there! are! limited! baseline! data! to! use! for!

comparison.!

!

Outcomes! of! patients! admitted! to! NHS! hospitals! with! LGIB! are! currently!

unknown.!Without! these! data,! we! are! unable! to! determine! factors! influencing!

outcome,!and!how!risk!factors!for!adverse!outcome!could!be!modified.!The!use!of!

diagnostic! and! therapeutic! intervention! is! likely! to! be! influenced! by! its!

availability!as!opposed!to!clinical!evidence!for!efficacy.!

!

Resource!utilisation!remains!unquantified!in!the!UK!and!estimates!from!around!

the!world!often! include!UGIB,!which!has!a!different! clinical! course.!The! lack!of!

epidemiological!and!resource!data!means!that!appraisal!of!current!management!

strategies!often!relies!on!expert!opinion,!not!rigorous!scientific!study.!The!close!

scrutiny!of!healthcare!delivery!by!consumers!and!providers!means!that!this!is!no!

longer!accepted!as!adequate.!!

!

!

!

!

!

!

!!!!!!!

! 32!

1.2!Aims!of!the!thesis!!

In!the!UK!there!are!no!national!guidelines!on!optimal!standards!of!care!for!LGIB,!

no! large!epidemiological!studies!and! limited!reports!on!patient!outcomes.6!The!

work! in! this! thesis! aims! to! critically! appraise! the! literature! on! optimal!

investigation!and!treatment,!and!provide!unprecedented!national!data!on!acute!

LGIB!in!the!UK.!These!observational!data!will!be!used!to!identify!organisational!

and! patientOrelated! factors! that! influence! patient! outcome! and! to! design! a!

strategy!to!modify!them.!Presenting!features!will!be!used!to!develop!a!model!to!

identify! features! that! predict! adverse! outcomes! that! can! be! used! to! triage!

patients!on!initial!clinical!assessment.!

!

!

1.3!Outline!of!the!thesis!!

Chapter! 2! is! a! systematic! review! of! diagnostic! and! therapeutic! treatment!

modalities!for!acute!LGIB,!aiming!to!identify!the!best!diagnostic! intervention!to!

identify! the! source!of! bleeding,! and! the!optimum! treatment! to! arrest! bleeding.!

Interventions! are! appraised! using! diagnostic! yield,! rates! of! reObleeding,! RBC!

transfusion!and!complications.!Chapters!3,!4!and!5!detail! the!methodology!and!

results!of!the!first!national!observational!study!of!patients!presenting!with!acute!

LGIB.! Chapter! 6! describes! a! risk! score! to! aid! the! triage! of! LGIB! at! initial!

assessment,!and!Chapter!7!described!an!analysis!of!patients!who!develop!LGIB!

whilst!receiving!antiplatelet!and!anticoagulant!medications.!

!

!

! 33!

CHAPTER!2!

!

SYSTEMATIC! REVIEW:! DIAGNOSTIC! AND! THERAPEUTIC! TREATMENT!

MODALITIES!FOR!ACUTE!LOWER!GASTROINTESTINAL!BLEEDING!

!

2.1!Introduction!

The!treatment!of!LGIB!involves!determining!the!site!and!source!of!bleeding,!and!

choosing!the!most!appropriate! interventions!to!achieve!haemostasis.!There!are!

several!possible!interventions!including!colonoscopy,!computerised!tomographic!

angiography!(CTA),!mesenteric!angiography!(MA)!and!nuclear!scintigraphy.!The!

diagnostic! and! subsequent! therapeutic! yields!of! each!modality! are!unclear! and!

are!likely!to!be!influenced!by!timing,78!pathology,79!haemodynamic!status80!and!

patient!related!factors.37!There!is!little!evidence!in!the!literature!informing!their!

optimal! use,! hence! the! development! of! recommendations! in! guidelines! is!

limited.47!!

!

As! well! as! diagnosis,! endoscopy! offers! endotherapy,! including! adrenaline!

injection,!thermocoagulation!or!clipping.!Extravasation!of!contrast!on!CTA!or!MA!

may! identify! bleeding! that! is! amenable! to! embolisation.! In! comparison! to!

colonoscopy,!CTA!is!better!tolerated!by!patients!but!may!only! identify!a!source!

where!there!is!active!bleeding.81!Delays!between!CTA!and!angiography!may!lead!

to! a! blush! on! CTA! becoming! nonOapparent! on! a! subsequent! mesenteric!

angiogram.82!!

!

! 34!

Given! uncertainties! around! the! optimum! approach! to! investigation! and!

management! of! LGIB,!we! conducted! a! systematic! review! of! the! diagnostic! and!

therapeutic! yields! of! colonoscopy,! CTA! and!MA.!This! takes! the! form!of! several!

direct!head!to!head!comparisons!between!modalities,!each!of!which!is!reported!

separately,! aiming! to! mirror! the! clinical! questions! encountered! by! clinicians!

involved!in!the!acute!management!of!LGIB.!!

!

2.2!Methods!

This! review! was! registered! on! the! PROSPERO! register! of! systematic! reviews!

(CRD42016025100)!and!conducted!in!accordance!with!the!Preferred!Reporting!

Items! for! Systematic! Reviews! and! MetaOAnalyses! (PRISMA)! statement83! and!

MetaOAnalysis!of!Observational!Studies!in!Epidemiology!(MOOSE)!group.84!

)

Search)strategy)

MEDLINE,! PubMed,! EMBASE,! CDSR,! CENTRAL,! DARE,! HTA! &! NHSEED,! the!

Transfusion! Evidence! Library,! ClinicalTrials.gov! and! the! WHO! International!

Clinical! Trials! Registry! Platform!were! searched! for! articles! published! between!

2000!and!12th!November!2015!without!language!restrictions!(Appendix!2).!The!

search!was!limited!to!publications!since!2000!due!to!the!more!recent!adoption!of!

CTA! and! therapeutic! endoscopy,! reflective! of! modern! day! practice.! Any! nonO

English! language! articles! were! translated.! References! that! were! likely! to! be!

related! to! UGIB! were! also! identified! and! preOscreened! by! one! reviewer! (KO).!!

Any!potentially!relevant!references!were!added!to!the!results!and!underwent!full!

screening!with!the!other!identified!studies.!I!also!hand!searched!reference!lists!of!

relevant!narrative!and!systematic!reviews.!

! 35!

)

Study)eligibility)

As!recent!guidelines!on!this!topic!have!demonstrated!a!lack!of!randomised!data!

in!this!area,6!47!cohort!studies!(nonOrandomised!studies!of!intervention,!NRSI)!as!

well!as!randomised!controlled!trials!(RCTs)!were!included.!Studies!were!eligible!

if! they!included!at! least!two!different! interventions!for!LGIB.!Those!reported!in!

conference! proceedings! were! also! included.! Case! reports! and! series! were! not!

eligible.!!

!

Screening!criteria!were!as!follows:!

• Participants! had! a! diagnosis! of! acute! LGIB! that! required! hospital!

admission,!(including!exclusive!subgroups!such!as!diverticular!bleeds)!

• Participants!aged!≥!16!years!

• One!group! in! the! study! received! colonoscopy,!CTA,!MA,! embolisation!or!

endoscopy!therapy!(surrogate!terms!such!as!haemorrhoid!banding!were!

also!eligible)!!

• Published!in!year!2000!or!later!

• Study! compared! two! interventions,! timing! of! intervention! or! shocked!

status!of!the!patient!

• Study! reported! at! least! one! of! diagnostic! yield,! therapeutic! yield,! RBC!

transfusion,! length!of! stay! (LOS),!mortality,! complications! related! to! the!

intervention,!need!for!further!procedure!

!

Pairs! of! authors! screened! all! search! results.! Where! a! decision! regarding!

eligibility! could!not!be!made!on! title! and!abstract! screen!alone,! full! texts!were!

! 36!

retrieved.! As! there! is! considerable! variation! in! the! reporting! quality! of! nonO

randomised! studies,! those! that! contained! two! comparator! groups! but! lacked!

transparently! reported!methodology! or! that! reported! a! cohort! design!without!

methodological! concordance! were! screened! to! determine! whether! they! met!

criteria!to!truly!be!categorised!as!a!cohort!study!as!described!by!Dekkers!et)al.85!

!

Participants))Adult! patients! (≥16! years)! hospitalized! with! acute! LGIB! of! any! cause! were!

eligible.! Studies! of! obscureOovert! GI! bleeding! (defined! as! clinical! evidence! of!

bleeding! without! an! obvious! aetiology! after! endoscopic! and! radiologic!

evaluation)7!were! only! eligible! if! participants!were! hospitalised!with! bleeding.!

Patients!with!obscureOoccult!GI!bleeding! (defined!as!bleeding! from!the!GI! tract!

without!an!obvious!aetiology!in!the!absence!of!clinically!evident!bleeding7)!

or!UGIB!were!excluded.!!

!

Interventions)and)comparisons)

Interventions! included! flexible! sigmoidoscopy,! colonoscopy,! CTA,! MA,!

therapeutic!endoscopy!and!mesenteric!embolisation.!Comparisons!comprised!of:!

colonoscopy/sigmoidoscopy! versus! CTA;! colonoscopy/sigmoidoscopy! versus!

other! (e.g.! standard! care);! CTA! versus! other;! timing! of!

colonoscopy/sigmoidoscopy,! CTA! and! MA! in! relation! to! presentation! with!

bleeding.! Modes! of! haemostasis! were! also! compared:! endoscopic! haemostasis!

versus! embolisation;! endoscopic! haemostasis! versus! other! and! embolisation!

versus! other.! Specific! types! of! endoscopic! therapy! (including! adrenaline!

! 37!

injection,! banding,! haemoclipping,! thermocoagulation! and! snare! polypectomy)!

were!also!compared.!!

!

)

Outcomes)

Primary! outcomes! were! diagnostic! or! therapeutic! yield.! Diagnostic! yield! was!

defined!as!identification!of!the!source!of!bleeding.!Therapeutic!yield!was!defined!

as! the! proportion! of! participants! that! received! haemostatic! therapy,! either!

during! or! after! the! intervention.! Secondary! outcomes! were! reObleeding,! red!

blood! cell! (RBC)! transfusion,! length! of! hospital! stay! (LOS),! mortality! and!

complications! related! to! the! intervention! (perforation! at! lower! GI! endoscopy,!

complications!of!sedation,!contrast!reactions,!vascular!entry!site!complications,!

nonOtarget!embolisation,!mesenteric!ischaemia).!!

!

Data)extraction)

Two!independent!review!authors!extracted!the!following!data!from!each!study:!

1. General! study! information:! study! ID,! publication! type,! publication! date,!

funding!source,!conflict!of!interest!statement!

2. Study!methods:!country,!setting,!recruitment!dates,!recruitment!or!cohort!

allocation! method,! randomisation,! blinding,! methods! of! matching! or!

adjusting!for!confounders,!specified!primary!outcome!

3. Intervention:! number! of! treatment! arms! or! cohorts,! description! of!

intervention,! any! coOinterventions! (such! as! method! of! bowel!

preparation),! timing! of! intervention,! person! performing! or! interpreting!

intervention,!criteria!to!treat!bleeding!

! 38!

4. Participants:! age! gender,! baseline! haemodynamic! status,! baseline!

antiplatelet,!anticoagulant!and!NSAID!use!

5. Outcomes:! diagnostic! yield! and! study! specific! definition! of! diagnostic!

yield,! therapeutic! yield! and! treatment!methods! available! for! use! in! the!

study,! reObleeding! and! definition! of! reObleeding,! participants! requiring!

RBC! transfusion,! volume!of! red! cell! transfusion,! length!of! intensive! care!

(ICU)! stay,!LOS,!mortality! (inpatient! and!up! to!30!days),! cause!of!death,!

number!of! participants! requiring! a! further!procedure! and! rationale! and!

number!of!participants!with!a!complication!related!to!the!intervention.!

!

If!studies!included!upper!and!lower!GIB!extraction!was!limited!to!data!pertaining!

only! to! LGIB.! Study! screening! and! data! extraction! was! performed! using!

Covidence!Systematic!Review!Software!(Veritas!Heath!Innovation!Ltd,!Australia).!!

)

Quality)of)evidence)

Risk!of!bias!in!RCTs!was!assessed!using!the!Cochrane!risk!of!bias!tool,86!using!the!

following!seven!domains:!

• Sequence!generation!(selection!bias)!

• Allocation!concealment!(selection!bias)!

• Blinding!of!participants!and!personnel!(performance!bias)!

• Blinding!of!outcome!assessors!(detection!bias)!

• Incomplete!outcome!data!(attrition!bias)!

• Selective!outcome!reporting!(reporting!bias)!

• Other!sources!of!bias!

!

! 39!

NRSI!were!assessed!using!the!NewcastleOOttawa!Scale87!using!the!following!eight!

domains:!

• Representativeness!of!exposed!cohort!

• Selection!of!nonOexposed!cohort!

• Ascertainment!of!exposure!

• Demonstration!that!outcome!of!interest!was!not!present!at!the!start!of!the!

study!

• Comparability:! study! controls! for! haemodynamic! status,! study! controls!

for!any!additional!factor!

• Ascertainment!of!outcome!

• Was!follow!up!long!enough!for!outcomes!to!occur?!

• Adequacy!of!follow!up!

!

Statistical)analysis)

Continuous! outcomes! were! recorded! as! mean,! standard! deviation! (SD)! and!

number!of!participants!and!compared!using!mean!difference!(MD)!and!95%!CI.!

Dichotomous!outcomes!were!recorded!as! the!number!of!events!and!number!of!

participants!and!analysing!using!RR!and!95%!CI! for!RCTs!and!odds!ratios!(OR)!

and!95%!CI!for!NRSI.!Where!the!number!of!observed!events!was!small!(less!than!

5%!of!the!sample)!Peto!ORs!and!95%!CI!were!used.!!

!

RCTs! and! NRSI! were! analysed! seperately88.! Statistical! heterogeneity! was!

analysed! using! I2! statistics! and! values! >50%! were! considered! significantly!

heterogeneous.89! If! heterogeneity! between! RCTs! was! not! significant,! metaO

analysis! was! undertaken! using! fixedOeffect! metaOanalysis,! otherwise! randomO

! 40!

effects! metaOanalysis! was! undertaken.90! To! aid! clinical! interpretation,! effect!

estimates!from!RCTs!were!reported!as!RRs.88!!

!

Due!to!the!nonOrandomised!nature!of!NRSI,!these!studies!are!likely!to!be!at!risk!

of!bias,!particularly!selection!and!reporting!bias.86!For!this!reason,!metaOanalysis!

of!NRSI!was!restricted! to! randomOeffects!metaOanalysis!and!estimates! reported!

as!OR,!regardless!of!heterogeneity.!NRSIs!were!deemed!comparable!if!they!had!a!

NewcastleOOttawa! score! ≥891.! No! tests! for! funnel! plot! asymmetry! were!

undertaken!as! the!number!of! studies! in!each!comparison!was! fewer! than!1088.!

MetaOanalysis! was! undertaken! using! Review! Manager! 5.3! (Cochrane!

Collaboration,!Denmark).!!

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! 41!

2.3!Characteristics!of!reviewed!studies!

Searches! identified! 5839! records! potentially! eligible! references! and! 40! from!

2410!preOscreened!records.!The!flowchart!of!the!search!is!shown!in!Figure!1.!On!

review! of! full! texts,! 507! studies!were! excluded,! including! 193!with! the!wrong!

design,! 47! without! the! interventions! of! interest! and! 165! with! the! wrong!

comparison.!41!studies!did!not!differentiate!lower!from!UGIB.!!

Figure!1:!PRISMA!flowOchart!of!eligible!studies!

!

Records(iden+fied(through(other(sources((n=2)(

Records(excluded,(did(not(meet(eligibility(criteria(

(n=5353)(

Studies(assessed(for(full@text(eligibility((n=528)(

Full@text(studies(excluded((n=507)(

Wrong(study(design((n=193)(Wrong(comparator(or(no(comparator((n=165)(

Wrong(interven+on((n=47)(Pa+ents(not(hospitalised(

(n=37)(UGIB(or(unable(to(classify(

(n=41)(Includes(paediatric(popula+on((n=19)(

Wrong(outcomes((n=5)((

Records(iden+fied(in(databases(search((n=5879)(

Eligible'studies'(n=21)'

Mul+ple(reports(of(same(study(excluded(

(n=5)(

Non4randomised'studies'(cohort'studies)'

(n=13)'

Randomised'controlled'trials'(n=3)'(

! 42!

There!was!a!paucity!of!data!across!all!interventions!and!comparators;!3!RCT,!13!

NRSI! and! 3! onOgoing! studies! met! the! criteria! for! inclusion,! including! six!

conference!abstracts92O97.!Eleven!studies!compared!at! least!two!different!modes!

of! investigation! or! treatment! and! five! examined! different! timings! of! the! same!

intervention!(Table!1).!!No!studies!reported!subgroups!based!on!haemodynamic!

status!of!the!participant.!We!found!no!studies!of!flexible!sigmoidoscopy.!

! 43!

Table!1:!Summary!of!evidence!by!comparison!investigated!and!study!methodology!

!

Comparator! RCTs! NRSIs! OnUgoing!trials!Colonoscopy!vs!CTA!!

! Nagata!2015!Yabutani!2014!

!

Colonoscopy!vs!other!(eg!standard!care)!!

Green!2005!! Yamaguchi!2006!!!

!

CTA!vs!other!(inc!standard!care)!

! Ketwaroo!2012!!Sun!2011!!Jacovides!2015!!

!

Diagnostic!MA!vs!other! Leung!2012!! ! Chen!NCT02069262!

Timing!of!colonoscopy!A) Early!(<24!hours)!

vs!late!(>24!hours)!

!Laine!2010!!

!Abeldawi!2014!Nagata!2016!Strate!2003!RodriguezOMoranta!2007!

!!

Timing!of!radiology!A)!Urgent!CTA!vs!nonOurgent!B)!Urgent!MA!vs!nonOurgent!

!!!!

!!!

!

Therapeutic!endoscopy!vs!mesenteric!embolisation!

! ! !

Therapeutic!endoscopy!vs!other!

! Jensen!2000!! Matsuhashi!!JPRNOUMIN000008287!

Embolisation!vs!other! ! ! !Endoscopic!agent!A!vs!B! ! Nakano!2015!!

Ishii!2011!!Barkun!NCT02135627!

!!!The!characteristics!of!each!study!are!included!in!Table!2.!Although!eligibility!was!

restricted!to!publication!since!2000,!several!studies!were!conducted!years!before!

publication.!Jensen!et)al)included!a!historical!control!that!was!captured!between!

1986! and! 199298! and! Green! et) al) published! their! results! 10! years! after!

recruitment!had!finished78.!The!case!definitions!of!LGIB!are!included!in!Table!2.!

Eleven!studies!included!patients!with!LGIB!of!any!cause45!61!64!71!78!93O95!99O101,!four!

were!limited!to!patients!with!diverticular!bleeding92!96O98!and!one!was!limited!to!

! 44!

obscureOovert! bleeding102.! The! number! of! participants! enrolled! in! each! study!

was!small,!ranging!from!60O100!in!the!RCTs!and!27O326!in!the!NRSI.!!

!

Most!trials!were!conducted!in!older!patients!and!where!reported,!anticoagulant,!

NSAID! and! particularly! antiplatelet! use! was! common.! Five! studies! reported!

baseline! haemodynamic! status64! 71! 78! 101! 102.! The! RCTs! included! a! higher!

proportion!of!shocked!patients!than!the!NRSIs.!!

!

!

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!

!

!

!

!

! 45!

Table!2:!Study!characteristics!!

Study! Design!! Study!years!

Study!population! Interventions! Total!Participants!(N)!

Age! (mean!±SD)!

Shock*!N!(%)!

Medications!on!admission,!N!(%)!Anticoagulants! Antiplatelets! NSAIDs!

Green! 2005!(USA)!

RCT! 1993P1995!

Patients! admitted!with! haematochezia!with! clinical! or!laboratory!evidence!of!significant!blood!loss!

Colonoscopy!<8!hours!after!admission!

50! 68±3! 30!(60.0)!

NR! NR! 29!(60.0)!

Standard! care:! red!cell! scan! if! ongoing!bleeding,!colonoscopy!

50! 71±4! 34!(68.0)!

NR! NR! 26!(52.0)!

Laine! 2010!(USA)!

RCT! 2002P2008!

Patients! admitted!with! haematochezia!with! a! high! risk!feature**!

Colonoscopy! <12!hours!after!admission!

36! 52±3! 27!(75.0)!

NR! NR! NR!

Colonoscopy! 36P60h!hours!after!admission!

36! 52±2! 31!(86.1)!

NR! NR! NR!

Leung! 2012!(USA)!

RCT! 2005P2009!

Patients! admitted!with! melena! or!hematochezia! with!nonPdiagnostic! upper!GI! endoscopy! and!colonoscopy!

Capsule!endoscopy! 30! 58.6±19.9! 10!(33.3)!

1!(3.3)! 6!(20.0)! 6!(20.0)!

Angiography! 30! 53.3±20.9! 9!(30.0)! 0! 8!(26.7)! 3!(10.0)!

Albeldawi!2014!(USA)!

Retrospective!cohort!

2011P2012!

All!acute!LGIB!! Colonoscopy! <24!hours!after!admission!!

24! 66.8±!13.8! NR! 2!(8.3)! 13!(54.2)! 2!(8.3)!

Colonoscopy! >24!hours!after!admission!!

33! 69.3±11.1! NR! 7!(21.2)! 19!(57.6)! 3!(9.1)!

Ishii! 2011!(Japan)!


2004P2010!and!2009P2010!

Patients! with! colonic!diverticular!haemorrhage!!

EBL! 16! NR! NR! NR! NR! NR!EC! 48! NR! NR! NR! NR! NR!

Jacovides!2015!(USA)!

Historical!control!

2005P2012!

All! patients!hospitalised! with!LGIB!!

Historical! protocol:!red! cell! scan,! CTA! or!colonoscopy!

78! 68±15!!

NR! NR! NR! NR!

New! protocol:! CTA,!colonoscopy!

83! 70±15! NR! NR! NR! NR!

! 46!

Jensen!2000!(USA)!

Historical!control!!

1986P1992!and!1994P1998!

Patients! with!haematochezia! and!diverticulosis!

Medical! and! surgical!intervention!

17! 66±3!!

NR! NR! NR! 3!

Medical! and!endoscopic!therapy!

10! 67±4! NR! NR! NR! 3!

Nagata!2016!(Japan)!


2009P2014!

All! patients! admitted!with!acute!overt!LGIB!


163! 67.9±17.4!!

17!(10.4)!

9!(5.5)! 63!(38.7)! 23!(14.1)!

Colonoscopy! >24!hours!after!admission!!

163! 66.4±16.9!!

19!(11.7)!

6!(11.7)! 54!(33.1)! 20!(12.3)!

Nagata!2015!(Japan)!

Retrospective!Cohort!

2008P2013!

Patients! admitted!with! LGIB! who!underwent!colonoscopy!!

Urgent! CTA! then!colonoscopy!

126! 68.3±16.5!!

5!(4.0)! 7!(5.6)! 55!(43.7)! 33!


97! 67.7±16.5!!

1!(1.0)! 4!(4.1)! 36!(37.1)! 13!(13.4)!

Nakano!2015!(Japan)!


2004P2014!

Patients! undergoing!endoscopic! therapy!for! colonic!diverticular!haemorrhage!!

EBL! 50! 67±13!!

NR! NR! 15! 4!

EC! 39! 64±13! NR! NR! 13! 3!

Sun! 2011!(USA)!


2007P2008!and!2008P2010!

All! patients!hospitalised! with!acute!GIB!!

CTA! 53! NR! NR! NR! NR! NR!Red!cell!scan! 46! NR! NR! NR! NR! NR!

Yabutani!2006!(Japan)!

Single!retrospective!cohort!

2010P2012!

Patients! diagnosed!with! diverticular!bleeding!!

CTA!and!colonoscopy! 57! NR! NR! NR! NR! NR!

Yamaguchi!2006!(Japan)!

Single!retrospective!cohort!

1999P2004!

Consecutive! patients!with!haematochezia!!

Ultrasound! and!colonoscopy!

111! 58! (range!18P96)!

NR! NR! NR! NR!

Ketwaroo!2012!(USA)!

Retrospective!cohort!!!!

2010P2011!

Suspected!acute!LGIB!! CTA! 46! 68.2±17! NR! NR! NR! NR!Red!cell!scan! 46! 70±15!

!NR! NR! NR! NR!

! 47!

Strate! 2003!(USA)!!!!!!

Retrospective!cohort! P!subgroup!

1996P1999!

All! patients! admitted!with! ICDP9! codes!representing! LGIB,! or!a! wide! range! of!diagnoses! associated!with!LGIB!


69! NR! NR! NR! NR! NR!

Colonoscopy! >24!hours!after!admission!


RodriguezP!Moranta!2007!(Spain)!

Prospective!cohort!

2005P2006!

Consecutive! patients!admitted!with!LGIB!



Colonoscopy! >24!hours!after!admission!


*Shock!defined!as!decrease!of!SBP!to!<90!mm!Hg,!paleness,!cold!sweat,!dizziness,!syncope,!or!unconsciousness!(Nagata!A);!SBP!≤!115mmHg,!HR!≥!100!and!syncope!(Nagata!B);!SBP!≤!100mmHg!on!presentation102!**High! risk! features! defined! as! HR>100,! SBP<100mmHg,! orthostatic! changes! in! systolic! blood! pressure! >! 20! mmHg! or! in! heart! rate>! 20! beats/min,! blood!transfusion,!or!drop!in!Hb!≥!1.5g/dl!within!a!6Ph!period103!!!!!NR;!not!reported

! 48!

2.5$Choice$of$investigation$of$acute$lower$gastrointestinal$bleeding$

Colonoscopy)versus)CTA))

No! RCTs! compared! colonoscopy! with! CTA.! The! two! eligible! NRSIs! were!

retrospective,! one! comparing! early! colonoscopy! and! CTA! (within! 24! hours! of!

admission)! with! early! colonoscopy! alone! in! 223! participants64,! and! one!

comparing!early!colonoscopy!with!CTA!(timings!not!defined)!in!a!single!cohort!of!

114!patients!with!diverticular!bleeding!that!had!both!tests92.!!

!

The!was!no!difference!in!the!diagnostic!yield!of!CTA!combined!with!colonoscopy!

versus!colonoscopy!alone!(OR!1.31,!95%!CI!0.26!to!6.63)!although!the!diagnosis!

of!lesions!with!active!bleeding,!adherent!clot!or!visible!vessels!was!higher!in!the!

CTA! group! (OR! 2.14,! 95%! CI! 1.16! to! 3.95,! 223! participants).! Patients! in! this!

group! subsequently! received! more! endoscopic! haemostasis! (OR! 3.47,! 95%! CI!

1.74!to!6.91),!but!there!was!no!difference!in!terms!of!rePbleeding!(OR!1.08,!95%!

CI!0.51!to!2.28)!or!participants!receiving!RBC!transfusion!(OR!1.71,!95%!CI!0.86!

to! 3.39).! Mortality,! LOS! and! complications! were! not! reported.! The! study! by!

Yabutani! et) al! described! only! diagnostic! yield,! demonstrating! no! difference!

between!CTA!and!colonoscopy!(OR!1.36,!95%CI!0.63!to!2.95,!114!participants).!!

$

Colonoscopy)versus)other))

We!identified!one!RCT78!that)randomised!100!patients!to!colonoscopy!within!8!

hours!or!standard!care!(red!cell!scanning,!angiography!or!elective!colonoscopy).!

The!diagnostic!yield!was!higher!in!the!group!randomised!to!urgent!colonoscopy!

(RR!1.91,!95%!CI!1.03!to!3.53),!but!there!was!no!difference!in!therapeutic!yield!

(endoscopic!haemostasis!or!vasopressin!infusion,!RR!1.7!95%!CI!0.87!to!3.34)!or!

! 49!

rePbleeding!(RR!0.73,!95%!CI!0.37!to!1.44),!although!volume!of!RBC!transfusion!

was!smaller!in!the!colonoscopy!group!(mean!difference!P0.8!units,!95%!CI!P0.62!

to!P0.98).!We!identified!one!NRSI;99!a!study!of!111!participants!who!underwent!

ultrasound! followed! by! colonoscopy.! The! diagnostic! yield! of! colonoscopy! was!

superior!to!that!of!ultrasound!(OR!3.78!95%!CI!2.07!to!6.91).!

!

CTA)versus)other)

No!RCTs!were!identified.!The!three!eligible!NRSIs!all!compared!CTA!with!nuclear!

scintigraphy;!two!retrospective!cohort!studies!of!92P99!participants94!95!and!one!

before! and! after! study! of! a! protocol! that! prioritised! CTA! over! nuclear!

scintigraphy!in!161!participants45.!CTA!demonstrated!a!higher!diagnostic!yield!in!

the!study!by!Ketwaroo!et)al)but!there!was!no!difference!in!the!study!by!Sun!et)al)

(OR!4.03,!95%!CI!1.67!to!9.72,!92!participants!and!OR!0.49!95%!CI!0.20!to!1.21,!

99!participants,!respectively).!Neither!study!reported!therapeutic!yield!for!both!

study!arms!or!any!of!the!secondary!outcomes.!The!protocol!study!by!Jacovides!et)

al)demonstrated!no!difference!in!diagnostic!yield!(OR!0.85!95%!CI!0.33!to!2.19),!

therapeutic!yield!(defined!as!embolisation!during!first!MA,!OR!1.10,!95%!CI!0.55!

to!2.20)!or!LOS!(MD!3!days,!95%!CI!P16.58!to!22.58).!

$

Diagnostic)MA)versus)other))

We! identified! one! RCT! comparing!MA! to! capsule! endoscopy,102! and! no! NRSIs.!

The!study!by!Leung!et)al)was!conducted!in!patients!with!obscurePovert!bleeding!

(defined! as! those! presenting! with! melaena! or! haematochezia! with! a! nonP

diagnostic!upper!GI!endoscopy!and!colonoscopy)!randomising!60!participants!to!

MA! or! capsule! endoscopy.! Initially! capsule! endoscopy! was! superior! to! MA! in!

! 50!

terms!of!diagnostic!yield!(RR!2.67,!95%!CI!1.21!to!5.88),!however!in!the!capsule!

endoscopy! arm! 4! patients! had! active! bleeds! from! the! small! bowel,! which! if!

regarded!as!negative!findings,!rendered!the!diagnostic!yield!nonPsignificant!(RR!

2.00,! 95%! CI! 0.86! to! 4.63).! Therapy! was! limited! to! surgery! (there! was! no!

angiographic! intervention)! and! there! was! no! significant! difference! between!

patients! that! received! MA! versus! those! that! received! capsule! endoscopy! (RR!

0.67,! 95%! CI! 0.12! to! 3.71).! ! There! was! also! no! difference! in! the! risk! of! reP

bleeding!(RR!0.50!95%!CI!0.19!to!1.29),!transfusion!(RR!1.0,!95%!CI!0.22!to!4.56)!

or! death! (RR! 1.0,! 95%! CI! 0.28! to! 3.63)! in! the!MA! group! compared! to! capsule!

endoscopy.!!!

!

We!found!one!onPgoing!trial,!again!in!overtPobscure!GIB,!randomising!patients!to!

receive!MA!or!MA!in!combination!with!laparoscopy!(Chen!et)al,!NCT02069262).!!

!

! 51!

2.5$Timing$of$first$line$investigation$

Colonoscopy)

One!RCT,71!one!prospective93!and! three!retrospective!NRSI61!93!100!101! compared!

early! and! late! colonoscopy.! Laine! et) al) randomised! 72! patients! and! the! NRSI!

ranged! from! 57P326! participants.! One! study! defined! early! colonoscopy! to! be!

within! 12! hours,71! three! studies! defined! early! colonoscopy! to! be! within! 24!

hours93! 100! 101! and! one! subdivided! their! cohort! into! consecutive! 12! hours!

groups61.! For! the! purpose! of! this! comparison! early! colonoscopy! is! defined! as!

within!24!hours!of!admission.!!

$

For! diagnostic! yield,! three! studies! categorised! diverticula61! 71! 101! or!

haemorrhoids! 61! 71! as! definite! (based! on! the! presence! of! active! bleeding! or!

stigmata! of! recent! haemorrhage)! or! presumptive! sources! (presence! of!

diverticulosis! or! haemorrhoids! without! bleeding! in! absence! of! other! potential!

bleeding!sources).!RodriguezPMoranta!et)al)reported!only!definite!diagnoses,!but!

did!not!define!this,!and!Albeldawi!et)al)did!not!define!diagnosis.!

!

When! presumptive! and! definite! diagnoses! are! included! in! diagnostic! yield,! no!

difference!was!observed!between!early!versus! late!colonoscopy!in!the!RCT!(RR!

1.17,!95%!CI!0.87!to!1.56)!or!pooled!analysis!of!the!NRSI!(OR!0.68,!95%!CI!0.31!

to!1.49,!3!studies,!527!participants,!I2=9%,!Figure!2a).!When!diagnostic!yield!was!

limited! to! definite! diagnoses,! early! colonoscopy! was! associated! with! a! higher!

diagnostic! yield! in! the! NRSI! (OR! 1.86,! 95%! CI! 1.21! to! 2.86,! 3! studies,! 650!

participants!I2=42%,!Figure!2b)!although!this!was!not!significant!in!the!RCT!(RR!

1.12,!95%!CI!0.70!to!1.78).!!

! 52!

!

!

!

!

!

!

!

!!!!!!!!!!!Figure!2:!Forest!plot!of!comparison!of!NRSI!a)!presumptive!diagnoses,!b)!definite!diagnoses.!95%!CI,!95%!confidence!interval!!

!

!

All#studies#employed#endoscopic#haemostasis#with#a#minimum#of#three#available#

modalities# (clipping,# banding,# thermocoagulation,# argon# plasma# coagulation,#

epinephrine# injection),# the# specific# type# depending# on# pathology# and#

endoscopist’s# preference.# The# therapeutic# yield# was# superior# in# the# early#

colonoscopy#group# in#the#pooled#analysis#of# the#NRSI#(OR#3.08,#95%#CI#1.93#to#

4.90,#4#studies,#707#participants#I2=7%,#Figure#3a),#but#not#significant#in#the#RCT#

(RR#1.0,#95%#CI#0.36#to#2.81).##

#

Mean# LOS# was# reported# in# three# studies# 71# 93# 101.# Early# colonoscopy# was#

associated#with#a#shorter#LOS#in#NRSI#(MD#2.64#days,#95%#CI#1.54#to#3.73,#two#

studies,#506#participants,#I2=0%)#and#in#the#RCT#(MD#0.40#days,#95%#CI#0.06#to#

0.74,#72#participants)#(Figure#3b).##

#######################

53#

! 54!

