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Ontario College of Family Physicians

51st Annual Scientific Assembly

New oral Anticoagulants

November 30, 2013November 30, 2013

Dr John BlakelyDr John Blakely

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Faculty/Presenter DisclosureFaculty/Presenter Disclosure

• Faculty: Dr. John Blakely• Program: 51st Annual Scientific Assembly

• Relationships with commercial interests:

- None

33

Disclosure of Commercial Disclosure of Commercial SupportSupport

• This program has received no financial or in kind support or benefits from anyone in any form.

Potential for conflict(s) of interest:

- I run an anticoagulant clinic.

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Mitigating Potential BiasMitigating Potential Bias

• The presentation is about data

• Opinion is clearly identified

55

DisclosuresDisclosures

• 51 years running anticoagulant clinics51 years running anticoagulant clinics

• Dosing sessions about 1,600 / monthDosing sessions about 1,600 / month

• Mean INR 107 consecutive clinics 2.53Mean INR 107 consecutive clinics 2.53

• INR SD 0.5 INR SD 0.5

• IC Bleed rate ≈ 2 / 1000 patient years (4?)IC Bleed rate ≈ 2 / 1000 patient years (4?)

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DisclosuresDisclosures

• Little experience with warfarin–NOAC Little experience with warfarin–NOAC transitions & NOAC bleedingtransitions & NOAC bleeding

• Major interest in logic of trials Major interest in logic of trials analysisanalysis

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New Oral AnticoagulantsNew Oral Anticoagulants

• Read the EU executive summaryRead the EU executive summary

• Check renal function (q 3 – 6 months)Check renal function (q 3 – 6 months)

• Check compliance with pill countsCheck compliance with pill counts

88

Backwards PresentationBackwards Presentation

• Conclusions firstConclusions first

• Then supporting evidence Then supporting evidence

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New Anticoagulants in Atrial New Anticoagulants in Atrial FibrillationFibrillation

• Dabigatran – should not have been approved Dabigatran – should not have been approved for atrial fibrillation for atrial fibrillation

• Rivaroxaban, apixaban Rivaroxaban, apixaban

– – atrial fibrillation -should have been atrial fibrillation -should have been approved for institutional use approved for institutional use (only)(only)

• New agents unlikely to solve poor INR controlNew agents unlikely to solve poor INR control

1010

New Anticoagulants in VTENew Anticoagulants in VTE

• Rivaroxaban OK in orthopedic Rivaroxaban OK in orthopedic thrombprophylaxisthrombprophylaxis

• Bioequivlence overstated in VTEBioequivlence overstated in VTE

1111

Assessing Treatment ValueAssessing Treatment Value

• Efficacy Efficacy – Demonstration of anticoagulant effectDemonstration of anticoagulant effect

•Requires double blind double dummy trialRequires double blind double dummy trial

• Effectiveness Effectiveness – Prevention of strokes in practicePrevention of strokes in practice

•Requires practice conditions; ‘hard’ Requires practice conditions; ‘hard’ endpointsendpoints

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SupervisionSupervision

• Warfarin requires considerable supervisionWarfarin requires considerable supervision

• “ “It would be good to have an It would be good to have an anticoagulant that did not need regular anticoagulant that did not need regular supervision”supervision”

• NO!!! Supervision improves complianceNO!!! Supervision improves compliance (& all human activities)(& all human activities)

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SupervisionSupervision

• Built-in supervision warfarin’s greatest Built-in supervision warfarin’s greatest advantageadvantage

• Lack of supervision greatest weakness of new Lack of supervision greatest weakness of new agentsagents

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What is the Evidence ThatWhat is the Evidence That Less Supervision Less Supervision

Has Has Positive Results?Positive Results?

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Supervision Improves At Supervision Improves At LeastLeast

• Tuberculosis treatmentTuberculosis treatment– primary drug resistanceprimary drug resistance– acquired drug resistance acquired drug resistance – relapse.relapse.

