Drug, Duration and Dose

Michael B Streiff, MD FACP

Professor of Medicine and Pathology

Medical Director, Johns Hopkins Anticoagulation Service

Johns Hopkins Comprehensive Hemophilia Treatment Center

Chairman, VTE Guideline Committee for the National Comprehensive Cancer Network

Disclosures- Michael B. Streiff, MD

• Research support

– AHRQ

– Boehringer-Ingelheim

– Janssen

– NIH/NHLBI

– PCORI

– Portola

– Roche

• Consulting

– Bayer

– CSL Behring

– Daiichi-Sankyo

– Janssen

– Pfizer

– Portola

• Educational Grants

– Covidien

Why we need warfarin- Body weight

• Nearly 40% of US adults were obese in 2014 (Ogden CL, et al. NCHS

Data Brief, No. 219. 2015)

• Limited number of patients with extremes of body weight in DOAC RCTs (De Caterina R Clin Card Res 2017)

• Weight > 100 kg associated with 2-fold risk of recurrent VTE in RECOVER pooled analysis (Schulman S Circulation 2014)

• Real world survey of 1353 Afib DOAC pts. noted low weight pts. 4-fold higher risk of major bleed (Park CS Heart Rhythm 2016)

• DOAC peak plasma levels below 5th percentile in 21 percent of patients with weight > 120 kg (Piran S et al RPTH 2018)

• ISTH SSC Guidance document suggests DOACs should not be used in patients > 120 kg or BMI > 40 kg/M2 (Martin K et al. JTH

2016)

Why we need warfarin- Renal Disease

• All DOACs cleared to some extent by kidneys

• DOAC drug levels increase with decreasing renal function

• Patients with poor renal function excluded from the RCTs of DOACS in VTE

– Only 5-8% of participants had CrCl 30-50 ml/min

• Apixaban has been associated with equivalent bleeding and lower thromboembolism in AF

– Retrospective cohort not an RCT

Fanikos J et al Am J Med 2017; Sionitis K et al Circulation 2018

Why we need warfarin-Antiphospholipid syndrome

• Prospective RCT in triple positive APS

• Riva 20 mg (15 mg CrCl 30-50) v. warfarin (INR 2-3)

• Rivaroxaban associated excess TE

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0 100200300400500600700800

Thro

mb

oe

mb

olis

m, M

ajo

r B

leed

, or

V

ascu

lar

Dea

th (

%)

Days

Riva (N=59) Warf (N=61)

Pengo V et al Blood 2018

HR 7.4

(95% CI 1.7-33)

P=0.008

Why we need warfarin

• Liver disease

– Patients with elevated AST/ALT/T Bili or Child-Pugh Class B/C excluded from RCTs

• Bariatric surgery

– DOACs absorbed in stomach and small bowel

• Gastrointestinal Bleeding

• Poor Adherence

• Cost

Martin K et al Am J Med 2017

Duration: Less is more for most

• Classification of Venous Thromboembolism:

– Unprovoked vs. Provoked

– Provoked: Transient vs. persistent risk factor

• A substantial proportion events provoked (Heit JA et

al Arch Intern Med 2002; White RH et al Ann Intern Med 1998; Albertsen IE et al. Am J Med 2018 )

41

25

1518

05

1015202530354045

Perc

ent

White RH et al Ann Intern Med 1998

N=23,564

Transient risk factors associated with low risk of recurrence

• Metaanalysis of 15 RCT or observational studies

• Follow up 12- 24 months

• Recurrent VTE

– Provoked 3.3% per pt.-yr

– Unprovoked 7.4% per pt-yr

• Limited duration of therapy appropriate for most patients with provoked VTE

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4.2

7.4

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7

8

Re

curr

en

t V

TE (

% p

er

pat

.-yr

)

N=5159

Iorio A et al Arch Intern Med 2010

Not all idiopathic VTE recur

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60

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Re

curr

en

t V

TE (

%)

Follow Up (years)

Ridker, 2003

Prandoni, 2007

Eichinger,2010

Ridker P et al. NEJM 2003; Prandoni P et al. Haematologica 2007; Eichinger S et al. Circulation 2010

Bleeding is more deadly then VTE

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RecurrentUnprovoked VTE

Unprovoked VTE MedicallyProvoked VTE

SurgicallyProvoked VTE

Perc

ent

Recurrent VTE Major Bleeding

Case Fatality Rate of Bleeding 3 fold higher than VTE!

