Target-Specific Oral Anticoagulants

Deborah Sturpe, PharmD, MA, BCPS

The speaker has no actual or potential disclosures to report.

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Session Goals

Compare and contrast the efficacy and safety of oral anticoagulant drugs

Select an oral anticoagulant that maximizes benefit-to-risk ratio for an individual patient

Recommend a plan for managing bleeding complications of oral anticoagulants

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TSOAC BASICSTarget Specific Oral Anticoagulants

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OAC Options and Mechanism of Action

Vit K Antagonist

Warfarin (Coumadin®)

Direct Thrombin Inhibitor

Dabigatran (Pradaxa®)

Factor Xa Inhibitor

Apixaban (Eliquis®)

Edoxaban (Savaysa™)

Rivaroxaban (Xarelto®)

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TSOAC Indications

Non-Valvular AFib

Acute VTE treatment

Recurrent VTE ppx

VTE ppx post hip/knee

replacement

Dabigatran ✔✔

(after 5-10 days parenteral tx)

✔

Apixaban ✔ ✔ ✔ ✔

Edoxaban ✔✔

(after 5-10 days parenteral tx)

Rivaroxaban ✔ ✔ ✔ ✔

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TSOAC Usual Dosing

Non-Valvular AFib

Acute VTE treatment

Recurrent VTE ppx

VTE ppx post hip/knee

replacement

Dabigatran 150 mg BID 150 mg BID 150 mg BID N/A

Apixaban 5 mg BID10 mg BID x 7 days, then 5 mg BID

2.5 mg BID 2.5 mg BID

Edoxaban 60 mg daily 60 mg daily N/A N/A

Rivaroxaban20 mg daily with evening meal

15 mg BID with food x 21 days, then 20 mg daily with food

20 mg daily with food

10 mg daily

Note that 15 mg and 20 mg rivaroxaban tablets must be taken with food, but 10 mg tablet does not.

Remember that dabigatran MUST remain in original packaging!

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TSOAC “Dosing Pains”Based on Patient Characteristics

Dabigatran

AFib

VTE

Do not use CrCl < 15 mL/minReduce dose to 75 mg BID if CrCl 15-30 mL/min

Do not use CrCl < 30 mL/min

Apixaban

AFib

VTE

Reduce to 2.5 mg BID if TWO of the following: Age ≥ 80 Scr ≥ 1.5 mg/dL Weight ≤ 60 kg (132 lbs)

No adjustments

Edoxaban

AFib

VTE

Do not use if CrCl < 15 mL/min or > 95 mL/minReduce dose to 30 mg daily if CrCl 15-50 mL/min

Do not use if CrCl < 15 mL/minReduce dose to 30 mg daily if CrCl 15-50 mL/min or weight ≤ 60 kg (132 lbs)

Rivaroxaban

AFib

VTE

Do not use if CrCl < 15 mL/minReduce dose to 15 mg daily with evening meal if CrCl 15-50 mL/min

No adjustments

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TSOAC “Dosing Pains”Based on Co-Administered Drugs

Dabigatran

Dronaderone or ketoconazole: If for AFib and CrCl < 30, do not use If for AFib and CrCl 30-50, reduce dose to 75 mg BID If for VTE and CrCl < 50, do not useRifampin – do not use (any indication)

Apixaban

Ketoconazole, itraconazole, ritonavir, or clarithromycin: If supposed to be on 2.5 mg BID, do not use If supposed to be on dose > 2.5 BID, reduce dose by 50% Rifampin, carbamazepine, phenytoin, or St. Johns’ wort Avoid use (any indication)

Edoxaban

Verapamil, quinidine, azithromycin, clarithromycin, erythromycin, itraconazole, or ketoconazole: If for VTE, reduce dose to 30 mg daily (no adjustment in AFib)Rifampin Avoid use

Rivaroxaban

Ketoconazole, itraconazole, ritonavir, indinavir, or conivaptan: Avoid useRifampin, carbamazepine, phenytoin, or St. Johns’ wort Avoid use (any indication)

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Are Prescribing Practices Appropriate?

Three publications (2 hospital, 1 outpatient) focusing on dabigatran and/or rivaroxaban

Total n = > 700 patients

High rates of inappropriate use in all reports (up to 50%)

Non-indicated conditions (especially valvular disease)

Use in those with CrCl below cutoffs or in those without data to calculate baseline CrCl

Wrong dose

Wrong administration

Concurrent heparin or LMWH

Larock AS et al. Ann Pharmacother 2014;48;1258-68.