!

!

!

!

!!!!!!!!!!!!!!!!!Figure!3:!Forest!of!plot!of!comparison!of!NRSI!a)!therapeutic!yield,!b)!length!of!stay.!95%!CI,!95%!confidence!interval!!

!

!

3a.$Therapeu+c$yield$

3b.$Length$of$stay$

! 55!

Re%bleeding!was!reported!in!the!RCT!and!two!NRSI100!101,!but!all!varied!in!their!

definition!(Table!3)!so!were!not!pooled.!There!was!no!difference!in!re%bleeding!

between!early!and!late!colonoscopy!in!the!RCT!(RR!1.6,!95%!CI!0.58!to!4.43,!72!

participants),! or! the! NRSI! (Nagata! et# al# OR! 1.96,! 95%! CI! 0.94! to! 4.11,! 326!

participants,!and!Albeldawi!et#al#OR!0.7,!95%!CI!0.2!to!2.44,!57!participants).!!

!

Table!3:!Inter%study!variability!in!the!definition!of!re%bleeding!

Study!! Definition!of!re%bleeding!

Green!2005! Haematochezia!!(defined!as!any!one!of!!>3!bloody!bowel!movements!in!<8!h,! ICU! admission,! >5%! decrease! in! Hct! in! <12! h,! transfusion! of! >3! units!RBC,!hemodynamic! instability! in!previous!6h!defined!as! angina,! syncope,!pre%syncope,! orthostatic! vital! signs,! MAP! <80! mmHg! or! HR>110)! after!clinical!cessation!of!the!index!bleeding!event!!

Laine!2010! Haematochezia! persisting! for>24h,! recurrent! haematochezia! after! initial!resolution! (e.g,! brown! stool! followed! by! haematochezia),! HR>! 100! or!SBP<100mmHg!after!hemodynamic!stability!for!≥1h,!or!hemoglobin!drop>!2g/dl!after!stable!hemoglobin!values≥!3h!apart!

Nagata!2016! Significant! amounts! of! fresh! bloody! or! wine%coloured! stools! after! index!colonoscopy!with! unstable! vital! signs;! SBP≤90!mmHg! or! HR≥110! or! the!need!for!blood!transfusion!

Strate!2003! Blood! per! rectum! after! 24! h! of! stability! accompanied! by! a! drop! in!Hct≥20%,!and/or!a!requirement!of!additional!blood!transfusions!

Abeldawi!2014! After!clinical!cessation!of!index!bleeding!event!during!hospitalization!

Nagata!2015! Significant! fresh!bloody!or!wine! coloured! stool! accompanied!by!unstable!vital! signs;! SBP≤90! mmHg! or! HR≥110! and! non%response! to! ≥2! units!transfused!blood!!

Jensen!2000! Self%limited! or! recurrent! haematochezia! that! required! no! more! than! an!additional! 2! units! of! packed! red! cells! or! continued! or! recurrent!haematochezia!that!required!at!least!3!units!of!packed!red!cells!

Ishii!2011! Clinical!evidence!of!recurrent!bleeding!

*Hct,!haematocrit.!

!

RBC!transfusion!was!reported!in!the!RCT71!and!one!NRSI101;!patients!in!the!early!

group!of!the!RCT!received!more!transfusions!(mean!difference!0.8!units,!95%!CI!

0.65! to! 0.95,! 72! participants),! but! in! the! NRSI! there! was! no! difference! in! the!

! 56!

number!of!participants!receiving!RBC!transfusion!(OR!1.00,!95%!CI!0.62!to!1.63,!

326!participants).!

#

Adverse! events! were! reported! in! two! studies71! 101.! Laine! et# al! reported! one!

perforation!in!the!late!colonoscopy!group!(RR!0.33,!95%!CI!0.01!to!7.92).!Nagata!

et# al# reported! no! major! colonoscopy%related! adverse! events! in! either! cohort.!

Mortality!was!reported!in!two!studies71!100.!There!were!no!deaths!in!the!study!by!

Albeldawi!et#al,!but!there!were!two!deaths!in!the!urgent!colonoscopy!arm!in!the!

RCT!by!Laine!et#al!(RR!5.00,!95%!CI!0.25!to!1.00).!One!patient!developed!a!fatal!

intracranial!haemorrhage!and!the!other!had!a!prolonged!hospitalisation!due! to!

medical!co%morbidities!and!died!after!a!cardio%respiratory!arrest.!!

!

CTA#and#MA#

To!maximise!study!eligibility!we!did!not!pre%specify!definitions!of!urgent!or!non%

urgent!CTA!or!MA.!No!studies!were!identified.!

! 57!

2.6!Choice!of!treatment!for!acute!lower!gastrointestinal!bleeding!

#

Therapeutic#endoscopy#versus#mesenteric#embolization#

We!identified!no!RCTs,!NRSIs!or!on%going!trials.!!

#

Therapeutic#endoscopy#versus#other#

One! prospective! cohort! study! compared! endoscopic! therapy! (adrenaline! or!

thermocoagulation)!to!a!historical!control!comprising!of!conservative!or!surgical!

treatment! in! patients! with! diverticular! bleeding.98! Patients! that! received!

endoscopic! treatment!were! less! likely! to!require!surgery! for!bleeding!(Peto!OR!

0.14,!95%!CI!0.02!to!0.88,!27!participants),!re%bleed!(Peto!OR!0.10!95%!CI!0.02!to!

0.51)!or! receive!a!RBC! transfusion! (Peto!OR!0.10!95%!CI!0.02! to!0.51).!An!on%

going! RCT! is! comparing! endoscopic! therapy! with! barium! impaction! for!

diverticular!bleeding!(Matsuhashi!et#al,#JPRN%UMIN000008287).!!

!

Mode#of#Endoscopic#haemostasis##

No!RCTs!were!identified.!Two!retrospective!cohort!studies!were!identified,!both!

comparing! endoscopic! band! ligation! (EBL)! with! endoclipping! in! diverticular!

bleeding.96!97! The! primary! outcome! in! both! studies!was! re%bleeding;! Ishii! et#al!

reporting! 60! day! rates! of! 1/16! (6.2%)! and! 16/48! (33.3%)! for! EBL! and!

endoclipping!respectively,!although!this!was!not!significantly!different!(OR!7.50,!

95%!CI!0.91!TO!61.94,!64!participants).!Seven!patients!in!the!endoclipping!group!

required!radiological!control!of!bleeding!versus!none!in!the!EBL!group!however!

this! was! non%significant! (Peto! OR! 4.37,! 95%! CI! 0.72! to! 26.37).! Nakano! et# al!

followed!patients!for!two!years!and!also!found!that!large!numbers!of!patients!re%

! 58!

bled! in! each! group! (EBL! 24/50,! 48.0%;! endoclipping! 18/39,! 46.2%)! although!

there!was! no! difference! between! the! two!modalities! (OR! 0.93! 95%! CI! 0.40! to!

2.15,! 89! participants).! No! patient! experienced! complications! related! to!

endoscopy!in!either!study.!!

!

One!on%going!RCT!comparing!TC%325! (Hemospray)!monotherapy!at! endoscopy!

to!standard!endoscopic!therapy!in!patients!with!UGIB!or!LGIB!due!to!malignancy!

was!identified!(Barkun!et#al,!NCT02135627).!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

! 59!

2.7!Assessment!of!methodological!quality!

The!RCTs!were!all!deemed!at!high!or!unclear!risk!of!bias!due!to!blinding!(Table!

4).!Laine!et#al#stated!that!their!trial!was!not!blinded.!Green!et#al#also!stated!that!

the! physicians! caring! for! the! patients!were! not! blinded! and! gave! no! detail! on!

blinding!of!outcome!assessors.!Leung!at#al#stated!that!patients!and!investigators!

were# unaware! of! the! randomisation! sequence! but! patients! were! assigned! to!

physically!different!interventions!(capsule!endoscopy!or!MA)!so!blinding!is!likely!

to!have!been!broken.!The!nature!of!the!interventions!used!in!these!studies!makes!

blinding!difficult.! For! some!objective! outcomes,! this!may!be! acceptable! but! for!

other! more! subjective! outcomes! such! as! diagnostic! yield! this! may! introduce!

significant!bias.!!

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

! 60!

Table!4:!Assessment!of!methodological!quality;!Cochrane!risk!of!bias!for!RCTS,!Newcastle%Ottawa!for!NRSI!!

RCT! Sequence!generation!

Allocation!concealment!

Blinding!of!participants! and!personnel!!

Blinding!of!outcome!assessors!

Incomplete!outcome!data!

Selective!outcome!reporting!

Other!!

Green!2005!

Low! Unclear! High! Unclear! Low! Unclear! Low!

Laine!2010!

Low! Low! High! High! Low! Low! High!

Leung!2012!

Low! Low! High! Unclear! Low! High! Low!

NRSI! Representativeness!(1)!

Selection!of! non%exposed!(1)!

Ascertainment! of!exposure!(1)!

Outcome! of!interest!not!present!at! start!of! study!(1)!

Comparability!(2)!

Assessment! of!outcome!(1)!

Follow! up!long!enough!and!adequate!(2)!

Adeldawi!2014!

1! 1! 1! 1! 1/0! 1! 1/1!

Ishii!2011!

0! 1! 1! 1! 0/0! 1! 1/1!

Jacovides!2015!

1! 1! 1! 0! 0/1! 1! 1/1!

Jensen!2000!

0! 1! 1! 1! 0/0! 1! 1/1!

Nagata!2016!

1! 1! 1! 1! 1/1! 1! 1/1!

Nagata!2015!

1! 1! 1! 1! 1/0! 1! 1/1!

Nakano!2015!

0! 1! 1! 1! 0/0! 1! 1/0!

Sun!2011!

0! 0! 1! 1! 0/0! 1! 1/1!

Yabutani!2006!

0! 1! 1! 0! 1/1! 1! 1/1!

Yamaguchi!2006!

1! 1! 1! 1! 1/1! 1! 1/1!

Ketwaroo!2012!

0! 0! 1! 1! 0/0! 1! 1/1!

! 61!

Strate!2003!

1! 1! 1! 1! 1/1! 1! 1/1!

Rodriguez%!Moranta!2007!

1! 1! 1! 1! 1/1! 1! 1/1!

!!

Re%bleeding! may! also! be! subject! to! bias! due! to! lack! of! blinding.! Additionally,!

there! was! considerable! inter%study! variation! in! the! definition! re%bleeding.!!

Several!studies!characterised!re%bleeding!by!the!persistence!of!on%going!signs!of!

bleeding71! 101! 102! but! these! definitions! may! have! also! captured! patients! with!

failed! haemostatic! intervention,! not! true! re%bleeding.! Most! studies! used! a!

definition! that! included! a!period!of! clinical! stability61!78! although! some!did!not!

define!the!criteria!that!would!need!to!be!met!to!establish!a!new!bleeding!event97!

100!(Table!3).!!

!

The!trial!by!Leung!et#al!was!deemed!to!be!at!high!risk!of!bias!as!not!all!outcomes!

pre%specified! in! the! study!protocol!were! reported,!particularly!LOS.!Due! to! the!

nature! of! the! procedure,! LOS!may!be! longer! for! capsule! endoscopy,!which! has!

implications!for!its!use!in!the!acute!inpatient!setting.!The!study!by!Laine!et#al#was!

subject!to! ‘other’!source!of!bias!as! it!was!terminated!early!because!the!hospital!

changed!its!protocol!on!allowing!colonoscopy!in!the!emergency!room,!although!

the!reasons!for!this!are!not!given.!!

!

Risk!of!bias!in!the!NRSI!was!assessed!using!the!Newcastle%Ottawa!scale.!The!two!

most! common! areas! of! poor! performance! in! the! NRSI! were! selection! of!

participants,! particularly! representativeness! of! the! exposed,! and! the!

! 62!

comparability! of! cohorts.! Six! studies! scored! no! stars! for! representativeness! of!

LGIB!as! they!studied!a!single!pathology92!96%98!or!a!single! intervention! that!was!

related!to!severity!of!bleeding94!95.!This!limits!the!generalisability!of!these!results!

to!the!LGIB!population!as!a!whole.!!

!

Three!studies!included!no!data!on!whether!they!adjusted!for!confounders94!95!97,!

one! study!provided!no!data! on! confounders! and! also!populated!one! treatment!

arm! using! an! intervention! that! is! likely! to! be! related! to! severity! of! bleeding!

(endoscopic!haemostasis)98!and!one!study!compared!baseline!demographics!for!

each! group,! but! did! not! include! cardiovascular! parameters! or! baseline!

transfusion!requirements.96!There!is!likely!to!be!significant!baseline!imbalances!

between!the!cohorts!in!these!studies.!None!were!deemed!of!sufficient!quality!to!

permit!data!synthesis.!

!

!

!

!

!

!

!

!

!

!

!

!

! 63!

2.8!Implications!for!practice!in!the!United!Kingdom!

!

LGIB! presents! a! significant! healthcare! burden! in! the! UK10! but! there! is!

considerable! uncertainty! regarding! its! optimal! management.6! This!

comprehensive! review! of! the! diagnostic! and! therapeutic! yield! of! treatment!

modalities!demonstrates!a!paucity!of!evidence!across!the!majority!of!diagnostic!

and!therapeutic!techniques.!!

!

Colonoscopy! is! recommended!as! the! first%line!diagnostic!procedure! for!LGIB! in!

international! guidelines47! but! questions! remain! regarding! its! timing! and!

suitability! for! all! patients.! The! limited! studies! comparing! interventions!

demonstrate! higher! diagnostic! rates! with! colonoscopy! compared! to! standard!

care! algorithms,! but! that! identification! of! lesions!with! active! bleeding!may! be!

enhanced!by!the!concomitant!use!of!CTA.!However,!this!did!not!translate!into!an!

increase! in! therapy,! and! when! haemostasis! was! undertaken,! most! studies!

showed! no! or!minimal! impact! upon! clinically! important! outcomes! such! as! re%

bleeding!or!RBC!transfusion.!!

!

The!area!with! the!greatest! evidence!was! timing!of! colonoscopy,! although!most!

studies!were!non%randomised.!Early! colonoscopy!was! associated!with! a!higher!

diagnostic!yield,!rate!of!haemostasis!and!a!reduction!in!LOS.!However,!there!was!

no!evidence!that!earlier!colonoscopy!had!any!impact!upon!death!or!re%bleeding.!

Paradoxically!there!was!higher!RBC!transfusion! in!the!early!colonoscopy!group!

of!the!RCT,!although!this!may!represent!baseline!imbalances!between!the!groups,!

as! the! initial! haemoglobin! was! also! lower! in! the! early! arm.71! It! is! not! known!

! 64!

whether! colonoscopy!within! 24! hours! of! presentation! is! routinely! available! in!

hospitals!in!the!UK.!!

!

In!contrast!to!OGD!in!UGIB,!colonoscopy!in!the!acute!setting!can!be!challenging!to!

perform,! requires!rapid!bowel!preparation!and!may!be!poorly! tolerated!by! the!

patient.!Only!two!studies!reported!complications,!but!overall!early!colonoscopy!

appeared!safe.!In!one!RCT,#two!patients!who!received!urgent!colonoscopy!died.71#

Although!neither!was!attributed!to!the!intervention,!the!potential!to!cause!harm!

in!patients!with!extensive!co%morbidities!should!not!be!underestimated.!!

!

The!impact!of!early!colonoscopy!on!length!of!hospital!stay!has!clear!benefits.!A!

micro%costing!analysis!of!UGIB!admissions!reported!an!average!cost!of!£2458!per!

patient,!most!of!which!was!due!to!the!cost!of!the!hospital!bed.73!Outcomes!other!

than! LOS! must! also! be! considered;! there! was! no! difference! in! re%bleeding! or!

death.!The!value!of!investment!in!24%hour!lower!GI!endoscopy!services!therefore!

requires!further!assessment.!

!

Most!of!these!studies!on!timing!of!colonoscopy!were!conducted!in!patients!who!

were! subsequently! diagnosed! with! diverticular! bleeding,! limiting! the!

generalizability!of!these!findings!to!other!sources!of!bleeding.!The!proportion!of!

patients!admitted!with!LGIB!due!to!diverticular!bleeding!in!the!UK!is!not!known.!!

!

Timing! of! colonoscopy! has! been! the! focus! of! three! recent! systematic! reviews.!

Kouanda!et#al! and! Seth!et#al! included!RCTs! and! cohort! studies,! but! differed! in!

their! classification! of! several! large! database! studies! that! we! rejected! as! case!

! 65!

series,! or! restricted! their! search! to! English! language! studies.104!105! Regardless,!

the! authors! reported! similar! findings;! there! was! no! difference! in! rates! of! re%

bleeding,! death! or! transfusion.! In! contrast! to! the! present! review,! Seth! et! al!

reported! that! there! was! no! difference! in! therapeutic! yield! or! LOS! with! early!

colonoscopy.! For! therapeutic! yield,! the! authors! did! not! include! data! from!

Albeldawi!et! al! in! the!meta%analysis,! but! the! reasons! for! this! are!not! clear.! For!

LOS,! the! authors! pooled! estimates! from! RCTs! with! NRSI,! which! contravenes!

Cochrane!guidance,88! and!may!account! for! the!different! findings! to! the! current!

review.!Sengupta!et#al!used!a!similar!study!classification!system!to! the!present!

review,! and! also! pooled! estimates! from! RCTs! and! NRSI,! but! also! reported! no!

difference!in!clinical!outcomes!with!early!colonoscopy.91!

!

We! found! only! minimal! studies! examining! therapeutic! intervention! at!

colonoscopy.! These! studies! included! combinations! of! clipping,! banding,! argon!

laser,!heater!probe!or! forceps,!adrenaline! injection!or!snare!polypectomy.!Only!

banding! and! clipping!were! examined! in! their! own! right.!Re%bleeding! following!

endoscopic! haemostasis! was! reported! as! 6%48%! in! the! cohort! studies,96! 97! 101!

raising! questions! regarding! the! efficacy! of! endoscopic! haemostasis.! This! is!

important! given! the! absence! of! evidence! comparing! it! to! other! treatment!

options,!notably!embolisation.!This!uncertainty!is!reflected!in!the!infrequent!use!

of! endoscopic!haemostasis! reported! in!population! studies!of! LGIB,8!12! although!

its!utilisation!in!the!UK!is!not!known.!!

!

In! the! acute! setting! CTA! may! be! an! alternative! to! colonoscopy,! although! we!

found! only! two! studies! directly! comparing! these! two! interventions.! 64! 92! Pre%

! 66!

colonoscopy! CTA! was! associated! with! higher! diagnosis! of! vascular! lesions! in!

comparison! to! colonoscopy! alone.! There! were! no! studies! to! inform! optimum!

timing!or!patient!selection!with!regard!to!severity!of!bleeding.!Studies!on!upper!

and!lower!GIB!have!reported!that!CTA!has!a!comparable!diagnostic!yield!to!that!

of!MA79!but! further!research!comparing! it!with!other! first%line! investigations! is!

required.! The! quoted! minimum! 0.4ml/min! required! volume! of! blood! loss! to!

demonstrated! extravasation! of! contrast! is! based! on! animal! studies106.! Further!

areas! of! research! should! focus! on! the! clinical! outcomes! of! endotherapy! and!

embolization,!and!the!role!of!CT.!

!

There!are!several!limitations!to!this!review.!Most!evidence!originates!from!NRSI,!

with! significant! bias,! which! limits! the! strength! of! the! conclusions! that! can! be!

drawn! from! this! review.! More! randomised! data! particularly! on! the! timing! of!

colonoscopy! is! urgently! required.! Systematic! review!of!NRSIs! is! limited!by! the!

variable! description! of! study!methodology,!making! their! classification! difficult.!

This! is! evidenced! by! the! different! studies! that! are! included! in! reviews! of! the!

same!topic!with!similar!inclusion!criteria.91!104!105!

!

In! summary,! whilst! there! was! a! paucity! of! high! quality! evidence! across! all!

interventions!we!found!that!colonoscopy!within!24!hours!had!higher!diagnostic!

and! therapeutic! yields,! and! shorter! LOS.! Chapters! 3,! 4! and! 5! present! the! first!

national! study! of! LGIB! undertaken! in! the! UK,! and! provide! data! on! current!

practice!in!the!UK,!including!the!frequency!and!timing!of!inpatient!colonoscopy,!

and!diagnostic! yields! in! a!UK!population!of! acute!admissions.!The! study!of! the!

! 67!

organisation!of!services!provides!data!on!whether!the!provision!of!colonoscopy!

within!24!hours!is!currently!feasible!in!the!NHS.!!

!

! 68!

CHAPTER!3!

NATIONAL!OBSERVATIONAL!STUDY!OF!ACUTE!LOWER!

GASTROINTESTINAL!BLEEDING:!METHODOLOGY!

!

This! chapter! describes! how! the! observational! study! process! was! piloted,! how!

hospitals!were!recruited,!cases!identified!and!data!collected!and!analysed.!!

!

3.1!Recruitment!of!sites!

All!NHS!Trusts!in!England!admitting!acute!surgical!and!medical!admissions!were!

contacted! directly! in! June! 2015! and! invited! to! participate.! Letters! and! emails!

explaining! the! rationale! and! aims! were! sent! to! the! Medical! Director,! Chief!

Executive,! Clinical! Audit! Department! and! the! haematologist! with! primary!

responsibility! for! transfusion,! as! well! as! transfusion! practitioners! within! each!

acute!hospital.! If! there!was!no!response,!a! further!two!written!invitations!were!

sent! in! July! and! August! 2015.! If! there! was! no! response! after! three! formal!

requests! it!was! assumed! that! the! hospital!would! not! be! participating.!Medical!

Directors!were!asked!to!give!permission!for!their!hospital! to!participate!and!to!

provide! the! contact!details! of! their!Clinical! Lead! for! Surgery.!The!Clinical! Lead!

was!then!provided!with!information!about!the!methodology!and!timeline!of!the!

study!and!asked!to!nominate!a!local!lead!to!co%ordinate!the!project.!!

!

This!study!was!offered!to!NHS!hospitals!in!Scotland,!Wales!and!Northern!Ireland!

via! their! national! blood! services.! Independent! hospitals! were! not! invited! to!

participate!since!GI!bleeds!are!predominantly!managed!in!the!NHS.!In!June!2015!

! 69!

there!were!140!eligible!NHS!trusts!in!England,!and!the!aim!was!to!recruit!80%!of!

these.!!

!

3.2!Case!Identification!

Eligible! cases! included! all! unselected! patients! that! presented! with! LGIB! that!

resulted! in!an!admission! to!hospital!or!developed!whilst!patients!were!already!

admitted! for!another!reason.!There!are!no!hospital!diagnostic!codes!specific! to!

LGIB,! limiting! case! identification! from! hospital! registries.! Methods! aimed! at!

identifying!LGIB!cases!by!mapping!to!‘classification!trees’!using!codes!such!as!the!

ICD76! have! been! shown! to! have! varying! performance.77! A! previous! large!

prospective!audit!on!UGIB! successfully! addressed! this! constraint!by! contacting!

clinical! teams.33! Cases! were! therefore! identified! by! clinical! teams,! using!

presenting! symptoms! as! opposed! to! examination! findings! or! discharge!

diagnoses.! Cases! were! identified! prospectively! and! followed! until! death,!

discharge!or!28th!day!of!admission.!Central!data!collectors!monitored!each!case!

for!28!days!post%discharge!for!re%admission.!!

!

Pilot#study#1#

To! establish! a! pattern! of! hospital! admission! locations! for! patients! with! acute!

LGIB,! five! hospitals! (including! a! tertiary! referral! centre! for! interventional!

radiology! and! a! small! district! general! hospital)! were! asked! to! describe! their!

referral! pathways! and! pilot! the! process! of! case! identification.! Eleven! potential!

departments!and!wards!were!identified!as!likely!to!accommodate!patients!with!

LGIB.! Over! a! two! week! period,! each! hospital! was! instructed! to! contact! each!

! 70!

location! multiple! times! to! identify! locations! with! the! highest! and! lowest! case!

yield!by!recording!the!number!of!identified!cases!per!department!(Table!5).!!

Table!5:!Pilot!case!identification!tool!!Location! Present! in!

your!hospital!(Y/N)!

Frequency!of!contact!

Number! of!cases!identified!Week!1!

Number! of!cases!identified!Week!2!

Comment!

Surgical! Assessment!Unit!

! Daily! ! ! !

Endoscopy!unit! ! Daily! ! ! !On%call! Surgical!Registrar!

! Daily! ! ! !

A&E!Nurse!in!Charge! ! Daily! ! ! !Medical! Assessment!Unit!

! Daily! ! ! !

Blood!Bank!!

! X3!per!week! ! ! !

Adults!Wards!!


Emergency!theatre! ! X2!per!week! ! ! !GI!Bleed!Unit! ! Daily!! ! ! !Interventional!Radiology!Suite!


Death!Certificates! ! Weekly! ! ! !!!Feedback! on! ease! of! case! identification,! time! spent! and! suggestions! for! other!

locations!were!collected.!Of!the!five!hospitals,!only!one!site!was!able!to!provide!

data!for!the!complete!time!period,!identifying!28!cases!of!LGIB.!The!low!response!

rate!of! the!other!hospitals! indicates! that! this!kind!of! case!ascertainment! is!not!

reproducible! or! reliable.! A! recent! national! audit! of! severe! gastrointestinal!

haemorrhage!demonstrated! that!unlike!UGIB,!which!may!present! to!a! range!of!

departments! and! specialities,! LGIB! presents! to! a! more! limited! selection! of!

locations6,! namely! surgery,! gastroenterology! and!general!medicine!wards.!This!

was!also!demonstrated!by!the!28!cases!identified!in!this!pilot!study;!all!but!one!

case!was!identified!by!daily!contact!with!the!admitting!surgical!team!and!acute!

medical!admissions!unit.!To!maximise!case!ascertainment!in!this!national!study,!

study!leads!were!asked!to!have!daily!contact!with!surgical!admission!units!and!

! 71!

the!surgical!on%call!team,!daily!contact!with!medical!admission!units!and!on%call!

team!and!to!visit!the!gastroenterology!wards!three!times!per!week.!!

!!!Cases!were!eligible!if!they!fulfilled!the!following!criteria:!!

• Age!≥!16!years!

• History! of! bright! or! dark! blood! per! rectum,! maroon! coloured! stool! or!

blood!mixed!in!with!stool,!clots!per#rectum!or!passage!of!melaena!without!

haematemesis.!!

!

Melaena! without! haematemesis! was! included! so! that! cases! of! small! bowel!

bleeding!were!unlikely!to!be!missed.!Previous!reports!have!shown!that!it!can!be!

difficult! to!distinguish!upper! from!lower!GI!sources!of!bleeding6!so! to!optimise!

the! identification! of! LGIB! the! inclusion! criteria! were! deliberately! broad.!

Inevitably! a! small! number! of! patients! with! UGIB! would! be! captured! in! the!

dataset,!but!this!reflects!the!uncertainties!that!may!exist!in!routine!clinical!care.!

Once!data!collection!was!complete,!UGIB!cases!were!identified!using!presenting!

features!and!findings!at!OGD.!The!following!cases!were!excluded:!!

• Definite!UGIB!(proven!stigmata!of!UGIB!on!OGD)!

• Probable!UGIB!(no!stigmata!of!haemorrhage!but!abnormal!OGD)!

• !Suspected! UGIB! (presentations!with!melaena! only! but! no! confirmatory!

OGD)!

!

!

!

! 72!

3.3!Data!Collection!!Over!two!months!between!1st!September!2015!and!31st!October!2015,!two!broad!

categories!of!data!were!collected;!organisational!and!individual!patient!data.!!

#

Organisation#data:#

Organisational!data!recorded!the!availability!of!services!for!the!investigation!and!

treatment! of! LGIB.! The! questionnaire!was! available! as! a! paper! version! and! an!

electronic! survey.! Outcomes! included! the! in%! and! out%of%hours! availability! of!

endoscopy,!interventional!radiology!and!surgery.!Data!on!how!patients!accessed!

these! investigations! and! treatment! in! hospitals! without! onsite! services! were!

collected.!Each!hospital!was!asked!to!complete!one!copy!of!this!questionnaire.!

!

Individual#patient#data:#

This!dataset!captured!the!clinical!characteristics!and!outcomes!of!patients!with!

acute! LGIB.! The! data! collection! questionnaire! included! questions! on! clinical!

examination! findings,! the! timing! and! results! of! endoscopy,! radiology! and!

surgery,! the!prevalence!of!different!aetiologies!of!LGIB!and!the!use,! timing!and!

volume! of! blood! products.! Outcomes! included! length! of! stay,! in%hospital!

morbidity! and! mortality,! 28%day! re%admission! rates,! re%bleeding! rates! and!

transfusion! requirements.! Data! on! anticoagulation! and! antiplatelets! were!

collected,! including! methods! of! their! reversal.! All! data! were! obtained!

prospectively!from!patient!notes!and!electronic!hospital!records.!

!!In! each! hospital,! a! team! consisting! of! a! study! lead,! case! identifier! and! several!

data!enterers!collected!the!data! in!each!NHS!trust.!The! lead!ensured!that!cases!

! 73!

are!being!identified!and!entered!and!that!the!data!were!complete!and!accurate.!

The! leads! were! predominantly! colorectal! or! general! surgical! consultants! or!

registrars,! although! gastroenterologists! and! transfusion! practitioners! also!

participated.! I! co%ordinated! the! leads! and!worked!with! the! case! identifier! and!

case!enterers!in!each!site!as!needed.!!

!!#!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

! 74!

3.4!Pilot!Study!2!!!The! questionnaires! were! subject! to! an! extensive! pilot! process.! First,! I! piloted!

both!questionnaires!on%site!at!three!NHS!hospitals.!I!worked!with!a!study!lead!at!

each!site!to!trial!the!organisational!questionnaire!and!the!patient!questionnaire!

on! real! cases! of! LGIB! that! they!had! identified! that!week.! The! terminology!was!

checked! to! ensure! applicability! across! sites! and! to!make! sure! that! all! required!

data!were!readily!reported!in!medical!notes!and!electronic!records.!!

!

!Secondly,! ten!NHS!hospitals!were! asked! to!pilot! the!questionnaires! externally.!

Each!site!was!asked! to!review!the!questionnaires!and!record! feasibility!of!data!

collection!for!each!question!via!a!grading!system!of!1%3!to!represent!agreement!

or!disagreement!with!validity!and! feasibility!both!of!question!content,!wording!

and!availability!of!information!

!

Seven! sites! returned! the! organisational! questionnaire! pilot! and! all! but! two!

questions! were! answered! as! expected.! The! questions! found! to! be! difficult! to!

complete! asked! for! a! recording! of! the! availability! of! guidelines! on! the!

management! of! LGIB,! which! were! uniformly! unanswered.! On! review! it! was!

decided!that!the!data!collected!by!these!questions!were!not!essential!and!time%

consuming!to!capture.!These!questions!were!removed!from!the!dataset.!!

!

Six!hospitals!were!asked!to!identify!and!complete!patient%specific!questionnaires!

on!five!cases!of!LGIB!to!determine!the!feasibility!of!collecting!the!data!in!a!clinical!

setting.! The! questionnaires! took! 30%40! minutes! to! complete! per! case." All!

! 75!

mandatory!questions!were!deemed!feasible!and!accessible.!The!remainder!of!the!

questions! were! reviewed! and! clarified.! No! questions! were! excluded.! Wording!

and! phrasing! was! amended! for! questions! deemed! ambiguous! based! upon! the!

pilot! exercise.! Answers! were! reviewed! to! ensure! data! was! interpretable! and!

reproducible.!

!!Electronic#Data#Entry#Pilot##An!electronic!version!of!the!questionnaire!was!created!which!was!incorporated!

into! a! password! protected! website.! The! website! was! trialled! on! true! cases! of!

LGIB!as!identified!in!the!pilot!study!and!any!coding!problems!addressed.!!

!

#!!!!!!!!!!!!!!!!!!!!!!!!!!

! 76!

3.5!Data!Analysis!!Data!were!entered! into!an!online!questionnaire,!which!was!accessed!by!a! site%

specific,!password%protected!website.!Paper!versions!of!the!questionnaire!were!

posted! to! sites! to! facilitate! the! collection! of! data! for! those! sites! with! limited!

computer!access.!Cases!and!sites!were!given!a!unique!code!to!enable!data!entry!

without!using!any!patient!or!hospital!identifiers.!!

!

Throughout! the!data! capture!period,! the!website!automatically!downloaded!all!

data!into!a!central!database!regardless!of!whether!the!site!had!indicated!that!the!

data!were! complete.!This! allowed!monitoring!of! the!participants’!progress! and!

regular!counts!of! the!registered!cases.!Once!a!site! indicated!that! it!had!entered!

complete!data! for! a! case,! the! central! study! team!were! alerted,! and! the!dataset!

checked!for!any!missing!mandatory!data!or!nonsensical!responses.!Study!Leads!

within! each! hospital! were! contacted! to! provide! additional! or! corrected! data!

where!necessary.!This!happened!on!a!daily!basis!throughout!and!after!the!study!

period! to!ensure!data!were!as! complete!as!possible.!Whilst! the! study!was! live,!

the! central! project! team! also! reviewed! any! cases! that! were! incomplete! but!

inactive! for! more! than! one! week! and! contacted! the! hospital! study! lead! to!

encourage!their!completion.!!

!Once! all! datasets!were! indicated! as! finished! by! the! local! site,! checked! for! any!

missing! data! and! incorrect! entries! amended! they! were! downloaded! into! one!

unifying!database.!Any!duplicates!were! removed.!Variations! in! spelling!of!drug!

names,!abbreviations!and!treatments!were!standardised.!!

!

! 77!

Although!most! questions! required! a! single! fixed! response,! there! were! several!

with!an!‘other’!option.!Where!appropriate!these!were!recoded!as!one!of!the!other!

fixed!responses!or!compiled!into!an!appendix.!!

!

