a cancer clot conundrum...gi gerd+ esophagitis (2017) hiatus hernia diverticulosis msk/skin...

ACancerClotConundrum

GeneralMedicineCasePresentationJenniferPitman,PharmacyResident

September26th 2017

Objectives• UnderstandthepathophysiologyandriskfactorsforVTEincancer

• RecallcurrentguidelinesandtrialsfortreatmentofVTEincancer

• EvaluatetheroleofNOACsintreatmentofVTEincancerpatients

• RecommendappropriatetherapyforacancerpatientwithVTE,consideringpt specificfactors

Patient:EDID: 73 yo female,54kg

CC: WorseningSOB,especially onexertion

HPI: • SurgicaladmissionAug21-27 forexcisionofupperleftlobelungnodule(metastaticmelanoma)

• ERvisitonAug29forSOBà prescribedmoxifloxacinandoralprednisoneforAECOPD

• Noimprovementà re-admittedSept5th withPEdiagnosisAllergies: Caffeine,metals

FamilyHx: Unknown

SocialHx: • Livesaloneinmobilehome; singlewithnochildren• EtOH- recoveringalcoholic(sobersince1990)• Smoking- Exsmoker(20-30pack-years)• Marijuana- regular(daily)useruntillungtumordiagnosisFeb/17

VaccinationStatus:

Ptdeclined toanswer

Patient:PMHxCNS Hx ofsubstanceabuse(EtOH,marijuana)

NeuralgiaParesthesia(2001)

HEENT MacularDegeneration

RESP COPD

CV AorticSclerosis

GI GERD +Esophagitis(2017)HiatusHerniaDiverticulosis

MSK/SKIN OsteoarthrosisOsteopeniaPsoriasisRightCarpalTunnelSyndrome

HEME Metastaticmelanoma

Surgical Leftlungupperloberesection(2017)Leftshinsquamouscellcarcinomaexcision(2016)Colonoscopyandpolypectomy(2016)Melanomainsitu excision(2012)

Patient:MPTA

CNS Gabapentin100mgPOTIDRESP Ciclesonide 100 mcginhale1-2puffsdaily

Tiotropium/olodateraol 2.5/2.5mcginhale2puffsoncedailySalbutamol100mcginhale2puffsQID

SuspectedExacerbationAug29:-Moxifloxacin400mgPOdailyx7days-Prednisone50mgPOdailyx5days

CV ?Metoprolol37.5mgPOBIDGI Pantoprazole40mgPOdailyHEME Hydromorphone 1-3mgPOq4hPRN

ReviewofSystemsVitals T 36.3OC,HR100,RR16,BP132/84mmHg,O2 97%on1L/minCNS/Psych A&Ox3,CAM-, emotional andfrustratedafterterminalcancer

diagnosisCV NSR,Twaveabnormality(?anteriorischemia),Trop46,QTc 500RESP SOB, drycough,CTshowingmultiplebilateralPEs andleftpleural

effusion, leftchestpain (surgicalsite)GI Abdomenflatandsoft, bowelsoundspresentx 4,diarrhea2O to

homemadelaxativeRenal/GU Scr 66mmol/L, CrCl 56mL/min(calculated), stableMSK/Skin Independent tomobilize,lowfallsriskHematology Metastaticmelanoma, WBC10.4,Hgb 142,MCV92,PLT354,B12

511Fluids/Lytes Na136, K4.0,Ca2.22,Mg0.81,PO40.88

CurrentConditions&Medications• MedicalProblems

– Bilateralpulmonaryemboli

– Malignantmelanoma– Leftchestpain∘2toleft

loberesection– COPD– Constipation– GERD+esophagitis– Osteoarthrosis– HiatusHernia– Diverticulosis– MacularDegeneration– Psoriasis– Hx ofSubstanceAbuse

• MedicationsinHospital– Dalteparin 10,000unitssubcutdaily

– Acetaminophen1gPOQIDPRN– Hydromorphone1mgsubcut or

2mgPOq4hPRN– Fluticasone/Salmeterol250/25mcg

onepuffq12h– Tiotropium18mcgonepuffdaily– Ipratropium/salbutamol2.5mLneb

inhaledq4hPRN– BowelProtocol– Pantoprazole40mgPOdaily– Zopiclone 7.5mgPOHSPRN

CourseinHospital• AdmittedtoVGHgeneralmedicineflooronSeptember5th– Threenightstay