N Engl J Med 1994; 330:1179-1184N Engl J Med 1994; 330:1179-1184April 28, 1994

DOI: 10.1056/NEJM199404283301702DOI: 10.1056/NEJM199404283301702

• Emergency Physicians Emergency Physicians compliance with guidelinescompliance with guidelines

• Obstetric services in Norway.Obstetric services in Norway. Tidsskr Nor Laegeforen. 2008 May 15;128(10):1179-81.Tidsskr Nor Laegeforen. 2008 May 15;128(10):1179-81.

• Exercise therapyExercise therapy European Journal of Vascular and Endovascular Surgery : the Official Journal of the European

Society for Vascular Surgery[2007, 34(1):1-9][2007, 34(1):1-9]

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Supervision Improves At Supervision Improves At LeastLeast

• Building factories in BangladeshBuilding factories in Bangladesh

• Parking trains in QuebecParking trains in Quebec

• Taking pills (anywhere)Taking pills (anywhere)

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Physician Supervision Less Physician Supervision Less EffectiveEffective

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Physician Supervision Less Physician Supervision Less EffectiveEffective

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PROBEPROBE

• Prospective Randomized Open trial Prospective Randomized Open trial with Blinded End-point assessmentswith Blinded End-point assessments

• Introduced in 1992 without validation Introduced in 1992 without validation as it was as it was ‘‘‘‘self evident that results self evident that results would be the same as double blind.would be the same as double blind.‘‘ ‘‘

Blood Pressure 1992, Vol. 1, No. 2 , Pages 113-119 Blood Pressure 1992, Vol. 1, No. 2 , Pages 113-119

2020

PROBE testedPROBE tested

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Impact of double-blind vs. open study Impact of double-blind vs. open study design on the observed treatment design on the observed treatment effects of new oral anticoagulants in effects of new oral anticoagulants in atrial fibrillation: a meta-analysisatrial fibrillation: a meta-analysis

• Thirteen studies, 61,620 patients. (All phase II or III trials eligible)Thirteen studies, 61,620 patients. (All phase II or III trials eligible)

• Embolism & stroke PROBE produced 14% overestimateEmbolism & stroke PROBE produced 14% overestimate

• 1/6 chance of equal efficacies producing the result observed1/6 chance of equal efficacies producing the result observed • Hemorrhagic stroke 67% overestimate Hemorrhagic stroke 67% overestimate

• Warfarin management ?Warfarin management ?

J Thromb HaemostJ Thromb Haemost; 2013 Jul;11(7):1240-50; 2013 Jul;11(7):1240-50

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PROBE testedPROBE tested

• XimelagatranXimelagatran– At risk atrial fibrillatorsAt risk atrial fibrillators– Stroke & systemic embolismStroke & systemic embolism

• SPORTIF lll PROBESPORTIF lll PROBE– unblinded trial, blinded adjudicatorsunblinded trial, blinded adjudicators– QuestionnaireQuestionnaire

• SPORTIF VSPORTIF V– Double blind, double dummyDouble blind, double dummy

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SPORTIF lllSPORTIF lllMethodMethod PROBE PROBEMean INRMean INR 2.4 2.4TTRTTR 68% 68%Strokes/Yr ximelagatan 1.6%Strokes/Yr ximelagatan 1.6%Strokes/Yr warfarin 2.2%Strokes/Yr warfarin 2.2%Excess strokesExcess strokes 37.5% 37.5%

PROBE efficacy overestimate PROBE efficacy overestimate 43%43%

p = 0.003p = 0.003

Lancet 2003; 362:1691-Lancet 2003; 362:1691-9898

SPORTIF VSPORTIF VDouble BlindDouble Blind 2.52.5 66%66% 1.6%1.6% 1.2%1.2% - 25%- 25%

JAMA 2005; 293, 6JAMA 2005; 293, 6

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PROBE trial DesignPROBE trial Design(unblinded trial, blinded adjudicators)(unblinded trial, blinded adjudicators)

• SPORTIF: PROBESPORTIF: PROBE overestimated the double overestimated the double blind result by 43% blind result by 43% (V published (V published February 9, lll February 9, lll Nov Nov 22 22 2005) 2005)

• Re-Ly (PROBE) recruiting began December 22 Re-Ly (PROBE) recruiting began December 22 20052005

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Re-LyRe-Ly

• PROBE trials arePROBE trials are– EasierEasier– Less expensiveLess expensive– Produce more positive resultsProduce more positive results– Acceptable !!Acceptable !!