Data!were!collected!on!several!baseline!co%morbidities,!including!those!listed!in!

the!Deyo!modification107!of! the!Charlson!Co%Morbidity! Index.108!This! is! a! score!

based! on! combinations! of! co%morbidity,! which! can! be! used! to! predict! 1%year!

mortality.108!The!Charlson!index!has!been!used!in!administrative!datasets!but!its!

application! to! clinical! data! is! more! difficult! as! some! of! the! definitions! are!

subjective.! To! enable! its! use! in! a! clinical! setting! we! made! the! following!

amendments;! (1)! mild! or! and! moderate! liver! disease! was! stratified! into! non%

cirrhotic! and! cirrhotic! respectively! for! ease! of! categorisation! using! medical!

notes;!(2)!Congestive!cardiac!failure!is!usually!classified!by!the!New!York!Heart!

Association!criteria109!but!these!criteria!may!not!be!reproducible!in!a!review!of!

surgical!notes.!This!was!changed!to!include!patients!on!pharmacotherapy!or!with!

clinical! examination! findings! consistent! with! heart! failure;! (3)! Peptic! ulcer!

disease!was!classified!by!the!use!of!pharmacological!acid!suppression;!(4)!Renal!

disease! was! re%classified! as! chronic! kidney! disease! stage! 2%3! and! stage! 4! to!

represent! moderate! and! severe! respectively110! (Appendix! 1).! A! Charlson! Co%

morbidity! index! was! calculated! for! each! case.! A! retrospective! review! of! a!

national! database! showed! that! a! Charlson! index! ≥! 2! was! independently!

associated!with!in%hospital!mortality!in!patients!admitted!with!LGIB.12!

!!!

! 78!

The! discharge! diagnosis!was! determined! by! using! the! following! hierarchy:! (1)!

diagnostic! CT,! endoscopy,! proctoscopy,! examination! under! anaesthesia! (EUA),!

laparoscopy!or! laparotomy,! (2)!diagnostic!digital! rectal!examination!(DRE),! (3)!

diagnosis!as!documented!in!medical!notes!or!discharge!papers.!These!were!then!

mapped!to!the!ICD%10:!Classification!of!diseases!of!the!digestive!system.76!!

!!Calculating!the!hospital!resources!required!by!patients!admitted!with!acute!LGIB!

requires!estimates!of!bed!occupancy!and! frequency!of! inpatient!and!outpatient!

investigation! and! treatment.! ! Hospital! bed! requirements!were! described! using!

data!on!LOS,!new!discharge! to!a!nursing!home!or!rehabilitation! facility!and!re%

admission! rates.! Patients! were! only! included! in! re%admission! rates! if! they!

survived!to!discharge.!

!

The! frequency! and! waiting! time! for! investigations! were! calculated! and!

comparisons!by!type!of!investigation!were!made.!LOS!for!patients!who!received!

inpatient! treatment!(as!well!as! investigation)!were!compared!to! those!who!did!

not.!!

!!Statistical#Methods###Missing! data! are! reported! for! each! variable!within! each! corresponding! results!

table.! Data! are! reported! as! numerator! and! percentage,! and! as! median! and!

interquartile! range! (IQR)! as! appropriate.! Categorical! data! are! compared! using!

Chi! square! test! and! continuous! data! by! Wilcoxon! rank! sum.! The! ability! of!

Charlson! Co%morbidity! Index! to! discriminate! mortality,! re%bleeding! and! re%

! 79!

admission!was! examined! by! calculating! the! area! under! the! receiver! operating!

characteristic! curve.! Statistical! analysis! was! undertaken! using! SAS! version! 9.4!

(SAS!Institute!Inc.,!NC,!USA)!and!Stata!version!14!(StataCorp,!TX,!USA).!

!

3.6!Study!Definitions!

Table!6:!Study!definitions!!

Acute!lower!gastrointestinal!bleeding!(LGIB)!Bright! or! dark! blood! per# rectum,! maroon! coloured! stool,! blood!mixed! in!with!stool,!clots!per#rectum!or!passage!of!melaena!without!haematemesis!Clinically!significant!bleeding!Bleeding! associated! with! systolic! blood! pressure! <100mmHg,! heart! rate!≥100!beats!per!minute!and!≥1!unit!red!cell!transfusion!Shock!Heart!rate!≥100!beats!per!minute!and!systolic!blood!pressure<100mmHg.!ReZbleeding!(further!bleeding)!Additional!transfusion!requirements!and/or!a!decrease!in!Hct!≥20%!after!24!hours!of!clinical!stability13!ReZadmission!due!to!further!LGIB!Further!episodes!of!LGIB!that!result!in!an!unplanned!admission!to!hospital,!within!28!days!of!discharge!InZhospital!mortality!All!cause!mortality!up!to!28!days!after!admission!with!LGIB!

!

Unlike! UGIB,! there! is! no! widely! accepted! definition! of! re%bleeding! associated!

with! LGIB.! Comparatively! less! is! known! about! its! frequency! and! course,! and!

simply!quantifying!the!numbers!of!patients!that!experience!further!symptoms!of!

bleeding!may! lead! to! falsely!high! reporting,! capturing! trivial!bleeds!or!delayed!

transit!of!luminal!blood!after!the!initial!bleed!has!stopped.!The!definition!used!in!

this!study!was!that!described!by!Strate!et#al,#and!captures!re%bleeding!by!using!

associated!change!in!Hct!or!need!for!further!transfusion!after!a!period!of!clinical!

stability.13!Definitions!of!the!other!study!outcomes!are!defined!in!Table!6.!

!!!!!

! 80!

3.7!Ethical!Considerations!!!This! study!was! carried!out! as!part!of! the!National!Comparative!Audit!of!Blood!

Transfusion!programme,!which!is!supported!by!the!National!Blood!Transfusion!

Committee!in!England.!This!study!details!routine!observational!data!collected!to!

support!the!audit!findings.!The!audit!examined!established!methods!of!care!and!

did! not! influence! patient! management! whilst! it! was! being! conducted,! it! is!

therefore! not! subject! to! ethical! consideration! by! the! NHS! Research! Ethics!

Committee.111!As!stated! in! the!NHS#Code#of#Practice#(2003)!patient! information!

may! be! collected! for! clinical! audit! without! prior! patient! consent.! No! patient!

identifiers!are!collected!as!part!of!this!audit.112!!

"

!!!!!!!!!!!!!!!!!!!!!!!!

! 81!

!CHAPTER!4:!NATIONAL!OBSERVATIONAL!STUDY!OF!ACUTE!LOWER!

GASTROINTESTINAL!BLEEDING:!RESULTS!!!4.1!Patient!Data!!!4.1.Aims!and!Objectives!!The! overall! objective! was! to! characterise! the! clinical! characteristics,!

management!strategies!and!outcomes!of!patients!with!acute!LGIB!presenting!to!

UK!hospitals.!Specific!objectives!included:!

1. Description! of! the! use! of! inpatient! investigations! (lower! GI! endoscopy,!

CTA,! interventional! radiology,! nuclear! medicine! and! surgery)! and! their!

associated! diagnostic! yield! (including! factors! associated! with! failed!

investigation),!complications!and!effect!on!LOS,!re%admissions,!morbidity!

and!mortality.!

2. Evaluation! of! therapeutic! modalities! (endoscopic! haemostasis,!

embolisation!and!surgery)!focussing!on!indication,!therapeutic!yield!with!

regard! to! re%bleeding,! need! for! further! procedures! and! the! associated!

impact!on!outcomes.!

3. Quantification!of!blood!product!transfusion!!

4. Identification!of!patient!specific! risk! factors! for!poor!outcome!to!aid! the!

triage!of!patients!presenting!with!LGIB.!!

!

Reporting!contemporaneous!data!on!presenting!characteristics,! requirement!of!

inpatient! investigation! and! success! of! treatment! will! allow! the! future!

development!of!guidelines!on!the!optimal!management!of!LGIB!with!the!aim!of!

! 82!

improving!patient!care,!reducing!variation!in!practice!and!ultimately!improving!

outcomes.!

!

4.2!Sample!Size!!!Of! 174! hospitals! invited,! 143! (82.2%)! participated,! identifying! 2781! potential!

cases!of!LGIB.!Of!these,!41!were!excluded,!as!they!were!incomplete,!duplicate!or!

cases! of! haematemesis.! There! were! 212! patients! with! proven,! probable! or!

suspected!UGIB!who!were!also!excluded,!leaving!2528!cases!of!LGIB!for!analysis!

(Figure!4).!!

!Figure!4:!Flow!chart!of!excluded!and!included!cases!!

!!!!Estimates! of! the! incidence! of! lower! GI! bleeding! are! scarce,! since! there! are! no!

previous! population! based! studies! of! lower! GI! bleeding! in! the! UK.! The! largest!

study!arising!from!Europe!is!by!Lanas!et#al!who!collected!data!from!10!Spanish!

hospitals!over!a!period!of!10!years!using!hospital!discharge!codes,!and!reported!

2781"cases"iden.fied"

Incomplete"(n=22),""duplicates"(n=9),"

haematemesis"(n=10)"

41"cases"excluded"

Proven"UGIB"(n=107),"probable"UGIB"(n=37),"suspected"UGIB"(n=68)"

212"cases"excluded"2528"cases"LGIB"

! 83!

an! incidence! for! LGIB! of! 33/100,000.2! If! a! comparable! incidence! of! LGIB! is!

assumed!in!the!UK,!the!expected!annual!incidence!would!be!21,120!cases!(based!

upon!UK!population!of!64!million).!Although!all!hospitals!in!the!UK!were!invited!

to! participate,! 143/174! (82.2%)! provided! data,! therefore! we! would! estimate!

17,360! cases! per! annum! from! these! hospitals,! or! 2893! in! two! months.! This!

method!may!over%estimate!the!number!of!cases!in!the!UK!as!Lanas!et#al!captured!

patients!using!14!different!ICD%9!codes,!which!included!patients!with!conditions!

other!than!LGIB,!such!as!intestinal!perforation.2!This!is!likely!to!have!lead!to!an!

over%estimation!of!the!incidence!of!lower!GI!bleeding!in!their!study.!Additionally!

the!estimated!UK!population!of!64!million! includes!children.!Accordingly,! these!

figures! support! the! representativeness! of! the! sample! captured! in! this!

observational!study.!

!Most! cases! were! admitted! under! general! surgery! (2105/2528,! 83.3%),!

310/2528! (12.3%)! under! general! medicine! and! only! 54/2528! (2.1%)! under!

gastroenterology.! Gastroenterology! admissions! were! younger! (median! age! 59!

years,!IQR!43%80)!than!those!admitted!to!general!medicine!(74!years,!IQR!50%84,!

p<0.05)!or!general!surgery!(73!years,!IQR!58%83,!p<0.01).!

!

!

!

!!!!!!!!

! 84!

4.3!Patient!Characteristics!!!!The! median! age! of! patients! was! 74! years! (57%83);! 1319/2528! (52.2%)! were!

female! and! 1455! (57.6%)! had! a! Charlson! Co%morbidity! Index! ≥1.! Malignancy,!

diabetes!and!myocardial!infarction!(MI)!were!the!most!common!co%morbidities,!

reported!in!392!(15.5%),!377!(14.9%)!and!285!(11.3%)!cases,!respectively.!!

!

Patients!who!developed!LGIB!whilst! hospitalised! for! another! reason! (inpatient!

bleeds)! represented!185/2528! (7.3%)!of!LGIB!cases.!They!were!older! (median!

age! 73! vs! 78! years,! p<0.001)! with!more! co%morbid! illness,! including! diabetes!

(21.6%! vs! 14.4%),! stroke! (16.2%! vs! 8.0%)! and! MI! (16.2%! vs! 10.9%)! in!

comparison!to!new!admissions.!!

!

Bright! red! blood! per# rectum! was! the! most! common! presenting! symptom,!

reported! in! 1836/2528! (72.6%)! cases! and!more! common! in! acute! admissions!

than!inpatient!bleeds.!Inpatients!were!more!likely!to!present!with!melaena,!clots!

per#rectum#and!shock.!Presentation!with!haemodynamic!shock!was!uncommon,!

reported! in! just! 58/2528! (2.3%)! cases.! Anaemia!was! also! uncommon! (median!

Hb! 122g/l,! full! range! 36%192);! a! minority! presented! with! Hb! ≤80g/l! (272,!

10.8%).!A!total!of!408!(16.1%)!patients!had!previously!been!admitted!with!LGIB,!

with!95/408!(23.3%)!in!the!preceding!28!days!!(Table!7).!

!!!!!!!!

! 85!

Table! 7:! Presenting! features! and! demographics! of! patients! admitted! with! or! who!developed!LGIB!whilst!an!established!inpatient!!! Acute!admissions!

N!=!2331!N!(%)!

Inpatients!N!=!185!N!(%)!

All!patients!§!Total!N!=!2528!N!(%)!

Median!Age!(IQR)! 73!(56%83)! 78!(66%85)! 74!(57%83)!Gender!Female!(Missing)!

!1204!(51.7)!6!

!112!(60.5)!0!

!1319!(52.2)!7!

Charlson!CoZmorbidity!index!0!1!≥2!(Missing)!!Cardiac!failure!Myocardial!Infarction!Diabetes!Stroke!Chronic!respiratory!disease!Colorectal!cancer!Non%colorectal!cancer!Liver!disease!Dementia!

!!1016!(43.6)!530!(22.7)!778!(33.4)!7!!136!(5.8)!255!(10.9)!335!(14.4)!186!(8.0)!268!(11.5)!108!(4.6)!234!(10.0)!50!(2.1)!136!(5.8)!!

!!42!(22.7)!39!(21.1)!104!(56.2)!0!!22!(11.9)!30!(16.2)!40!(21.6)!30!(16.2)!30!(16.2)!20!(10.8)!29!(15.7)!5!(2.7)!14!(7.6)!!

!!1066!(42.2)!570!(22.5)!885!(35.0)!7!!159!(6.3)!285!(11.3)!377!(14.9)!217!(8.6)!298!(11.8)!128!(5.1)!264!(10.4)!55!(2.2)!150!(5.9)!!

Presenting!features!Bright!red!blood!per#rectum#Clots!per#rectum#Melaena!Abdominal!pain!(Missing)!

!1723!(73.9)!313!(13.4)!99!(4.2)!474!(20.3)!5!

!110!(59.5)!29!(15.7)!20!(10.8)!17!(9.2)!0!

!1836!(72.6)!344!(13.6)!120!(4.7)!492!(19.5)!6!

Haemodynamic!Status*!Normal!Isolated!tachycardia!Shock!(Missing)!

!1851!(79.4)!368!(15.8)!48!(2.1)!64!

!144!(77.8)!19!(10.3)!9!(4.9)!13!

!2004!(79.3)!388!(15.3)!58!(2.3)!78!

Admitting!Hb!!Median!(IQR)!!Hb!≤!70!Hb!71%80!Hb!81%90!Hb!91%100!Hb!101%110!Hb!111%120!Hb!≥!121!(Missing!data)!

!!124!(101%139)!!127!(5.4)!118!(5.1)!137!(5.9)!181!(7.8)!210!(9.0)!291!(12.5)!1253!(53.8)!14!

!!107!(88%124)!!13!(7.0)!14!(7.6)!29!(15.7)!20!(10.8)!28!(15.1)!23!(12.4)!57!(30.8)!1!

!!122!(100!%138)!!140!(5.5)!132!(5.2)!166!(6.6)!201!(8.0)!240!(9.5)!314!(12.4)!1320!(52.2)!15!

Previous! admission! with!LGIB!(Missing)!

396!(17.0)!!443!

11!(5.9)!!50!

408!(16.1)!!495!

Medications!Aspirin!Clopidogrel!Dual#antiFplatelet#Warfarin!

!532!(22.8)!203!(8.7)!65!(2.8)!249!(10.7)!

!51!(27.6)!32!(17.3)!10!(5.4)!21!(11.4)!

!584!(23.1)!235!(9.3)!75!(3.0)!270!(10.7)!

! 86!

DOACs!(total)!Apixaban#Dabigatran#Rivaroxiban#(Missing)!NSAIDs!(Missing)!

122!(5.2)!35#(1.5)#15#(0.6)#72#(3.1)#1!130!(5.6)!0!

7!(3.8)!3#(1.6)#1#(0.5)#3#(1.6)#11!15!(8.1)!0!

131!(5.2)!38#(1.5)#16#(0.6)#77#(3.0)#12!146!(5.8)!0!

§! Includes! 10! patients! classified! as! ‘other’! presentation! and! 2! with! missing! data! on! mode! of!presentation.!*On!admission!or!first!set!of!observations!after!developing!LGIB.!Shock!defined!as!HR≥100! and! SBP<100mmHg.! 24! (0.9%)! patients! appeared! twice! in! the! dataset! as! they! were!admitted!with!further!LGIB!during!the!audit!period.!!!!Medications#

At! the! time! of! presentation! with! bleeding,! 742/2528! (29.4%)! patients! were!

taking! antiplatelet! agents;! 584! (23.1%)! of! all! patients! were! taking! aspirin.!

Warfarin! use!was! reported! in! 270! (10.7%)! patients! and!DOACs! in! 131! (5.2%)!

patients!(Table!7).!Aspirin!was!withheld!in!417/584!(71.4%,!missing!data!in!21!

cases),! and! clopidogrel! in! 167/235! (71.1%,!missing! data! in! 13)! patients.!Most!

patients!had! their!DOAC!stopped! (116/131,!88.5%),! five!patients!also! received!

prothrombin!complex!concentrate!and!3!fresh!frozen!plasma!(FFP).!!

!

Most! patients! had! normal! coagulation! profiles! on! presentation! (median!

international! normalised! ratio,! INR! 1.1,! IQR! 1.0%1.2).! There! were! 267/2528!

(10.6%)!cases!presenting!with!an!INR!>1.5,!and!58!(2.3%)!with!an!INR!≥5!(INR!

missing! in!404).!Of! those!presenting!with! an! INR!>1.5,! 195/267! (73.0%)!were!

taking!warfarin,!26!were!taking!a!DOAC,!3!had!liver!disease!with!cirrhosis!and!1!

had!a!congenital!bleeding!disorder.!!

!!!!!!!!

! 87!

4.4.Use!of!Blood!Components!!Red! blood! cell! transfusion!was! administered! in! 666/2528! (26.3%)! cases!with!

258!(10.2%)!receiving!≥4!units!during!admission!(Table!8).!!

Table!8:!Inpatient!Interventions!for!LGIB!!! All!patients,!N!=!2528!

N!(%)!Transfusion!Red!cell!transfusion!(all)!Received�≥4#units#Median!units!(range)!(Missing!data)!FFP!Platelets!(Missing!data)!

!666!(26.3)!258!(10.2)!3!(1%17)!35!56!(2.2)!44!(1.7)!30!

Endoscopy!Colonoscopy!Flexible!sigmoidoscopy!Rigid!sigmoidoscopy!or!proctoscopy!TOTAL!(Missing!data)!Endoscopic!Haemostasis!(Missing!data)!OGD!(Missing!data)!Other!endoscopy**!(Missing!data)!

!99!(3.9)!543!(21.5)!84!(3.3)!726!(28.7)!47!54!(2.1)!141!285!(11.3)!39!10!(0.4)!58!

Radiology!CT!Abdomen/pelvis!CT!Angiography!TOTAL!(Missing!data)!

!507!(20.1)!149!(5.9)!656!(25.9)!77!

Interventional!Radiology!Mesenteric!Angiography!Mesenteric!Embolisation!(Missing!data)!

!37!(1.5)!19!(0.8)!61!

Nuclear!medicine!Red!cell!scan!(Missing!data)!

!1!(0.04)!42!

No!inpatient!investigation*!(Missing!data)!

1213!(48.0)!55!

Surgery!Laparotomy!for!bleeding!Transanal!surgery!for!bleeding!(Missing!data)!

!6!(0.2)!26!(1.0)!53!

*Inpatient! investigation! includes! rigid! sigmoidoscopy,! proctoscopy,! flexible!sigmoidoscopy,! colonoscopy,! OGD,! CT! abdomen/pelvis,! CTA,! mesenteric! angiography!and!red!cell!scanning!**!Other!endoscopy:!capsule!endoscopy,!push!enteroscopy!

! 88!

Most!patients!were!transfused!with!an!Hb!>80g/l.!Shock!was!uncommon!even!in!

patients! transfused! at! higher! Hb! thresholds.! When! RBC! transfusion! was!

categorised! by! Hb! threshold,! around! 70%! of! patients! in! each! category! had!

normal!vital!signs!(Table!9).!

Table!9:!The!frequency!of!shock!and!transfusion!by!admitting!Hb!!Admitting!Hb! Total!

patients!transfused!at! this!threshold!N!!

Normal!admitting!vital!signs!N!(%)!

Shocked!N!(%)!

Isolated!tachycardia!N!(%)!

Missing!Data!N!!

Hb!≤!70!!Hb!71%80!!Hb!81%90!!Hb!91%100!!Hb!101%110!!Hb!111%120!!Hb!≥!121!!

139!!122!!115!!100!!66!!50!!74!

106!(76.2)!!88!(72.1)!!82!(71.3)!!78!(78.0)!!45(68.2)!!36!(72.0)!!55!(74.3)!

12!(8.6)!!9!(7.4)!!5!(4.3)!!2!(2.0)!!3!(4.5)!!1!(2.0)!!4!(5.4)!

16!(11.5)!!20!(16.4)!!25!(21.7)!!18!(18.0)!!15!(22.7)!!11!(22.0)!!15!(20.3)!

5!!5!!3!!2!!3!!2!!0!

!

Surprisingly,! 190/666! (28.5%)! of! all! RBC! transfusions! were! administered! to!

patients! with! an! admitting! Hb! >100g/l,! of! whom! only! 8/190! (4.2%)! were!

shocked.!Early!transfusions!(within!12!hours!of!presentation)!accounted!for!only!

153/405!(37.7%)!transfusions!that!were!given!with!Hb!>80g/l.!!

!

FFP! was! administered! to! 56/2528! (2.2%)! patients! and! 44! (1.7%)! received!

platelet! transfusions! (Table! 8).! The! indication! for! FFP! included! correction! of!

abnormal! coagulation! tests! (15/56)! and! use! in! a!major! haemorrhage! protocol!

(MHP,!15/56).!Most!patients!who!received!FFP!to!correct!abnormal!coagulation!

! 89!

tests!were! taking! anticoagulants;! 8! taking!warfarin! and!3! a!DOAC.! For!platelet!

transfusions,! 8/44! patients! were! thrombocytopenic! with! a! platelet! count!

<30x109/l,! 15! received! platelets! to! reverse! antiplatelet! drugs! and! 12! received!

platelets! as! part! of! a! major! haemorrhage! protocol.! A! major! haemorrhage!

protocol!was!administered! to!53/2528! (2.1%)!patients! in!whom!FFP,!platelets!

and! cryoprecipitate! were! given! in! 21! (39.6%),! 12! (22.6%)! and! 6! (11.3%)!

respectively.!!

!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

! 90!

!4.5!Endoscopy!and!Endoscopic!Haemostasis!!!The!most! frequent! inpatient! investigation!was! flexible! sigmoidoscopy,! used! in!

543/2528! (21.5%)! cases.!OGD! (285,! 11.3%)! and! colonoscopy! (99,! 3.9%)!were!

used!less!frequently.!Capsule!endoscopy!and!push!enteroscopy!were!rarely!used!

(Table!8).!!

!

The!highest!diagnostic!yields!were!on!flexible!sigmoidoscopy!(418/543,!77.0%)!

and!colonoscopy! (71/99,!71.7%).! !Bedside!proctoscopy!or! rigid! sigmoidoscopy!

was!undertaken!in! just!73/2528!(2.9%)!patients.! In!the!group!of!2455!patients!

that! did! not! undergo! proctoscopy! or! rigid! sigmoidoscopy,! 526/2455! (21.4%)!

had! an! inpatient! flexible! sigmoidoscopy,! with! readily! identifiable! anorectal!

pathologies! (anal! cancer,! anal! fissures,! haemorrhoids! and! rectal! prolapse)!

identified!in!69/526!(13.1%)!of!these.!!In!the!patients!that!underwent!inpatient!

colonoscopy! the! most! common! diagnoses! were! diverticular! bleeds! (34/99,!

34.3%),! haemorrhoids! (13/99,! 13.1%),! colitis! (7/99,! 7.1%),! colorectal! cancers!

(5/99,! 5.1%)! and! angiodysplasia! (4/99,! 4.0%).! Evidence! of! bleeding! with! no!

identifiable!source!was!found!in!13/99!(13.1%)!of! inpatient!colonoscopies,!and!

7/99!(7.1%)!were!reported!as!normal!investigations.!!

!

The!median!time!to!procedure!was!3!days!(IQR!2%5)!for!flexible!sigmoidoscopy,!2!

days! (IQR! 1%4)! for! OGD! and! 4! days! (IQR! 2%7)! for! colonoscopy.! Overall! 14/99!

(14.1%,!missing!data! in!6)!patients!who!had!a! colonoscopy!had! the!procedure!

performed! within! 24! hours! of! admission.! The! majority! of! flexible!

sigmoidoscopies! and! colonoscopies! were! performed! in! the! endoscopy!

! 91!

department! (475/543,! 87.5%,! missing! data! in! 17,! and! 85/99,! 85.9%,! missing!

data!in!1,!respectively),!with!39/543!(7.2%)!flexible!sigmoidoscopies!and!10/99!

(10.1%)!colonoscopies!performed!in!emergency!theatre.!44!patients!underwent!

a! repeat! lower! GI! endoscopy:! 14! for! further! bleeding,! 10! due! to! poor! bowel!

preparation,! six! patients! had! a! full! colonoscopy! after! an! initial! non%diagnostic!

flexible! sigmoidoscopy! and! three! were! repeated! to! allow! therapeutic!

intervention!(missing!data!in!11).!!

!

Endoscopic! haemostasis!was! very! infrequently! used,! reported! in! just! 54/2528!

(2.1%)! of! the! total! cohort! and! 54/642! (8.4%)! of! the! cases! undergoing!

endoscopy:! 36/54! endoscopic! therapies! were! delivered! at! flexible!

sigmoidoscopy,!14!at!colonoscopy,!3!at!proctoscopy!and!one!unknown.!The!most!

frequent!methods!were!banding!(n=13),!argon!laser!(n=11)!and!clipping!(n=9).!

Two! modalities! were! used! in! 12/54! cases! and! three! in! 3/54.! Re%bleeding!

following!endotherapy!occurred!in!7/54!(13.0%)!patients,!of!whom!one!required!

embolisation,! one! underwent! angiography! that! did! not! demonstrate! contrast!

extravasation!and!two!required!further!endoscopic!haemostasis.!No!cases!of!re%

bleeding! required! surgical! intervention.! Two! perforations! were! reported! at!

endoscopy,! both! requiring! surgical! intervention.! Both! followed! flexible!

sigmoidoscopy,! one! showing! pseudomembranous! colitis! and! one! multiple!

colonic!ulcers.!Neither!had!attempted!endoscopic!haemostasis.!!

!!

Overall!77!patients!were!admitted!with!LGIB!following!an!endoscopic!procedure,!

49/77!(66.6%)!of!which!were!indicated!as!post%polypectomy!bleeds.!Of!these!49!

! 92!

post%polypectomy!bleeds,!only!six!underwent!inpatient!lower!GI!endoscopy,!four!

receiving! endotherapy.! An! additional! four! underwent! CTA! and! two! were!

successfully!embolised.!

!

!!4.6!Radiology!!CT! abdomen/pelvis!was! undertaken! in! 507/2528! (20.1%)! cases,! but! CTA!was!

used!in!only!149!(5.9%)!and!formal!angiography!in!just!37!(1.5%)!(Table!8).!CT!

abdomen/pelvis! and! CTA! lead! to! a! diagnosis! of! the! source! of! bleeding! in!

283/507! (55.8%)! and! 74/149! (49.7%)! scans! respectively.! The! most! frequent!

diagnoses! found! on! CT! abdomen/pelvis! were! colitis! (170/507,! 33.5%)! and!

diverticular! disease! (123/507,! 24.2%).! Colorectal!mass! lesions!were! identified!

on! 42/507! (8.9%)! scans,! whereas! no! source! of! bleeding! was! identified! on!

138/507!(27.2%).!The!median!time!to!procedure!was!2!(1%3)!days!and!1!(0%2)!

day!for!CT!abdomen/pelvis!and!CTA!respectively.!!

!

Of! the! 37! patients! that! underwent! mesenteric! angiography,! only! 19! (51.3%)!

went!on!to!have!embolisation.!Re%bleeding!following!embolisation!was!reported!

in! 7/19! patients,! of! whom! one! underwent! successful! re%embolisation! and! one!

required! surgical! control.! Two! patients! developed! mesenteric! ischaemia!

following! embolisation,! one! requiring! surgical! resection.! Both! survived! to!

hospital!discharge.!

!

!!!

! 93!

!4.7!Surgery!!Six! (0.2%)! patients! underwent! laparotomy! for! bleeding,! one! following!

embolisation.! Three! patients! had! pre%operative! CTA! identifying! an! actively!

bleeding!rectal!cancer!and!two!had!diverticular!bleeds.!Both!diverticular!bleeds!

were!demonstrated!by!extravasation!of!contrast,!but!these!patients!proceeded!to!

surgery! without! angiography.! Another! patient! had! a! CT! abdomen/pelvis! that!

identified!angiodysplasia.!Another!had!no!pre%operative! investigations.!Surgery!

was!conducted!between!8pm!and!8am! in!3/6!cases!and!all!were!performed!or!

supervised! by! a! consultant! surgeon.! Three! of! six! patients! who! underwent!

laparotomy!for!bleeding!died;!all!had!significant!co%morbidities!(Table!10).!!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

! 94!

!Table!10:!Patients!who!required!emergency!laparotomy!for!LGIB!!Patient!characteristics!(age)!

PreDoperative!investigation!

Charslon!Index!

ASA*! Time! to!laparotomy**!(hours)!

Source! of!bleeding!

Procedure! Outcome!

Male!(79)!!!Male!(51)!!!Female!(89)!!!Male!(72)!!!!Male!(69)!!!!Male!(68)!!!

CTA!–!no!blush!!!CT!Abdomen/pelvis!!CTA!–!blush!!!None!!!!MA!blush!–!embolisation!–!further!bleeding!!CTA!D!blush!

0!!!0!!!0!!!3!!!!2!!!!3!!!

2!!!2!!!4!!!3!!!!Not!known!!!4!

23!!!40!!!6!!!72!!!!28!!!!72!

Rectal!cancer!!!Angiodysplasia!!!Diverticular!bleed!!Suspected!diverticular!bleed!!NonDhodgkins!lymphoma!!!Diverticular!bleed!!

Anterior!resection!!!Right!hemicolectomy!!!Right!hemicolectomy!!!Subtotal!colectomy!!!!Subtotal!colectomy!!!!Laparotomy!!

LOS!28!days!!!LOS!21!days!!!LOS!24!days!!!PostDoperative!death!!!PostDoperative!death!!!IntraDoperative!death!

*!American!Society!of!Anaesthestiologists!physical!status!classification!**Time!between!presentation!and!start!of!surgery.!!!

! 95!

4.8$Clinically$significant$bleeding$$Only! 36/2528! (1.4%)! patients! met! the! pre<defined! criteria! for! clinically!

significant!bleeding.!The!most!common!investigations!were!CT!abdomen/pelvis!

(8/36),! CTA! (7/36)! and! flexible! sigmoidoscopy! (7/36).! Angiography! was!

undertaken! in! two,! one! receiving! embolisation.! None! underwent! endoscopic!

haemostasis!or!laparotomy!for!bleeding,!14!received!no!inpatient!investigation.!

$

$4.9$Patients$undergoing$no$inpatient$investigations$!Nearly!one!half!of!patients! (1213/2528,!48.0%)!had!no! investigations! for!LGIB!

during! their! admission.! Of! these,! 210/1213! (17.3%)! received! RBC! transfusion!

and! 126/1213! (10.4%)!were! re<admitted! by! 28! days;! 59/126! (46.8%)! due! to!

further!LGIB.!!Hospitals!reported!that!105/1213!(8.7%)!patients!did!not!warrant!

further!inpatient!investigation!as!they!had!been!investigated!previously.!A!total!

of!93/1213!(7.7%)!had!an!anorectal!source!that!was!identified!on!digital!rectal!

examination.!Outpatient! investigation!was!planned! in!518/1213!(42.7%)!cases,!

the!most! frequent!being! flexible!sigmoidoscopy!or!colonoscopy!(490!requests),!

CT!colonography!(25!requests)!and!CT!abdomen/pelvis!(16!requests).!

!

Hospitals!were!asked!why! the! remaining!497/1213! (41.0%)!patients!were!not!

scheduled! for! outpatient! investigation.! Frequent! reasons! were! ‘trivial,! self<

limiting!bleeding!with!no!change! in!haemodynamic!status’,!and! ‘unknown’.!Ten!

patients!refused!investigation,!and!62!(5.1%)!were!considered!to!be!for!palliative!

care!only.!!

!

! 96!

Compared!to!patients!that!underwent!inpatient!investigation,!patients!who!were!

not! investigated! were! less! likely! to! be! transfused! (445/1254,! 35.5%,! missing!

data! in! 61! vs! 210/1211,! 17.3%,!missing! data! in! 2,! respectively! p<0.0001)! and!

had! a! shorter! length! of! stay! (median! 5! days,! IQR! 3<9! vs! 2! days! IQR! 1<4,!

respectively! p<0.001)! although!no! difference!was! seen! in! in<hospital!mortality!

(mortality! in! the! investigated! group! 42/1248,! 3.4%,! missing! data! in! 67,! vs!

42/1210,! 3.4%,!missing! data! in! 3,! p=0.89)! or! re<admission! due! to! re<bleeding!

(investigated! group! 51/1261,! 4.0%,! missing! data! in! 54,! vs! 59/1212,! 4.9%,!

missing!data!in!1,!p=0.32).!!

!4.10$Outcomes$!!Diagnoses)

The! most! commonly! reported! sources! of! bleeding! were! diverticular! disease!

(668/2528,! 26.4%),! benign! anorectal! disorders! (422,! 16.7%)! and! colitis! (344,!

13.6%).!Haemorrhoids!were!reported!as!the!source!of!bleeding!in!305!(12.1%).!

Angiodysplasia! accounted! for! only! 1%! of! cases.! Bleeding! due! to! diverticulosis!

and! ischaemic! colitis! increased! with! age,! but! other! pathologies! were! largely!

constant!!(Table!11).!!!

!In!576/2528!(22.8%)!cases,!patients!were!discharged!with!no!formal!diagnosis.!

In! this! ‘unknown’! group,! 248/576! (43.1%)! had! investigations! that! were! non<

diagnostic!and!the!remainder!had!no!investigations!(328/576,!56.9%).!!