Carley B et al. Am J Cardiol 2014;113:650-54.

Armbruster AL et al. Am Halth Drug Benefits 2014;7:376-84.

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Are Patients Adhering to Therapy?

National cohort (n = 5376) of Veterans Affairs patients started on dabigatran between Oct 2010-Sept 2012 for NVAF

28% of cohort non-adherent to therapy at 1 year (<80%)

Poor adherence associated with increased stroke and all-cause mortality

Shore S et al. Am Heart J 2014;167:810-17.

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CLINICAL DATATSOACs

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TSOAC – Major Clinical Trials

Non-Valvular AFibVTE Treatment /

Prevention

VTE ppx post hip/knee

replacement

Dabigatran RE-LYRE-COVERRE-MEDYRE-SONATE

N/A

ApixabanARISTOTLEAVERROES

AMPLIFY ADVANCE

Edoxaban ENGAGE AF-TIMI48 Hokusai VTE N/A

Rivaroxaban ROCKET-AF EINSTEIN RECORD

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Clinical TrialsDefinitions of Bleeding Outcomes

Major bleeding = accompanied by Hgb drop ≥ 2 gm/dL or transfusion of ≥ 2 units PRBC occurring at a critical site or resulting in death

Clinically relevant nonmajor bleeding = does not satisfy criteria for major bleeding, but does lead to hospitalization, physician intervention, and/or alteration in antithrombotic therapy

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TSOAC Atrial Fibrillation Trial CharacteristicsAPIX = apixaban DE = dabigatran etexilate EDOX = edoxabanRIVA = rivaroxaban VKA = vitamin K antagonist

ARISTOTLE RE-LY ENGAGE AF-TIMI48 ROCKET-AF

Treatment Arms of Interest

APIX 5mg (or 2.5) BIDWarfarin to INR 2-3

DE 150 mg BIDWarfarin to INR 2-3

EDOX 60 mg (or 30) dailyWarfarin to INR 2-3

RIVA 20 mg (or 15) dailyWarfarin to INR 2-3

Study Goal Non-inferiority Non-inferiority Non-inferiority Non-inferiority

Major Inclusion Criteria

Afib or AFlutter and at least one additional stroke risk factor

Afib and at least one additional stroke risk factor AFib with CHADS2 ≥ 2 AFib with CHADS2 ≥ 2

Major Exclusion Criteria

CrCl < 25 mL/minConcurrent ASA/Plavix

Increased bleeding riskCrCl < 30 mL/min

High bleed riskCrCl < 30 mL/min

High bleed riskCrCl < 30 mL/min

Baseline Characteristics

Median age 7035% female57% prior VKA use15% CrCl 30-50 mL/min30% CHADS2 ≥ 3

Median age 7137% female50% prior VKA use32% CHADS2 ≥ 3

Median age 7238% female59% prior VKA use23% CHADS2 4-6

Median age 7340% female62% prior VKA use87% CHADS2 ≥ 3

Granger CB et al. NEJM 2011;365:981-92. Connolly SJ et al. NEJM 2009;361:1139-51.

Patel MR et al. NEJM 2011; 365:883-91. Riugliano RP et al. NEJM 2013;369:2093-104.

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TSOAC Atrial Fibrillation ResultsEvent Rates per Year