N Engl J Med 2009;361:1139-1151N Engl J Med 2009;361:1139-1151

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Dabgatran in Atrial Dabgatran in Atrial FibrillationFibrillation

• Trial design was invalidTrial design was invalid

• Probable overestimate of efficacyProbable overestimate of efficacy

• Probable overestimate of warfarin Probable overestimate of warfarin strokes prevented / bleeds causedstrokes prevented / bleeds caused

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Re-LyRe-Ly

• PublishedPublished IC bleeding advantage IC bleeding advantage nullified by % noncompliance ofnullified by % noncompliance of

CHADS 2 scoreCHADS 2 score

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ComplianceCompliance

In ‘real life’ (practice) compliance is the keyIn ‘real life’ (practice) compliance is the key

Rivaroxaban & apixaban have not been Rivaroxaban & apixaban have not been tested.tested.

Do unsupervised anticoagulants prevent as Do unsupervised anticoagulants prevent as many strokes as well managed warfarin?many strokes as well managed warfarin?

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The Compliance TrapThe Compliance Trap

• Most (83%) patients believe they take every pillMost (83%) patients believe they take every pill

• Properly questioned, only 64% of these actually Properly questioned, only 64% of these actually dodo

• ““Compliance assumption trap” Compliance assumption trap” may be a significant cause of strokemay be a significant cause of stroke

Dtsch Med Wochenschr. 2007 Jan 26;132(4):139-44. 2007 Jan 26;132(4):139-44.

..

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Patients Poorly Managed on Patients Poorly Managed on Warfarin do Poorly on New Warfarin do Poorly on New

AgentsAgents

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Effect by Effect by INR Time in Therapeutic INR Time in Therapeutic RangeRange

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Dabigatran Effect by Dabigatran Effect by

INR Time in Therapeutic INR Time in Therapeutic RangeRange

3333

Effect of TTR on rivaroxabanEffect of TTR on rivaroxaban

RocketRocket

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Loss of Riveroxaban EfficacyLoss of Riveroxaban Efficacywith Decrease in TTR with Decrease in TTR (p (p =.016)=.016)

Ratio excess events over 4th quartile

0.00

0.20

0.40

0.60

0.80

1.00

1.20

1.40

1.60

1 2 3 4

quartile

even

t ra

te Series1

Series2

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Effect of TTR on apixabanEffect of TTR on apixaban

ARISTOTLEARISTOTLE

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Effect of TTR on apixabanEffect of TTR on apixabanCentreCentre

TTRTTRApixabanApixaban

Events/Events/100pt-yrs100pt-yrs

WarfarinWarfarin

Events/Events/100pt-yrs100pt-yrs

<58%<58% 1.751.75 2.282.28

58 - 6558 - 65 1.301.30 1.611.61

65 - 7265 - 72 1.211.21 1.551.55

> 72> 72 0.830.83 1.021.02

The heart.org Aug 28 2011The heart.org Aug 28 2011

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New Anticoagulants in Atrial New Anticoagulants in Atrial FibrillationFibrillation

• Dabigatran – data unreliable, Dabigatran – data unreliable, overestimateoverestimate

• Rivaroxaban & apixabanRivaroxaban & apixaban– OK when supervised exactly as warfarinOK when supervised exactly as warfarin– Validated supervision likely rareValidated supervision likely rare– Not tested in practiceNot tested in practice– Probably ideal for institutional use Probably ideal for institutional use – Poor remedy for poor INR controlPoor remedy for poor INR control

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Venous Thromboembolic Venous Thromboembolic DiseaseDisease

• Compliance not an issue in hospitalCompliance not an issue in hospital

• Compliance probably betterCompliance probably better– Treating rather than preventing eventsTreating rather than preventing events– With short term treatmentWith short term treatment

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Assessing Treatment ValueAssessing Treatment Value