!!!

! 97!

Table!11:!Discharge!Diagnoses!by!age!!

! Age!<!60!N=699!N!(%)!

Age!60>79!N=938!N!(%)!

Age!≥!80!N=889!N!(%)!

All!patients !Total!N!=!2528*!N!(%)!

Diverticular+Disease+ 94+(13.4)+ 259+(27.6)+ 315+(35.4)+ 668+(26.4)+Colitis+Infective)Ischaemic))Inflammatory)bowel)disease)Undetermined)

163+(23.3)+20!(2.9)!12!(1.7)!43!(6.2)!88!(12.6)!

116+(12.4)+16!(1.7)!44!(4.7)!8!(0.9)!48!(5.1)!

65+(7.3)+5!(0.6)!29!(3.3)!11!(1.2)!20!(2.2)!

344+(13.6)+41!(1.6)!85!(3.4)!62!(2.5)!156!(6.2)!

Malignancy+Colon)Rectum)Anal)Othera)

18+(2.6)+5!(0.7)!10!(1.4)!2!(0.3)!1!(0.1)!

71+(7.6)+19!(2.0)!37!(3.9)!6!(0.6)!9!(1.0)!

65+(7.3)+37!(4.2)!24!(2.7)!1!(0.1)!3!(0.3)!

154+(6.1)+61!(2.4)!71!(2.8)!9!(0.4)!13!(0.5)!

Benign+anorectal+disordersb+Haemorrhoids)

171+(24.5)+126!(18.0)!

127+(13.5)+86!(9.2)!

124+(13.9)+93!(10.5)!

422+(16.7)+305!(12.1)!

Polyp(s)+ 11+(1.6)+ 28+(3.0)+ 24+(2.7)+ 64+(2.5)+Angiodysplasia+ 5+(0.7)+ 11+(1.2)+ 9+(1.0)+ 25+(1.0)+PostFendoscopyc+ 18+(2.6)+ 46+(4.9)+ 13+(1.5)+ 77+(3.0)+PostFoperatived+ 23+(3.3)+ 15+(1.6)+ 5+(0.6)+ 43+(1.7)+Small+bowel+sourcee+ 2+(0.3)+ 11+(1.2)+ 3+(0.3)+ 16+(0.6)+Drugs+(presumed+aetiology)f+ 9+(1.3)+ 21+(2.2)+ 13+(1.5)+ 43+(1.7)+Otherg+ 10+(1.4)+ 13+(1.4)+ 6+(0.7)+ 29+(1.1)+Unknown+ 160+(22.9)+ 194+(20.7)+ 222+(25.0)+ 576+(22.8)+(Missing!data)+ 9! 28! 30! 67!

*Includes!2!patients!where!age!unknown!aOther! malignancy:! acute! myeloid! leukaemia,! non>hodgkin’s! lymphoma,! post>transplant! lymphoproliferative! disorder,! bladder! or! gynaecological! origin,!neuroendocrine!tumour,!pancreatic,!prostate,!urothelial,!disseminated!intra>abdominal!malignancy!bBenign!anorectal:!anal!fissure,!solitary!rectal!ulcer,!fistulae,!rectal!prolapse,!proctitis,!perianal!haematoma,!rectal!varices,!anorectal!trauma!

! 98!

cPost>endoscopy:! diagnostic,! post>polypectomy,! transrectal! ultrasound! biopsy! of! the! prostate! and! other! biopsy,! haemorrhoid! banding,! endoscopic! mucosal!resection!dPost>operative:!colorectal!resection,!EUA!rectum,!haemorrhoidectomy,!prolapse!surgery,!haemorrhoidal!artery!ligation,!trans>anal!minimally!invasive!surgery!eSmall!bowel!source:!Meckel’s,!small!bowel!ischaemia,!intussusception,!obstruction,!small!bowel!tumour!fDrugs:!!warfarin,!DOAC,!aspirin,!clopidgrel,!laxatives,!low!molecular!weight!heparin,!mycophenolate!mofetil,!steroids!gOther:!chronic!anastomotic!ulcer,!arterioenteric!fistula,!arteriovenous!malformation,!caecal!varices,!chronic!anastomotic!dehiscence,!chronic!perineal!sinus,!colon!perforation,!decompensated!liver!disease,!endometriosis,!stoma!granulation!tissue,!HHT,!intussusception,!large!bowel!obstruction,!pouchitis,!volvulus!+!!

! 99!

Re#bleeding*

Continued* bleeding! was! reported! in! 279/2528! patients! (11.0%,! 135! cases!

missing!data)!during!the!first!24!hours!of!admission!(defined!as!the!requirement!

of! ≥2! units! red! cell! and/or! a! decrease! in! haematocrit! ≥20%13).! ! Re#bleeding!

(defined!by!additional!blood!transfusion!requirements!and/or!a!further!decrease!

in!haematocrit!≥20%!after!24!hours!of!clinical!stability13!occurred!in!343/2528!

patients!(13.6%,!missing!data!in!126).!283!(11.2%)!patients!had!one!episode!of!

reHbleeding,!43!(1.7%)!had!two!(each!preceded!by!24!hours!of!clinical!stability)!

and!17!had! three!or!more.!ReHbleeding!occurred!a!median!of!3!days! (IQR!2H5)!

after! presentation! with! the! index! bleed.! ReHbleeding! was! more! common! in!

inpatients! (26.5%! vs! 12.6%),! and! patients! taking! aspirin! (107/552,! 19.4%,!

p<0.0001,! 32! cases! missing! data),! versus! those! taking! no! antiplatelet! or!

anticoagulant!agents!(156/1365,!11.4%).!There!was!no!difference!in!reHbleeding!

in!patients!taking!warfarin!(38/254,!15.0%!p=0.11,!16!cases!missing!data).!The!

relationship!between!Charlson!CoHmorbidity! Index!and!reHbleeding! is!shown! in!

Figure! 5.! The! area! under! the! receiver! operator! characteristic! curve! was! nonH

discriminative!at!0.59.!

!

!

!

!

!

!

!

! 100!

Figure! 5:! The! relationship! between! Charlson! CoHmorbidity! Index! and! death! and! reH

bleeding!

!

!

!

The!highest!rate!of!reHbleeding!was!seen!in!angiodysplasia!(9/25),!but!significant!

numbers! of! patients! diagnosed! with! diverticular! bleeding! (98/668,! 14.7%,! 21!

cases! missing! data),! haemorrhoids! (30/305,! 9.8%,! 16! cases! missing! data)! or!

inflammatory,! infective! or! undetermined! colitis! (33/344,! 9.6%)! also! reHbled!

during!admission.!

!

In#hospital*mortality*

InHhospital!mortality!was!85/2528!(3.4%),!although!was!considerably!higher!for!

inpatients! compared! to! new! admissions! (33/185,! 17.9%! vs! 51/2296,! 2.2%,!

p<0.0001)!and!in!patients!who!reHbled!(24/338,!7.0%,!p<0.0001,!missing!data!in!

! 101!

5! cases).! In! four! (0.2%)! patients! the! cause! of! death! was! attributed! to!

uncontrollable!haemorrhage,!most!deaths!were!attributed!to!comorbidity!(Table!

12).!!

Table! 12:! Outcomes! and! cause! of! death! in! patients! admitted! with! or! who! developed!

LGIB!whilst!an!established!inpatient!

!

! Acute&admissions&N&=&2331&N&(%)&

Inpatients&&N&=&185&N&(%)&

All&patients&&Total&N&=&2528&N&(%)&

In&hospital&mortality&All!

Due!to!LGIB!

(Missing)!

!

Primary&cause&of&death*&GI!malignancy!

NonHGI!malignancy!

IntraHabdominal!Sepsis!

Pneumonia!

Myocardial!infarction!

and!heart!failure!

Stroke!

Frailty!

Other§!

Unknown**!

!

51!(2.2)!

3!(0.1)!

34!

!

!

!

7!

2!

10!

4!

4!

!

0!

0!

4!

17!

!

33!(17.8)!

1!(0.5)!

1!

!

!

!

3!

2!

7!

3!

3!

!

2!

1!

1!

10!

!

85!(3.4)!

4!(0.2)!

36!

!

!

!

10!

4!

17!

7!

7!

!

2!

1!

5!

28!

ReCbleeding &(Missing)!&

293!(12.6)!

113!

49!(26.5)!

12!

343!(13.6)!

126!

Median&length&of&stay&(IQR)&(Missing)!

3!(1H6)!

!

115!

9!(5H21)!

!

39!

3!(1H7)!

!

156!

ReCadmission&within&28&days&All!

Due!to!further!LGIB!

Unknown&

!

!

244!(10.5)!

107!(4.6)!

505!

!

!

16!(8.6)!

4!(2.2)!

26!

!

!

260!(10.3)!

111!(4.4)!

535!

All!patients!includes!12!cases!where!mode!of!presentation!was!unclassified!

*As!documented!on!the!primary!cause!of!death!on!the!death!certificate!

**Unknown:!death!certificate!not!available.!

§Other:! decompensated! liver!disease,! infective! endocarditis,! status! epilepticus,! chronic!

obstructive!pulmonary!disease,!dementia!

ReHbleeding! defined! as! additional! blood! transfusion! requirements! and/or! a! further!

decrease!in!Hct!≥20%!after!24!hours!of!clinical!stability13!

!

!

!

! 102!

The! four! patients! that! died! due! to! haemorrhage! also! had! significant! coH

morbidities;! two! had! metastatic! colorectal! cancers! that! were! the! source! of!

bleeding!and!two!had!severe!aortic!stenosis.!The!latter!two!did!not!have!a!source!

of!LGIB!localised.!

!

Figure! 5! shows! the! relationship! between! Charlson! CoHmorbidity! Index! and!

mortality.!The!area!under! the!receiver!operating!characteristic!curve!was!0.75,!

reflecting! reasonable! ability! of! Charlson! CoHmorbidity! Index! to! discriminate!

between!patients! that!survived! to!discharge!and!those! that!did!not.! In!contrast!

the!CHstatistic!for!Charlson!Index!and!reHadmission!was!0.57.!

!

Length*of*Stay*and*Hospital*Transfer*

The!median!LOS!was!3!days!(IQR!1H7)!and!was!longer!for!patients!that!developed!

LGIB!as!an!inpatient!(9!days,!IQR!5H21!vs!3!days,!IQR!1H6,!Table!12).!136/2528!

patients! (5.4%,! missing! data! in! 344)! were! discharged! to! a! nursing! home! or!

rehabilitation! facility,!which! added!on! average! an! extra!2!days! to! total! LOS.! In!

total,! 56/2528! (2.2%)! patients! required! transfer! to! another! hospital! for!

treatment.! Only! 6! cases! were! transferred! for! interventional! radiology!

procedures!(Table!13).!

!

!

!

!

!

!

!

!

!

!

!

!

! 103!

Table!13:!Transfer!Status!

!

! All&patients &Total&N&=&2528&N&(%)!

Requiring&transfer&to&another&hospital&(Missing)!

!

For!ITU!

For!endoscopy!

For!surgical!input!

For!radiology!input!(non!interventional)!

For!interventional!radiology!input!

Other!

!

56&(2.2)&(11)!

!

0!

7!(0.3)!

40!(1.6)!

0!

6!(0.2)!

3!(0.1)!

!

!

&

Re#admission*

ReHadmission! occurred! in! 260/2528! (10.3%)! patients! by! 28! days,! and! in! 111!

(4.4%)! cases! this!was! attributed! to! further! LGIB.! ReHadmission! due! to! further!

bleeding!was!highest!for!patients!diagnosed!with!haemorrhoidal!or!diverticular!

bleeding!(18/305,!5.9%,!missing!data! in!50,!and!38/668,!5.5%,!missing!data! in!

155,!respectively).!The!majority!of!patients!reHadmitted!with!further!LGIB!had!no!

inpatient!investigations!during!their!index!admission!(59/111,!53.2%).!

!

!

!

!

!

!

!

!

!

!

! 104!

4.11&Discussion&!

!

This! is! the! largest!and!most!comprehensive!study!of!LGIB!conducted!to!date! in!

the!UK!and!has!defined!its!causes,!interventions,!processes!of!care!and!outcomes.!

Patients!were!elderly!with!a! large!burden!of! coHmorbidity,! such! that!over!oneH

third! had! a! Charlson! coHmorbidity! index! ≥2.! At! the! time! of! presentation,! 28%!

were! taking! aspirin,! clopidogrel! or! a! nonHsteroidal! antiHinflammatory,! with! an!

additional! 16%! taking! either! warfarin! or! a! DOAC.! Overall! 16%! had! been!

admitted!with! LGIB! before,! 14%! reHbled! during! admission! and! 4.4%!were! reH

admitted! with! further! bleeding.! Over! half! of! the! latter! were! not! investigated!

during!their!index!admission.!!

!

Haemodynamic! instability!was!present! in!only!18%!of! cases,! the!majority!with!

just!an!isolated!tachycardia!and!normal!blood!pressure.!Thus!it!is!surprising!that!

RBCs! were! transfused! to! over! one! quarter! of! patients,! despite! only! 11%!

presenting! with! a! Hb! <80! g/L.! ! This! indicates! a! liberal! approach! to! RBC!

transfusion!in!realHlife!practice!which!is!contrary!to!guideline!recommendations!

for!transfusion.30!Randomised!data!from!UGIB!and!other!critically!ill!populations!

indicate! a! causal! relationship! between! transfusion! above! Hb! >70H80! and! reH

bleeding! and! death.32!34!113!114

! Thus!many! transfusions! in! this! study! would! be!

considered! inappropriate!and!require!critical!review!of! institutional!practice! in!

line!with!patient!blood!management!initiatives.115!

!

This! study! showed! that! case! fatality! rates! following! LGIB! are! low! and!

considerably!lower!than!those!reported!from!other!populationHbased!studies.!In!

! 105!

a! study! from! 10! Spanish! hospitals,! Lanas! et* al! reported! mortality! of! 8.8%,!

although! the! ICDH10! coding! for! LGIB! case! ascertainment! may! have! captured!

cases!of!UGIB.2!The!reported!inHhospital!mortality!in!the!present!study!is!limited!

by!the!duration!of!hospital!admission!(3!days)!so!may!not!be!directly!comparable!

to! studies! with! a! longer! follow! up.! Although,! another! database! study! of! LGIB!

reported! a! similar! inHhospital!mortality! of! 3.9%.12! The! present! study! confirms!

that! death! due! to! uncontrolled! bleeding! is! very! rare,! with! a! strong! observed!

association! between! increasing! comorbidity! and! mortality.! The! almost! 8Hfold!

increase!in!unadjusted!mortality!seen!in!inpatient!bleeds!is!also!likely!to!reflect!a!

greater! burden! of! comorbidity,! but! may! also! reflect! more! severe! bleeding,! as!

previously!noted!for!UGIB.33!116

!!

!

Decisions! regarding!withholding! antiplatelets! in! patients! presenting!with! LGIB!

are!difficult!since!continued!antiplatelet!use!is!associated!with!reHbleeding117!but!

withholding!them!may!lead!to!increased!cardiovascular!morbidity.103!Guidelines!

recommend!that!patients!receiving!aspirin!for!secondary!prevention!of!high!risk!

cardiovascular! disease! should! not! have! this! drug! stopped.47! This! study!

demonstrates! that! this!principle! is!not!being!adhered! to! in!many!patients!with!

LGIB! suggesting! uncertainty! as! to! optimal! management.! DOACs! can! also! be! a!

challenging,!as!most!have!no!specific!antidote!at!this!time.!This!is!a!key!area!for!

further!research!and!will!be!examined!in!Chapter!7.!

!

It!was! surprising! that! just! 29%! cases! underwent! lower! GI! endoscopy! (flexible!

sigmoidoscopy,! colonoscopy! and! anoscopy),! 8.4%! resulting! in! therapeutic!

intervention! to! arrest! bleeding,! given! guideline! recommendations.47! Studies!

! 106!

examining! the! role! of! colonoscopy! have! not! demonstrated! that! inpatient!

endoscopy! improves! clinical! outcomes,61! although! the! systematic! review!

(Chapter!2)! suggests! that! if!undertaken!as!an! inpatient,! colonoscopy!within!24!

hours! is! associated!with! a! higher! diagnostic! and! therapeutic! yield! and! shorter!

LOS.!Whether!hospitals!have!the!facilities!to!support!this!is!examined!in!Chapter!

5.!!

!

Hospitals! reported! that!outpatient! investigations!were!planned! for!only!half! of!

the!48%!that!were!not!investigated!for!LGIB!as!an!inpatient.!In!the!primary!care!

setting,! there! is! clear! guidance! from! NICE! that! patients! aged! 50! or! over! with!

unexplained!rectal!bleeding!should!be!referred!for!specialist!assessment!within!

two!weeks.118!The!proportion!of!patients!discharged!without!reported!plans!for!

endoscopic! evaluation! therefore! raises! concerns! regarding! the! potential! for!

missed!lesions.!In!addition,!considering!that!more!than!half!of!the!4.4%!that!were!

reHadmitted!due!to!further!bleeding!had!not!been!investigated!during!their!index!

admission,! this! may! suggest! that! early! discharge! without! investigation! was!

inappropriate.! Indeed,! the! proportion! of! patients! undergoing! flexible!

sigmoidoscopy! or! colonoscopy!was! lower! than! reports! of! 34.7H46.3%! in! other!

observational!studies!of!LGIB,5!12!and!raises!the!question!of!how!diagnoses!such!

as!diverticular!bleeding!or!angiodysplasia!were!confidently!made.!!

!

The!most!common!discharge!diagnosis!was!diverticular!bleeding,!and!across!all!

age! groups! benign! anorectal! conditions!were! the! second!most! common! cause.!

This! is! consistent! with! other! populationHbased! studies! from! Europe! and! the!

USA.8!12!Angiodysplasia!accounted!for!only!1%!LGIB,!which!is!less!frequent!than!

! 107!

previously! reported.53! The! proportion! of! LGIB! attributed! to! polyps! and! colon!

cancer! is! also! lower,8! 12

! but! this! may! be! due! to! the! use! of! hospital! codes! or!

endoscopy!referrals!to!identify!cases!in!previous!studies.!!

!

Mesenteric! embolisation! and! surgical! intervention!were! used! in! just! 0.8%!and!

0.2%! cases! respectively.! Embolisation! is! often! reserved! for! severe! bleeds! to!

avoid!surgery,!or!where!endoscopic!investigation!fails.47!It!is!recommended!that!

hospitals! have! 24/7! access! to! interventional! radiology! for! this! purpose,! either!

onHsite!or!through!a!network;6!although!just!6!cases!required!transfer!to!another!

institution! to! access! this! facility.! ! Whether! the! low! frequencies! of! both!

endoscopic! haemostasis! and! embolisation! are! due! to! lack! of! availability! are!

examined! in!Chapter!5.!Regardless,! the!case! fatality! rates!were! low,! suggesting!

that!most!patients!who!did!not!have!haemostatic! intervention!did!not! come! to!

harm.!!

!

The!sources!of!bleeding!requiring!emergency!laparotomy!were!varied,!although!

the!number!was!small.!Ideally,!laparotomy!should!be!last!resort!and!carried!out!

only!after!attempts!at! colonoscopic!or! interventional! radiological!management,!

although! only! one! patient! who! required! laparotomy! underwent! attempted!

embolisation.!Considering!laparotomy!was!performed!more!than!24!hours!after!

presentation!in!4/6!cases,!a!reHbleeding!plan!may!have!been!useful!to!allow!the!

organisation! and! planning! of! minimally! invasive! treatment! should! further!

bleeding!occur.!Consultant!staff!should!be!involved!with!the!decisionHmaking!and!

surgery!in!this!rare!and!highly!coHmorbid!group!of!patients,!as!evidenced!by!the!

50%!surgical!mortality!rate.!!

! 108!

ReHbleeding! is! frequently! encountered! after! UGIB,! is! well! defined119! and!

associated! with! poor! prognosis.33! Comparatively! less! is! known! about! its!

frequency! and! course! after! LGIB! and! there! are!no! accepted!definitions.! Simply!

quantifying! the! numbers! of! patients! that! experience! further! symptoms! of!

bleeding!may! lead! to! falsely!high! reporting,! capturing! trivial!bleeds!or!delayed!

transit!of!luminal!blood!after!the!initial!bleed!has!stopped.!The!definition!used!in!

this!study!was!that!described!by!Strate!et*al,*and!captures!reHbleeding!by!using!

associated!change!in!Hct!or!need!for!further!transfusion!after!a!period!of!clinical!

stability.13!Accordingly,! 13.6%!patients! reHbled!during! admission! and! a! further!

4.4%!were!reHadmitted!for!further!LGIB!by!28!days.!This!is!higher!than!previous!

reports!of!reHbleeding!of!8%!during!index!admissions.13!Sites!were!instructed!to!

check!each!patient’s!status!at!28!days!using!their!own!electronic!patient!records,!

although! it! is! possible! that! reHadmissions! to! other! institutions!may! have! been!

missed,!thus!this!is!a!conservative!estimate.!

!

Limitations! of! this! study! should! be! acknowledged.! Sites! were! instructed! to!

capture! consecutive! cases! in! order! to! represent! an! unselected! caseHmix! of!

presentations,! although! it! is! inevitable! that! some! cases!will! have! been!missed.!

However,!we!followed!the!same!methodology!of!case!ascertainment!used!in!the!

previous!BSG/NHSBT!study!of!UGIB33!and!that!was!shown!to!have!captured!over!

85%!of!cases!when!compared!with!national!hospital!episode!statistics!data!over!

the!same!time!period.120!Using!European!data!reporting!an!incidence!of!33/100!

000,2!we!estimate!an!annual!UK!incidence!of!21!120!cases.!Limiting!this!figure!to!

the! 82.2%! UK! hospitals! that! participated! would! equate! to! 17360! cases! per!

annum,!or!2893!in!2!months,!which!is!very!close!to!the!case!ascertainment!in!this!

! 109!

study.!To!explore!whether!data!were!skewed!by!a!few!large!centres,!the!largest!

5%!hospitals!(identified!by!the!number!of!acute!beds!in!2015!as!reported!by!NHS!

England)121!were!removed!and!mortality!recalculated.!The!overall!mortality!was!

unchanged!(3.41%).!A!further!limitation!is!that!the!lack!of!investigation!in!many!

patients! renders!many!of! the!diagnoses!presumptive,! although! the! frequencies!

are!consistent!with!other!studies.!8!12!

&

In! summary,! this! is! the! first! nationwide! study! of! LGIB! and! one! of! the! most!

detailed! of! its! kind.! Most! patients! had! minor! bleeding,! only! oneHquarter! of!

patients!underwent!inpatient!lower!GI!endoscopy,!which!infrequently!resulted!in!

the!use!of!endotherapy.!Radiological!or!surgical!intervention!was!rarely!required!

to! control! bleeding.! Further! research! into! risk! stratification! is! needed! to! allow!

avoidance!of!admission!or!facilitation!of!early!discharge!of!low!risk!patients,!this!

is! described! in! Chapter! 6.! The! optimal! management! of! patients! who! develop!

bleeding!whilst!receiving!anticoagulants,!DOACs!or!antiplatelets!is!a!critical!area!

for! further! exploration,! and! this! is! discussed! in! Chapter! 7.! Critical! review! of!

excessive!transfusion!practice!is!also!needed!as!is!research!informing!the!role!of!

colonoscopy!in!the!acute!setting.!!

&&&&&&&&&&&&&

! 110!

CHAPTER&5&!

THE& ORGANISATION& OF& SERVICES& FOR& THE& INVESTIGATION& AND&

MANAGEMENT&OF&LOWER&GASTROINTESTINAL&BLEEDING&!

!

Data!on!the!organisation!of!services!for!LGIB!was!provided!by!138!hospitals.!Of!

these,! two! (1.4%)! indicated! that! they! did! not! routinely! admit! LGIB! (a! tertiary!

centre! for! oncology! and! a! heart! and! lung! specialist! hospital).! These! hospitals!

were!therefore!excluded!from!any!analysis!of!results!that!apply!to!routine!LGIB!

admissions.!!

*5.1&Endoscopy&**24/7!access!to!endoscopy!was!investigated!both!in!hours!(defined!as!9amH5pm!

Monday! to! Friday)! and! out! of! hours! (defined! as! 5.01pmH8.59am! Monday! to!

Friday! and! throughout! the!weekend).! These!were! examined! separately! (Table!

13).!!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

! 111!

Table!13:!the!availability!of!in!and!out!of!hours!lower!GI!endoscopy!in!the!UK!

!

! UK!hospitals!

N=!136*!!

n!(%)!!

Does! your! hospital! provide! inHhours**!

colonoscopy! or! flexible! sigmoidoscopy! for!

lower!GI!bleeding?!

*****Yes******No******Unknown*

!

!

!

134!(98.5)!

2!(1.5)!

0!

Does! your! hospital! provide! outHofHhours**!

colonoscopy! or! flexible! sigmoidoscopy! for!

lower!GI!bleeding?!

*****Yes******No******Unknown!

!

!

!

99!(72.8)!

37!(27.2)!

0!

*Hospitals!that!do!not!routinely!admit!LGIB!were!excluded!

**! Defined! in! hours! (defined! as! 9amH5pm! Monday! to! Friday)! and! out! of! hours! (defined! as!

5.01pmH8.59am!Monday!to!Friday!and!throughout!the!weekend)!

!

!

Of! the! 136! sites! that! routinely! admit! LGIB,! 134/136! (98.5%)! stated! that! they!

provided! inHhours! colonoscopy! and! flexible! sigmoidoscopy.! This! reduced! to!

99/136! (72.8%)! in! the! out! of! hours! period.! In! total! only! 99/136! (72.8%)!

hospitals!are!able!to!provide!24/7!access!to!onHsite!lower!GI!endoscopy!for!LGIB.!!

!

Hospitals!that!did!not!provide!24/7!access!to!lower!GI!endoscopy!were!asked!to!

report!how!they!would!manage!patients!who!may!require!this!service,!only!one!

reported! that! they! had! an! agreed! referral! protocol! to! another! hospital,! 8/136!

(5.9%)!reported!ad!hoc!arrangements,!5/136!(3.7%)!reported!no!arrangements!

at!all!and!four!reported! ‘other!arrangements’!(missing!data! in!19/136!(14.0%).!

The!‘other!arrangements’!included!a!service!limited!to!mornings!at!the!weekend!

and!a!lower!GI!endoscopy!service!that!was!only!available!in!emergency!theatre,!

depending!on!the!speciality!of!the!onHcall!surgeon.!!

!

! 112!

Hospitals!that!provided!out!of!hours!lower!GI!endoscopy!for!LGIB!were!asked!to!

report!the!competency!of!their!endoscopists;!82/99!(82.8%)!reporting!that!all!of!

the! endoscopists! on! their! rota! were! proficient! at! haemostatic! therapy! during!

colonoscopy! or! flexible! sigmoidoscopy.! Additionally,! 77/136! (56.6%)!hospitals!

reported! that! they! had! defined! emergency! slots! that! could! be! used! to! provide!

urgent!lower!GI!endoscopy!for!LGIB!during!the!day.!!

*****5.2&Interventional&Radiology&*!

Overall,!73/136!(53.7%)!hospitals!reported!that!they!provided!onHsite! inHhours!

interventional! radiology! (IR)!but! this! reduced! to!50/136! (36.8%)! in! the!out!of!

hours!setting.!The!greatest!changes!between!inH!and!out!of!hours!IR!were!seen!in!

the!number!of!hospitals!reporting!‘ad!hoc!arrangements’!and!‘no!arrangements’!

(Table!14).!No!arrangements!were!reported!by!8/136!(5.9%)!hospitals!in!hours,!

but!this!increased!to!17/136!(12.5%)!in!the!out!of!hours!setting.! ‘Other’!and!‘ad!

hoc’!arrangements!included!the!transfer!of!patients!to!other!hospitals!without!a!

formalised!pathway!and!the!reliance!on!a!small!number!of!radiologists!(1H2)!who!

were!not!always!available.!!

!

!

!

!

!

!

!

! 113!

Table!14:!The!availability!of!in!and!out!of!hours!interventional!radiology!in!the!UK!

!

! UK!hospitals!

N=!136*!!

n!(%)!

What!are!the!arrangements!for!inHhours*!

interventional!radiology!for!lower!GI!

bleeding?!

*****On#site*service******Agreed*referral*protocol*to*another********hospital******Ad*hoc*arrangements******No*arrangements*in*place******Other*****

!

!

!

73!(53.7)!

19!(14.0)!

!

34!(25.0)!

8!(5.9)!

2!(1.5)!

!

What!are!the!arrangements!for!outHofH

hours*!IR!for!lower!GI!bleeding?!******

*****On#site*service******Agreed*referral*protocol*to*another********hospital******Ad*hoc*arrangements******No*arrangements*in*place******Other*****

!

!

50!(36.8)!

22!(16.2)!

!

44!(32.4)!

17!(12.5)!

3!(2.2)!

!

*Defined!as! in!hours,!9amH5pm!Monday! to!Friday!and!out!of!hours,!5.01pmH8.59am!Monday! to!

Friday!and!throughout!the!weekend,!!

!

!

Of! the! 50! hospitals! that! provided! out! of! hours! onsite! IR,! 27/50! (54%)! also!

provided!cover!for!external!sites,!7/50!providing!it!for!three!or!more!sites.!

The!median!number!of!consultant!radiologists!on!rotas!in!these!hospitals!was!5!

(range!1H9,!50!hospitals).!Out!of!hours!support!staff!such!as!radiographers!and!

specialised!IR!nurses!were!available!in!29/50!(58%)!of!these!hospitals.!

&&&5.3&Specialist&elderly&care&*Only! 28/136! (20.6%)! hospitals! reported! that! elderly! patients! admitted! with!

LGIB!under!the!care!of!general!surgeons!were!routinely!reviewed!by!Care!of!the!

Elderly!doctors.!

! 114!

5.4&Guidelines&

All!hospitals!that!participated!in!the!study,!regardless!of!whether!they!routinely!

admit! patients! with! LGIB! were! included! in! this! analysis! (n=138).! Overall!

133/138! (96.4%)! hospitals! reported! providing! separate!written! guidelines! for!

blood!transfusion!in!patients!with!major!haemorrhage.!Written!guidelines!on!the!

management! of! GI! bleeding! were! provided! by! 100/138! (72.5%)! hospitals,!

although!only!43/138!(31.2%)!included!LGIB.!!

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

&

! 115!

5.5&Discussion&

!

In! the! UK! 24/7! lower! GI! endoscopy! and! interventional! radiology! are! only!

available!in!72.8%!and!36.8%!hospitals!that!routinely!admit!patients!with!LGIB,!

respectively.! Overall,! 82/136! (60.3%)! hospitals! had! out! of! hours! endoscopy!

rotas! that!were! exclusively! staffed! by! endoscopists! trained! in! the! provision! of!

endoscopic! haemostasis.! ! Most! hospitals! that! provided! out! of! hours! onsite! IR!!

also!covered!external!sites,!the!median!number!of!interventional!radiologists!on!

an!out!of!hours!rota!was!5,!and!only!58%!had!oncall!support!staff!available.!The!

majority! of! hospitals! provided!written! guidance! on!blood! transfusion! in!major!

haemorrhage,! but! only! 31.2%! had! a! guideline! on! LGIB.! Only! 20.6%! hospitals!

provided! routine! specialist! elderly! care! for! older! patients! admitted! under!

surgical!teams.!

!

In!their!2015!report,!the!NCEPOD!recommended!that!‘patients!with!any!acute!GI!

bleed!should!only!be!admitted!to!hospitals!with!24/7!access!to!onsite!endoscopy,!

IR! (onsite! or! covered! by! a! formal! network).’6! This! study! demonstrated!

deficiencies! in! the! provision! of! endoscopy! and! IR! in! hospitals! that! routinely!

admit!LGIB!in!the!UK.!To!rectify!this!would!require!considerable!investment.!In!

UGIB,! economic! modelling! suggests! that! in! high! volume! centres,! the! cost! of!

providing!out!of!hours!endoscopy!would!be!offset!by!savings!achieved!through!a!

reduction!in!LOS.122!In!LGIB,!this!may!be!supported!by!the!association!between!

colonoscopy!within! 24! hours! and! reduced! LOS! as! demonstrated! in! Chapter! 2.!

However,! in! the! observational! patient! study,! inpatient! flexible! sigmoidoscopy!

and!colonoscopy!were!undertaken!in!only!21.5%!and!3.9%!cases,!with!a!median!

! 116!

waiting!time!of!3!and!4!days,!respectively.!Despite!the!low!numbers!of!patients!

receiving!endoscopy!and! the! long!waiting! time! in! those! that!did,!most!patients!

did! not! come! to! harm.! This! raises! questions! whether! a! blanket! investment! in!

endoscopy!provision!for!all!comers!with!LGIB!is!economically!justified.!!

!

Centralisation!of!specialist!services!has!meant!that!many!hospitals!have!lost!their!

onsite!IR!services.!The!most!frequently!absent!mode!of!treatment!for!LGIB!was!

IR,! and! embolisation! was! the! least! common! minimally! invasive! mode! of!

haemostasis!in!the!observational!study.!!The!lack!of!IR!provision!was!particularly!

notable!out!of!hours,!with!only!36.8%!hospitals!providing!on!an!onsite!service.!It!

might!be!expected!that!the!difference!is!accounted!for!by!an!increase!in!the!use!

of! formal!referral!protocols!out!of!hours,!but!this!was!not!the!case.!The!biggest!

increases!were!seen!in! ‘ad!hoc’!and! ‘no!arrangements.’!Additionally,! the!patient!

study! demonstrated! that! only! 0.2%! patients! admitted! with! LGIB! required!

transfer!for!IR!treatment.!!

!

Embolisation! is! not! suitable! for! all! causes! of! LGIB.! Multifocal! or! postHsurgical!

anastomosis! bleeds! may! not! be! amenable! due! to! the! risk! of! ischaemic!

complications.43! Previously,! anorectal! bleeds! were! also! thought! to! be! at!

particular! risk! of! ischaemia,! but! recent! evidence! on! the! safety! and! efficacy! of!

embolisation! in! the! treatment! of! bleeding! haemorrhoids123! has! started! to!

challenge!this.!In!the!observational!patient!study!12.1%!of!all!LGIB!was!reported!

to! be! due! to! hemorrhoids! so! this! may! greatly! extend! the! role! of! IR! in! LGIB,!

although! whether! embolisation! is! superior! to! endoscopic! management! of!

haemorrhoids!remains!unclear.!!