ARISTOTLEMean TTR 62%

RE-LYMean TTR 64%

ENGAGE AF-TIMI48Mean TTR 65%

ROCKET-AFMean TTR 55%

Stroke or Systemic Embolism

Ischemic

Hemorrhagic

APIX Warfarin

APIX Warfarin

APIX Warfarin

1.27%*1.60%NNT 303

0.97%1.05%

0.24%*0.47%NNT 434

DEWarfarin

DEWarfarin

DEWarfarin

1.11%*1.69%NNT 172

0.92%*1.20%NNT 357

0.10%*0.38%NNT 357

EDOX§

Warfarin

EDOXWarfarin

EDOXWarfarin

1.18%*1.50%NNT 313

1.25%1.25%

0.26%*0.47%NNT 476

RIVAWarfarin

RIVAWarfarin

RIVAWarfarin

1.7%2.2%

1.34%1.42%

0.26%*0.44%NNT 556

Major Bleeding

Intracranial

Gastrointestinal

APIX Warfarin

APIX Warfarin

APIX Warfarin

2.13%*3.09%NNT 104

0.33%*0.80%NNT 213

0.76%0.86%

DEWarfarin

DEWarfarin

DEWarfarin

3.11%3.36%

0.30%*0.74%NNT 227

1.51%1.02%*NNH 204

EDOXWarfarin

EDOXWarfarin

EDOXWarfarin

2.75%*3.43%NNT 147

0.39%*0.85%NNT 217

1.51%1.23%*NNH 357

RIVAWarfarin

RIVAWarfarin

RIVAWarfarin

3.6%3.4%

0.5%*0.7%NNT 500

3.2%2.2%*NNH 100

Major or Clinically Relevant Bleeding

APIX Warfarin

4.07%*6.01%NNT 52

Not reported EDOXWarfarin

11.10%*13.02%NNT 52

RIVAWarfarin

14.9%14.5%

* = statistically superior at p < 0.05

§ In patients with CrCl > 95 mL/min, warfarin outperformed edoxaban in CVA reduction (edoxaban NNH 250)

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TSOAC Atrial Fibrilliation ResultsImpact of Time in the Therapeutic Range

Real-world time in therapeutic range (TTR) is only ~ 50%

10% improvement in TTR = 10% reduction in event rates

Event rates are highest at INR extremes (INR < 1.5 or > 5) with more than half of major events occuring in those in the bottom TTR quartile (10-20% TTR)

Published data showing no impact of TTR on superiority of dabigatran and rivaroxaban are criticized for examing center TTR (cTTR) as opposed to individual TTR (iTTR)

Dlott JS et al. Circulation 2014;129:1407-14. White HD et al. Arch Int Med 2007;167:239-45.

Jones M et al. Heart 2005;91:472-77. Veeger NJ et al. J Thromb Haemost 2006;4:1625-27.

Wallentin L et al. Lancet 2010;376:975-83. Piccini JP et al. J Am Heart Assoc 2014;3:e000521.

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Re-examining RE-LY and ARISTOTLEEvent Rates/Year Based on iTTR

Bussey HI. http://www.clotcare.com/warfarin_vs_dabigatran.aspx

WarfarinAll quartiles

Warfarin iTTR > 67%1st and 2nd quartile

Warfarin iTTR < 53%4th quartile

Dabigatran 150 mg BID

Stroke or Systemic Embolism 1.69% 1.3% 2.2% 1.11%

Major Bleeding 3.36% 2.7% 4.6% 3.11%

For composite outcome of stroke, systemic embolism, major bleeding and death versus 4th

quartile warfarin:

• Dabigatran NNT 20

• Warfarin 1st

-2nd

quartile NNT 15

Favor apixaban Favor warfarin

Wallentin L et al. Circulation 2013;127:2166-2176.

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TSOAC “Acute” VTE Trial Characteristics

AMPLIFY(6 months duration)

RE-COVER(6 months duration)

Hokusai(3-12 months)

EINSTEIN & EINSTEIN-PE(3, 6, or 12 months)

Treatment Arms of Interest

APIX 10 mg BID x 7 days, then 5 mg BID Enox + Warfarin to INR 2-3

≥ 5 day parenteral tx and INR ≥ 2.0, then:DE 150 mg BIDWarfarin to INR 2-3

≥ 5 day parenteral tx and INR ≥ 2.0, then:EDOX 60 mg (or 30) dailyWarfarin to INR 2-3

RIVA 15 mg BID x 21 days,

then 20 mg dailyEnox + VKA to INR 2-3

Study Goal Non-inferiority Non-inferiority Non-inferiority Non-inferiority

Major Inclusion Criteria DVT or PE Unprovoked DVT or PE DVT or PE

Confirmed DVT w/o PE (EINSTEIN)Confirmed PE w/ or w/o DVT (EINSTEIN-PE)

Major Exclusion Criteria

High bleed riskIVC filterPotent CYP3A4 inhibitorsCrCl < 25 mL/min

High bleed riskIVC filterPE + hemodynamic issuesCrCl < 30 mL/min

High bleed riskIVC filterCrCl < 30 mL/min

High bleed riskIVC filterStrong CYP3A4 drugsCrCl < 30 mL/min

Baseline Characteristics

Median age 5761% female65% DVT25% PE9% DVT + PE16% previous VTE2.5% thrombophilia10% provoked

Median age 5542% female69% DVT21% PE10% DVT + PE25% previous VTE

Mean age 5643% female60% DVT30% PE10% DVT + PE18% previous VTE28% provoked

Mean age 56 and 5843% and 48% female25% co-DVT/PE (PE study)19% previous VTE6.5% and 5% thrombophilia40% and 36% provoked

.Agnelli G et al. NEJM 2013;369:799-808. Schulman S et al. NEJM 2009;361:2342-52.