• Treatmentinitiatedwithdalteparin 10,000unitsSCdailyformultiplebilateralPEsinsettingofmalignancy– Terminaldiagnosis,3-6months

• Ptresistanttoself-injectingathomeandhaslittlehomesupport– PhysicianinquiringaboutDOACsasPOalternative

DRPs1. EDisexperiencingSOBandmultiplebilateral

PEsandrequiresanticoagulationtherapy2. EDhasleftchestpainsecondarytosurgeryandrequirespain

management3. EDisexperiencingdiarrheasecondarytohomemadelaxativeand

requirestherapyevaluation4. EDisariskofconstipationsecondarytohydromorphoneandrequires

therapyevaluation5. EDisexperiencingtachycardiaandrequirestherapyevaluation6. EDisatriskofAchillestendonitisandtendonrupturesecondaryconcomitant

touseofprednisone+moxifloxacin

GoalsofTherapy• ReduceriskofVTErecurrence• Improveorresolveshortnessofbreath• MinimizeADRssecondarytoanticoagulation• Facilitateeaseofadministrationofanticoagulationtherapy

• Maintainorimprovequalityoflife

VTERiskinCancer• VTEIncidenceinCancer

– 15%,ranging3.8%- 30.7%

• CancerType– Higherriskinclinicallyaggressive(pancreatic,brain,stomach)and

hematologic(leukemia,lymphoma)cancers

• CancerStage– Higherriskwithdiseaseprogression(metastaticdisease)

• Timeafterdiagnosis– Higherriskinfirst3-6months

• MajorSurgery– 2-4foldhigherriskofVTEpostsurgerycomparedtonon-cancer

patients

Deitcher.Semin Thromb Hemost 2003;29(3):247-58.Wun etal.BestPract ResClin Haematol 2009;22(1):9-23.

HypercoagulabilityinCancer

ChemotherapyHormonalTherapyMalignantCells

ImmobilityExtrinsic tumor vascular compression

Complex cell interactionsSurgery

Central venous catheters

FactorsforED:Surgery,immobility,malignancy

Picciolietal.Semin Thromb Hemost 2006;32(7):694-9.Mandalaetal.AnnOncol 2011;22Suppl 6:vi85-92.

CurrentGuidelinesNCCNGuidelines2017:• LMWHpreferred• ForptswhorefuseorhavecompellingreasontoavoidLMWH,apixaban or

rivaroxabanareacceptable

CHEST2016Guidelines:CancerPatients• LMWHoverVKA(Grade2B)• LMWHoverdabigatran,rivaroxaban,apixaban,oredoxaban (Grade2C)• Extended(noscheduledstopdate)over3monthsoftherapy(Grade1B)

ASCO2015GuidelineUpdate:• LMWHforatleast6months• DOACsnotcurrentlyrecommended

– ReferencedbyBCCANov2016

Whatweknow…CANTHANOX(2002)

CLOT(2003) ONCENOX(2006)

LITE(2006) CATCH(2015)

Population SymptomaticVTE,n=138

SymptomaticVTE,n=672


SymptomaticDVT,n=200


Interventions Enoxaparinvswarfarin

Dalteparin vswarfarin

Enoxaparin(1or1.5mg)vswarfarin

Tinzaparin vswarfarin

Tinzaparin vswarfarin

Outcomes CompositeVTEandMB

VTE,MB VTE,MB VTE,MB VTE*,MB,CRNMB

Results: VTE RR=2.02(0.88-4.65)Favorsenox.

HR =0.48,P=0.002Favorsdalt.

3.4%vs3.1%vs6.7%(NSS)

RR=0.44,P=0.044Favorstinz.

HR=0.65(0.41=1.03)Favorstinz.