! 117!

Like! endoscopy,! improving! access! to! IR! services!will! also! require! considerable!

investment,! both! in! equipment! and! trained! personnel.! European! guidelines!

recommend! a! minimum! of! 6! consultant! radiologists! on! an! out! of! hours! rota!

covering!<1,000,000!population,124!which!we!have!demonstrated! is!not!current!

practice! in!most! IR!units! in! the!UK.!There! are!no!health! economic!data! on! the!

extension!of!IR!services,!but!as!embolisation!was!only!used!in!a!minority!of!LGIB!

patients,!like!endoscopy,!it!may!not!be!justified.!!

!

In! Chapter! 4.2! we! demonstrated! that! LGIB! patients! tend! to! be! elderly! with!

extensive! coHmorbidities! and! that! the! majority! are! admitted! under! general!

surgeons.! The! organisational! data! show! that! only! 20.6%! hospitals! provide!

routine! specialist! elderly! care! for! these! patients.! In! orthopaedic! surgery! the!

involvement!of!specialist!elderly!care!physicians! is!routine!and!associated!with!

reduced!complications,!mortality!and!LOS.125!A!similar!effect!has!been!reported!

in! elderly! patients! undergoing! urological! or! gastrointestinal! surgery,126! and!

elective! nonHcardiac! surgery.127! Although! the! benefit! of! routine! care! of! the!

elderly! review!has!not!been! studied! in!LGIB,! the!number!of! elderly!patients! in!

this!population!may!justify!an!intervention!targeted!at!this!group.! !Additionally!

as! most! hospitals! already! have! inHhouse! care! of! the! elderly! services,! the!

implementation!of!a!routine!assessment!protocol!may!be!less!costly!to!introduce!

than!the!other!organisational!interventions!for!LGIB.!!

!

!

Despite! the! almost! standard! provision! of!major! haemorrhage! protocols! across!

the! UK,! many! patients! with! LGIB! receive! potentially! unnecessary! RBC!

! 118!

transfusions.128!The!observational! study!demonstrated! that! shock!and!anaemia!

were! very! uncommon,! so!most! patients! will! not! trigger! a!major! haemorrhage!

protocol! and! therefore! will! not! be! covered! by! these! with! these! guidelines.!

Although! there! is! national! guidance! on! RBC! transfusion,30! the! deviation! from!

restrictive!transfusion!practice!may!be!due!to!the!lack!of!guidance!that!is!specific!

to! LGIB.! As! well! the! economic! considerations,! overHtransfusion! may! be!

associated! with! harm,! as! demonstrated! in! UGIB.32! The! lack! of! specific! LGIB!

guidance!that!includes!transfusion!should!be!addressed!as!a!priority.!!

!

!

Limitations! of! this! study! should! be! acknowledged.! The! study! lead! in! each! site!

was!asked!to!complete!the!organisational!questionnaire,!and!these!were!mostly!

surgeons.!Although!they!were!asked!to!visit!different!departments!it!is!likely!that!

some!of!the!responses!regarding!alternative!care!areas,!such!as!IR!may!not!be!as!

accurate!as!if!they!were!completed!by!a!specialist!in!that!area!e.g.!a!radiologist.!

Despite! this,! the! findings!on! the! in!and!out!of!hours!provision!of!services!were!

very!similar!to!those!found!by!the!NCEPOD!in!2013.6!Drawing!conclusions!on!the!

tailoring!of!resources!for!LGIB!is!difficult,!as!even!though!a!hospital!may!have!the!

provision!for!a!certain!intervention,!it!may!not!used.!This!is!particularly!relevant!

to! interventions! that! are! dependent! on! operator! skill,! such! as! endoscopic!

haemostasis.!An!endoscopist!will!need!to!perform!a!minimum!number!of! these!

procedures! to! maintain! their! skills,! but! only! 54! patients! received! endoscopic!

haemostasis!across!the!whole!study.!The!reported!82.8%!of!endoscopists!being!

proficient! at! haemostasis! in! LGIB! may! not! be! an! accurate! reflection! of!

endoscopists’! skills! and! their! confidence! at! undertaking! this! complex!

intervention.!!

! 119!

!

In! conclusion,!many!hospitals! do! not! have! comprehensive! lower!GI! endoscopy!

services! and! the!majority!do!not!have! comprehensive! IR! support.!Despite! this,!

most! patients! do! not! come! to! harm.! Further! research! into! identifying! which!

interventions!may! have! the! greatest! benefit,! such! as! the! institution! of! routine!

care! of! the! elderly! specialist! input! is! required.! Another! key! area! for! further!

research! is! appropriate! triage,! specifically! identifying! low! risk! patients,!where!

admission! and! inHhospital! intervention! can! be! avoided.! This! is! discussed! in!

Chapter!6.!!

!

!

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! 120!

!

CHAPTER&6:& SAFE&DISCHARGE&AFTER&ACUTE&LOWER&GASTROINTESTINAL&BLEEDING:&DERIVATION&AND&VALIDATION&OF&A&NOVEL&RISK&SCORE!&&

6.1&Introduction!

The! prediction! of! adverse! outcomes! such! as! severe! bleeding,! need! for!

intervention!or!death!is!a!research!priority!of!the!clinicians!who!care!for!patients!

with! LGIB.! In! Chapter! 4! we! identified! that! the! majority! of! patients! neither!

required!endoscopic,!radiological!or!surgical! intervention,!nor!suffered!adverse!

events!such!as!reHbleeding!or!death.!Of!the!patients!that!were!hospitalised!with!

LGIB,!48%!received!no!inpatient!investigation.!!

!

There! are! several! extensively! validated! risk! stratification! scores! for! UGIB,66!67

!

but! there! is! no! equivalent! for! LGIB.! Risk! scores! or! severity! indicators! have!

previously!been!proposed,13!69!129

!but!have!been!found!to!be!not!predictive11!130

!

or! remain!unvalidated! in!wider!populations.!Most!scoring! tools!seek! to!predict!

adverse! outcomes,! but! the! results! of! the! observational! study! described! in!

Chapter!4!found!that!severe!bleeding!and!inHhospital!death!are!uncommon,12!131

!

and! thus! many! patients! could! be! safely! discharged! at! presentation! and!

investigated!as!an!outpatient.!The!aim!of!this!risk!score!is!to!identify!this!latter!

group! of! patients,! therefore! avoiding! unnecessary! admission! and! diverting!

hospital!resources!to!patients!that!would!derive!greater!benefit.!!

!

Data!were!used!from!the!observational!study!to!develop!a!clinical!risk!score!to!

identify! patients! that! could! be! safely! discharged! from! the! emergency!

! 121!

department.!The!risk!score!was!externally!validated!and!compared!to!previously!

published!risk!scoring!systems!for!LGIB!as!well!as!scores!specific!to!UGIB.!

!

6.2&Methods&

&

6.2.1.&Study&design&and&participants&

!

Data! used! to! derive! the! prediction! model! were! identified! from! the! national!

observational! study! of! acute! LGIB! as! described! in! Chapter! 4.131! As! this! is! a!

secondary! analysis! of! routine! anonymous! data! collected! for! an! audit,! ethical!

approval!was!not!required,132!as!confirmed!by!the!Joint!Research!Office!at!Oxford!

University!Hospitals!NHS!Foundation!Trust.!!

!

Since! the! aim! of! the! score! was! to! aid! decisions! about! admission! to! hospital,!

patients! who! developed! LGIB! whilst! already! hospitalised,! or! who! were!

transferred! between! hospitals! or! other! treatment! facilities! were! excluded,!

leaving! data! from! 2336! acute! admissions! to! develop! the! model.! External!

validation!was!performed!using!a!cohort!of!288!patients!admitted!with!LGIB!to!

two! hospitals! within! Imperial! College! NHS! Healthcare! NHS! Trust! in! an!

observational! study! that! was! unrelated! to! the! national! study! described! in!

Chapter! 4.133! These! hospitals! did! not! participate! in! the! national! observational!

study.!This!cohort!was!chosen!as,!to!our!knowledge,!it!was!the!largest!available!

database!reporting!all!elements!of!the!composite!outcome!and!those!of!all!of!the!

other! six! scores! that!were!assessed! for! comparative!performance.!This!dataset!

was! retrospectively! populated! using! electronic! health! data! from! consecutive!

! 122!

presentations! to! the! emergency! department! in! each! hospital! with! a! primary!

diagnosis! of! LGIB! over! 5! years,! between! 2007! and! 2011.! Inpatient! bleeds! and!

cases! transferred! from! other! hospitals! were! excluded.! Cases! of! UGIB! were!

excluded!using!presenting!features,!OGD!and!angiography!findings.133!!

!

6.2.2.Outcomes&

Our!primary!objective!was!to!develop!and!validate!a!riskHscoring!tool!to!identify!

patients! that! could! be! safely! discharged! after! presentation! with! LGIB.! Safe*

discharge!was!defined!as! the!absence!of!all!of! the! following!after!presentation:!

reHbleeding,! defined! as! additional! blood! transfusion! requirements! and/or! a!

further! decrease! in! Hct! ≥20%! after! 24! hours! clinical! stability13;! any! RBC!

transfusion! during! the! episode! of! LGIB;! therapeutic! intervention! to! control!

bleeding,!defined!as!endoscopic,!radiological,!or!surgical!haemostasis;!inHhospital!

death,!all!cause;!reHadmission!with!further!LGIB!within!28!days.!

!

6.2.3&Statistical&Analysis&

Model*development*

Prior! to!any!statistical!modelling,!we!selected!18!candidate!predictor!variables!

that! were! considered! to! be! biologically! and! clinically! plausibly! related! to! the!

outcome! of! safe! discharge:! age,! gender,! previous! admission! with! LGIB,!

cardiovascular!disease,!active!malignancy,! liver!disease,!renal!disease,!blood!on!

DRE,! heart! rate! (HR),! systolic! blood! pressure! (SBP),! regular! use! of! oral!

antiplatelet! or! NSAIDS,! use! of! oral! anticoagulants,! Hb,! (g/L),! platelet! count!

(109/L),! white! cell! count! (10

9/L),! INR,! serum! urea! (mmol/L),! and! creatinine!

(μmol/L)!at!initial!assessment.!!The!list!of!candidate!variables!was!also!limited!to!

! 123!

those! routinely! collected! during! hospital! admission.! Variables! with! large!

amounts!of!missing!data!were!omitted,!as!it!was!likely!they!would!be!missing!in!

clinical! practice.! Data! on! coHmorbidities! were! defined! using! the! Charlson! coH

morbidity! index,108! which! we! previously! amended! to! allow! application! to!

medical!notes!(Appendix!1).134!

!

To! develop! a! risk! score,! the! suggested! sample! size! requirements! to! avoid!

overfitting! are! between! 5H10! events! per! candidate! variable.135! Based! on! 10!

eventsHperHvariable,! a! dataset! comprising! 180! events! is! required.! In! the!

development!cohort,!1599/2336!patients!were!safely!discharged,!737!not!safely!

discharged,!both!substantially!larger!than!the!minimum!180!events!required.!To!

validate! a! risk! score,! a! minimum! of! 100! events! are! required! for! calibration!

purposes,! and! much! lower! sample! sizes! are! required! for! calculating!

discrimination! (i.e.! the! cHstatistic).136! The! validation! cohort! included! >! 100!

events,!and! therefore!meeting!recommended!sample!sizes! for!model!validation!

for!the!outcome!of!safe!discharge.!

!

The! following! multivariate! logistic! regression! modelling,! multiple! imputation!

and! bootstrapping! was! performed! by! Professor! Gary! Collins.! Fractional!

polynomials137!were!used! to!explore! the!presence!of!nonlinear!relationships!of!

continuous! predictors! (age,!HR,! SBP,!Hb,! platelet! count,!white! cell! count,! urea,!

creatinine,! INR),! however! a! linear! relationship! was! found! to! be! a! good!

approximation.!We! assumed!missing! data! occurred! at! random! and! performed!

multiple! imputation! using! chained! equations! using! the! aregImpute! function! in!

the!R!statistical!software!package!for!imputing!missing!data!in!the!development!

! 124!

cohort!(R!Foundation!for!Statistical!Computing,!Vienna,!Austria).!!The!validation!

cohort!had!complete!data!on!all!necessary!predictors.!We!used!a!multivariable!

logistic!regression!model!with!backwards!elimination!to!select!predictors!using!

the!Akaike!Information!Criteria!(P=0·157).!Missing!values!were!predicted!on!the!

basis!of!all!other!predictors!as!well!as!the!outcome.!!Fifty!imputed!data!sets!were!

generated! with! imputed! values! reflecting! the! uncertainty! associated! with! the!

imputations.!!The!internal!validity!of!the!prediction!model!to!obtain!an!unbiased!

and! optimism! corrected! estimation! of!model! performance!was! assessed! using!

bootstrapping.! The! entire! modelling! process,! including! variable! selection,! was!

repeated!in!each!of!the!200!bootstrap!samples.!Performance!measures!evaluated!

include! the! discrimination! (cHstatistic),! with! 95%! confidence! intervals! (CI),!

where! a! value! of! 0·5! indicates! no! discrimination! and! a! value! of! 1! indicates!

perfect!discrimination.!!

!

To! increase! the! uptake! and! usability! of! the! model,! we! created! a! simplified!

scoring!system!following!the!approach!by!Sullivan!et*al.138!Values!are!assigned!to!

risk!factor!categories,!and!their!total!sum!assigned!predicted!probabilities!of!safe!

discharge.!

!

Model*Validation*

The! predicted! probabilities! were! calculated! for! each! patient! in! the! validation!

cohort! using! the! regression! coefficients! from! the! model! obtained! on! the!

development! cohort.!Discrimination!was! assessed!by! calculating! the! cHstatistic.!

Using! the! val.prob.ci.2! package! in! R,! a! calibration! plot,! with! 95%! confidence!

bands,!was!constructed!to!assess!the!agreement!between!the!observed!outcome!

! 125!

of! safe! discharge! with! the! predicted! probabilities! from! the!model.139! A!model!

with!perfect!calibration!should!lie!on!the!line!at!45Hdegrees!for!agreement!with!

the!outcome.!!

*

6.2.4&Comparative&assessment&with&previously&described&scores&

Previously!developed!scores!for!LGIB;!BLEED,129!NOBLADS,

69!and!Strate

13!were!

calculated!for!each!patient!(methodology!in!Appendix!3).!Although!Blatchford67,!

Rockall66! and! AIMSH65

140! scores! have! been! designed! for! UGIB! there! is! some!

evidence! that! they! have! predictive! value! in! LGIB.141! 142

! These! were! also!

calculated,!although!Rockall!was!limited!to!preHendoscopy!variables!as!several!of!

the! endoscopic! findings! are! specific! to! UGIB.! To! compare! the! discriminative!

ability!of!these!scores,!the!cHstatistic!for!each!was!calculated!for!safe!discharge.!CH

statistics! were! also! calculated! for! adverse! outcomes! (inHhospital! death,! reH

bleeding,! RBC! transfusion,! haemostatic! intervention,! and! reHadmission! with!

further!bleeding)!in!comparison!to!the!new!model.!The!DeLong!test!was!used!to!

compare!cHstatistics!for!each!model!and!each!outcome!against!the!new!model.143!

We! followed! the!TRIPOD!statement! for!reporting! this!clinical!prediction!model!

study.144

&

&

&

&

&

&

&

! 126!

6.3&Results&

6.3.1.&Demographics&and&presenting&features&

The!mean!age!was!68±19!years!in!the!derivation!cohort!and!66±19!years!in!the!

validation! cohort.! CoHmorbidity! was! common,! the! most! frequent! being!

cardiovascular! disease! in! both! cohorts.! Oral! antiplatelet! or! NSAID! use! was!

common,! found! in!over!40%!cases,! although!a!higher!proportion!of!patients! in!

the! derivation! dataset! were! receiving! oral! anticoagulants! (Table! 15).! In! the!

derivation!cohort!1599/2336!(68.5%)!patients!were!safely!discharged.!Patients!

that! required! admission! did! so! for! the! following! reasons:! 576/2336! (24.7%)!

received!RBC!transfusion,!323/2336!(13.8%)!reHbled,!58/2336!(2.5%)!required!

therapeutic! intervention! to! control! bleeding,! 52/2336! (2.2%)! died! and!

107/2284! (4.7%)! were! reHadmitted! with! further! LGIB.! In! both! cohorts,!

diverticular! disease! was! the! most! common! source! of! bleeding! (Table! 16).! As!

missing!data!accounted!for!38%!INR!values!this!predictor!was!excluded!from!any!

further!analysis.!!

!

! 127!

Table!15:!Demographic!data!for!candidate!variables!in!the!development!and!validation!cohort!

Variable( label( in(development(dataset((

Development(data((n=2336)( External(validation(data((n=288)(

Not(safely(discharged((n(=(737)( Safely(discharged((n(=(1599)( Not(safely(discharged((n(=(104)( Safely(discharged((n(=(184)(

Summary( Missing(data( Summary( Missing(data( Summary( Missing(data( Summary( Missing(data(

Mean( (SD)( [IQR];(n((%)(

n((%)(Mean( (SD)([IQR];(n((%)(

n((%)(Mean( (SD)([IQR];(n((%)(

n((%)(Mean( (SD)([IQR];(n((%)(

n((%)(

Age$ 72'46$(17'37)$ 0$ 66'48$(19'00)$ 0$ 69'50$(17'19)$ 0$ 64'49$(20'56)$ 0$Male$Gender$ 381$(51'7%)$ 0$ 748$(46'8%)$ 0$ 58$(55'8%)$ 0$ 93$(50'5%)$ 0$Previous$ LGIB$admission1$

187$(25'4%)$ 139$(18'9%)$ 208$(13'0%)$ 304$(19'0%)$ 42$(40'4%)$ 0$ 49$(26'6%)$ 0$

CVS$disease2$ 420$(57'0%)$ 0$ 733$(45'8%)$ 7$(0'4%)$ 62$(59'6%)$ 0$ 103$(56'0%)$ 0$Cancer3$ 138$(18'7%)$ 0$ 190$(11'9%)$ 7$(0'4%)$ 24$(23'1%)$ 0$ 37$(20'1%)$ 0$Liver$disease4$ 23$(3'1%)$ 0$ 27$(1'7%)$ 7$(0'4%)$ 2$(1'9%)$ 0$ 8$(4'3%)$ 0$Renal$disease5$ 87$(11'8%)$ 0$ 85$(5'3%)$ 7$(0'4%)$ 12$(11'5%)$ 0$ 11$(6'0%)$ 0$Blood$on$DRE$$ 451$(61'2%)$ 96$(13'0%)$ 843$(52'7%)$ 185$(11'6%)$ 61$(58'7%)$ 4$(3'8%)$ 82$(44'6%)$ 12$(6'5%)$HR$ 85.84$(17'93)$ 16$(2'17%)$ 83'11$(16'80)$ 45$(2'8%)$ 86'24$(17'54)$ 0$ 86'58$(16'92)$ 0$BP$ 123.71$(24'78)$ 15$(2'04%)$ 136'82$(40'45)$ 41$(2'6%)$ 132'19$(28'97)$ 0$ 141'91$(50'49)$ 0$Oral$ antiplatelet$ or$NSAID$

390$(52'9%)$ 2$(0'3%)$ 703$(44'0%)$ 7$(0'4%)$ 44$(42'3%)$ 0$ 72$(39'1%)$ 0$

Oral$anticoagulant$ 132$(17'9%)$ 2$(0'3%)$ 243$(15'2%)$ 7$(0'4%)$ 5$(4'8%)$ 0$ 6$(3'3%)$ 0$Hb$ 97'04$(28'35)$ 2$(0'3%)$ 129'50$(19'15)$ 12$(0'8%)$ 97'86$(24'43)$ 0$ 123'23$(22'38)$ 0$Platelet$count$ 274'42$(124'37)$ 4$(0'5%)$ 259'09$(88'87)$ 17$(1'1%)$ 247'71$(98'60)$ 0$ 233'70$(81'06)$ 0$WBC$(median,$IQR)$ 9'2$(6'80,$12'48)$ 7$(1'0%)$ 9'5$(7'10,$12'80)$ 19$(1'2%)$ 7'5$(5'45,$10'85)$ 1$ 7'10$(5'20,$9'70)$ 1$Urea$(median,$IQR)$ 7'35$(5'20,$10'30)$ 19$(2'6%)$ 5'90$(4'50,$8'00)$ 53$(3'3%)$ 6'25$(4'48,$8'80)$ 0$ 5'60$(3'75,$8'30)$ 1$Creatinine$ 107'94$(82'87)$ 16$(2'2%)$ 88'57$(54'68)$ 34$(2'1%)$ 115'39$(88'29)$ 0$ 98'72$(70'64)$ 0$INR$(median,$IQR)$ 1'10$(1'00,$1'30)$ 266$(36'1%)$ 1'10$(1'00,$1'20)$ 629$(39'3%)$ 1'10$(0'10,$1'10)$ 0$ 0'1$(0'1,$1'10)$ 8$

1. Any!episode!LGIB!resulting!in!hospital!admission!2. Myocardial!infarction,!angina,!congestive!heart!failure,!hypertension!3. Any!active!cancer!excluding!basal!cell!and!squamous!cell!carcinomas!of!the!skin!4. Chronic!liver!disease!with!or!without!cirrhosis!!5. Chronic!kidney!disease!stage!≥2!(eGFR!≤!60

! 128!

Table 16: Sources of bleeding !

! Development*Cohort*N=2336**N*(%)*

Validation*Cohort*N=288*N*(%)*

Diverticular!disease!Colitis!Colorectal!cancer!Haemorrhoids!and!other!benign!anorectal!disorders!Polyps!Post<polypectomy!Angiodysplasia!Small!bowel!bleeding!Unknown!Other*!(missing)!

645!(27.6)!268!(11.5)!106!(4.5)!390!(16.7)!!!55!(2.4)!50!(2.1)!23!(1.0)!8!(0.3)!550!(23.5)!131!(5.6)!93!

84!(29.2)!37!(12.8)!13!(4.5)!38!(13.2)!!!7!(2.4)!3!(1.0)!12!(4.2)!3!(1.0)!68!(23.6)!26!(9.0)!2!

*Aortoenteric fistula, drug induced LGIB, caecal varices, arteriovenous malformation, colonic perforation, colonic endometriosis, intussusception, Meckel’s diverticulum, post-endoscopic biopsy, stenting, post-trans anal endoscopic microsurgery

!The! most! common! interventions! were! flexible! sigmoidoscopy! in! the!

development! cohort! (487/2336,! 20.8%)! and! colonoscopy! in! the! validation!

cohort! (67/288,! 23.3%).! OGD! was! undertaken! in! 256/2336! (11.0%)! of! the!

development! cohort! and! 37/288! (12.8%)! of! the! validation! cohort.! Mesenteric!

angiography!was!rarely!undertaken!(Table!17).!!

*

Table 17: Diagnostic and therapeutic interventions ! Development Cohort

N=2336 N (%)

Validation Cohort N=288 N (%)

OGD (missing) Colonoscopy (missing) Flexible sigmoidoscopy (missing) Capsule endoscopy (missing) Endoscopic haemostasis (missing) Mesenteric angiography ± embolisation (missing)

256 (11.0) 37 92 (3.9) 46 487 (20.8) 44 8 (0.3) 49 41 (1.8) 153 32 (1.4) 57

37 (12.8) 9 67 (23.3) 8 43 (14.9) 8 1 (0.3) 0 13 (4.5) 0 15 (5.2) 0

!

! 129!

!6.3.2*Predicting*safe*discharge*

!

Multivariable! logistic! regression!analysis! identified! the! following!predictors! for!

safe! discharge:! age,! female! gender,! no! previous! LGIB! admissions,! no! blood! on!

DRE,!HR,!SBP,!and!Hb!(Table!18).!!

!

Table 18: Final prediction model for safe discharge !Predictor** Coefficient* Standard*error* PBvalue*

Intercept! <5·0502! 0·5748! <0·0001!Age! <0·0070! 0·0034! 0·0387!Gender! <0·2764! 0·1125! 0·0140!Previous!LGIB!admission! <0·3228! 0·1474! 0·0285!

DRE!findings! <0·4970! 0·1357! 0·0003!Heart!rate! <0·0117! 0·0033! 0·0003!Systolic!blood!pressure! 0·0135! 0·0025! <0·0001!

Haemoglobin! 0·0532! 0·0026! <0·0001!!!

!

Fractional! polynomials! suggested! linear! fit! for! all! continuous! predictors.! The!

optimism! corrected! c<statistic!was! 0·84! (95%!CI! 0·82! to! 0·86)! reflecting! good!

discriminative! ability! of! the! model! to! differentiate! patients! who! were! safely!

discharged! from!those!who!were!not.!The!simplified!risk!score!with!associated!

component!variables!is!described!in!Table!19.!The!score!is!calculated!by!adding!

the!points!associated!with!each!clinical!component.!!

*

!!!

! 130!

!!!Table!19:!A!score!to!predict!the!safe!discharge!of!patients!presenting!with!acute!LGIB!!

Predictor)) Score)component)value)

Age)<40$40%69$>70$

$0$1$2$

Gender)Female$Male)

$0$1$

Previous)LGIB)admission)No$Yes)

$0$1$

DRE)findings)No$blood$Blood)

$0$1$

Heart)rate)<70$70%89$90%109$>110)

$0$1$2$3$

Systolic)blood)pressure)50%89$90%119$120%129$130%159$>160)

$5$4$3$2$0$

Haemoglobin)36%69$70%89$90%109$110%129$130%159$>160$

$22$17$13$8$4$0$

!!!!!

!

!

! 131!

The!c<statistic!of!the!validation!model!was!0·79!(95%!CI!0·73!to!0·84)!with!good!

calibration!(Figure!6).!

Figure 6: Calibration plot of the final prediction model for safe discharge in the validation cohort. 95% CI around the observed predictions (triangle) at tenths of predicted risk. *

!

!

!

!

!

!

! 132!

Figure!7!shows!the!distribution!of!scores!and!the!proportion!of!safe!discharges!

for!the!development!cohort.!The!score!ranges!from!3<33!(median!14).!45!(1·9%)!

patients!scored!≥30.!!

!

Figure!7:!The!distribution!of!scores!and!associated!proportion!of!safe!discharges!!

!

!

!

!

!

!

!

!

!

0!10!20!30!40!50!60!70!80!90!100!

0! 3! 6! 9! 12! 15! 18! 21! 24! 27!30+!

Patients*(n)*

Score*

No!safe!discharge!Safe!discharge!

! 133!

Table!20!shows!the!probability!of!safe!discharge!at!each!score.!A!patient!with!a!

score! of! eight! has! a! 95%! chance! of! safe! discharge.! In! total! 191/2336! (8.2%)!

patients!scored!8!or!less!and!20!were!unsafe!discharges.!!

Table!20:!probability!of!safe!discharge!by!total!score!!

Total!score! Probability! of! safe!discharge!

0!1!2!3!4!5!6!7!8!9!10!11!12<13!14<15!16<17!

0·99!0·99!0·99!0·98!0·98!0·97!0·96!0·96!0·95!0·93!0·91!0·89!0·87<0·89!0·77<0·81!0·67<0·72!

18<20! 0.50<0.62!21<23! 0.33<0.45!24<26! 0.20<0.28!27<29! 0.11<0.16!≥30! <0.1!

!$

For!absolute!numbers!of!patients!safely!discharged!at!each!score!see!Table!21.!

The!mean!length!of!stay!in!patients!scoring!≤8!was!4±5.5!days,!and!5±6.1!days!in!

patients!that!scored!>8.*

!

! 134!

Table 21: Number of patients safely discharged by score! Score Safely discharged

% (N) Development cohort Validation cohort

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20

0 0 0 100.0 (1) 80.0 (8) 100.0 (8) 88.2 (15) 83.3 (25) 81.7 (49) 88.2 (75) 80.9 (76) 84.5 (71) 79.0 (64) 85.1 (57) 71.6 (53) 81.5 (53) 76.5 (39) 56.5 (26) 51.2 (21) 58.0 (29) 34.0 (17)

0 0 0 100.0 (1) 0 0 100 (2) 100 (8) 91.7 (11) 86.7 (13) 85.0 (17) 76.5 (13) 76.5 (13) 83.3 (10) 61.5 (8) 73.7 (14) 83.3 (10) 47.1 (8) 69.2 (9) 80.0 (8) 28.6 (4)

!!!!

!

!

!

!

*

*

*

*

*

*

! 135!

6.3.3*Comparison*of*the*new*score*with*previously*published*scores*

!

In!comparison!to!Blatchford,!Rockall,!AIMS<65,!BLEED,!Strate,!and!NOBLADS!the!

new! model! demonstrated! superior! ability! to! discriminate! patients! who! were!

safely! discharged! (Table! 22).! For! adverse! outcomes,! the! most! discriminative!

score! for! in<hospital! death!was! AIMS<65! (c<statistic! 0·78),! for! re<bleeding!was!

the! new! model! and! the! Blatchford! score! (c<statistics! 0·74! and! 0·74),! for!

therapeutic!intervention!was!BLEED!(c<statistic!0·65)!and!for!re<admission!with!

further!bleeding!was! the!new!model! (c<statistic!0·68).!No!score!had!a! superior!

performance! across! all! adverse! outcomes,! although! the! new! model!

demonstrated! superior! predictive! ability! for! RBC! transfusion! (c<statistic! 0·92),!

re<bleeding!and!re<admission!with!bleeding!as!well!as!safe!discharge!

!!Table!22:!C<statistics! for!the!new!model!against!existing!models! for!safe!discharge!and!adverse!clinical!outcomes.!!P<values!are!from!the!DeLong!test,!with!reference!to!the!new!model.!!

Model*

Death*(n=52;*2.2%)*

ReBbleeding*(n=323;*13.8%)*

Haemostatic*Intervention*(n=58;*2.5%)*

RBC*Transfusion*(n=576;*24.7%)*

ReBadmission*(n=107;*4.7%)*

Safe*Discharge*(n=1599;*68.5%)*

New!model! 0·67! 0·74! 0·61! 0·92! 0·68! 0·84!

Blatchford! 0·73!(p=0·02)!

0·74!(p=0·71)!

0·59!(p=0·23)!

0·86!(p<0·001)!

0·62!(p<0·001)!

0·80!(p<0·001)!

Aims65! 0·78!(p=0·02)!

0·63!(p<0·001)!

0·60!(p=0·53)!

0·63!(p<0·001)!

0·53!(p<0·001)!

0·64!(p<0·001)!

BLEED! 0·68!(p=0·85)!

0·63!(p<0·001)!

0·65!(p=0·28)!

0·66!(p<0·001)!

0·54!(p<0·001)!

0·65!(p<0·001)!

STRATE! 0·67!(p=0·53)!

0·66!(p<0·001)!

0·59!(p=0·68)!

0·73!(p<0·001)!

0·58!(p<0·001)!

0·69!(p<0·001)!

NOBLADS! 0·72!(p=0·12)!

0·62!(p<0·001)!

0·50!(p=0·04)!

0·66!(p<0·001)!

0·57!(p<0·001)!

0·64!(p<0·001)!

ROCKALL! 0·75!(p=0·06)!

0·61!(p<0·001)!

0·62!(p<0·05)!

0·64!(p<0·001)!

0·53!(p<0·001)!

0·64!(p<0·001)!

!!*****

! 136!

6.4*Discussion**!

This! chapter! has! described! the! derivation! of! an! externally! validated! clinical!

prediction!model! and! simple! risk<scoring! tool! comprising! seven! variables! that!

can!be!routinely!used!to!discriminate!between!LGIB!patients!who!can!be!safely!

managed!as! an!outpatient! and! those!who!will! benefit! from!hospital! admission.!

This!risk!score!is!created!from!a!large!prospectively!acquired!national!database!

of!LGIB!in!the!UK.!It!uses!simple!demographic!and!physical!examination!findings!

in!combination!with!a!single!blood!test!so!is!easily!applicable!by!the!bedside.!!A!

patient! scoring! ≤8! points! at! presentation! has! a! 95%! chance! of! safe! discharge!

from!the!emergency!department.!We!would!advocate!the!use!of!this!threshold!in!

patients!with!no!other!indications!for!hospital!admission.!

!

LGIB! is!widely!recognised!as!a!clinical!area!with!paucity!of!data! to! inform!care!

pathways!and!treatment!guidelines.145!146!In!comparison!to!UGIB,!which!has!seen!

improvements! in! outcomes,2! hospitalisations! due! to! LGIB! are! increasing! and!

mortality!has! remained! constant.2!53!A! risk! score! that! allows!accurate! triage! at!

initial! assessment!has!potential! to!avoid!hospitalisation! in! favour!of!outpatient!

management.!!

!

The! prediction! model! was! built! from! several! constructs! that! were! defined! a!

priori,! which!we! anticipated!would! identify! the! cohort! of! patients! who!would!

come!to!no!harm!following!presentation!with!LGIB.!One!construct!was!to!ensure!

there!was!no! re<bleeding! (for!which!we!used!a!previously!described!definition!

that!required!24!hours!of!stability13).!RBC!transfusion!and!need!for!endoscopic,!

! 137!

radiological! or! surgical! intervention! to! control! bleeding! were! incorporated! to!

capture!adverse!events! that!occurred!within! the!24!period!not! captured! in! the!

re<bleeding! definition,! as! well! as! throughout! the! patient’s! admission.! Re<

admission! with! LGIB! was! included! to! ensure! no! patient! was! subsequently!

readmitted!with!LGIB!within!28!days.!The!data!used!in!this!study!were!collected!

over!two!separate!periods;!2007!to!2011!for!the!validation!cohort,!and!2015!for!

the! development! cohort.! Although! there! are! no! obvious! differences! in! the!

management!of!LGIB!between!the!two!periods,!this!interval!could!have!resulted!

in!differences!between! these! two!populations.!This!may!be!beneficial!however,!

as!the!score!demonstrates!efficacy!in!different!patient!populations.!

!

In!both!the!derivation!and!validation!cohorts!over!60%!patients!presenting!with!