• Efficacy Efficacy – Demonstration of anticoagulant effectDemonstration of anticoagulant effect

•Requires double blind double dummy trialRequires double blind double dummy trial

• Effectiveness Effectiveness – Prevention of strokes in practicePrevention of strokes in practice

•Requires practice conditions; ‘hard’ Requires practice conditions; ‘hard’ endpointsendpoints

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Extended Use of Dabigatran, Extended Use of Dabigatran, Warfarin, or Placebo in Venous Warfarin, or Placebo in Venous ThromboembolismThromboembolism

(RESONATE)(RESONATE)•RecurrenceRecurrence– dabigatran 1.8% dabigatran 1.8% – warfarin group 1.3% warfarin group 1.3% – hazard ratio with dabigatran, 1.44; 95% hazard ratio with dabigatran, 1.44; 95% – P=0.01 for noninferiorityP=0.01 for noninferiority– 1/9 chance equal efficacies would produce result1/9 chance equal efficacies would produce result

– ““p -0.01” is statistical distance between result p -0.01” is statistical distance between result & committee decision & committee decision ≤≤ 285% (3.7% ) worse is non-inferior 285% (3.7% ) worse is non-inferior

N ENGL J MED 2013; 368:709-718N ENGL J MED 2013; 368:709-718February 21, 2013DOI: DOI: 10.1056/NEJMOA1113697 10.1056/NEJMOA1113697

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Re-Cover Re-Cover Dabigatran VS Warfarin Dabigatran VS Warfarin in Treatment of Acute in Treatment of Acute

Venous Venous ThromboembolismThromboembolism

P < 0.001 for the prespecified non-inferiority margin

• “Dabigatran Can Replace Warfarin in Venous Thromboembolism”

• 1/3 chance that equal efficacies would produce the observation

NEJM.ORG Dec 10 2009NEJM.ORG Dec 10 2009

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If well managed warfarin is If well managed warfarin is optimal, how do we manage it optimal, how do we manage it well?well?

• Cumulative record of INRs, doses, indication, review date, Cumulative record of INRs, doses, indication, review date, INR target, tab strengthINR target, tab strength

• Written warfarin safe practice instructions & dosing Written warfarin safe practice instructions & dosing calendar. calendar.

• Insist on a dosette™ box for warfarin (identifies missed Insist on a dosette™ box for warfarin (identifies missed doses; take them ‘now’). doses; take them ‘now’).

• Dosing algorithm. Aim for the target, not the bottom of Dosing algorithm. Aim for the target, not the bottom of the range.the range.

• One tablet strength only. Give weekly doses as One tablet strength only. Give weekly doses as combinations of whole & half tabletscombinations of whole & half tablets

• Know about changes in concomitant therapy within a Know about changes in concomitant therapy within a week week

• Standard questions for out of range INRsStandard questions for out of range INRs• Bridge therapy protocol Bridge therapy protocol • Don’t stop warfarin for dentistry, screening colonoscopy, Don’t stop warfarin for dentistry, screening colonoscopy,

minor superficial surgeryminor superficial surgery• INR turnaround ≤ 24 hour, positive contact every INRINR turnaround ≤ 24 hour, positive contact every INR• Most INR perturbations are ‘one off’. Use ‘one off’ Most INR perturbations are ‘one off’. Use ‘one off’

corrections.corrections.• Modify maintenance dose if change understood or 2 – 3 Modify maintenance dose if change understood or 2 – 3

consecutive ‘one offs’ consecutive ‘one offs’

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SummarySummary

• The ‘PROBE’ trial design overestimates The ‘PROBE’ trial design overestimates efficacyefficacy

• Anticoagulant effect is not enough. Warfarin Anticoagulant effect is not enough. Warfarin alternatives must be effective unsupervisedalternatives must be effective unsupervised

• New anticoagulants are not a fix for poorly New anticoagulants are not a fix for poorly managed warfarinmanaged warfarin

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Ontario College of Family Physicians

51st Annual Scientific Assembly

New oral Anticoagulants

November 30, 2013November 30, 2013

Dr John BlakelyDr John Blakely