Results: Bleed NSSbleeds NSSbleeds NSSbleeds HR0.58(0.4-0.84)CRNMB

Bottomline:LMWH>warfarin

MB=majorbleed,CRNMB=clinicallyrelevantnon-majorbleed*includedincidentalfindings

Whatweknow…Trials Einstein-DVT,

PE(2010,2013)RE-COVERII(2011)

Amplify(2013) Hokusai-VTE(2013)

Population SymptomaticVTE,n=655




Interventions Rivaroxabanvsenoxaparin/warfarin

Dabigatran*vsUFHorLMWH/warfarin

Apixaban vsenoxaparin/warfarin

Edoxaban* vsenoxaparinorUFH/warfarin

CancerSubgroup:VTE

HR=0.67 (0.34-1.30)

RR=0.75# RR=0.56 (0.13-2.37)

HR=0.53 (0.28-1.00)

CancerSubgroup:MajorBleeding

HR=0.42(0.18-0.99

Notreported RR=0.45 (0.08-2.46)

HR=0.80 (0.35-1.83)

BottomLine:DOAC=warfarin

*InitialtreatmentwithLMWHorUFH(≥5days)#Manualcalculation

Howdotheywork?

of apixaban were associated with an increased rate ofclinically relevant bleeding, whereas this outcome didnot occur with the lower dose of apixaban. Dabigatranwas noninferior to warfarin for the extended treat-ment of VTE, with an improved safety profile (86). Thelower dose of apixaban was as effective as and saferthan the higher dose for the extended treatment ofVTE in patients with clinical equipoise regarding thecontinuation or cessation of anticoagulation therapy(87). An ongoing clinical trial is aimed at assessing the

clinical value of full-dose rivaroxaban compared withthe prophylactic dose and aspirin in the extendedtreatment of VTE (88).

In a meta-analysis of Phase III placebo-controlledstudies on extended treatment, both all-cause mor-tality and recurrent VTE were lower with NOACsthan with placebo (0.6% per year vs. 1.1% per year[p ¼ 0.01] and 1.9% per year vs. 10.9% per year[p < 0.0001], respectively) (45). No significant dif-ference between treatments was observed in case

CENTRAL ILLUSTRATION New Anticoagulants for Venous Thromboembolism: Mechanisms of Actionof Anticoagulant Agents and of Antidotes for New Oral Anticoagulant Agents

Becattini, C. et al. J Am Coll Cardiol. 2016;67(16):1941–55.

The coagulation cascade and anticoagulant agents. Targets of anticoagulation and targets of the antidotes idarucizumab and andexanet. AT ¼ antithrombin;LMWH ¼ low-molecular-weight heparin; TF ¼ tissue factor; TFPI ¼ tissue factor pathway inhibitor; VKAs ¼ vitamin K antagonists.

J A C C V O L . 6 7 , N O . 1 6 , 2 0 1 6 Becattini and AgnelliA P R I L 2 6 , 2 0 1 6 : 1 9 4 1 – 5 5 New Anticoagulant Agents for Venous Thromboembolism

1951

Becattini etal.JAmColl Cardiol 2016;67(16):1941-55

TherapeuticAlternatives• LMWH

– Dalteparin 200units/kgsubcut dailyx30days,then150units/kgSCdaily

– Enoxaparin1mg/kgsubcut BID– Tinzaparin 175units/kgsubcut daily

• DOACs– Rivaroxaban15mgPOBIDx21days,then20mgPOdaily– Apixaban 10mgPOBIDx7days,then5mgPOBID– Dabigatran150mgPOBID(LMWH/UFHforfirst5-10days)– Edoxaban 60mgPOdaily(LMWH/UFHforfirst5-10days)

ClinicalQuestion

P 73yearoldfemalewithbilateral pulmonaryemboliandmetastaticmelanoma(palliative)

I LowMolecularWeightHeparin

C DirectOralAnticoagulant

O Recurrent ofVTE,majorandminorbleeding

LiteratureSearchPubMed(N=263) ((((((((anticoagulants[MeSH Terms])OR((edoxaban[MeSH Terms])ORedoxaban))