LGIB! were! safely! discharged.! The! estimated! number! of! admissions! to! UK!

hospitals! annually!with!LGIB! is!21,120!cases.131!The!use!of! this! risk! score!may!

avoid! admission! in! many! of! these,! provided! there! is! a! clear! plan! and! prompt!

access!to!outpatient!tests.!This!has!benefits!in!terms!of!reducing!the!exposure!to!

unnecessary!inpatient!stay,!financial!advantages!and!the!prioritising!of!access!to!

inpatient! beds! to! other! more! acutely! unwell! patients.! In! the! UK! the! median!

length!of! stay! is!3!days! for!LGIB.131!Whilst! there! are!no! costs! for!LGIB,! a! large!

micro<costing!study!in!UGIB!demonstrated!a!mean!cost!per!patient!of!£2458,!of!

which!60%!is!attributed!to!the!expense!of!the!inpatient!bed.73!Assuming!similar!

costs!for!LGIB,!avoiding!admission!in!60%!would!equate!to!an!estimated!saving!

of! £18·7m! per! year,! across! NHS! hospitals! in! the! UK,! although! patients! will!

require!outpatient!resources.!

! 138!

Previous!studies!have!identified!that!advancing!age,!unstable!vital!signs,!markers!

of! anaemia,! and!blood!on!DRE!are!predictive! of! adverse!outcomes.11!13!69!129!133!

We! have! additionally! identified! gender! and! previous! hospital! admission! with!

LGIB! as! risk! factors.! The! predictive! value! of! male! gender! is! consistent! with!

another!study!of!LGIB12!and!may!be!due!to!a!higher!burden!of!co<morbid!illness.!

Recurrent!admission! is! likely! to!be!a!marker!of!pathologies! that!are!difficult! to!

manage,! and! prone! to! re<bleeding,! such! as! diverticular! bleeding.147! Use! of!

anticoagulant!and!antiplatelet!drugs!were!included!in!the!model!but!found!not!to!

be!statistically!predictive!of!safe!discharge!and!thus!do!not!feature!in!the!score.!

Given!previous!observational!evidence!that!these!drugs!may!be!associated!with!

increased! severity! of! bleeding131! 13! 133! this! was! unexpected.! However,! even! a!

small!derangement!in!vital!signs,!such!as!SBP!90<120mmHg,!HR!90<109!and!Hb!

130<159g/dL!which!might!be!found!with!these!drugs,!reaches!the!recommended!

threshold!score!of!>8!for!admission.!The!impact!of!anticoagulant!and!antiplatelet!

drugs!on!clinical!outcomes!is!discussed!further!in!Chapter!7.!

!

Although!there!have!been!previous!attempts!at!designing!a!risk!score!for!LGIB,69!

129!13!these!studies!were!limited!by!a!reliance!on!endoscopy!referrals69!or!disease!

classification!codes! for!case!ascertainment.13!Reliance!on!endoscopy! to! identify!

LGIB!cases!may!introduce!unnecessary!investigation!and!delay!in!the!assessment!

of!these!cases.!Accounting!for!bowel!preparation,!it!would!take!a!minimum!of!48!

hours! from! presentation! to! perform! a! colonoscopy! (in! those! hospitals! able! to!

provide!a!7!day!service),! limiting!the!use!of!a!score!that!relies!on!endoscopy!at!

initial! assessment.! Important! subgroups! presenting! with! LGIB! such! as!

inflammatory!bowel!disease13!or!post<endoscopy!bleeds129!were!often!excluded!

! 139!

in!the!previous!scores,!limiting!their!generalizability!to!an!unselected!population.!

Prior!scores!sought!to!predict!severe!haemorrhage!or!mortality,13!69!129!which!we!

have!previously! shown!occurs! in! only!1·4%!and!4·3%!cases! respectively.131! In!

the! present! study,! cases! were! identified! by! clinical! teams! using! presenting!

features! and! the! predicted! outcome! was! safe! discharge,! which! is! much! more!

common.!!

!

Strate! et# al# designed! a! score! comprising! seven! predictors! of! severe! LGIB!

(continued!bleeding,! re<bleeding,! or! re<admission!within! one!week)!using!data!

from!252!patients.13!In!our!current!study,!this!score!performed!well!at!predicting!

RBC! transfusion,! but!was! less! discriminative! for! re<bleeding! and! re<admission.!

The!different!performance!may!be!accounted!for!by!the!differing!rates!of!severe!

bleeding,! which!was! found! in! 49%! cases! in! their! original! data,! but! only! 1·4%!

patients! in!the!current!study.131!A!similar!study!of!132!patients!who!also!had!a!

lower!frequency!of!severe!LGIB!demonstrated!no!significant!association!between!

the!Strate!score!and!severe!bleeding.130!!

!

Aoki!et#al#developed!the!NOBLADS!score,!using!data!from!439!patients!with!LGIB!

confirmed!on!colonoscopy,!identifying!eight!predictors!of!severe!bleeding.69!The!

score!was! validated! using! prospectively! collected! data! from! 161! patients!who!

also!received!colonoscopy.!In!the!current!study,!the!NOBLADS!score!did!predict!

re<bleeding!and!RBC!transfusion,!although!was!not!as!discriminative!as!the!new!

score.!It!is!also!limited!by!the!exclusive!use!of!colonoscopy!to!identify!cases.!!

!

! 140!

The!BLEED!score!was!originally!developed!in!an!intensive!care!population!of!103!

patients!with!GI!bleeding.129!It!was!designed!to!predict!in<hospital!complications!

and!mortality! but! in! the! present! study! was! the! best! predictor! of! haemostatic!

intervention! (albeit! a!weak! effect)! and! did! not! discriminate! the! other! adverse!

outcomes.!This!is!consistent!with!another!study!that!did!not!validate!this!score.11!

!

The!scores!that!have!been!developed!for!UGIB,!Rockall,!Blatchford!and!AIMS<65!

have! been! shown! to! have! some! ability! to! predict! in<hospital!mortality! or! RBC!

transfusion! in! LGIB.141!142! The! current! study! supports! these! findings,! although!

none! of! the! scores! consistently! discriminated! all! of! the! adverse! outcomes! that!

were! studied.! These! scores! did! predict! safe! discharge,! but! were! not! as!

discriminative!as!the!new!score.!Overall!the!best!predictor!for!adverse!outcomes!

in! LGIB!was! the! Blatchford! score,67!with! c<statistics! consistently! above! 0·7! for!

death,!re<bleeding!and!RBC!transfusion.!In!combination!with!the!new!score,!this!

may!be!clinically!useful!when!assessing!patients!who!are!not!safe!for!discharge.!

As!UGIB! tends! to! have! a!more! severe! course! than!LGIB,! if! there! is! any! clinical!

uncertainty!about!the!origin!of!the!GI!bleed,!the!Blatchford!score!should!be!used!

in!preference!to!the!new!score.!

!

Triaging!patients!for!outpatient!management!of!LGIB!raises!important!questions!

about! timing! and! access! to! resources.! There! are! currently! limited! data!

supporting! the!optimum!timing!of! investigation148!although! it! is! recommended!

that! patients! aged! 50! or! over! with! unexplained! rectal! bleeding! should! have!

specialist!assessment!within!two!weeks.149!Gastrointestinal!malignancy!accounts!

for! only! 6%! of! LGIB! admissions,131! so! whether! other! groups! of! patients! also!

! 141!

require! rapid! assessment! requires! further! study.! There! is! urgent! need! for!

randomised! data! comparing! the! diagnostic! yields! of! urgent! and! elective!

outpatient! colonoscopy,! as! an! increase! in! outpatient! endoscopy! service!

requirements!may!have!significant!organisational!implications.!

!

There!are!several!limitations!to!this!study.!Two!components!of!the!safe!discharge!

outcome! relied! on! the! presence! of! RBC! transfusion! (re<bleeding! as! well!

transfusion!itself),!which!may!be!imprecise,!as!many!of!the!transfusions!may!be!

deemed! unnecessary,! when! stratified! by! vital! signs! and! anaemia.131! However,!

this!may!have!led!to!an!under<estimation!of!the!proportion!of!patients!that!could!

have!been!safely!discharged.!The!effect!of!liberal!RBC!transfusion!on!the!number!

of!patients! classified!as!not! safe! for!discharge!could!be! further!explored!by! re<

classifying! the! transfusions! as! necessary! or! potentially! unnecessary.! The! latter!

could!be! identified! as! transfusions! that!were! given! at! a!Hb! trigger! of! >100!g/l!

and! no! haemodynamic! stability.! Further! study! could! look! to! include! these!

patients! in! the! safe! discharge! group! (if! these! patients! were! admitted! for!

transfusion!only),!and!further!analysis!undertaken!to!determine!the!probability!

of! safe! discharge! at! different! points! thresholds,! in! an! attempt! to! increase! the!

proportion!of!patients!classified!as!safe!for!discharge!identified!by!the!score.!!

!

The! composite! outcome! of! safe! discharge! included! death! which! occurred! in!

hospital,! but! not! out! of! hospital! death.! Patients! who! had! unremarkable! index!

admissions!(no!transfusion,!re<bleeding,!or!intervention!to!control!bleeding)!but!

died!out!of!hospital!after!discharge!would!not!have!been!identified.!Both!cohorts!

included!only!patients!that!were!admitted,!therefore!assessment!of!the!safety!of!

! 142!

clinical!decisions!in!patients!that!were!not!admitted!is!beyond!the!scope!of!this!

paper.!

!

In!both!cohorts,!only!25<38%!patients!received!endoscopic!evaluation,!and!a!lack!

of!blood!on!DRE!or!lower!GI!endoscopy!may!suggest!that!some!patients!did!not!

have!true!LGIB.!However,!all!cases!were! identified!by!clinicians!at!presentation!

and!assessed!to!have!LGIB!based!upon!clinical!signs!and!symptoms,!as!opposed!

to!retrospective!review!of!hospital!records!or!from!administrative!databases.!In!

clinical!practice!cases!do!present!with!a!history!of!LGIB,!without!demonstrable!

bleeding! on!DRE! or! colonoscopy,! since! bleeding! can! be! intermittent! in! nature.!!

INR!was!missing!in!895!cases!in!the!development!cohort.!Of!these,!207!patients!

did!not!have!a!clotting!screen!taken,!511!LGIB!patients!had!only!an!APTT!(no!PT!

or!INR),!but!not!an!APTT!ratio!(and!it!was!not!possible!calculate!this!as!we!did!

not! have! data! on! the! normal! range,! which! differs! between! analyser)! and! the!

remaining! 177! patients! had! truly! missing! data! on! coagulation! testing.! The!

variability! in!coagulation!screen!is!reflective!of!real<life!practice!and!in!keeping!

with!a!similar!UK!study!of!4478!cases!of!non<variceal!UGIB,!which!also!found!that!

INR!was!not!routinely!checked!in!40%!cases.150!

!

Sites! were! instructed! to! capture! all! consecutive! cases! but! it! is! inevitable! that!

some! cases! will! have! been! missed.! We! are! unable! to! provide! a! ratio! of!

hospitalized!cases!to!non<hospitalized!cases,!as!there!are!no!national!registries!of!

GP! referrals! or! prospective! ED! registries.! The! latter! are! populated! by! hospital!

codes,! which! use! the! ICD<10! classification! trees.! ICD<10! is! inaccurate! in!

identifying!LGIB!patients,!as!there!are!no!pathology<specific!codes.!!

! 143!

!

Although!the!validation!cohort!originated!from!an!external!database!of!cases,!like!

the! development! cohort,! it! was! sampled! from! a! UK! population! of! patients.!

Different! racial! groups!do!display!different! trends! in!LGIB!diagnoses,51! but! the!

frequency! of! clinical! outcomes,! such! as! mortality! are! consistent! between!

geographically!diverse!populations.12!131! It!would!be!beneficial! to!prospectively!

validate! the! new! score! in! populations! with! different! risk! profiles.! Although! a!

substantial! undertaking,! an!RCT!would! be! a! useful!way! to! further! validate! the!

score.!

!

In!summary,!the!new!score!has!been!developed!using!one!of!the!largest!and!most!

comprehensive!databases!of!LGIB,! and!externally!validated.! It!uses! seven!basic!

predictors!that!are!easily!quantifiable!and! is!simple!to!calculate.! In!comparison!

to!six!other!risk!scores,! it!was!the!best! in!predicting!safe!discharge.! It!could!be!

routinely! incorporated! into! triage! pathways! for! acute! medical! and! surgical!

admissions! to! identify! LGIB! patients! who! can! be! safely! discharged.! Further!

independent!validation!in!external!cohorts!and!in!differing!healthcare!systems!is!

welcomed.!

*

*

*

*

*

*!!

! 144!

CHAPTER* 7:* ACUTE* LOWER* GASTROINTESTINAL* BLEEDING* IN* PATIENTS*RECEIVING*ANTICOAGULANT*OR*ANTIPLATELET*DRUGS**!7.*1*Introduction*

!

In! Chapter! 4,! the! observational! study! demonstrated! that! 29.4%! patients! who!

present!with!LGIB!are!receiving!antiplatelet!drugs,!10.7%!are!receiving!warfarin!

and! 5.2%! are! receiving! DOACs.! Similar! frequencies! are! reported! in! large!

database! studies! of! LGIB.16! 13! Despite! the! frequent! use! of! these! medications,!

there! is! paucity! of! data! to! inform! the! clinical! course! and! outcomes! of! patients!

with!LGIB!who!are!taking!these!drugs,!as!well!as!uncertainty!as!to!whether!they!

should!be!temporarily!halted!or!continued.!Single!centre!studies!have!indicated!

an!increased!risk!of!severe!bleeding!with!aspirin,!clopidogrel!and!warfarin<use,13!

16!117! but! is! not! known!whether! the! use! of! DOACs! also! has! an! adverse! impact!

upon!clinical!outcomes.!

!

The!ability!to!reverse!the!effect!of!drugs!which!promote!bleeding!is!important!in!

the! acute! setting.! The! anticoagulant! effect! of!warfarin! can! be! rapidly! reversed!

with!prothrombin!complex!concentrates!(PCC)!and!vitamin!K.!DOACs!have!short!

half<lives,! and! can! usually! be! managed! by! discontinuing! the! drug! although!

antidotes! are! becoming! available.151! 152! Platelet! dysfunction! associated! with!

antiplatelet!drugs!is!less!easily!managed;!there!is!no!drug!that!directly!reverses!

their! effects.! Antiplatelet! drugs! bind! irreversibly! to! platelets,! the! duration! of!

effect!dependent!on! the! lifespan!of! the!platelet! (4<10!days).153!Withholding! the!

drug! for! a! shorter! time! is! unlikely! to! have! an! appreciable! effect! on! platelet!

! 145!

function.! Simply! transfusing! platelets! may! have! a! limited! beneficial! effect! on!

outcomes!due!to!the!short!half<life!of!transfused!platelets.154!!

!

The! increased! risk! of! bleeding! seen! with! anticoagulant! and! antiplatelet! drugs!

must!be!balanced!against!the!risk!of!cardiovascular!complications!if!the!drug!is!

stopped.! For! this! reason,! the! American! College! of! Gastroenterology! LGIB!

Guideline! recommends! continuing! aspirin! for! secondary! prevention.155! It! also!

recommends!withholding!non<aspirin!antiplatelets!for!up!to!7!days,155!although!

evidence! for! this! is! inferred! from! studies! of! UGIB156! or! patients! undergoing!

gastrointestinal!procedures157!as!opposed!to!patients!with!LGIB.!

!

This!chapter!describes! the!clinical! course!of!patients!admitted!with!acute!LGIB!

who!are!taking!warfarin,!antiplatelets!and!DOACs!and!compare!their!risk!profiles!

to! a! control! group! of! patients!with! LGIB!who!were! not! receiving! any! of! these!

medications.! The! outcomes! of! interest! are! re<bleeding! during! admission,! in<

hospital! mortality,! adverse! cardiovascular! outcomes! and! re<admission! with!

further! bleeding.! In! addition! the! impact! of! withholding! antiplatelets! during!

admission!on!re<bleeding!and!adverse!cardiovascular!events!is!explored.!!

!

!

!

!

!

!

!

! 146!

7.2*Methods*

This! is!a!post<hoc!analysis!of!the!prospectively!collected!data!from!the!national!

observational!study!described!in!Chapter!4.!Anticoagulant!and!antiplatelet!drug!

use! was! established! from! medical! notes! and! drug! charts.! Patients! receiving!

single! or! dual! antiplatelet! therapy! (DAPT),! warfarin! or! DOACs! as! a! regular!

medication! upon! presentation! with! bleeding! were! identified.! Patients! taking!

concurrent! oral! NSAIDs! (n=146)! or! combinations! of! antiplatelet! drugs! with!

warfarin,! DOACs,! or! parenteral! anticoagulation! were! excluded! (n=237).! The!

latter! group! were! excluded! from! this! analysis,! as! due! to! the! number! of! drug!

combinations! it! was! not! possible! to! classify! them! into! discrete! groups! of! a!

meaningful!size.!A!control!group!of!patients!within! the!same!study!cohort!who!

were!taking!no!antiplatelet!drugs,!anticoagulants!or!NSAIDs!was!also!identified.!!

!

7.2.1*Study*definitions*

Re<bleeding! was! defined! as! additional! transfusion! requirements! and/or! a!

decrease!in!Hct!≥20%!after!24!hours!of!clinical!stability.13!Need!for!intervention!

was!defined!as!the!need!for!a!procedure!to!arrest!bleeding,!including!endoscopic!

haemostasis,!mesenteric!embolisation!or!laparotomy!for!bleeding.!Re<admission!

with!bleeding!was!defined!as!re<bleeding!up!to!28!days!post<discharge.!!

!

Adverse! cardiovascular! outcome! was! defined! as! in<hospital! acute! coronary!

syndrome,! ischaemic! stroke,! other! ischaemic! vascular! event! or! cardiovascular!

death.! Cardiovascular! death!was! defined! as! fatal! ischaemic! stroke,!myocardial!

infarction!(MI)!or!death!from!an!ischaemic!event.!

!

! 147!

7.2.2*Statistical*methods*

Continuous!data!are!presented!as!mean!and!SD!or!median!and!IQR.!Categorical!

data!are!compared!using!Fisher’s!exact!test.!

!

Kaplan%Meier$curves$of$time$to$ in%hospital$re%bleeding$for$each$group$were$plotted$

(GraphPad$ Prism$ v7,$ San$ Diego,$ USA).$ Cox$ proportional$ hazards$ (PH)$ regression$

models$ were$ then$ used$ to$ analyse$ the$ in%hospital$ re%bleeding$ outcome.$ For$ each$

patient,$time$to$event/censoring$was$derived$as$follows:$

• For$ those$ patients$ who$ experienced$ re%bleeding:$ number$ of$ days$ after$

admission$when$the$re%bleeding$event$occurred.$$

• For$those$patients$who$are$censored:$number$of$days$they$were$followed$up$

for$until$death,$discharge$or$the$study$end%point$of$28$days$post%discharge$$

Paul!Bassett!(independent!statistics!consultant)!performed!the!following!cox!and!

multivariate! logistic! regression! modelling.! Univariate! and! multivariate! cox! PH!

regression! models! were! used! to! analyse! the! association! between! group! of!

patients!and!time!to!re<bleeding.!The!hazard!ratio!and!95%!CI!for!re<bleeding!are!

presented!for!the!groups!of!patients!compared!to!the!control!group.!The!baseline!

covariates! included! in! the!multivariate! cox! regression!model! are;! age,! gender,!

Charlson!co<morbidity! index,!HR! (beats!per!minute),! SBP! (mmHg),! frank!blood!

on!DRE,!Hb,! reversal! of! antiplatelet! or! anticoagulant! drug! (reversal! versus!no<

reversal! versus! no! drug)! and! admission! status! (new! presentation! versus!

established! inpatient!versus!other).!These! covariates!were!determined!a!priori!

upon!clinical!plausibility.!

!

! 148!

The$remaining$outcomes$(adverse$cardiovascular$outcome,$in%hospital$mortality$and$

28%day$re%admission)$were$analysed$using$logistic$regression$models.$Univariate$and$

multivariate$ logistical$ regression$ models$ were$ fitted$ and$ the$ OR$ and$ 95%$ CI$ are$

presented$ for$ the$ antiplatelet$ and$ anticoagulant$ groups$ compared$ to$ the$ control$

group.$ The$ risk$ factors$ included$ in$ the$multivariate$ logistic$ regression$models$ are$

described$ above$ in$ the$ cox$ PH$ regression$models.$ Cases$with$missing$ data$ on$ the$

study$ outcomes$ were$ excluded$ from$ both$ the$ cox$ PH$ and$ multivariate$ logistic$

regression$models.$

!

Finally! the! cox! PH! regression! analyses! for! re<bleeding! was! repeated! on! a!

subgroup! of! single! antiplatelet! users! who! had! complete! data! on! whether! the!

antiplatelet!drug!was! stopped!during!admission.!The!purpose!of! this! subgroup!

analysis! was! to! assess! for! an! association! between! continuing! the! antiplatelet!

during!admission!with!LGIB!and!re<bleeding.!HR!and!95%!CI!are!presented! for!

the!patients!who!had!their!antiplatelet!withheld! for!<5!days!and!for! those!who!

had!it!withheld!for!≥!5!days,!in!comparison!to!a!group!of!patients!who!had!their!

antiplatelet!continued!after!presentation!with!bleeding.!A!threshold!of!five!days!

was! chosen! as! this! is! the! average! time! to! normal! platelet! function! after!

antiplatelet!drug!discontinuation.158!

!

!

*

*

*

! 149!

*

7.3*Results**

We! identified! 504! patients! taking! a! single! antiplatelet! drug,! 79! taking! DAPT!

drugs,! 232!patients! taking!warfarin,! 102!patients! taking! a!DOAC! and! a! control!

group!of!1218!patients! taking!none!of! these!drugs!(Figure!8).!The!DOAC!group!

included! 63! patients! taking! rivaroxaban,! 26! taking! apixaban! and! 13! taking!

dabigatran.! Most! patients! taking! an! antiplatelet! drug! were! taking! aspirin! or!

clopidogrel,!only!16!were! receiving! ticagrelor,!6!dipyridamole!and!1!prasugrel.!

No!patients!were!receiving!abciximab.!!

!

Figure!8:!Flow<chart!of!cases!!

!

!

!

2528$pa'ents$with$LGIB$

Control$$

(n=1218)$

Single$an'platelet$$

drug$(n=504)$

Dual$an'platelet$

$drug$(n=79)$

Warfarin$(n=232)$

DOAC$$

(n=102)$

NSAIDs$excluded$(n=146)$

Combina'ons$of$an'coagulants,$

an'platelets$or$DOACs$excluded$(n=237)$Missing$data$on$

an'coagulant,$an'platelet$or$DOAC$status$excluded$(n=10)$

! 150!

!

7.3.1.Characteristics* of* patients* taking* antiplatelet* or* oral* anticoagulant*

drugs*

!

Patients! taking! antiplatelet! or! oral! anticoagulant! drugs! were! elderly;! patients!

receiving! DOACs! represented! the! oldest! group! of! patients! (79.9! years! ±10.8,!

Table!23).!Patients!in!the!DAPT!group!had!the!highest!burden!of!cardiovascular!

co<morbidities! such! as!MI! and! peripheral! vascular! disease! (47/79,! 59.5%! and!

11/79,!13.9%!respectively)! although! the!highest! rates!of!previous! stroke!were!

seen!in!patients!taking!DOACs!(21/102,!20.6%).!!

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

! 151!

!!Table!23:!Patient!characteristics!by!drug!group!!! Control!

!!N=1218!N!(%)!

Single!antiplatelet!user!N=504!N!(%)!

Dual!antiplatelet!user!N=79!N!(%)!

DOAC!!!N=102!N!(%)!

Warfarin!!!N=232!N!(%)!

Age!(years)! 61.4!±!20.47! 77.9!±!10.91! 73.4!±!11.37! 79.9!±!10.77! 78.6!±!10.11!! ! ! ! ! !! ! ! ! ! !Female!Gender! 662!(54.5%)! 245!(48.7%)! 34!(43.6%)! 56!(54.9%)! 124!(53.5%)!! ! ! ! ! !! ! ! ! ! !Charlson! Co<morbidity!Index!!

! ! ! ! !

0! 700!(57.8%)! 123!(24.4%)! 10!(12.7%)! 27!(26.5%)! 75!(32.3%)!1! 200!(16.5%)! 174!(34.5%)! 29!(36.7%)! 25!(24.5%)! 56!(24.1%)!2+! 312!(25.7%)! 207!(41.1%)! 40!(50.6%)! 50!(49.0%)! 101!(43.5%)!! ! ! ! ! !! ! ! ! ! !Hypertension! 356!(29.4%)! 266!(52.8%)! 40!(50.6%)! 54!(52.9%)! 121!(52.2%)!MI! 39!(3.2%)! 102!(20.2%)! 47!(59.5%)! 12!(11.8%)! 29!(12.5%)!CCF! 37!(3.1%)! 32!(6.4%)! 6!(7.6%)! 20!(19.6%)! 33!(14.2%)!Peripheral!vascular!disease!

21!(1.7%)! 27!(5.4%)! 11!(13.9%)! 1!(1.0%)! 10!(4.3%)!

Stroke! 33!(2.7%)! 74!(14.7%)! 11!(13.9%)! 21!(20.6%)! 27!(11.6%)!Diabetes! 133!(10.9%)! 97!(19.3%)! 15!(19.0%)! 5!(4.9%)! 44!(19.0%)!! ! ! ! ! !! ! ! ! ! !HR! 85.5!±!16.86! 82.0!±!17.20! 78.9!±!15.67! 81.6!±!17.33! 81.3!±!16.07!! ! ! ! ! !SBP!(mmHg)! 132.1!±!24.78! 133.7!±!26.66! 129.1!±!22.93! 125.0! ±!

20.54!131.8!±!27.96!

! ! ! ! ! !Shocked!participant*!

27!(2.3%)! 11!(2.2%)! 0!(0.0%)! 4!(4.1%)! 4!(1.8%)!

! ! ! ! ! !! ! ! ! ! !Admitting!Hb! 121.7!±!27.96! 116.8!±!26.08! 111.5!±!23.36! 106.5! ±!

30.38!114.4!±!24.07!

! ! ! ! ! !*!Shock!defined!as!HR>100!and!SBP<100mmHg!Missing!data:!age!0,!gender!0.3%,!co<morbidities!0.3%,!HR!2.5%,!SBP!2.2%,!shocked!status!2.6%,!admitting!Hb!0.5%.!!DOAC,!direct!oral!anticoagulant;!MI,!myocardial! infarction;!CCF,!congestive!cardiac! failure;!HR,!heart!rate;!SBP,!systolic!blood!pressure;!Hb,!haemoglobin.!$!$Presentation!with! haemodynamic! shock!was! uncommon! across! all! groups! and!

there! was! no! difference! in! patients! taking! antiplatelet! drugs! (single! p=1.00,!

DAPT! p=0.41),! warfarin! (p=0.81)! or! DOACs! (p=0.09)! in! comparison! to! the!

control! group.! In! comparison! to! the! control! group,! patients! taking! DOACs!

! 152!

(p<0.0001),! single! antiplatelet! drugs! (p<0.001)! or! warfarin! (p<0.0001)!

presented!with!significantly!lower!Hb!concentrations,!with!the!lowest!presenting!

mean! Hb! observed! in! the! DOAC! group.! Clinically! significant! anaemia!

(Hb<80g/dL)!was!found!in!22/102!(21.6%)!of!the!DOAC!group,!24/232!(10.3%)!

of!the!warfarin!group,!50/504!(9.9%)!of!the!single!antiplatelet!drug!group,!8/79!

(10.1%)!of!the!DAPT!group!and!119/1218!(9.8%)!of!the!control!group.!

!

7.3.2*Management*of*warfarin,*antiplatelets*and*DOACs*

!

In! the! warfarin! group,! 210/232! (90.5%)! patients! had! their! warfarin! stopped!

during! admission! and! 99/232! (42.7%)! had! it! reversed! either! with! vitamin! K!

alone! (81! patients),! PCC! alone! (3! patients)! or! both! (15! patients).! In! the!DOAC!

group! 92/102! (90.2%)! patients! had! their! drug! stopped! during! admission! but!

only! 6/102! (5.9%)! received! treatment! in! an! attempt! to! reverse! its! effect;! 4!

patients!receiving!PCC!and!2!FFP.!No!patient!received!a!specific!antidote!to!the!

DOAC,!although!this!study!was!performed!before!the!widespread!availability!of!

idarucizumab.151! In! the! antiplatelet! drug! groups,! 376/504! (74.6%)! patients!

taking!a!single!antiplatelet!drug!had!their!antiplatelet!drug!withheld!and!58/79!

(73.4%)!patients!taking!DAPT!had!at!least!one!antiplatelet!drug!withheld.!Only!8!

patients!receiving!an!antiplatelet!drugs!received!a!platelet!transfusion,!6!of!these!

were! in! the! single! antiplatelet! drug! group.! Of! the! 376! patients! who! had! their!

single! antiplatelet! withheld,! 166/376! (44.2%)! restarted! it! before! or! upon!

discharge.!In!the!DAPT!group,!this!figure!was!30/79!(38.0%).!

!

!

! 153!

Although!DOAC!patients! tended! to! present!with! the! lowest!Hb! concentrations,!

proportionally! more! patients! taking! antiplatelet! drugs! received! a! RBC!

transfusion,!the!highest!proportion!being!seen!in!the!patients!taking!DAPT!drugs!

(34/79,!43%!vs!256/1213,!21.1%!control!group,!p!<0.0001,!Table!24).!Patients!

taking!single!antiplatelet!drugs!or!DOACs!were!also!more!likely!than!those!in!the!

control! group! to! receive! RBC! transfusion! (160/499,! 32.1%,! p<0.0001! and!

32/102,!30.5%,!p<0.05),!respectively.!There!was!no!difference!in!the!number!of!

patients! that! received! RBC! transfusion! in! the!warfarin! group! compared! to! the!

control!(60/231,!26.0%!vs!256/1213,!21.1%!p=0.118).!!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

!

! 154!

Endoscopic!haemostasis,!mesenteric! embolisation!and! laparotomy! for!bleeding!

were! uncommon! across! all! groups! (Table! 24).! Despite! proportionally! more!

patients!on!single!or!dual!antiplatelet! therapy! receiving!RBC! transfusion,! there!

was! no! difference! in! the! proportion! of! patients! requiring! intervention! for!

bleeding!when!compared!to!the!control!(control!34/1145,!3.0%;!single!10/472,!

2.1%!p=0.40;!dual!3/74,!4.1%,!p=0.49).!!

!!!Table!24:!Interventions!for!LGIB!by!antiplatelet!and!anticoagulant!exposure!!! Control!

!!N=1218!N!(%)!

Single!antiplatelet!exposed!N=504!N!(%)!

Dual!antiplatelet!exposed!N=79!N!(%)!

DOAC!exposed!!N=102!N!(%)!

Warfarin!exposed!!N=232!N!(%)!

Red!cells! ! ! ! ! !Transfused?! 256!(21.1%)! 160!(32.1%)! 34!(43.0%)! 32!(31.4%)! 60!(26.0%)!! ! ! ! ! !Volume! 0.67!±!1.648! 1.01!±!1.774! 1.41!±!2.245! 1.11!±!1.903! 0.88!±!1.825!(missing!data)! ! ! ! ! !! ! ! ! ! !Endoscopic!haemostasis!

26!(2.2%)! 6!(1.3%)! 1!(1.3%)! 1!(1.0%)! 6!(2.7%)!

! ! ! ! ! !! ! ! ! ! !Mesenteric!embolisation!

7!(0.6%)! 4!(0.8%)! 2!(2.6%)! 2!(2.0%)! 1!(0.5%)!

! ! ! ! ! !! ! ! ! ! !Laparotomy! for!bleeding!

3!(0.3%)! 0!(0.0%)! 0!(0.0%)! 0!(0.0%)! 0!(0.0%)!

! ! ! ! ! !! ! ! ! ! !Combined!intervention*!

34!(3.0%)! 10!(2.1%)! 3!(4.1%)! 3!(3.0%)! 7!(3.2%)!

(missing!data)! ! ! ! ! !! ! ! ! ! !!*!Patients!may!have!had!more!than!one!intervention!!Missing! data:! transfused! participants! 0.5%,! RBC! transfusion! volume! 2.3%,! endoscopic! haemostasis! 3.8%,! mesenteric!embolisation!2.1%,!laparotomy!for!bleeding!1.4%,!combined!intervention!2.7%.!!DOAC,!direct!oral!anticoagulant!

!!

*

! 155!

7.3.3.Diagnoses*

The!most!common!source!of!LGIB!was!diverticula!across!all!groups,!the!highest!

frequency! seen! in! the! single! antiplatelet! drug! group! (188/504,! 37.3%).! In!

comparison! to! the! control,! fewer!patients! in! the! antiplatelet! and! anticoagulant!

groups! were! diagnosed! with! benign! anorectal! causes! or! inflammatory! bowel!

disease.!At!least!20%!patients!in!each!group!were!discharged!without!a!diagnosis!

(Table!25).!!

!

Table!25:!Sources!of!LGIB!by!drug!exposure!!! !

Control!N=1218!N!(%)!




Warfarin!exposed!!N=232!N(%)!

Diverticular!bleed!IBD!Other!colitis!Ischaemic#colitis#Benign!anorectal!conditions!Colorectal!cancer!Angiodysplasia!Unknown!Other!!

280!(23.0)!48!(3.9)!137!(11.2)!36!(3.0)!239!(19.6)!!70!(5.7)!14!(1.1)!324!(26.6)!127!(10.4)!!

188!(37.3)!5!(1.0)!29!(5.8)!24!(4.8)!56!(11.1)!!24!(4.8)!3!(0.6)!129!(25.6)!45!(8.9)!!

19!(24.1)!1!(1.3)!3!(3.8)!2!(2.5)!6!(7.6)!!5!(6.3)!1!(1.3)!24!(30.4)!17!(21.5)!!

31!(30.4)!1!(1.0)!2!(2.0)!2!(2.0)!16!(15.7)!!9!(8.8)!0!(0)!22!(21.6)!19!(18.6)!!

67!(28.9)!3!(1.3)!7!(3.0)!7!(3.0)!32!(13.8)!!12!(5.2)!2!(0.9)!52!(22.4)!55!(23.7)!

*!Patients!may!have!had!more!than!one!diagnosis!Missing!data:!control!2.3%,!single!antiplatelet!2.2%,!dual!1.3%,!DOAC!0%,!warfarin!4.7%.!!**

*

*

*

*

*

*

*

! 156!

7.3.4.*ReBbleeding*

Time!to!in<hospital!re<bleeding!for!all!groups!is!shown!in!Figure!9.!!

Figure!9:!Kaplan<Meier!graph!of!time!to!in<hospital!re<bleeding!!

!

!