Hokusai-VTE. NEJM 2013;369:1406-15. EINSTEIN. NEJM 2010;363:2499-510 EINSTEIN-PE. NEJM 2012;366:1287-97.

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TSOAC “Acute” VTE StudiesEvent Rates

AMPLIFYTTR 61%

RE-COVERTTR 60%

Hokusai§

TTR 63.5%EINSTEIN⌃ (TTR 57.7%)

EINSTEIN-PE⌘ (TTR 62.7%)

Recurrent VTE or VTE-related Death

APIX Warfarin

2.3%2.7%

DEWarfarin

2.4%2.1%

EDOXWarfarin

3.2%3.5%

EINSTEINRIVAWarfarin

EINSTEIN-PERIVAWarfarin

2.1%3.0%

2.1%1.8%

Major Bleeding APIX Warfarin

GI: APIX GI: Warf

0.6%*1.8%NNT 83

0.3%0.7%

DEWarfarin

GI: DEGI: Warf

1.6%1.9%

53 events35 events

EDOXWarfarin

1.4%1.6%

EINSTEINRIVAWarfarin

EINSTEIN-PERIVAWarfarin

0.8%1.2%

1.1%*2.2%NNT 91

Major or Clinically Relevant Bleeding

APIX Warfarin

4.3%*9.7%NNT 19

DEWarfarin

5.6%*8.8%NNT 31

EDOXWarfarin

8.5%*10.3%NNT 55

EINSTEINRIVAWarfarin

EINSTEIN-PERIVAWarfarin

8.1%8.1%

10.3%11.4%

* = statistically superior at p < 0.05

§ = 12% treated x 3 months, 26% treated x 3-6 months, 62% treated > 6 months (with 40% reaching 12 months)

⌃ = 12% treated x 3 months, 63% treated x 6 months, 25% treated x 12 months

⌘ = treated x 3 months, 57% treated x 6 months, 38% treated x 12 months

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TSOAC VTE Extension Trial Characteristics

AMPLIFY EXT(12 months)

RE-MEDY(6-36 months)

EINSTEIN EXT(6 or 12 months)

ELATE(mean 2.4 years)

Treatment Arms of Interest

APIX 2.5 mg BIDPlacebo

DE 150 mg BIDWarfarin to INR 2-3

RIVA 20 mg dailyPlacebo

Warfarin to INR 1.5-1.9Warfarin to INR 2-3

Study Goal Superiority Non-inferiority Superiority Non-inferiority (efficacy)Superiority (safety)

Major Inclusion Criteria

DVT and/or PE and Already tx for 6-12 monthsNo recurrent eventsClinical equipoise to cont tx

DVT and/or PE and Already tx for 3-12 monthsInvestigators deemed patient at increased risk for recurrence

DVT and/or PE andAlready tx for 6-12 monthsClinical equipoise to cont tx

Unprovoked VTE andAlready tx ≥ 3 months

Major Exclusion Criteria

High bleed riskDocumented thrombogenic mutationCrCl < 25 mL/min

High bleed riskIVC filter

High bleed riskIVC filterStrong CYP3A4 drugsCrCl < 30 mL/min

High bleed riskAPLA positive

Baseline Characteristics

Mean age 5742% female91.5% unprovoked VTE13% previous VTE

Mean age 54.539% female18% known thrombophilia

Mean age 5842% female73.5% unprovoked VTE16% previous VTE8% known thrombophilia

Mean age 5745% female70% previous VTE26% Factor V Leiden10% prothrombin mutation

.Agnelli G et al. NEJM 2013;368:699-708. Schulman S et al. NEJM 2013;368:709-18.

EINSTEIN. NEJM 2010;363:2499-510. Kearon C et al. NEJM 2003;349:631-9.