OR((apixaban[MeSH Terms])ORapixaban))OR((dabigatran[MeSH Terms])ORdabigatran))OR((rivaroxaban[MeSH Terms])ORrivaroxaban)))AND((heparin,lowmolecularweight[MeSH Terms])ORlowmolecularweightheparin))AND((cancer[MeSH Terms])ORcancer))AND((((pulmonaryembolism[MeSH Terms])ORpulmonaryembolism))OR((venousthrombosis[MeSH Terms])ORvenousthromboembolism)) Filters: publishedinthelast5years

EMBASE(N=26) cancer.mp ormalignantneoplasm/AND exp*venousthromboembolism/orexp*lungembolism/ANDexp*rivaroxabanorexp*dabigatranetexilate/orexp*dabigatran/orexp*apixaban/orexp*edoxaban/ANDexp*lowmolecularweightheparin/

CochraneCRCT(N=2)

cancer.mp orexp*neoplasms/ANDexp*venousthromboembolism/orexp*pulmonary embolismANDdabigatran.mp orapixaban.mp orrivaroxaban.mporedoxaban.mp ANDexp*heparin,low-molecular-weight/

Resultsspecific toPICO

2 RCTprotocols4Retrospectiveanalyses(2included)1Prospective cohort

Rossetal.2017Comparativeeffectivenessandsafetyofdirectoralanticoagulants(DOACs)versus

conventionalanticoagulationforthetreatmentofcancer-relatedvenousthromboembolism:aretrospectiveanalysis

P Cancerpatientswith anICD-9 diagnosisofVTE, treatedwithatherapeuticdoseofanticoagulantattheUniversityofTexasMDAndersonCancerCentreduring2014-2105

I Lowmolecular weightheparins

C DOACs (Apixaban orRivaroxaban)

O Primary:VTErecurrenceat6and 12monthsafterinitiationofanticoagulationSecondary:Clinicallyrelevantbleeding;eventfreesurvivalforVTErecurrence

Design Retrospectivecohortanalysis withelectronicmedicalrecorddata

Rossetal.Thromb Res2017;150:86-89.

Rossetal. 2017

formulations were asked to choose hypothetically between theirexisting treatment and an equally-effective oral agent. The majority ofpatients reported that they would choose the oral agent, but notedthat the most important factor regarding their treatment was efficacy[10].

The development of DOACs and their approval for the treatment ofVTE has resulted in the availability of several alternative options fortreatment that are likely to be better tolerated by patients, resulting inan improvement in quality of life [10]. In order to significantly alter clin-ical practice, newanticoagulants need to bedemonstrated to be as effec-tive as LMWH formulations at preventing VTE recurrence and as safe asLMWH formulations with regards to clinically relevant bleeding. Ouranalysis suggests that there is no significant difference in the rate ofVTE recurrence, clinically relevant non-major bleeding, or major bleed-ing when using oral DOACs versus subcutaneous LMWH. Our findingsare consistent with other reported studies describing that VTE is morecommonly found in malignancies of advanced stage [1], and mostoften in the form of a pulmonary embolismwith or without concurrentlower extremity deep venous thrombosis [4]. Catheter-associatedthrombosis was common, and this continues to represent an area of

potential research in the prevention of cancer-related VTE. Themajorityof cases of VTE in our study occurred in patients with stage III or IV dis-ease. This correlates with established data showing that cancers withthe highest one-year death rate and those that aremetastatic at presen-tation are most strongly associated with the incidence of VTE [1].

We found that the most cases of VTE recurrence presented withinthe first 3 months after the index event and the initiation ofanticoagulation. Similarly, clinically relevant hemorrhagic events oc-curred early during the course of treatment, regardless of the anticoag-ulant that was in use. Our findings are consistent with recentprospective data reporting on these outcomes [3,12]. The DALTECANstudy found that the rate of major bleeding in the first 12 months oftreatment with the LMWH agent dalteparin was 10.2%, and most

Table 1Baseline characteristics at the time of diagnosis of index VTE event.