Most! re<bleeding!occurred!within! the! first! 5!days! (Figure!9).! In! comparison! to!

the!control!group,!the!highest!rates!of! in<hospital!re<bleeding!were!observed!in!

the!DAPT!group!(38.0%,!95%!CI!22.3!to!52.7,!p=0.0005)!followed!by!the!single!

antiplatelet!group!(28.2%,!95%!CI!22.8!to!33.6,!p=0.04).!!Re<bleeding!rates!in!the!

DOAC!(20.0%,!95%!CI!0.5! to!30.5,!p=0.52)!and!warfarin!group!(23.1%,!95%!CI!

15.1! to! 31.1,! p=0.99)!were! similar! to! the! control! group! (19.4%,! 95%!CI! 16! to!

22.8).!

!

!!!!!

! 157!

Table!26:!Unadjusted!patient!outcomes!!

! !Control!N=1218!N!(%)!




Warfarin!exposed!N=232!!N!(%)!

!Re<bleeding!!Re<admission!with!LGIB!!All!cause!in<hospital!mortality!Cardiovascular#death*#Death#due#to#haemorrhage#!Combined!cardiovascular!outcome**!!Median!length!of!stay!(IQR)!!

!149!(12.2)!!59!(4.8)!!!25!(2.1)!1!!1!!!4!(0.3)!!!!3!(1<6)!!!

!98!(19.4)!!22!(4.4)!!!12!(2.4)!1!!1!!!11!(2.2)!!!!4!(2<7)!!!

!23!(29.1)!!6!(7.6)!!!6!(7.6)!1!!0!!!2!(2.5)!!!!4!(2<7)!!!

!14!(13.7)!!2!(2.0)!!!3!(2.9)!0!!1!!!0!(0)!!!!4!(2<8)!

!33!(14.2)!!10!(4.3)!!!9!(3.9)!2!!0!!!2!(0.9)!!!!4!(2<7)!

*Cardiovascular!death:!fatal!stroke,!myocardial!infarction!or!other!fatal!arterial!ischaemic!event!**!Combined!cardiovascular!outcome:!acute!coronary!syndrome,!stroke!or!cardiovascular!death!Missing! data:! re<bleeding! 4.2%,! re<admission! with! LGIB! 23.7%,! in<hospital! mortality! 1.3%,! combined! cardiovascular!outcome!1.7%,!length!of!stay!5.3%!!*On! univariate! cox! PH! analysis,! only! the! single! and! the! dual! antiplatelet! drug!

groups!had!significantly!higher!risk!of! in<hospital! re<bleeding! in!comparison! to!

the!control!group!(Table!27).!On!multivariate!regression!both!the!single!and!dual!

antiplatelet!drug!groups!remained!significantly!associated!with!an!increased!risk!

of! re<bleeding! (single! antiplatelet! therapy!HR!3.57,! 95%!CI! 1.13! to!11.28,! dual!

antiplatelet!therapy!HR!5.38,!95%!CI!1.56!to!18.54).!Rates!of!re<bleeding!in!the!

DOAC!and!warfarin!groups!were!not!significantly!different!to!the!control!group.!

There! was! no! association! between! any! group! and! re<admission! with! further!

bleeding!in!the!uni<!or!multivariate!analysis.!!

!

!!

! 158!

Table! 27:! Univariate! and! multivariate! regression! models! for! re<bleeding,! re<admission! with!bleeding,!mortality!and!adverse!cardiovascular!outcomes!!

! Univariate!regression!! Multivariate*!regression!

OR! (95%! CI,! HR!for! cox!regression)!

P<value! OR! (95%! CI,! HR!for! cox!regression)!

P<value!

InBhospital*reBbleeding***Control!

!!1!

!!0.003!

!!1!

!!0.001!

Single!antiplatelet!! 1.40!(1.08,!1.80)! ! 3.57!(1.13,!11.28)! !Dual!antiplatelet!! 2.19!(1.40,!3.42)! ! 5.38!(1.56,!18.54)! !DOAC!! 0.85!(0.49,!1.47)! ! 1.72!(0.49,!6.02)! !Warfarin!!!! 0.99!(0.68,!1.45)! ! 2.00!(0.56,!7.17)! !!ReBadmission*with*further*bleeding*Control!Single!antiplatelet!Dual!antiplatelet!DOAC!Warfarin!!Mortality*Control!Single!antiplatelet!Dual!antiplatelet!DOAC!Warfarin!!Adverse*cardiovascular*outcome*Control!Single!antiplatelet!Dual!antiplatelet!DOAC!Warfarin!!!

!!!!1!0.88!(0.53,!1.45)!1.68!(0.69,!4.08)!0.39!(0.09,!1.61)!0.91!(0.46,!1.82)!!!1!1.16!(0.58,!2.33)!3.93!(1.56,!9.89)!1.43!(0.42,!4.82)!1.76!(0.78,!3.95)!!!!!1!6.75!(2.14,!21.29)!8.20!(1.48,!45.50)!<!2.72!(0.50,!14.94)!

!!!0.41!!!!!!!!0.11!!!!!!!!!0.03!

!!!!1!0.49!(0.02,!10.78)!0.88!(0.04,!21.52)!0.19!(0.01,!5.55)!0.70!(0.03,!16.94)!!!1!0.10!(0.01,!1.04)!0.35!(0.03,!4.27)!0.09!(0.01,!1.31)!0.10!(0.01,!1.32)!!!!!!<!<!<!<!<!

!!!0.41!!!!!!!!0.08!!!!!!!!!!

*!Adjusted! for!age,!gender,!Charlson!co<morbidity! index!(0!versus!1!versus!2+),!HR,!SBP,! frank!blood! on! rectal! examination,! Hb,! reversal! of! antiplatelet/anticoagulant! agent! and! admission!status!!**!All!analyses!employ!logistic!regression!modelling!except!in<hospital!re<bleeding!which!is!a!cox!regression!with!hazard!ratios!!

*

! 159!

7.3.5*Mortality*

The! highest! unadjusted! rates! of! in<hospital! mortality! were! seen! in! the! dual!

antiplatelet! drug! group! (Table! 26).! Mortality! due! to! severe! haemorrhage! was!

very!uncommon!across!all!groups.!There!was!no!significant!association!between!

antiplatelet! or! anticoagulant! group! and! all<cause! mortality! in! the! uni<! or!

multivariate!analysis!(Table!27).!!

!

7.3.6*Adverse*cardiovascular*outcomes*

Cardiovascular!death!was!uncommon!across!all!groups.!Adverse!cardiovascular!

outcomes!were! infrequent!and!as! follows;! the! control!group! included!one! fatal!

MI,! two! cases!of!ACS!and!an! ischaemic! limb,! the! single! antiplatelet!drug!group!

included! one! fatal!MI,! seven! ACS! and! three! strokes,! the! dual! antiplatelet! drug!

group! included!one! fatal! stroke! and!one!ACS,! the!warfarin! group! included!one!

fatal! MI! and! one! fatal! ischaemic! gut.! There! were! no! adverse! cardiovascular!

outcomes! in! the! DOAC! group.! Univariate,! unadjusted! analysis! suggested! a!

significant!association!between!single!and!dual!antiplatelet!drug!use!and!adverse!

cardiovascular! outcomes! in! comparison! to! the! control! (single! antiplatelet!

therapy!OR!6.75,!95%!CI!2.14!to!21.19,!dual!antiplatelet!therapy!OR!8.20,!95%!CI!

1.48! to! 45.50).! The! number! of! events! was! too! few! to! perform! meaningful!

multivariate!analysis!(Table!27).!

!

*

*

*

*

! 160!

7.3.7*Withholding*antiplatelets*during*admission*

In! the! single! antiplatelet! drug! group! 385/504! (76.4%)! cases! had! data! on!

whether! the! antiplatelet! drug! was! withheld! during! admission;! in! 140/385!

(36.4%)! the!antiplatelet!drug!was!withheld! for!<5!days,! in!134/385!(34.8%)! it!

was!withheld! for! ≥! 5! days,! and! in! 111/385! (28.8%)! cases! it!was! not!withheld!

(Table!28).!!

!

Table!28:!Unadjusted!patient!outcomes!in!patients!who!were!receiving!a!single!antiplatelet!and!had!it!continued!and!those!that!had!it!interrupted!!

! Antiplatelet!user,!N=!385**!Continued!N=111!N!(%)!

Stopped!<5!days!!N=140!N!(%)!

Stopped!≥5!days!N=!134!N!(%)!

Re<bleeding! 11!(10.2%)! 14!(10.5%)! 38!(29.0%)!(missing!data)! (3)! (6)! (3)!! ! ! !Combined! cardiovascular!outcome!

1!(0.9%)! 3!(2.2%)! 5!(3.7%)!

(missing!data)! (1)! (2)! (0)!! ! ! !Cardiovascular#death*! 1!(0.9%)! 0!(0.0%)! 2!(1.5%)!(missing!data)! (1)! (1)! (0)!! ! ! !All<cause! in<hospital!mortality!

4!(3.6%)! 1!(0.7%)! 4!(3.0%)!

(missing!data)! (0)! (1)! (0)!! ! ! !Re<admission!with!LGIB! 3!(3.8%)! 8!(7.0%)! 5!(4.7%)!(missing!data)! (32)! (25)! (27)!

*!In<hospital!death!due!to!stroke,!MI!or!other!ischaemic!event!**119!patients!no!data!on!duration!of!single!antiplatelet!therapy!!

No!difference!was!observed! in!re<bleeding!rates!between!patients!who!had!the!

antiplatelet! drug! stopped! for! <5! days! compared! to! those! who! continued! it!

throughout! their!admission!on!univariate! (14/140,!10.5%!cases!of! re<bleeding,!

versus!11/111,!10.2%,!respectively,!HR!0.98,!95%!CI!0.45!to!2.17,!Table!29)!or!

multivariate!cox!regression!analysis!(HR!0.95,!95%!CI!0.41!to!2.21).!

*

! 161!

!Table!29:!Univariate!and!multivariate!regression!models!for!re<bleeding,!re<admission!with!bleeding,!mortality!and!adverse!cardiovascular!outcomes!in!patients!receiving!a!single!antiplatelet!drug!**Group! Univariate!cox!PH!regression!

(N=363)!Multivariate*!cox!PH!regression!

(N=340)!

HR!(95%!CI)! P<value! HR!(95%!CI)! P<value!

InBhospital*reBbleeding*Continued!

!!1!

!!

0.02!

!!1!

!!

0.29!Stopped!<5!days!! 0.98!(0.45,!2.17)!! ! 0.95!(0.41,!2.21)! !Stopped!≥5!days! 2.05!(1.04,!4.03)! ! 1.52!(0.72,!3.21)! !! ! ! ! !All*cause*mortality* ! ! ! !

Continued! 1! 0.21! 1! 0.43!Stopped!<5!days! 0.19!(0.02,!1.76)!! ! 0.21!(0.02,!2.21)! !Stopped!≥5!days! 0.82!(0.20,!3.37)! ! 0.57!(0.10,!3.17)! !! ! ! ! !Adverse*cardiovascular*outcomes*

! ! ! !

Continued! 1! 0.03! 1! 0.71!Stopped!<5!days! 2.42!(0.25,!23.62)!! ! 2.43!(0.20,!29.70)! !Stopped!≥5!days! 4.22!(0.49,!36.71)!! ! 2.68!(0.25,!28.83)! !

*Adjusted!for!age,!gender,!Charlson!co<morbidity!index!(0!versus!1!versus!2+),!heart!rate,!systolic!blood!pressure,!frank!blood!on!rectal!examination,!Hb,!reversal!of!antiplatelet/anticoagulant!agent!(no!reversal!versus!reversal!versus!no!drug),!admission!status!(new!presentation!versus!established!inpatient!versus!other).!!*Mortality! was! uncommon! across! all! groups;! 4/111! (3.6%)! in! patients! that!

continued!their!antiplatelet,!1/140!(0.7%)!in!patients!who!had!their!antiplatelet!

withheld! for! <5! days! and! 4/134! (3.0%)! in! patients!who! had! their! antiplatelet!

withheld!for!≥!5!days!(Table!28),!although!there!was!no!difference!on!univariate!

or!multivariate!regression!(Table!29).!There!was!no!difference!observed! in! the!

number!of!cardiovascular!events! in!patients!who!has! their!antiplatelet!stopped!

versus!continued,!but! the!number!of!events!were!very! few!overall:! !1(0.9%)! in!

the!group!that!continued!their!antiplatelet,!3!(2.2%)!in!the!group!that!stopped!it!

for!<5!days!and!5!(3.7%)!in!the!group!that!stopped!it!for!≥!5!days!(Table!28)!on!

! 162!

univariate!or!multivariate!regression,!although!the!small!number!of!events!limits!

conclusions!from!this!model!(Table!29).!

!

!

* *

! 163!

7.4*Discussion**

!

To!my!knowledge,!this!is!the!first!study!to!use!a!prospectively!collected!national!

sample! to! describe! the! clinical! course! of! patients! admitted!with! overt! LGIB! in!

relation!to!the!use!of!antiplatelet!or!anticoagulant!medications,!including!DOACs.!

The!key!finding!was!that,!compared!to!patients!not!taking!these!drugs,!patients!

taking!a!single!antiplatelet!agent!had!a!three<fold! increase! in!risk!of! in<hospital!

re<bleeding!and!those!taking!DAPT!had!a!five<fold!increase!in!risk.!This!did!not!

translate! into! an! increased! use! of! interventions! to! treat! bleeding,! or! increased!

risk! of! in<hospital! mortality,! however.! There! was! no! increased! risk! of! re<

bleeding,!need!for!therapeutic! intervention!or!in<hospital!mortality!observed!in!

patients!taking!warfarin!or!DOACs!in!comparison!to!the!control!group.!When!re<

bleeding!did!occur,!most!events!occurred!within!5!days!of! the! index!event!and!

plateaued!after!7!days!of!presentation.!

!

In! Chapter! 6,! although! we! included! use! of! antiplatelet! drugs! in! the! model! to!

develop! the! risk! score,! this! variable!was! not! found! to! be! associated!with! safe!

discharge!(including!negatively).!The!findings!of!the!present!study!are!therefore!!

unexpected.!Using!the!presenting!data!from!the!antiplatelet!groups!it!is!possible!

to!estimate!the!score!of!an!average!single!antiplatelet!patient!and!a!DAPT!patient.!

In!the!single!antiplatelet!group,!a!mean!age!of!77.9!years,!mean!HR!of!82,!mean!

SBP!of!133.7!and!a!mean!Hb!of!116.8!scores!13,!higher!than!the!suggested!score!

of!≥8! for!safe!discharge.!This! is!without! the! inclusion!of! the!sex,!previous!LGIB!

admission! and! DRE! findings! variables.! Using! the! equivalent! mean! data! for! a!

DAPT!patient!also!scores!13.!

! 164!

!

Previous!single!centre!studies!have!demonstrated!that!aspirin!is!associated!with!

an! increased! risk!of!developing!LGIB,16! increased!bleeding! severity13! and! long<

term!recurrence!of!bleeding.103!117!A!previous!study!has!compared! the!effect!of!

withholding! aspirin! after! discharge,! also! finding! that! patients! who! continued!

their!aspirin!post<discharge!experienced!a!three<fold!increase!in!re<bleeding,!but!

importantly!a!1.6<fold!reduction!in!the!risk!of!adverse!cardiovascular!events,!and!

a!three<fold!reduction!in!all<cause!mortality.103!Arguably!a!more!pressing!clinical!

dilemma! is! what! to! do! with! antiplatelet! medications! during! a! patient’s! acute!

admission!with!LGIB.!Clinical!guidelines!state! that! ‘in!patients!with!established!

high!risk!cardiovascular!disease!and!a!history!of!LGIB,!aspirin!used!for!secondary!

prevention!should!not!be!discontinued.’47!The!present!study!is!the!first!study!to!

compare! the! outcomes! of! patients! who! had! their! antiplatelet! drug! withheld!

during! their! hospital! admission! and! the! findings! support! this! guideline!

recommendation:! there! was! no! difference! in! re<bleeding! in! patients! that! had!

their! antiplatelet!withheld! for! less! than! 5! days,! versus! those! that! continued! it.!

These! findings! are! not! unexpected! considering! that! aspirin! and! clopidogrel!

irreversibly! bind! to! platelets,! so! their! effects! are! seen! for! 5<7! days! after!

ingestion.159!160!!!

!

Unlike! the! paper! by! Chan! et! al,! there!were! insufficient! adverse! cardiovascular!

events! to! explore! the! association! between! a! short! interruption! to! antiplatelet!

therapy!and!adverse!outcomes.!This!is!likely!due!to!the!short!follow!up!period!in!

the! present! study,! where! the! median! length! of! stay! was! 3<4! days.! In! UGIB,! a!

small,!single!centre!RCT!found!a!large!increase!in!cardiovascular!risk!with!even!a!

! 165!

short<term! interruption! to!antiplatelet! therapy.156!However,! a! randomised! trial!

of!4000!high!risk!cardiovascular!patients!undergoing!non<cardiac!surgery!found!

that! in! comparison! to! placebo,! peri<operative! aspirin! did! not! prevent! MI.161!

Given! the! potential! risk! of! adverse! cardiovascular! events! and! the! lack! of!

increased!risk!of!haemorrhage!related!death,!we!find!no!benefit! in! interrupting!

antiplatelet!drugs!in!the!short<term!in!LGIB.$This!represents!a!change!in!practice,!

as! in! the! current! national! study,! antiplatelet! drugs! were! withheld! in! >70%!

patients,!despite!guideline!recommendations.!!

!

!

In!some!patients!with!LGIB!there!may!be!a!need!to!withhold!antiplatelet!drugs,!

such!as! those!undergoing! emergency!procedures!or! surgery.!Guidelines!on! the!

management!of!antiplatelets!in!patients!undergoing!emergency!surgery!suggest!

the!use!of!tranexamic!acid,!and!if!there!is!excessive!bleeding!despite!this,!platelet!

transfusion!can!be!considered.162!Currently!these!recommendations!are!based!on!

non<randomised! data,! but! the! HALT<IT! trial163! will! assess! the! benefit! of!

tranexamic!acid!in!GI!bleeding!and!will!provide!the!first!randomised!evidence!for!

its!use!in!LGIB.!Evidence!supporting!platelet!transfusion!originates!from!a!pilot!

study!of! patients! undergoing! surgery.164! In! contrast,! a! case<control! study!of!GI!

bleeding! (including! 161! cases! LGIB)! found! that! platelet! transfusion! did! not!

improve! clinical! outcomes.154! These! findings! are! consistent! with! other!

therapeutic! areas! such! as! intra<cranial! bleeding.165! Antidotes! for! specific!

antiplatelet!drugs!are!also!being!developed!and!vasopressin!analogues!may!also!

have!a!role.166!

!

! 166!

The!risks!of! severe!bleeding!associated!with!novel!anticoagulant!drugs! in!LGIB!

have!been!demonstrated! in! administrative!databases.8!12! In! this! study,!patients!

receiving! DOACs! had! a! lower! presenting! Hb! concentration,! although!were! not!

more! likely! to! be! shocked,! require! haemostatic! intervention! or! develop! re<

bleeding.!Most!patients! receiving!DOACs!were!managed!by! simply!withholding!

the!drug!and!this!raises!questions!as!to!whether!antidotes!would!have!a!role!in!

this! setting.! Additionally,! as! most! patients! had! their! DOAC! withheld,! the! risk!

associated!with!their!continuation!is!unknown.!!

!

There! are! conflicting! reports! on! the! risks! of! LGIB! with! warfarin,! with! some!

studies! indicating! an! association!between!warfarin<use! and!bleeding! severity16!

167!and!others!finding!no!such!association.69!In!comparison!to!the!control!group,!

we!found!no!increased!risk!of!shock,!RBC!transfusion!or!re<bleeding.!The!current!

study!has!a!much!larger!sample!of!patients!taking!warfarin!than!previous!studies!

and! is! sufficiently! large! to! report! on!mortality,! finding! no! increased! risk! with!

warfarin!use.!These!findings!may!be!in!part!be!explained!by!the!relative!ease!of!

warfarin<reversal!with!vitamin!K!or!PCC,!which!was!used!in!over!40%!patients.!!

!

Strengths!of!the!study!include!its!size!and!prospective!data!collection!by!clinical!

teams.! Previous! large! studies! of! LGIB! have! used! administrative! databases! or!

colonoscopy! referrals! to! identify! cases,8!13!117! but! this! is! has! limited! efficacy! in!

LGIB,!as!codes!for!some!frequent!causes!of!LGIB!such!as!diverticular!bleeding!are!

not!widely!used,! and!most!patients!do!not!undergo! colonoscopy.131!The!use!of!

contemporaneous!medical! records!allowed! the!collection!of!detailed!data,! such!

! 167!

as! the! mode! and! timing! of! drug! reversal.! This! allowed! us! to! include! this!

important!variable!in!the!regression!models!used!in!this!study.!

!

There! are! several! limitations! to! this! study.! As! the! data! derive! from! an!

observational! study,! any! associations! are! susceptible! to! confounding,!

particularly! comparisons!between!groups!of!patients! that!had!drugs! continued!

or! withheld.! In! the! analysis! of! continuing! or! withholding! single! antiplatelets,!

rates!of! re<bleeding!may!have!been!higher! in! the!group! that!withheld! the!drug!

for!five!days!or!more!as!patients!were!followed!up!for!longer!than!those!that!had!

it!withheld! for!<5!days.! Further! studies!may!need! to!analyse! this! variable! as! a!

time<varying! covariate.! The! definition! of! the!main! outcome! re5bleeding,#used! a!

period! of! 24! hours! to! identify! a! recurrent! bleeding! event.! This!means! that! re<

bleeding! that! occurred! within! 24! hours! of! admission! may! not! have! been!

captured,! underestimating! the! frequency! of! severe! bleeding.! Mortality! data!

corresponded! to! the! entire! admission! though,!which!was!no!different!between!

drug!groups,!even! if! there!may!have!been!differences! in!severe!bleeding! in! the!

first! 24! hours! of! admission.! Missing! data! accounted! for! 23.7%! of! the! re<

admission!with!further!bleeding!outcome,!so!re<admission!rates!may!actually!be!

higher! than! reported! in! this! study.! Patients!were! identified! as! having! LGIB! by!

clinicians,! using! presenting! features,! but! only! 52%! in! the! original! study!

underwent! inpatient! investigation! of! the! source! of! bleeding.! It! is! therefore!

possible!that!a!proportion!of!the!remaining!patients!may!not!have!had!true!LGIB.!

Additionally,! it! is! not! possible! to! tell! whether! patients! who! experienced! re<

bleeding! bled! from! the! initial! lesion! or! from! a! difference! lesion.! This! is!

particularly!relevant!to!diverticular!bleeding,!which!was!the!most!common!cause!

! 168!

of!LGIB! in! this!study.!We!were!able! to!compare!outcomes!of!patients! receiving!

single! antiplatelet! therapy! who! discontinued! or! continued! the! drug,! but! not!

patients!who!were! receiving!DAPT,! as! the! total! number! of! the! latter!were! too!

few.!This!remains!a!key!area!for!further!research.!Additional!studies!should!aim!

to!determine!factors!that! influence!the!decision!to!withhold!antiplatelet!agents,!

such! as! type! and! timing! of! previous! ischaemic! events! to! further! explore! the!

rationale!for!continuing!or!withholding!these!drugs.!

!

In! summary! this! is! the! first! prospectively! designed! study! to! compare! the!

outcomes! of! patients! taking! antiplatelet! drugs! or! anticoagulants! at! the! time! of!

presentation! with! LGIB.! We! have! identified! that! patients! taking! antiplatelets!

have! the! greatest! risk! of! re<bleeding,! and! demonstrated! that! withholding! the!

drug! has! no! impact! on! rates! of! re<bleeding! and! may! expose! the! patient! to!

unnecessary!cardiovascular!risk.!When!triaging!LGIB!patients!the!increased!risk!

of! re<bleeding!with! antiplatelet! drugs!may!need! to! be! anticipated! and!patients!

managed! accordingly.! This! may! consist! of! having! a! lower! threshold! for!

investigation,! haemostatic! intervention! or! a! longer! period! of! observation! in!

hospital.!!

!

!

!

!******

! 169!

CHAPTER*8:*CONCLUSIONS**!

This! project! provides! the! first! national,! epidemiological! data! on! LGIB! in! a! UK!

population.!These!LGIB!data!provide!a!unique!basis!to!identify!trends!in!patient!

demographics,! presenting! features! and! outcomes,! which! has! implications! for!

organisational! level! services! as!well! as! individual! clinicians!managing! patients!

with!LGIB.!!

!

The! systematic! review! appraised! and! pooled! the! best! available! evidence! on!

modes!of!diagnostic!and!therapeutic!intervention.!Although!evidence!from!RCTs!

is! lacking,! the! systematic! review! identified! that! the! greatest! evidence! base!

related!to!colonoscopy!and!that!access!to!early!colonoscopy!may!have!benefits!to!

patients.!The!review!of!existing!service!organisation!demonstrated!which!areas!

of!care!are!currently!deficient!in!the!NHS.!The!size!of!the!LGIB!patient!database!

enabled!detailed!analysis!of!patient!risk! factors! for!adverse!outcomes,!allowing!

the!development!of!a!risk!score!to!aid!patient!triage!at!initial!assessment.!For!the!

first!time,!patients!can!be!reliably!identified!as!suitable!for!immediate!discharge!

and!outpatient!management,!with!associated!benefits!to!the!patient!and!the!NHS.!!

!

In!the!UK,!the!typical!LGIB!patient!is!elderly!and!co<morbid!illness!is!a!frequent!

finding.! The! challenge! in!managing! these! patients! lies! not!with! the! severity! of!

haemorrhage,! but! with! the! complex! interaction! with! their! co<existing! medical!

problems!and!medications.!Previous!population!based!studies!have!also!found!a!

high! burden! of! co<morbidity8! but! the! proportion! of! patients! developing! LGIB!

whilst!receiving!antiplatelets!(26.1%)!or!oral!anticoagulants!(15.9%)!was!higher!

! 170!

than!found!in!recent!previous!studies;!20.5<23.2%!and!5.7<11.4%,!respectively.69!

70!This!difference!is!possibly!accounted!for!by!the!timing!of!data!capture!between!

these!two!studies!and!the!current!study;!Sengupta!et#al!collected!data!from!2008<

2015,!Aoki!et#al!2009<2015.!This!reflects!the!trend!towards!increased!aspirin!and!

anticoagulant! prescriptions! particularly! in! the! elderly! population.168! 169! Data!

from! the!observational! study! (Chapter!4)! suggested! that!patients!who!develop!

LGIB!whilst!taking!aspirin!have!higher!rates!of!re<bleeding,!and!that!re<bleeding!

may! be! a! risk! factor! for! in<hospital!mortality.! This!was! further! investigated! in!

Chapter!7,!demonstrating!an!association!between!single!antiplatelet!and!DAPT<

use! and! re<bleeding! when! potential! confounders! were! controlled! for.!

Retrospective! studies! have! also! demonstrated! an! association! between! aspirin!

and! immediate13! and! long<term! re<bleeding! in! LGIB.103!However,! there!was!no!

association! between! antiplatelet! use! and! mortality! in! the! regression! analysis.!

Additionally!antiplatelet<use!does!not!appear!in!the!risk!score.!This!may!be!due!

to!an!association!between!antiplatelets!and!other!variables!that!are!included!in!

the!risk!score,!such!as!abnormal!vital!signs,!although!there!was!no!difference!in!

the! proportion! of! shocked! patients! between! the! antiplatelet! and! anticoagulant!

groups,!and!the!control!group!in!Chapter!7.!!

!

In!patients! taking!antiplatelet!medications,! it! is!plausible! that! in!comparison!to!

adverse! cardiovascular! events,! re<bleeding! is! not! an! important! determinant! of!

outcome.! Chan! et#al#conducted! a! retrospective! study! of! 295! aspirin<users!who!

developed! LGIB103! grouping! patients! into! those! that! discontinued! aspirin! on!

discharge! and! those! who! continued! it.! The! latter! group! experienced! more!

episodes! of! re<bleeding,! but! fewer! adverse! cardiovascular! events! and! deaths!

! 171!

over!5!years.!Although!the!study!reported!in!this!thesis!is!larger,!I!was!unable!to!

demonstrate! an! association! between! withholding! aspirin! during! the! index!

admission!and!adverse!cardiovascular!outcomes!because! the!number!of!events!

was!too!small,!possibly!due!to!the!short!period!of!follow!up.!Despite!this,!(and!in!

keeping!with!the!study!by!Chan!et#al),!the!conclusion!was!that!antiplatelet!drugs!

should!not!be!withheld!during!an!acute!admission!with!LGIB.!This!is!at!odds!with!

current! guideline! recommendations! that! imply! that! antiplatelets! should! be!

withheld,! stating! that! ‘non<aspirin! antiplatelet! therapy! should! be! resumed! as!

soon!as!possible!and!at!least!within!7!days.’47!However,!the!findings!of!the!study!

reported!in!this!thesis!are!limited!by!its!design;!prospective!observational!study.!

An!RCT!randomising!patients! to!continue!or! interrupt! their!antiplatelet!drug! is!

required!to!fully!address!this!question.!!

!

The! descriptive! data! on! the! outcomes! of! patients! taking! anticoagulants! is! an!

important! addition! to! the! evidence<base! surrounding! the! effect! of! these! drugs!

(including!DOACs)!on!GIB.!Previous!studies!were!small!and!often!did!not!capture!

enough!detail! regarding! the! type!and! timing!of! cardiovascular! events!or!major!

bleeds.!The!recent!multicentre!COMPASS!trial!randomised!27,395!patients!with!

stable!atherosclerotic!disease!to!aspirin!alone,!rivaroxaban!alone!or!combination!

therapy.170! In! comparison! to! aspirin! alone,! patients! treated! with! aspirin! plus!

rivaroxaban!had!a!24%!reduction! in! rates!of! cardiovascular! events,! but! a!70%!

increase!in!rates!of!major!bleeding.!The!leading!site!of!bleeding!was!the!GI!tract.!

If! this!study!does! lead!to!a!change!in!practice,!physicians!may!see!a!substantial!

increase!in!the!volume!of!drug<associated!LGIB.!!

!

! 172!

A!key!finding!from!the!observational!study!was!the!lack!of!intervention!in!most!

patients.!The!most!frequent!investigation!was!flexible!sigmoidoscopy,!performed!

in!21.5%!cases,!whereas!colonoscopy!was!performed!in!only!3.9%.!This!pattern!

of!investigation!is!at!odds!with!the!published!evidence!in!the!systematic!review!

(Chapter!2);!no!studies!comparing!flexible!sigmoidoscopy,!whereas!colonoscopy!

was!the!intervention!with!the!most!evidence.!This!may!be!because!most!studies!

originated!in!the!US,!where!colonoscopy!is!favoured!over!flexible!sigmoidoscopy.!

In! the! observational! study,! patients! waited! a! median! of! 4! days! for! their!

colonoscopy,!and!only!14%!patients!undergoing!colonoscopy!had!the!procedure!

within!24!hours.!Although!guidelines!recommend!that!‘in!patients!with!high<risk!

clinical! features! and! signs! or! symptoms! of! on<going! bleeding,! a! rapid! bowel!

purge! should! be! initiated! following! hemodynamic! resuscitation,! and! a!

colonoscopy!performed!within!24!h!of!patient!presentation,’47!evidence!from!the!

systematic! review! found! no! difference! in! important! clinical! outcomes! (re<

bleeding!or!RBC!transfusion)!between!early!and!late!colonoscopy.!The!guideline!

recommendations! may! therefore! not! be! justified,! although! results! of! the!

systematic!review!are!limited!by!the!quality!of!evidence!available!on!this!topic.!!

!

In! total! 48%!patients! admitted!with! LGIB! in! the! observational! study!were! not!

investigated! as! an! inpatient,! and! only! a! small! minority! of! patients! received!

endoscopic,! radiological! or! surgical! treatment.! Overall! mortality! was! low,! at!

3.4%.!The!group!of!non<investigated!patients!received!fewer!blood!transfusions!

and!there!was!no!difference!in!in<hospital!mortality!or!re<admission!with!further!

bleeding!in!comparison!to!the!group!that!were!investigated,!suggesting!that!they!

did!not!come!to!harm!(although!this!may!be!confounded!by!indication).!The!low!

! 173!

frequency! of! intervention! questions! the! rationale! for! patient! admission.! This!

finding!changed!the!initial!focus!of!the!risk!score!from!the!prediction!of!adverse!

outcomes,! to! the! identification!of! patients! that! could! safely! avoid! admission! in!

favour! of! outpatient! investigation! (Chapter! 6).! This! strategy! differs! from!

previous!attempts!by!other!groups!at!designing!a!risk!score!for!LGIB,!which!have!

aimed! to! predict! severe! haemorrhage,! complications! and! death.13! 68<70! 140! The!

clinical!usefulness!of!these!scores!is!limited!by!the!infrequency!of!the!events!they!

seek! to! identify! and! they! give! little! prognostic! information! on! the!majority! of!

patients!who!will!not!come!to!harm.!!

!

The!new!risk!score!aims!to!identify!the!large!group!of!patients!with!a!remote!risk!

intervention!or!adverse!events.!The! frequency!of!patients!who!met! the!criteria!

for!safe!discharge!was!unexpected;!68%!in!the!development!cohort!and!64%!in!

the!validation!cohort.!The!widespread!use!of!this!risk!score!has!the!potential!to!

transform! the!management! of! patients! admitted!with! LGIB.! In! the! preliminary!

paper!arising! from!Chapter!6171! it! is! recommended!that!a!score!of!≤8!points!at!

initial!assessment!can!be!used!as!the!threshold!for!hospital!discharge,!as!this!is!

associated!with!a!95%!chance!of! safe!discharge.!However,!only!11.9%!patients!

who!met! the!criteria! for!safe!discharge!scored!≤8!points.!Although! the!score! is!

externally! validated,! it! is! yet! to! be! validated! in! healthcare! systems!beyond! the!

UK,! and! in! populations! outside! of! study! conditions.!With! this! consideration! in!

mind,! a! conservative!points! threshold!was! selected! to!maximise!patient! safety,!

but! it! sacrificed! the! volume! of! patients! that! could! otherwise! be! discharged.!

Further!studies!may!demonstrate!that!higher!points!thresholds!are!safe,!in!which!

case!a!greater!proportion!of!patients!may!be! identified!by! the!score!as!safe! for!

! 174!

outpatient! management.! The! observational! study! may! serve! as! a! comparison!

dataset!for!rates!of!admission,!inpatient!and!outpatient!investigation,!should!the!

score!be!widely!adopted.!!