Rodger M Hematology 2018; Iorio A et al. Arch Intern Med 2010;

Wu C et al. Thromb Res 2014; Carrier M et al Ann Intern Med 2010

Real World Outcomes Worse than RCT Outcomes

• Retrospective cohort from US 2014-2016

• New diagnosis of VTE starting riva or apix

• In comparison to clinical trial populations, significantly higher events rates

• Real World Outcome rates > RCT rates

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Even

ts (

pe

r 1

00

pt-

yr)

Real World Trial

Dawwas GK et al Lancet Hematology 2019; Wu C et al Thromb Res 2014

Rivaroxaban Apixaban

VTE Duration of Therapy

• Recurrent unprovoked VTE, Antiphospholipid syndrome and other strong thrombophilia-long term therapy

• Cancer-associated VTE- duration of the cancer and its treatment

• First Unprovoked VTE- Assess risk of bleeding and recurrent VTE

• Provoked VTE- limited duration therapy

HERDOO2 Prediction Rule

• Derived in multicenter cohort of 665 unprovoked VTE pts.

• Low risk women = 1.6% per year vs. High risk women = 14.1% per year

• Recurrent VTE risk in men varied from 3.4% to 19.9% per year

• H = Hyperpigmentation (1 pt.)

• E= Edema (1 pt.)

• R=Redness (1 pt.)

• D= D dimer ≥ 250 mcg/L (1 pt.)

• O = Obesity (BMI ≥ 30) (1 pt.)

• O = Older age (≥ 65 yrs.) (1 pt.)

Low Risk 0-1 pt. High risk ≥ 2 pts.

Rodger M et al Can Med Assoc Journal 2008; Rodger M et al BMJ 2017

The DASH VTE prediction model

• Based upon meta-analysis of 1818 pts. from 7 studies

• DASH = abnormal Ddimer (2 pts.), Age ≤50 (1 pt.), male Sex (1 pt.) and Hormonal therapy (-2 pts.)

• The DASH score can be used to assess VTE recurrence risk

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um

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tive

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urr

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VTE

at

2 y

ears

(%

)

DASH point score

Derivation Validation

C-statistics: 0.54 for subjects aged > 65 years

versus 0.72 for subjects aged ≤ 65 years).

Tosetto A et al. JTH 2017

The Vienna Prediction Model

• Prospective cohort of 929 pts. with unprovoked VTE

• F/U 43 months

• Multivariate predictors: Sex, DVT v. PE, D dimer, Peak TG

• The Vienna Model can help estimate recurrence risk

Eichinger S, et al. Circulation. 2010

Version 2: https://cemsiis.meduniwien.ac.at/en/kb/science-

research/software/clinical-software/recurrent-vte/#calc-

params

Risk Stratification for Recurrent VTE: The Vienna Prediction Model

Eichinger S, et al. Circulation. 2010

Bleeding Risk Assessment: VTE-BLEED assessment model

• Bleeding RAM derived from RECOVER studies

• Predicts bleeding in AC pts. beyond 1 month

• Low risk (< 2 pts.) 2.8% v. high risk 12.6%

• Validated in Hokusai VTE and XALIA

• May be useful to identify pts. at risk for bleeding

Predictor Points

Active cancer 2

Anemia (Hgb < 12) 1.5

Hx/o Bleeding 1.5

CrCl 30-60 ml/min 1.5

Age ≥ 60 1.5

Male with HTN 1

Klok FA Eur Respir J 2016; Klok FA Thromb Haemost 2017; Kolk FA Brit J Haematol 2018

DOSE: Is low dose better than standard dose?

• RCT of low (INR 1.5-2) versus standard intensity (INR 2-3) for unprovoked VTE

• Duration of therapy- 2.4 years

• Low dose associated with higher recurrent VTE and similar bleeding

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Even

ts p

er 1

00

pt.

-yea

rs

INR 1.5-2 INR 2-3

P=0.03

Kearon C et al NEJM 2003

Low dose and standard dose rivaroxaban have similar outcomes• DB-RCT of riva (10 mg

or 20 mg) vs. aspirin for extended treatment after 6-12 mos. of AC

• Median Follow up 351 days

• Low and standard dose rivaroxaban have similar outcomes

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Recurrent VTE Major Bleed

Ou

tco

mes

(%

)

Riva 20 mg (N=1107) Riva 10 mg (N=1127)

HR 1.23(0.37–4.03)

Weitz JI et al. N Engl J Med 2017

HR 1.34(0.65–2.75)

No difference in outcomes with low-dose apixaban

• DB-RCT of apixaban vs. placebo for extended treatment of VTE

• Duration 1 year

• No difference in bleeding or recurrent VTE with low dose versus standard dose apixaban

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Recurrent VTE Major or CRNMBleed

Even

ts (

%)

Apixaban 5 mg (N=813)

Apixaban 2.5 mg (N=840)

Agnelli G et al NEJM 2012

RR 0.74

(0.46-1.22)

Conclusions

• Drug:

– Don’t give up on warfarin

• Duration:

– Most patients do not benefit from indefinite anticoagulation

– Select patients for discontinuation with RAM

• Dose:

– No evidence that low dose safer than standard dose

Questions ?