LMWH DOAC Total ⁎P-value

N (%) 123 (80) 30 (20) 153Gender (%)

Female 56 57 56 1.000Age (Years)

Median (IQR) 58(47–67)

64(53–69)

59(48–68)

0.223

ECOG performance status (%)0–1 85 80 84 0.4472 13 20 143 2 0 2

Cancer statusActive 117 21 138 0.001Recent history 2 5 7Remote history (diagnosisN2 yr. prior)

4 4 8

Solid tumors (number ofpatients)Localized disease 10 3 13Locally advanced disease 32 15 47 0.098Distant metastatic 50 8 58

CNS lesions (%) 15 10 14 0.703Liver metastases (%) 17 10 16 0.415Tumor primary (%)

Breast 22 23 22 0.787Lymphoma/myeloma 15 17 16Leukemia 12 7 11Colon 4 10 5Lung 4 3 4

VTE index event (%)Pulmonary embolism±otherDVT

44 57 47 0.190

Catheter-associated 30 17 28Proximal lower limb 15 10 14Distal lower limb 5 17 7Non-catheter associated upperlimb

0 0 0

Platelet count (103 per uL)Median (IQR) 206

(132–309)222(177–336)

211(140–309)

0.808

Creatinine clearance (mL/min)Median (IQR) 85

(67–101)90(69–99)

85(67–100)

0.465

Coagulopathy (INR N 1.5 oraPTT N 1.5 ULN) (%)

5 3 5 0.795

Active chemotherapy (%) 58 3 53 0.024Antiangiogenic therapy (%) 2 3 2 0.483Recent surgery (major surgerywithin 2 weeks - %)

7 17 9 0.151

⁎ Two-tailed Exact Fisher Test or MannWhitney Wilcoxon Test when appropriate.

Table 2Bleeding complications.

Case#

Treatmentgroup

Major ornon-major

Tumor type Bleeding site Plateletcount

1 DOAC Non-major Peripheral nerve Gastrointestinal Unknown2 DOAC Major ADC

colon/rectumGastrointestinal 138,000

3 DOAC Major ADC breast Nasopharyngeal 195,0004 DOAC Major Lymphoma Intracranial Unknown5 DOAC Non-major Lymphoma Subcutaneous Unknown6 DOAC Major Osteosarcoma Genitourinary 198,0007 LMWH Non-major ADC small bowel Gastrointestinal 268,0008 LMWH Major Leukemia (CLL) Retroperitoneal 195,0009 LMWH Major ADC breast Intracranial 27,00010 LMWH Major Lymphoma Subcutaneous 81,00011 LMWH Major Neuroendocrine Gastrointestinal 43,00012 LMWH Major Primary brain Intracranial 211,00013 LMWH Non-major ADC breast Subcutaneous 392,00014 LMWH Major ADC breast Intramuscular Unknown15 LMWH Non-major MDS Dental 115,00016 LMWH Non-major ADC breast Nasopharyngeal 171,00017 LMWH Major ADC

colon/rectumSplenic artery 89,000

18 LMWH Major Giant cell bone Paraspinal 657,00019 LMWH Non-major ADC pancreas Gastrointestinal 210,00020 LMWH Non-major Urothelial Genitourinary 72,00021 LMWH Non-major ADC

colon/rectumGastrointestinal 205,000

22 LMWH Non-major Hepatobiliary Subcutaneous 286,00023 LMWH Major Hepatobiliary Paraspinal 29,00024 LMWH Major Ovarian Gastrointestinal 721,00025 LMWH Major Renal cell Intra-articular 140,00026 LMWH Non-major ADC colon/rectal Gastrointestinal 375,00027 LMWH Major Gestational

trophoblasticGenitourinary 224,000

28 LMWH Major Thyroid Subcutaneous 70,000

Fig. 2. VTE recurrence-free survival rates.

88 Correspondence

Intervention LMWH DOAC P value

VTE Recurrenceat6months 5.7% 3.3% P=1.000

VTERecurrenceat12months 8.1% 6.7% P=1.000

Major Bleed 11% 13% P=0.746

ClinicallyRelevant Non-MajorBleed 7.3% 6.7% P=1.000

N=30

N=123

P=0.697


Rossetal. 2017• Limitations

– Smallsamplesize– Large(vague)inclusioncriteria– Dosesundefined– Outcomesundefined– Differingbaselinepopulations

• BottomLine– Pragmatic– RatesofVTErecurrenceandbleedsreasonablysimilarinbothgroups


Alzghari etal.2017“Re-CLOTStudy”Retrospectivecomparisonoflowmolecularweightheparin vs.warfarinvs.oral

Xa inhibitorsforthepreventionofrecurrentvenousthromboembolisminoncologypatients:TheRe-CLOTstudy

P Cancerpatients18yearsorolder,treatedwithanticoagulantsforaVTE,fromJune2013-September2015.

