Novel Oral Anticoagulant Agents: An Update in Pharmacotherapy

David Stewart, PharmD, BCPSAssociate Professor of Pharmacy Practice

East Tennessee State UniversityBill Gatton College of Pharmacy

stewardw@etsu.edu

Disclosures

Speaker’s Bureau for:Boehringer-Ingelheim Pharmaceuticals

Janssen Pharmaceuticals

At the conclusion of this program, the audience should be able to:

• List the new oral anticoagulant medications currently approved or in the approval process by the United States Food and Drug Administration

• Communicate basic principles of pharmacokinetics to other healthcare providers

• Identify appropriate indications for the use of new oral anticoagulant medications

• Develop patient specific plans utilizing newly approved oral anticoagulant agents for the treatment and prevention of venous thromboembolic events in various patient populations

Anticoagulant Timeline

1943Heparin

1954Warfarin

2010Dabigatran

2011Rivaroxaban

2012Apixaban

Rivaroxaban & Apixaban

Coagulation Cascade

XII XIIa

XI XIa

IX IXa

VIIa

Intrinsic Pathway (PTT) Extrinsic Pathway (PT)

XaX

VIII

II IIa

XIII

Fibrinogen Fibrin

XIIIa

Warfarin

Dabigatran

Va

VII

Summary TableParameter Apixaban Dabigatran RivaroxabanTarget Protein Factor Xa Thrombin (IIa) Factor Xa

Pro-Drug No Yes (etexilate) No

1˚ Elimination CYP3A4/P-gp Renal CYP3A4/P-gp

Renal Adjustment Avoid < 15 ml/min ↓ 15-30 ml/minAvoid < 15 ml/min

↓ 15-50 ml/minAvoid < 15 ml/min1

Drug-Drug Interact. CYP3A4/P-gp P-gp CYP3A4/P-gp

Onset of activity 3-4 hrs 1-2 hrs 2-4 hrs

t½ 8-15 hrs 12-18 hrs 5-9 hrs

Dosing interval Twice daily Twice daily Daily

Measuring tests PT/Anti-factor Xa ECT, TT, +/- aPTT PT/Anti-factor Xa

1Indication Specific. For VTE no adjustment and avoid use < 30 ml/min.

Measuring Dabigatran

Thromb Haemost 2010;103:1116-27.

Measuring Rivaroxaban & Apixaban

• Role of aPTT & PT/INR• Anti-Xa Assays– Chromagenic anti-Xa assays may be useful• Different assays vary in sensitivity• Must calibrate standard curve based on drug

concentration

– HepTest® accurate when modified for rivaroxaban (and likely apixaban)• Incubation period too long• Modified HepTest® may be useful

Ther Drug Monit 2010;32:673-9.

Measuring Rivaroxaban

J Thromb Haemost 2011;9:133-9.

aPTT not sensitive

PT is sensitive (Don’t rely on INR)

Highlights peak concentrations

Reversal of New Anticoagulants• Universal Xa antidote (PRT4445) in Phase 2 trials• FFP

– No data, unclear/unknown benefit• 3 factor PCC

– Unknown• 4 factor PCC

– Reverse rivaroxaban but not dabigatran (not available in US)• aPCC

– Baboon data showed transient reversal of rivaroxaban• Recombinant Factor VIIa

– Case reports only• Risk of arterial thrombosis

– All PCC’s and RFVIIa increase the risk of arterial thrombotic events in non-hemophiliac patients

– Must weigh potential risks with potential benefits• These effects may all be only transient

Portola Pharmaceuticals. Press Release: 10 December 2012. Am J Hematol. 2012;84:S141-5. Am J Health-Syst Pharm. 2012;69:1473-84. Circulation. 2011;124:1573-79.