!

Increasing! the! outpatient! management! of! LGIB! patients! has! important!

considerations.!The!systematic!review!was!designed!to!include!all!studies!on!the!

timing! of! investigation,! but! we! found! only! studies! that! compared! inpatient!

elective! colonoscopy! with! that! performed! within! 24! hours.! There! were! no!

studies! examining! the! optimum! timing! of! outpatient! investigation.! The!

observational! study! demonstrated! that! 70%! of! outpatient! endoscopies! were!

scheduled!to!be!performed!more!than!two!weeks!post<discharge.!Whether!this!is!

adequate! requires! further! study,! but! it! is! plausible! that! many! stigmata! of!

haemorrhage! may! have! disappeared! by! this! time.! If! the! colonoscopy! is! being!

performed! for! the! diagnosis! of! cancer,! NICE! recommends! that! endoscopy! is!

performed!within!two!weeks.118!

!

Reducing!the!number!of!patients!admitted!with!LGIB!is!likely!to!have!a!beneficial!

impact! on! inpatient! resources,! but! the! trade<off! is! increased! demand! on!

outpatient! resources.! The! study! of! the! organisation! of! services! (Chapter! 5)!

identified! that! 24/7! inpatient! lower! GI! endoscopy! was! available! in! 75%!

hospitals.!Additionally! there!was!a!deficit! in!endoscopists’! skills!with!regard! to!

the!ability!to!provide!therapy!at!colonoscopy.!The!current!volume!of!referrals!for!

outpatient!endoscopy!is!unknown!and!the!gap!in!endotherapy!skills!is!also!likely!

to! apply! in! the! outpatient! setting.! Quantifying! the! potential! increased! demand!

! 175!

associated!with!more! outpatient<based! care! requires! detailed! health! economic!

analysis.!

!

The! risk! score! can! also! be! used! to! predict! need! for! RBC! transfusion! and! re<

bleeding.! The! systematic! review! was! unable! to! identify! which! interventions!

reduced!these!outcomes!though;! there!was!no!difference! in!re<bleeding!or!RBC!

transfusion!with!colonoscopy!versus!CTA,!and!there!were!no!studies!comparing!

the!efficacy!of!endotherapy!with!that!of!mesenteric!embolisation.!The!optimum!

management! approach! to! patients! that! do! require! admission! remains! unclear!

therefore,!and!greatly!hindered!by!the!lack!of!evidence!in!this!area.!

!

Although!adverse!events!were!uncommon,! the!observational! study!did! identify!

that!patients!who!developed!LGIB!as!an!established!inpatient!were!at!increased!

risk.!During!hospital!admission,!17.9%!of!these!patients!died,!versus!2.2%!of!the!

de!novo!admissions!with!LGIB.!This!group!represents!an!opportunity!to!improve!

outcomes.! In! comparison! to! new! admissions,! the! inpatient! bleeds! were! older!

with! more! co<morbid! illness.! Early! assessment! by! the! medical! team! that!

normally!treats!GIB!and!involvement!of!Care!of!the!Elderly!physicians!may!help!

optimise!these!patients!and!initiate!prompt!minimally!invasive!treatment!where!

appropriate.!!

!

Suggestions*for*Future*Work*

The!risk!score!model!indicated!that!patients!scoring!≤8!points!on!the!risk!score!

can! be! safely! discharged.! Future! work! should! aim! to! address! the! question! of!

further!management.! NICE! recommends! performing! a! colonoscopy!within! two!

! 176!

weeks! for! patients! aged! over! 50! with! unexplained! rectal! bleeding.118! The!

national!bowel! cancer! screening!programme!reports!a! cancer!detection! rate!of!

7.8<11.6%.172! By! definition! LGIB! patients! already! have! a! potential! symptom!of!

cancer,! so! the! detection! rate! may! be! higher.! A! large! observational! study!

reporting! the!diagnostic! yield!of!outpatient! colonoscopy! could!provide!data!on!

the!utility! of! this! investigation! in!LGIB.!These!data! could!be!used! to! inform!an!

RCT,! randomising! patients! to! colonoscopy! within! two! weeks,! or! colonoscopy!

beyond!this!(current!practice).!In!younger!patients!with!a!low!risk!of!cancer,!this!

could! be! a! non<inferiority! trial,! comparing! no! investigation! or! flexible!

sigmoidoscopy!with!outpatient!colonoscopy.!!

!

Patients!who!score!>8!may!benefit! from!hospital!admission,!although!currently!

there! are! no! RCTs! comparing! CTA! with! colonoscopy! or! endotherapy! with!

embolisation.! These! are! both! required.! Chapter! 5! identified! deficiencies! in! the!

provision! of! all! of! these! interventions,! requiring! considerable! investment! in!

services,!which!will!require!clinical!justification.!!

!

Lastly,!the!area!of!work!that!is!most!likely!to!see!immediate!benefit!to!patients!is!

the!publication!and!adoption!of!a!national!guideline!on!the!management!of!LGIB.!

This! will! allow! standardisation! of! management! between! hospitals! and! also!

clearly!define!what! is!expected!with!regard!to!the!availability!of!care.!Although!

the!evidence!base!supporting!optimal!care! is!poor,! there!are!groups!of!patients!

where! improvements! can! be! made,! as! identified! in! this! thesis.! These! groups!

include!patients!with!severe!bleeding!who!may!benefit!from!improved!access!to!

IR! or! interventional! colonoscopy,! patients! who! develop! LGIB! whilst! receiving!

! 177!

antiplatelet! or! anticoagulant! drugs,! and! patients! who! develop! bleeding! as! an!

inpatient.! This! guideline! is! currently! being! developed! by! the!British! Society! of!

Gastroenterology!and!is!expected!to!be!completed!in!2018.!

!

In!summary,!this!thesis!describes!the!management!of!LGIB!patients!in!the!UK!in!

an! unprecedented! number.! The! observational! study! is! also! one! of! the! largest!

epidemiological! studies!of!LGIB!worldwide.!Although! its!aims!were! to! improve!

the! inpatient! management! of! these! patients! by! identifying! the! optimum!

approach! to! management! and! therapy,! and! designing! a! risk! score! to! predict!

adverse!outcomes,!the!paucity!of!evidence!for!the!optimum!management!meant!

that! identifying! patients! at! low! risk! of! harm! had! greater! clinical! value.! By!

reducing! the! number! of! hospital! admissions! with! LGIB,! clinicians! can! focus!

resources! on! the! small! group! of! patients! who! will! benefit! from! inpatient!

investigation!and!treatment.!!

! 178!

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159.!Awtry!EH,!Loscalzo!J.!Aspirin.!Circulation!2000;101(10):1206<18.!160.!Weber!AA,!Braun!M,!Hohlfeld!T,!et!al.!Recovery!of!platelet!function!after!

discontinuation!of!clopidogrel!treatment!in!healthy!volunteers.!British!journal!of!clinical!pharmacology!2001;52(3):333<6.!

161.!Devereaux!PJ,!Mrkobrada!M,!Sessler!DI,!et!al.!Aspirin!in!patients!undergoing!noncardiac!surgery.!The!New!England!journal!of!medicine!2014;370(16):1494<503.!

162.!Keeling!D,!Tait!RC,!Watson!H.!Peri<operative!management!of!anticoagulation!and!antiplatelet!therapy.!British!journal!of!haematology!2016;175(4):602<13.!

163.!Roberts!I,!Coats!T,!Edwards!P,!et!al.!HALT<IT<<tranexamic!acid!for!the!treatment!of!gastrointestinal!bleeding:!study!protocol!for!a!randomised!controlled!trial.!Trials!2014;15:450.!

164.!Thiele!T,!Sumnig!A,!Hron!G,!et!al.!Platelet!transfusion!for!reversal!of!dual!antiplatelet!therapy!in!patients!requiring!urgent!surgery:!a!pilot!study.!Journal!of!thrombosis!and!haemostasis!:!JTH!2012;10(5):968<71.!

165.!Baharoglu!MI,!Cordonnier!C,!Al<Shahi!Salman!R,!et!al.!Platelet!transfusion!versus!standard!care!after!acute!stroke!due!to!spontaneous!cerebral!haemorrhage!associated!with!antiplatelet!therapy!(PATCH):!a!randomised,!open<label,!phase!3!trial.!Lancet!(London,!England)!2016;387(10038):2605<13.!

166.!Buchanan!A,!Newton!P,!Pehrsson!S,!et!al.!Structural!and!functional!characterization!of!a!specific!antidote!for!ticagrelor.!Blood!2015;125(22):3484<90.!

! 189!

167.!Nagata!N,!Niikura!R,!Aoki!T,!et!al.!Risk!factors!for!adverse!in<hospital!outcomes!in!acute!colonic!diverticular!hemorrhage.!World!journal!of!gastroenterology!2015;21(37):10697<703.!

168.!Baker!D,!Wilsmore!B,!Narasimhan!S.!Adoption!of!direct!oral!anticoagulants!for!stroke!prevention!in!atrial!fibrillation.!Internal!medicine!journal!2016;46(7):792<7.!

169.!Narayan!SW,!Tordoff!JM,!Nishtala!PS.!Temporal!trends!in!the!utilisation!of!preventive!medicines!by!older!people:!A!9<year!population<based!study.!Archives!of!gerontology!and!geriatrics!2016;62:103<11.!

170.!Eikelboom!JW,!Connolly!SJ,!Bosch!J,!et!al.!Rivaroxaban!with!or!without!Aspirin!in!Stable!Cardiovascular!Disease.!New!England!Journal!of!Medicine;0(0):null.!

171.!Oakland!K,!Jairath!V,!Uberoi!R,!et!al.!Derivation!and!validation!of!a!novel!risk!score!for!safe!discharge!after!acute!lower!gastrointestinal!bleeding:!a!modelling!study.!The!lancet!Gastroenterology!&!hepatology!2017.!

172.!Logan!RF,!Patnick!J,!Nickerson!C,!et!al.!Outcomes!of!the!Bowel!Cancer!Screening!Programme!(BCSP)!in!England!after!the!first!1!million!tests.!Gut!2012;61(10):1439<46.!

!!!******************APPENDICES**Appendix!table!1:!modified!Charlson!Co<morbidity!Index!for!use!in!a!Clinical!Dataset!!Co<morbidities!were!collated!using!the!Deyo!modification!of!Charlson!Co<Morbidity!Index,108!which!links!definitions!of!the!conditions!used!in!the!Charlson!co<morbidity!index!to!ICD<9!criteria!to!aids!application!in!non<administrative!datasets.!The!application!of!the!Charlson!index!is!difficult!as!some!of!the!definitions!are!subjective.!To!enable!its!use!in!a!clinical!setting!we!made!the!following!amendments.*!Assigned!weight!

Charlson!weighted!condition!

Deyo!description! Amended!definition!

! 190!

1! Myocardial!Infarction!!Congestive!Heart!Failure!!Peripheral!Vascular!Disease!!!!!Stroke!without!hemiplegia!!Dementia!!!Chronic!Pulmonary!Disease!!!!Connective!Tissue!Disease!!!!!Peptic!Ulcer!Disease!!!Mild!Liver!Disease!!!!!Diabetes!!

Acute!or!old!!Heart!failure!!!Intermittent!claudication,!gangrene,!resection!and!replacement!of!lower!limb!arteries,!blood!vessel!replaced!by!prosthesis,!gangrene,!aortic!aneurysm!!!!Senile!or!presenile!dementias!!COPD,!pneumoconeosis,!chronic!repiratory!conditions!due!to!inhaled!fumes!and!vapours!!SLE,!systemic!sclerosis,!polymyositis,!adult!rheumatoid!arthritis,!rheumatic!lung,!polymyalgia!rheumatica!!Gastric,!duodenal,!gastrojejunal!ulcers!!alcoholic!cirrhosis,!cirrhosis!without!alcohol,!biliary!cirrhosis,!chronic!hepatitis!!!Includes!those!with!peripheral!circulatory!disorders!!

!!On!pharmacotherapy!or!clinical!examination!findings!consistent!with!congestive!heart!failure!!!!!!!!!Formally!diagnosed!dementia!!Addition!of!Asthma!!!!!!!!!!!Requiring!acid!suppression!with!PPI!or!H2!receptor!antagonist!Liver!disease!but!absence!of!hepatic!coma,!portal!hypertension,!other!sequelae!of!chronic!liver!disease,!oesophageal!varices!!!!!

2! Stroke!with!Hemiplegia!!Moderate!or!Severe!Renal!Disease!!!!!!Diabetes!with!End<

!!Chronic!glomerulonephritis,!nephritis!and!nephropathy,!chronic!renal!failure,!unspecified!renal!failure,!disorders!resulting!from!impaired!renal!function!!!Renal,!opthalmic!or!

!!!eGFR!≤!60!(renal!association!stage!2)!

! 191!

organ!Damage!!Any!Tumour,!leukaemia!or!lymphoma!

neurological!complications!

3! Moderate!or!Severe!Liver!Disease!

Hepatic!coma,!portal!hypertension,!other!sequelae!of!chronic!liver!disease,!oesophageal!varices!

*

6! Metastatic!Solid!Tumour!AIDS!

! !

!!!!!!!!!!!!!!!!!!!!!!!!!!!***********

! 192!

Appendix*2:*Systematic*review*search*terms**The!following!databases!were!searched!for!systematic!reviews,!RCTs!and!observational!(cohort)!studies,!from!2000!onwards,!on!12.11.15:!MEDLINE!(OvidSP,!1946!onwards)!PubMed!(epublications!only)!Embase!(OvidSP,!1974!onwards)!CDSR,!CENTRAL,!DARE,!HTA!&!NHSEED!(The!Cochrane!Library!2015,!Issue!3)!!Transfusion!Evidence!Library!!Ongoing!Trials:!ClinicalTrials.gov!!159!refs!WHO!International!Clinical!Trials!Registry!Platform:!36!refs!!!Searches!retrieved!10,667!references!plus!195!ongoing!trials,!which!were!reduced!to!8,260!refs!plus!87!ongoing!trials!when!duplicates!had!been!removed.!!!SEARCH!STRATEGIES!!MEDLINE!(OvidSP)!1.!exp!Lower!Gastrointestinal!Tract/!2.!exp!Intestines/!3.!Gastrointestinal!Tract/!4.!exp!Mesenteric!Arteries/!5.!(lower!gastrointestinal!tract*!or!lower!gastro<intestinal!tract*!or!lower!GI!tract*!or!large!intestin*!or!small!intestin*!or!mesenteric!arter*).tw,kf.!6.!or/1<5!7.!(h?emorrhag*!or!bleed*!or!re<bleed*!or!rebleed*!or!blood!loss*).mp.!8.!6!and!7!9.!exp!Gastrointestinal!Hemorrhage/!10.!((anal!or!anus!or!rectum!or!rectal!or!colon!or!colonic!or!colorectal!or!cecum!or!caecum!or!jejunum!or!cloaca!or!gut!or!ileum!or!diverticula*!or!lower!intestin*!or!large!intestin*!or!small!intestin*!or!bowel!or!lower!gastrointestinal!or!lower!gastro<intestinal!or!lower!GI!or!mesenteric)!adj6!(h?emorrhag*!or!bleed*!or!re<bleed*!or!rebleed*!or!blood!loss*)).tw,kf.!11.!(hematochezia!or!mel?ena!or!colonic!angiodysplasia!or!proctorrhagi*!or!rectocolic*!or!rectorrhagi*).tw,kf.!12.!or/8<11!13.!exp!Colonoscopy/!14.!Proctoscopy/!15.!(colonoscop*!or!coloscop*!or!sigmoidoscop*!or!proctoscop*!or!rectoscop*!or!enteroscop*!or!anuscop*).tw,kf.!16.!Endoscopy,!Gastrointestinal/!17.!Capsule!Endoscopy/!18.!(endoscop*!adj3!(capsule!or!video!or!lower!or!mesenteric!or!colon*!or!bowel)).tw,kf.!19.!pillcam.tw,kf.!20.!or/13<19!21.!Colonography,!Computed!Tomographic/!22.!((CT!or!computed!or!tomograph*!or!virtual)!adj2!(colonograph*!or!colonoscop*!or!pneumocolon*)).tw,kf.!23.!Tomography,!X<Ray!Computed/!24.!Radiology,!Interventional/!25.!(tomograph*!angiogra*!or!CTA!or!CT!angiogra*!or!mesenteric!angiogra*!or!GI!angiogra*!or!(radiolog*!adj2!(diagnos*!or!intervention*))).tw,kf.!26.!Angiography/!27.!or/21<26!28.!Hemostasis,!Endoscopic/!29.!((therap*!or!treatment*!or!h?emosta*!or!epinephrine!or!adrenaline!or!cyanoacrylate!or!inject*!or!band*!or!electrocauter*!or!argon!plasma!or!thermal!coagulat*!or!thermocoagulat*!or!

! 193!

thermo<coagulat*!or!heater!probe*!or!argon!coagulat*!or!laser!coagulat*!or!YAG!laser!or!ablat*!or!h?emoclip*!or!h?emospray!or!sclerotherap*)!adj10!endoscop*).tw,kf.!30.!(endotherap*!or!endoclip*!or!over<the<scope!clip*).tw,kf.!31.!20!or!28!or!29!or!30!32.!Embolization,!Therapeutic/!33.!(emboli?ation!or!emboli?ed!or!embolotherap*!or!angioemboli*!or!microemoboli*).tw,kf.!34.!27!or!32!or!33!35.!12!and!(31!or!34)!36.!limit!35!to!yr="2000!<Current"!!EMBASE!(OvidSP)!1.!exp!Large!Intestine/!2.!exp!Small!Intestine/!3.!exp!Anus/!4.!exp!Mesenteric!Artery/!5.!Intestine/!6.!Gastrointestinal!Tract/!7.!(lower!gastrointestinal!tract*!or!lower!gastro<intestinal!tract*!or!lower!GI!tract*!or!large!intestin*!or!small!intestin*!or!mesenteric!arter*).tw.!8.!1!or!2!or!4!or!5!or!6!or!7!9.!(h?emorrhag*!or!bleed*!or!re<bleed*!or!rebleed*or!blood!loss*).mp.!10.!Bleeding/!11.!9!or!10!12.!8!and!11!13.!Gastrointestinal!Hemorrhage/!or!Colon!Hemorrhage/!or!Hemorrhagic!Colitis/!or!Intestinal!Bleeding/!or!Intestine!Hematoma/!or!Large!Intestine!Hemorrhage/!or!Melena/!or!Rectum!Hemorrhage/!or!Small!Intestine!Hemorrhage/!14.!((anal!or!anus!or!rectum!or!rectal!or!colon!or!colonic!or!colorectal!or!cecum!or!caecum!or!jejunum!or!cloaca!or!gut!or!ileum!or!diverticula*!or!lower!intestin*!or!large!intestin*!or!small!intestin*!or!bowel!or!lower!gastrointestinal!or!lower!gastro<intestinal!or!lower!GI!or!mesenteric)!adj6!(h?emorrhag*!or!bleed*!or!re<bleed*!or!rebleed*!or!blood!loss*)).tw.!15.!(hematochezia!or!mel?ena!or!colonic!angiodysplasia!or!proctorrhagi*!or!rectocolic*!or!rectorrhagi*).tw.!16.!or/12<15!17.!Intestine!Endoscopy/!or!Capsule!Endoscopy/!or!Colonoscopy/!or!Push!Enteroscopy/!or!Rectoscopy/!or!Sigmoidoscopy/!18.!Gastrointestinal!Endoscopy/!19.!(colonoscop*!or!coloscop*!or!sigmoidoscop*!or!proctoscop*!or!rectoscop*!or!enteroscop*!or!anuscop*!or!pillcam*).tw.!20.!(endoscop*!adj3!(capsule!or!video!or!lower!or!mesenteric!or!colon*!or!bowel)).tw.!21.!or/17<20!22.!*Endoscopy/!and!*Hemostasis/!23.!((therap*!or!treatment*!or!h?emosta*!or!epinephrine!or!adrenaline!or!cyanoacrylate!or!inject*!or!banded!or!banding!or!electrocauter*!or!argon!plasma!or!thermal!coagulat*!or!thermocoagulat*!or!thermo<coagulat*!or!heater!probe*!or!argon!coagulat*!or!laser!coagulat*!or!YAG!laser!or!ablat*!or!h?emoclip*!or!h?emospray!or!sclerotherap*)!adj10!endoscop*).tw.!24.!(endotherap*!or!endoclip*!or!over<the<scope!clip*).tw.!25.!or/21<24!26.!Computed!Tomographic!Colonography/!27.!((CT!or!computed!or!tomograph*!or!virtual)!adj2!(colonograph*!or!colonoscop*!or!pneumocolon*)).tw.!28.!Computer!Assisted!Tomography/!29.!Interventional!Radiology/!30.!(tomograph*!angiogra*!or!CTA!or!CT!angiogra*!or!mesenteric!angiogra*!or!GI!angiogra*!or!(radiolog*!adj2!(diagnos*!or!intervention*))).tw.!31.!Abdominal!Angiography/!or!Superior!Mesenteric!Angiography/!32.!Pelvic!Angiography/!33.!or/26<32!34.!Artificial!Embolism/!

! 194!

35.!(emboli?ation!or!emboli?ed!or!embolotherap*!or!angioemboli*!or!microemoboli*).tw.!36.!or/33<35!37.!16!and!(25!or!36)!!PubMed!(epublications!only)!!#1!!!(lower!gastrointestinal!tract*!OR!lower!gastro<intestinal!tract*!OR!lower!GI!tract*!OR!large!intestin*!OR!small!intestin*!OR!mesenteric!arter*)!AND!(hemorrhag*!OR!haemorrhag*!OR!bleed*!OR!re<bleed*!OR!rebleed*!OR!blood!loss*)!#2!!!((anal!OR!anus!OR!rectum!OR!rectal!OR!colon!OR!colonic!OR!colorectal!OR!cecum!OR!caecum!OR!jejunum!OR!cloaca!OR!gut!OR!ileum!OR!diverticula*!OR!lower!intestin*!OR!large!intestin*!OR!small!intestin*!OR!bowel!OR!lower!gastrointestinal!OR!lower!gastro<intestinal!OR!lower!GI!OR!mesenteric)!AND!(hemorrhag*!OR!haemorrhage*!OR!bleed*!OR!re<bleed*!OR!rebleed*!OR!blood!loss*))!#3!!!(hematochezia!OR!melena!OR!melaena!OR!colonic!angiodysplasia!OR!proctorrhagi*!OR!rectocolic*!OR!rectorrhagi*)!#4!!!#1!OR!#2!OR!#3!#5!!!!(colonoscop*!OR!coloscop*!OR!sigmoidoscop*!OR!proctoscop*!OR!rectoscop*!OR!anuscop*!OR!pillcam!OR!endotherap*!OR!endoclip*!OR!over<the<scope!clip*)!#6!!!((capsule!OR!video!OR!lower!OR!mesenteric!OR!colon!OR!colonic!OR!bowel!OR!hemosta*!OR!haemostat*!OR!epinephrine!OR!adrenaline!OR!cyanoacrylate!OR!inject*!OR!banded!OR!banding!OR!electrocauter*!OR!argon!plasma!OR!thermal!coagulat*!OR!thermocoagulat*!OR!thermo<coagulat*!OR!heater!probe*!OR!argon!coagulat*!OR!laser!coagulat*!OR!YAG!laser!OR!ablat*!OR!hemoclip*!OR!hemospray!OR!sclerotherap*)!AND!endoscop*)!#7!!!#5!OR!#6!#8!!((CT!OR!computed!OR!tomograph*!OR!virtual)!AND!(colonograph*!OR!colonoscop*!OR!pneumocolon*))!#9!!(tomograph*!angiogra*!OR!CTA!OR!CT!angiogra*!OR!mesenteric!angiogra*!OR!GI!angiogra*!OR!(radiolog*!AND!(diagnos*!OR!intervention*)))!#10!(embolization!OR!embolized!OR!embolization!OR!embolised!OR!embolotherap*!OR!angioemboli*!OR!microemoboli*)!#11!!#8!OR!#9!OR!#10!#12!!#4!and!(#7!OR!#11)!#13!!((random*!OR!blind*!OR!"control!group"!OR!placebo*!OR!controlled!OR!cohort*!OR!nonrandom*!OR!observational!OR!retrospective*!OR!prospective*!OR!comparative!OR!comparator!OR!groups!OR!trial*!OR!"systematic!review"!OR!"meta<analysis"!OR!metaanalysis!OR!"literature!search"!OR!medline!OR!cochrane!OR!embase)!AND!(publisher[sb]!OR!inprocess[sb]!OR!pubmednotmedline[sb]))!#14!!#12!and!#13!!TRANSFUSION!EVIDENCE!LIBRARY!Clinical!Specialty:!Gastrointestinal!Disorders!Subject!Area:!Red!Cells!!ClinicalTrials.gov!Conditions/Search!Terms:!GI!bleeding!OR!lower!gastrointestinal!hemorrhage!OR!colorectal!bleeding!OR!colonic!bleeding!OR!intestinal!bleeding!OR!rectal!bleeding!OR!mesenteric!bleeding!OR!hematochezia!OR!melena!OR!bowel!bleeding!OR!diverticular!bleeding!Interventions:!endoscopy!OR!colonoscopy!OR!CT!OR!tomography!OR!proctoscopy!OR!endoclip!OR!colonography!OR!angiography!OR!embolization!OR!capsule!OR!pillcam!!!ICTRP!Conditions/Search!Terms:!GI!bleeding!OR!lower!gastrointestinal!hemorrhage!OR!colorectal!bleeding!OR!colonic!bleeding!OR!intestinal!bleeding!OR!rectal!bleeding!OR!mesenteric!bleeding!OR!hematochezia!OR!melena!OR!bowel!bleeding!OR!diverticular!bleeding!Interventions:!endoscopy!OR!colonoscopy!OR!CT!OR!tomography!OR!proctoscopy!OR!endoclip!OR!colonography!OR!angiography!OR!embolization!OR!capsule!OR!pillcam!!Results!!

! 195!

Relevant!references:!5850!Possibly!irrelevant!references:!2410!(contain!one!or!more!of!the!following!words!in!the!title:!upper!(not!lower),!abdominal!aortic!aneurysm,!cancer,!malignan*,!carcinoma*,!esophageal,!duodenal,!hepatic,!cirrho*,!stomach,!liver,!transplant*,!varice*,!pancreat*)!These!have!been!screened!by!one!reviewer!(KO)!and!identified!40!possible!relevant!references.!These!have!been!added!to!the!‘relevant!references’!for!full!screening!by!two!reviewers.!!!!!!!!

! 196!

Appendix 3: Previously described risk scores for upper and lower gastrointestinal bleeding !

!* Severe haemorrhage defined as requirement of >= 2 units red cells OR decrease in Hct of >=20% in first 24 hours, OR additional transfusion OR further decrease in Hct >=20% after 24 hours of clinical stability OR re-admission with LGIB within one week7

!!!!!!!

Score PRE-ENDOSCOPY ROCKALL66

BLATCHFORD67 BLEED129 AIMS65140 STRATE61 NOBLADS69

Variables Age <60 6-79 >80 Shock No shock HR>100 and SBP>100 SBP<100 Co-morbidity Nil major CHF, IHD, any major morbidity renal failure, liver failure, metastatic cancer

Urea 6.5-8 8-10 10-25 >25 Hb M 12.0 F 10.0-11.9 M 10.0-11.9 (no F) M <10 SBP 100-109 90-99 <90 Other HR>=100 Melaena Syncope Hepatic disease Cardiac failure

On-going bleeding SBP<100 PT>1.2 Erratic mental status Unstable co-morbid disease (defined as organ derangement requiring ICU admission)

Albumin <30g/l INR>1.5 Altered mental status SBP ≤90 Age>65

HR ≥100 SBP ≤115 Syncope Non-tender abdominal examination Bleeding per rectum in first 4 hours of presentation Aspirin use >2 active Charslon co-morbid conditions

NSAIDs No diarrhoea No abdominal tenderness SBP ≤100 Non-aspirin antiplatelet Albumin <30g/l >2 active Charslon co-morbid conditions

Predicted Outcomes

Death and re-bleeding Need for intervention In-hospital complications and mortality

LOS and mortality Severe haemorrhage* used a surrogate marker of patients that will ‘require substantial support and early interventions’*

Severe haemorrhage*, transfusion, LOS, need for intervention

Publishers’+Permissions++Chapter(2:(

Oakland+K,(Isherwood(J,(Lahiff(C,(Goldsmith(P,(Desborough(M,(Colman(KS,(Guy(R,(Uberoi(R,(Murphy(MF,(East(JE,(Hopewell(S,(Jairath(V.(Diagnostic(and(therapeutic(

treatment(modalities(for(acute(lower(gastrointestinal(bleeding:(a(systematic(

review.(Accepted(for(publication,(Endoscopy)International)Open.)(

(

(

(

Chapter(3:(

Oakland+K,(Guy(R,(Uberoi(R,(Seeney(F,(Collins(G,(GrantMCasey(J,(Mortensen(N,(Murphy(M,(Jairath(V(on(behalf(of(the(National(Comparative(Audit(in(Blood(

Transfusion(Lower(Gastrointestinal(Bleeding(Working(Group.+Study(Protocol:(First(nationwide(comparative(audit(of(acute(lower(gastrointestinal(bleeding(in(

the(United(Kingdom.(BMJ)Open.(2016(Aug(4;6(8):e011752.(doi:(10.1136/bmjopenM2016M011752.(

(

‘This&article&was&published&under&a&CC&BY&NC&agreement&meaning&it&can&be&reused,&in&any&non<commercial&way,&without&acquiring&permission&from&BMJ.&The&author&licence&you&agreed&to&also&permits&reuse&in&your&thesis&without&permission.’&&&(

(

(

(

(

(

(

Chapter(4:(

Oakland+K,(Guy(R,(Uberoi(R,(Hogg(R,(Mortensen(N,(Murphy(MF,(Jairath(V(on(behalf(of(the(UK(Lower(GI(Bleeding(Collaborative.(Acute(lower(gastrointestinal(

bleeding(in(the(UK:(patient(characteristics,(interventions(and(outcomes(in(the(

first(nationwide(audit.(Gut.(2017(Feb(1.(doi:(10.1136/gutjnlM2016M313428.((

(

(

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Licensed Content Title Acute lower GI bleeding in the UK: patient characteristics,interventions and outcomes in the first nationwide audit

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ACUTE LOWER GASTROINTESTINAL BLEEDING IN THE UNITEDKINGDOM

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(

Chapter(6:(

Oakland+K+and(Jairath(V,(Uberoi(R,(Guy(R,(Ayaru(L,(Mortensen(N,(Murphy(MF,((Collins(GS.(Safe(discharge(after(acute(lower(gastrointestinal(bleeding:(derivation(

and(validation(of(a(novel(risk(score.(Lancet)Gastroenterology)and)Hepatology,(2017(Jun(23(doi:(10.1016/S2468M1253(17)30150M4(

(

(

07/08/2017 11:36Doctors.net.uk Webmail :: RE: THELANCETGASTROHEP-D-17-00175R2: Your manuscript for The Lancet Gastroenterology & Hepatology

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Subject RE: THELANCETGASTROHEP-D-17-00175R2: Your manuscript for The Lancet Gastroenterology & HepatologyFrom Brierley, Robert (ELS-LOW) <[email protected]>To Kate Oakland <[email protected]>Date 2017-07-07 12:49

Dear Kate

Apologies for the delay in getting back to you; I had to run this past a couple of the other Lancet editors. This is absolutely fine—good luck with the writeup!

Best wishes

Rob

Rob BrierleyEditor-in-Chief, The Lancet Gastroenterology & Hepatologyhttp://www.thelancet.com/gastrohephttps://twitter.com/LancetGastroHep

From: Kate Oakland [mailto:[email protected]]Sent: 06 July 2017 14:22To: Brierley, Robert (ELS-LOW)Subject: Re: THELANCETGASTROHEP-D-17-00175R2: Your manuscript for The Lancet Gastroenterology & Hepatology

Hi Rob,

Apologies for being unclear. The thesis will contain the original word version of the submitted article (minus corrections, journal edits, etc as I cannot claim these as my own work), plus an expanded methods section. It will also reference the journal article in full, including the URL.

Is this permissible?

Many thanks

KateSent from my iPhone

On 6 Jul 2017, at 13:55, Brierley, Robert (ELS-LOW) <[email protected]<mailto:[email protected]>> wrote:Dear Kate

Sorry, I am still not entirely clear on the requirements here – and apologies if I’m just missing something obvious! Hosting the word document of the paper on the Imperial server will require it to be identical in terms of text to the main paper (rather than having shared content). We will provide the document for you, exporting it direct from our production software. However, the posted word document should be independent from any upload of your thesis (although you can obviously cite both the published paper and the URL for the word version in the thesis).

Best,

Rob


From: Kate Oakland [mailto:[email protected]]Sent: 06 July 2017 13:25To: Brierley, Robert (ELS-LOW)Subject: Re: THELANCETGASTROHEP-D-17-00175R2: Your manuscript for The Lancet Gastroenterology & Hepatology

Thanks Rob,

I can confirm it will be latter: word document, not identical to the original PDF, but some shared content.

BW

KateSent from my iPhone

On 6 Jul 2017, at 11:41, Brierley, Robert (ELS-LOW) <[email protected]<mailto:[email protected]>> wrote:Dear Kate

Thank you for your email. By “reprint”, do you mean actually include the laid out, final PDF version of the paper in the thesis? If so, I’m afraid the copyright agreement for the article means that this is not permitted. You are entitled to post a word-processed document (not the published journal article as PDF) of the peer-reviewed, accepted, and edited article on personal or institutional websites any time after publication in print or online, provided the word document also contains a link to the paper on thelancet.com<

Best wishes

Rob


From: Hook, Kayleigh (ELS-LOW)

From: [email protected]<mailto:[email protected]> [mailto:[email protected]]Sent: 05 July 2017 12:33To: Hook, Kayleigh (ELS-LOW) <[email protected]<mailto:[email protected]>>Subject: RE: THELANCETGASTROHEP-D-17-00175R2: Your manuscript for The Lancet Gastroenterology & Hepatology

Thanks Kayleigh!

I am currently writing my MD thesis at Imperial, and our risk score paper is a feature of this work. It is possible to be granted permission to reprint the article in my thesis?

The thesis will be added to Spiral, Imperial's institutional repository http://spiral.imperial.ac.uk/ and made available to the public under a Creative Commons Attribution-NonCommercial-NoDerivs licence.

I hope this is ok?

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