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TSOAC Extended VTE StudiesEvent Rates

AMPLIFY EXT RE-MEDYTTR 65.3% EINSTEIN-EXT§

ELATETTR 63% for low-intensity

TTR 69% for usual-intensity

Recurrent VTE or VTE-related Death

APIX Placebo

1.7%*8.8%NNT 14

DEWarfarin

1.8%1.3%

RIVAPlacebo

1.3%*7.1%NNT 17

Low intensityUsual intensity

1.9%0.7%*NNH 83

Major Bleeding APIX Placebo

0.2%0.5%

DEWarfarin

0.9%1.8%

RIVAPlacebo

0.7%0.0%

Low intensityUsual intensity

1.1%0.9%

Major or Clinically Relevant Bleeding

APIX Placebo

3.2%2.7%

DEWarfarin

5.6%*10.2%NNT 22

RIVAPlacebo

6.0%1.2%*NNH 21

N/A

* = statistically superior at p < 0.05

§ = 60% treated x 6 months, 40% treated x 12 months

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Additional Safety ConcernAcute Coronary Events and Dabigatran

Across all clinical trials, dabigatran does appear to result in statistically higher rates of acute coronary events compared to warfarin (odds ratio ~ 1.3 to 1.4)

Events have been noted in “real world” after patients switched from warfarin to dabigatran

Trend seen with most direct thrombin inhibitors (not observed to date with Factor Xa inhibitors)

Unknown if direct thrombin inhibitors actually harmful or if warfarin simply more effective

Anticipate that this will be an area of continued surveillance for all TSOACs

.Loke YK et al. Br J Clin Pharmacol 2014;78:707-17. Uchino K et al. Arch Intern Med 2012;172:397-402.

Bjerregaard T et al. Am J Med 2014;127:329-36. Davidson BL. CHEST 2015;147:21-24.

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Reversal & Treatment Strategies for Acute Major Bleeding

Oral Anticoagulants

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A ReviewAvailable Clotting Factor Supplements

Holbrook A et al. CHEST 2012;141(2)(Suppl):e152S-e184S.

PCC4 PCC3 aPCC FFP

Advantages

Contains inactivated factors II, VII, IX, and X

More rapid/complete VKA reversal compared to FFP

Contains inactivated factors II, IX and X

Contains activated factor VII and inactivated factors II, IX, and X

Contains all vitamin-K dependent clotting factors

Disadvantages Expensive ExpensiveLittle to no factor VII

ExpensiveMost prothrombotic

Potential for allergyPotential for infectionPreparation timeHigh volume

Available US Products Kcentra® Bebulin® VH

Profilnine® SD FEIBA NF NA

PCC = prothrombin complex concentrate FFP = fresh frozen plasma

TSOAC Issues:

• No antidotes (yet)

• FFP does not work (TSOAC simply inhibits what is being replaced)

• PCC may work (by hitting system with supraphysiologic levels of clotting factor) but data is scare and mostly from animal models or in vitro studies

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Approaches to Life-threatening Bleeding

Nutescu EA et al. Am J Health-Syst Pharm 2013;70:1914-29.

VKA Direct Thrombin Inhibitor Factor Xa Inhibitor

Hold drug

Vitamin K 10 mg IV (to sustain options below)

Clotting factor supplement (listed in order of preference)• PCC4• aPCC• PCC3• FFP

Hold drug

Activated charcoal if last dose taken within 2 hours

Hemodialysis

Clotting factor supplement (listed in order of preference)• aPCC• PCC4

Hold drug

Activated charcoal if last dose taken within past 2 hours

Clotting factor supplement (listed in order of preference)• PCC4• aPCC• PCC3

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Putting It All TogetherOral Anticoagulants

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Reasonable Conclusions TSOACs versus Warfarin

Would reserve TSOACs for patients with similar characteristics to those enrolled in clinical trials until more data available

Would be cautious using TSOACs in those with renal impairment

Would avoid TSOACs in patients who have demonstrated poor adherence with past medications

Would avoid TSOACs in patients who have high(er) baseline bleeding risk until antidotes are available

.

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Reasonable Conclusions TSOACs versus Warfarin cont.

TSOACs may be preferred over warfarin for treating AFib in those with poor INR control

Warfarin likely remains drug of choice for treating AFib in those with good INR control

TSOACs appear to be equally effective to enoxaparin/warfarin in treating VTE (“acute” and chronic)

TSOACs appear to have overall lower bleeding events compared to warfarin, but

Incidence of GI bleeding higher with many TOASCs comapred to warfarin

.

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Reasonable Conclusions Selecting Between TOASCs

.

Narrow down choices based on CrCl, concurrent medications, ability to adhere to BID regimens, and formulary status

Apixaban may have an edge over the other TSOACs in terms of GI bleed risk

For AFib, would lean to apixaban or dabigatran

Rivaroxaban not superior to warfarin

Edoxaban cannot be used in those with normal renal function

For VTE, would lean to apixaban or rivaroxaban (do not require parenteral therapy first)

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Questions?Thanks for attending!