Issues with New Anticoagulants

Summary of Afib Data

Apixaban(ARISTOTLE)

Dabigatran(RE-LY)

Rivaroxaban (ROCKET – AF)

# Patients > 18,000 > 18,000 > 14,000

Mean CHADS2 ≈ 2 ≈ 2 ≈ 3.5

TTR 62% 64% 55%

Efficacy vs. VKA Superior Superior1 Non-Inferior

Bleeding2 vs. VKA Decreased Similar Similar

1Dabigatran 150 mg BID group. 2Major bleeding per study design.

New Engl J Med 2009;DOI:10.1056/NEJMoa0905561. New Engl J Med 2011;DOI:10.1056/NEJMoa1009638. New Engl J Med 2011;DOI:10.1056/NEJMoa1107039.

Treatment of VTEApixaban Dabigatran Rivaroxaban

Comparator(s) Placebo Warfarin/Placebo Warfarin/PlaceboTreatment Type Chronic Acute/Chronic Acute/ChronicAcute Results N/A ≈ warfarin ≈ warfarinChronic Results > Placebo (both

doses)≈ warfarin &

> placebo > placebo

Follow-Up 12 months Up to 36 months Up to 24 monthsBleeding Outcomes (Acute) N/A ≈ warfarin ≈ warfarin

Bleeding Outcomes(Chronic)

≈ or > placebo (dose dependent)

< warfarin &> placebo > placebo

N Engl J Med 2012;DOI:10.1056/NEJMoa1113572. N Engl J Med 2010;DOI:10.1056/NEJMoa1007903. N Engl J Med 2009;DOI:10.1056/NEJMoa0906598. N Engl J Med 2013;368:699-708. N Engl J Med 2013;368:709-18.

Summary of Acute VTE Treatment Data

Dabigatran(RE-COVER)

Rivaroxaban(EINSTEIN)

# Patients > 2,500 > 3,400

Treatment Duration 6 months 6 months

Initial Therapy1 LMWH Rivaroxaban

TTR 60% 58%

Efficacy vs. VKA Non-Inferior Non-Inferior

Bleeding vs. VKA Similar Similar

VTE Type DVT & PE DVT & PE

1Initial therapy in study group, both studies “bridged” control group.

New Engl J Med 2012;DOI:10.1056/NEJMoa1113572. New Engl J Med 2010;DOI:10.1056/NEJMoa1007903. New Engl J Med 2009;DOI:10.1056/NEJMoa0906598.

Summary of Orthopedic VTE Data1

Comparator Apixaban(2.5 mg q12h)

Dabigatran(150 or 220mg/day)

Edoxaban(30 mg/day)

Rivaroxaban(10 mg/day)

Enoxaparin40 mg daily Superior Non-Inferior --- Superior

Enoxaparin20 mg q12h --- --- Superior ---

Enoxaparin30 mg q12h Non-Inferior Inferior --- Superior

Bleeding vs. Enoxaparin Similar Similar Similar Similar

1Includes patients undergoing both TKA and THA. Most studies excluded patients with CrCl < 30 ml/min.

Summary of these data available in: Pharmacother 2011;31:1175-91.

Additional Therapeutic Uses

• VTE Prophylaxis in Medical Patients– Only evaluated in extended durations vs. enoxaparin– No benefit for extended prophylaxis

• Acute Coronary Syndrome– Apixaban significantly increased risk of bleeding– Rivaroxaban (evaluated 2.5 mg and 5 mg BID)

• Primary Endpoint (CV Death, MI or CVA) showed benefit• TIMI Major Bleeding higher with rivaroxaban• Intracranial Hemorrhage higher with rivaroxaban

New Engl J Med 2011;365:2167-77. New Engl J Med 2012;366:9-19.New Engl J Med 2011 Online;DOI:10.1056/NEJMoa1110899.