I Enoxaparin

C Rivaroxaban,Apixaban, Warfarin

O PrimaryObjective:VTErecurrencewithin 3monthsSecondaryObjectives:VTErecurrenceafter 3months,mortalityandmajorbleedingwithin3monthsandbeyond

Design Retrospectivechartreview

Alzghari etal.JOncol PharmPract 2017;0(0):1-7.

Alzghari etal.2017“Re-CLOTStudy”

At three months after initial VTE occurrence, theVTE recurrence rates were similar between cohorts(Table 4). One patient presented with a recurrent

pulmonary embolism (PE) in the enoxaparin cohort(4.3%), two patients (one with a recurrent deepvenous thrombosis (DVT) and another with a recurrentPE) in the warfarin cohort (3.6%), and one DOACpatient presented with a recurrent DVT (2.1%).Fisher’s exact detected no significant difference wasdetected (p¼ 0.8319). At six months, the VTE recur-rence rate in the enoxaparin arm experienced a 13%compared to 5.4% with warfarin and 2.1% withDOAC (p¼ 0.73). When evaluating the VTE recur-rence during the entire data set, the DOAC cohorthad an 8.3% recurrence rate while the warfarin andenoxaparin cohorts 12.5% and 21.7%, respectively(Table 4). The median time to recurrence was 125days in the enoxaparin cohort compared with 210days with warfarin and 206 days with DOAC.Kaplan-Meier plot analysis showed no significant dif-ferences in VTE recurrence over time amongst the threegroups (Figure 1; p¼ 0.10)

In the warfarin patients with a goal INR of 2 to 3,the TTR at three months, six months, and the completedata set had a mean ("SD) TTR of 46.7%" 19.6,48.6%" 18.4, and 53.7%" 17.4, respectively.

Major bleeding rates are displayed in Table 5. Therate of major bleeding was highest in the warfarincohort (7.1%) compared to the DOAC or enoxaparincohorts, 6.3% and 4.4%, respectively (p¼ 1.000). Nopatient with brain metastases or a brain primary had amajor bleeding event.

Overall mortality is depicted in Table 5 in which thepatients in the enoxaparin arm experience a higher rateof death compared with the other arms. At three

Table 4. Recurrent venous thromboembolism.

Enoxaparin(n¼ 23),N (%)

Warfarin(n¼ 56),N (%)

DOAC(n¼ 48),N (%)

Recurrent VTE at 0–3 monthsTotal 1 (4.4) 2 (3.6) –

DVT 1

PE 1 1

Recurrent VTE at 0–6 monthsTotal 3 (13) 3 (5.4) 1 (2.1)

DVT 1 2 1

PE 1 1

DVT/PE 1

Recurrent VTE, 0 to >6 monthsTotal 5 (21.7) 7 (12.5) 4 (8.3)

DVT 2 5 3

PE 2 2 1

DVT/PE 1 – –

Time to recurrentVTE (days),median (range)

125 (86–628) 210 (63–990) 206 (94–312)

No statistically significant differences between the groups at three and sixmonths.DOAC: direct oral anticoagulants; VTE: venous thromboembolism;DVT: deep venous thrombosis; PE: pulmonary embolism.