Dabigatran and Myocardial Infarction

• Meta-analysis (January 2012)– 30,514 patients included– Multiple indications/populations– Dabigatran vs. Warfarin

• MI– RR: 1.33 (1.03-1.71); AR: 0.40%

• Mortality– RR: 0.89 (0.80-0.99); AR: 0.19%

• Long-term VTE Treatment• Dabigatran vs. Warfarin

– RR: 4.5 (13 events vs. 3 events); p = 0.02

Arch Intern Med. Online Jan 9, 2012;DOI:10.101/archinternmed.2011.1666. N Engl J Med 2013;368:709-18.

Use of Concomitant Antiplatelet Agents in Afib Studies

AntiplateletAgents

ARISTOTLE(Apixaban)

RELY(Dabigatran)

ROCKET-AF(Rivaroxaban)

ASA < 165 mg/day Yes < 100 mg/day

Clopidogrel Yes Yes Yes

Combination No Yes No

Aspirin Use (%) 31% 40% 36%

New Engl J Med 2009;361:1139-51. New Engl J Med 2011;365:883-91. New Engl J Med 2011;365:981-92.

Trials for other indications were similar.

Warfarin + ASA + Clopidogrel• Triple therapy

– Assumed appropriate for many patients post PCI– Lack of data to support use or non-use

• Until now – the WOEST Study– Clopidogrel + Warfarin vs. Clopidogrel + Warfarin + ASA– Patients on warfarin undergoing PCI– ≈ 65% DES– Primary Endpoint – Any bleeding event

• Any bleeding Event – HR (95% CI): 0.36 (0.26-0.50)• TIMI Major – HR (95% CI): 0.56 (0.25-1.27)• TIMI Major and minor – HR (95% CI): 0.40 (0.27-0.58)

– Secondary Endpoint – Composite of death, MI, CVA, Target-vessel revascularization, and stent thrombosis• Lower event rate in DOUBLE therapy group (p = 0.025)• All-cause mortality individually lower• Cardiac death, Any MI, STEMI, NSTEMI, CVA all numerically lower in DOUBLE therapy group

– Main limitation is open-label designLancet online early February 13, 2013 – DOI: 10.1016/S0140-6736(13)60054-9.

Take Home Points for Providers• Several new options currently or will exist to replace warfarin• Current approved indications include:

– Prophylaxis of VTE in orthopedic patients– Prevention of stroke in patients with Afib– Acute and chronic treatment of VTE

• Adverse event rates are high when not used/dosed appopriately• Agents vary based on various pharmacologic and pharmacokinetic

parameters– None of the new agents require monitoring– Would base choice of agent on patient specific factors– All of them can be “measured” if needed– Best technique for reversal is unknown for most at this time but likely is either

expensive, locally unavailable, or both• Cost will be a limitation if not covered by insurance

FDA Approved DosingParameter Dabigatran Rivaroxaban ApixabanDosing

Non-valvular Atrial fibrillation

150 mg BID(CrCl > 30 ml/min)

75 mg BID(CrCl 15-30 ml/min)

20 mg QD(CrCl > 50 ml/min)

15 mg QD(CrCl 15-50 ml/min)

5 mg BID(2.5 mg BID if age ≥ 80, weight ≤ 60 kg, or SCr ≥ 1.5 mg/dl)

Orthopedic VTE Px N/A 10 mg QD N/A

Treatment DVT/PE N/A20 mg QD X 21 days, then 15 mg QD (CrCl

≥ 30 ml/min)N/A

Timing of DoseAnytime

(With or Without Food)

15, 20 mg Dose – With Food

10 mg Dose – Anytime

Anytime(With or Without

Food)

Patient Education

• Dabigatran– Store in original container– Discard opened product after 4 months– Dyspepsia most common side effect (up to 30%)– Do not open capsule– Comprehensive Patient Guide Available Online1

• Rivaroxaban– Take with food

1Circ 2011;124:e209-e211. (DOI: 10.1161/CIRCULATIONAHA.111.019786)