0

0.0

0.2

0.4

Rec

urre

nce-

free

pro

babi

lity

0.6

0.8

1.0

10 20

Rivaroxaban/Apixaban

P = 0.10; log rank test

EnoxaparinWarfarin

30 40 50

Time to VTE recurrence (months)

60 70 80

Figure 1. Time to venous thromboembolism (VTE) recurrence.P¼ 0.10; log rank test

4 Journal of Oncology Pharmacy Practice 0(0)

Intervention Riv./Apix. Enoxaparin Warfarin PValue

VTE at3months%(n) 0%(0) 4.3% (1) 2.6% (2) P=0.8319

VTE>6 months%(n) 8.3%(4) 21.7% (5) 12.5%(7) P=0.100

MB>6months%(n) 6.2% (3) 4.2%(4) 7.1% (4) P=1.000

N=48(44rivaroxaban,4apixaban)N=23N=56

MB=majorbleed


Alzghari etal.2017“Re-CLOTStudy”• Limitations

– Smallsamplesize– Inclusioncriteria– Undefined(andmissing)outcomes– Dosesundefined– Warfarinoutoftherapeuticrange– Differingbaselinepopulation

• BottomLine– VTEratesforDOACsstillreasonablysimilartoenoxaparinandwarfarin


SummaryofEvidence

Rossetal.2017 Alzghari etal.2017

BottomLine • Similar ratesofVTEandbleeds• Lowqualityevidence

Relevance forED

• Appropriate population(CancerptswithVTE)• Appropriatecomparison(LMWHvsDOAC)• Insight intooutcomesofDOACvsLMWH

ClinicalTrialsintheWorks• Dalteparin vsRivaroxaban

– OC-11– CASTADIVA– PRIORITY

• Dalteparin vsApixaban– ADAM-VTE– CARAVAGGIO– Apixaban ordalteparin inreducingbloodclotsinpatientswithcancer

relatedvenousthromboembolism

• Dalteparin vsEdoxaban– CancerVenousThromboembolism

• Other– CONKO-011à LMWHsvsRivaroxaban– CANVASàLMWHsvsDOACs

AlternativesforED

• Consideringevidence(efficacy,safety),patientpreference,qualityoflifeinterminalillness…– Dalteparin 200units/kg(10,000units)subcut dailyx30days,then150units/kg(7500units)subcut daily

– Rivaroxaban15mgPOBIDx18days,then20mgPOdaily

RecommendationsforEDPrimaryDRP:• Dalteparin 10,000unitssubcut dailyx30days,then7500unitssubcut daily

SecondaryDRPRecommendations:• Painmanagementwithhydromorphoneandacetaminophen• Laxativeuseeducation• Constipationmanagementeducation• Restartmetoprolol37.5mgPOBID• MonitorforS/Sx oftendinopathies

MonitoringEfficacy Safety Frequency

CNS S/Sx ofPEAnxiety

Headtrauma(falls) Daily

RESP S/Sx ofPEDyspnea(RR),chestpain, cough

Daily

CV S/Sx ofPETachycardia(HR)

Daily

GI/GU Hematuria,hematemesis,melena,frankbloodinstool

Daily

MSK/SKIN Prolonged bleedingfromcutsornosebleeds,bruising,injectionsitehematoma/pain

Daily

Labs Thrombocytopenia (PLTs) Baseline, periodically

WhatHappened• Providededucationonthemedication• Cridge pharmacynursemakinghomevisitdailytoadministerdalteparin

• Attemptingfollowupcall

Questions

Mantha etal.2017Safeandeffectiveuseofrivaroxabanfortreatmentofcancer associatedvenous

thromboembolicdisease:aprospectivecohortstudy

P Cancer patientsattheMemorialSloan KetteringCancerCenterwithPEorsymptomaticproximalDVTwhowerestartedonrivaroxaban,fromJanuarytoMay2015

I Rivaroxaban15 mgPOBIDx3weeks,then20mgdailyfor6monthstotal(10mgPOBIDx3weeks,then15mgPOdailyif>75yearold)

C Nocomparator

O Efficacy:Recurrent VTESafety:Major bleeding,clinicallyrelevantnon-majorbleeding,deathfromanycause

Design ProspectiveCohortStudy

Mantha etal.JThromb Thrombolysis2017;43(2):166-171.

Mantha etal.20176Month CumulativeIncidenceEstimates(95%CI)

Outcome Recurrent VTE MajorBleed CRNMB<75yearsoldN=200 4.4%(1.4-7.4) 2.2%(0.0-4.2) 3.8%(1.0-6.5)≥75 yearsoldN=39 5.3%(0.0-12.1) 2.6% (0.0-7.4) 3.0%(0.0-8.7)

for 24 h. Rivaroxaban was not held in four cases: one was

a diagnostic endoscopy, and three were emergency proce-

dures. Documentation of rivaroxaban management was

unclear in one additional case.

No major bleeding episode occurred during the interrup-

tion of rivaroxaban, within 7 days of the procedure. Only

one patient developed a recurrent VTE following interrup-

tion for a procedure. That patient was a 52-year-old woman

with stage IV ovarian cancer who had multiple discontinu-

ations of rivaroxaban for debulking surgery and subsequent

abscess drainages. Three days after an abscess drainage,

prior to restarting rivaroxaban, she developed a symptom-

atic popliteal vein DVT. Of note, this patient was heterozy-

gous for both factor V Leiden and prothrombin G20210A,

with a history of multiple thromboses prior to her cancer,

and therefore was at particularly high risk for VTE.

Thrombocytopenia

There were 11 episodes of thrombocytopenia (platelets

<50,000/mcL) in ten patients (Table 2). Rivaroxaban was

held in seven episodes, and dose-reduced in one episode.

In three episodes rivaroxaban dose was not adjusted, two

of those cases only a single platelet count below 50,000/

mcL and one patient had already been on reduced dose of

rivaroxaban. There was no MB, CRNMB leading to drug

discontinuation, death or recurrent VTE associated with an

episode of thrombocytopenia.

Renal insufficiency

Transient renal insufficiency, as defined by a creatinine clearance of <30 mL/min (using Cockroft–Gault equation

[14]) was observed in seven episodes in five patients during rivaroxaban treatment (Table 2). Rivaroxaban dose was held

in two episodes, and not altered in five episodes. None of the patients experienced a major bleed, CRNMB, or recurrent

VTE event within 7 days of such an episode.

anticoagulation. The drug was stopped due to an upcom-

ing surgical procedure in eight cases (and not restarted), for

a medical reason in 18 cases, and following the patient’s

wishes in one case. Slightly more than half of patients (105

individuals) were observed for the full 6 months, with an

observation time range of 4–182 days for the whole cohort.

Additional events

Invasive procedures

There were 70 invasive procedures during the rivaroxaban

treatment period (Table 2). In 59 procedures rivaroxaban

was held for at least 48 h, and in six procedures it was held

Table 2 Management of rivaroxaban anticoagulation in the setting of thrombocytopenia, renal insufficiency, liver dysfunction and invasive pro-

cedures

Episodes of rivaroxaban interruption/

dose adjustments

Rivaroxaban

dose-reduced

Rivaroxa-

ban held

No change

in dosage

Major

bleeding

CRNMBa Recurrent

VTE

Death

or

hospice

Platelet count <50,000/mcL (N = 11) 1 7 3 0 0 0 0

Creatinine clearance <30 mL/min (N = 7) 0 2 5 0 0 0 1

Elevated liver enzymes (AST, ALT or bilirubin

>3 × upper limit of normal) (N = 18)

0 6 12 0 1 0 1

Interventionsb (N = 70) 0 65 4 0 0 1 3

aCRNMB leading to discontinuation of RivaroxabanbThe exact management approach is unknown in the case of one intervention

Fig. 1 Cumulative incidence for competing risks

Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease:… 169

123

Limitations:-Nocomparator-Selectionbias-Inclusioncriteria-Reduceddoseinelderly?

Mantha etal.JThromb Thrombolysis2017;43(2):166-171.

SummaryofEvidence

Rossetal.2017 Alzghari etal.2017 Mantha etal.2017

BottomLine • Similar ratesofVTEandbleeds

• Lowqualityevidence

• Similar ratesofVTEandbleeds

• Lowqualityevidence

• Recurrent VTE4.4%

• Bleeds2.2%• Lowquality

evidenceRelevanceforED

• Appropriate population(CancerptswithVTE)• Appropriatecomparison(LMWHvsDOAC)• Insight intooutcomesofDOACvsLMWH

a cancer clot conundrum...gi gerd+ esophagitis (2017) hiatus hernia diverticulosis msk/skin...

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