Novel Oral Anticoagulant Agents: An Update in Pharmacotherapy

David Stewart, PharmD, BCPSAssociate Professor of Pharmacy Practice

East Tennessee State UniversityBill Gatton College of Pharmacy

stewardw@etsu.edu

Summary TableParameter Apixaban Dabigatran RivaroxabanTarget Protein Factor Xa Thrombin (IIa) Factor Xa

Pro-Drug No Yes (etexilate) No

1˚ Elimination CYP3A4/P-gp Renal CYP3A4/P-gp

Renal Adjustment Avoid < 15 ml/min ↓ 15-29ml/minAvoid < 15 ml/min

Adjust < 50 ml/minAvoid < 15 ml/min1

Drug-Drug Interact. CYP3A4/P-gp Rifampin (P-gp) CYP3A4/P-gp

Onset of activity 3-4 hrs 1-2 hrs 2-4 hrs

t½ 8-15 hrs 12-18 hrs 5-9 hrs

Dosing interval Twice daily Twice daily Daily

Monitoring tests Anti-factor Xa ECT, TT, +/- aPTT Anti-factor Xa

FDA Indications None Non-valvular Afib. Non-valvular Afib. Ortho VTE Proph.

Clinical Uses AfibOrtho VTE Proph

Afib, VTE Afib, Ortho VTE Proph, VTE

1Orthopedic VTE prophylaxis doses (10 mg daily) do not require renal adjustment; do not use if CrCl < 30 ml/min.

Use of Concomitant Antiplatelet Agents

AntiplateletAgents

ARISTOTLE(Apixaban)

RELY(Dabigatran)

ROCKET-AF(Rivaroxaban)

ASA < 165 mg/day Yes < 100 mg/day

Clopidogrel Yes Yes Yes

Combination No Yes No

Aspirin Use (%) 31% 40% 36%

New Engl J Med 2009;361:1139-51. New Engl J Med 2011;365:883-91. New Engl J Med 2011;365:981-92.

RE-LY - ResultsEvent Dabi 110 vs Warf

HR (95% CI)Dabi 150 vs Warf

HR (95% CI)Dabi 150 vs Dabi 110

HR (95% CI)

Efficacy1˚ Endpoint* 0.91 (0.74-1.11) 0.66 (0.53-0.82) 0.73 (0.58-0.91)

All stroke 0.92 (0.74-1.13) 0.64 (0.51-0.81) 0.70 (0.56-0.89)

Ischemic Stroke 1.11 (0.89-1.40) 0.76 (0.60-0.98) 0.69 (0.54-0.88)

Hemorrhagic Stroke 0.31 (0.17-0.56) 0.26 (0.14-0.49) 0.85 (0.39-1.83)

MI published 1.35 (0.98-1.87) 1.38 (1.00-1.91) 1.02 (0.76-1.38)

MI revised 1.29 (0.96-1.75) 1.27 (0.94-1.71) Not available

All cause mortality 0.91 (0.80-1.03) 0.88 (0.77-1.00) 0.97 (0.85-1.11)

SafetyMajor bleeding 0.80 (0.69-0.93) 0.93 (0.81-1.07) 1.16 (1.00-1.34)

GI bleeding 1.10 (0.86-1.41) 1.50 (1.19-1.89) 1.36 (1.09-1.70)

All bleeding 0.78 (0.74-0.83) 0.91 (0.86-0.97) 1.16 (1.09-1.23)

IC bleeding 0.31 (0.20-0.47) 0.40 (0.27-0.60) 1.32 (0.80-2.17)

New Engl J Med 2009;361:1139-51. New Engl J Med 2010;363:1875-76. *Non-inferiority margin = 1.46

RE-LYSummary

• Dabigatran 110 mg BID vs. warfarin– Non-Inferior Efficacy– Lower major and overall bleeding rates– Similar GI bleeding rates

• Dabigatran 150 mg BID vs. warfarin– Superior efficacy– Lower overall bleeding rates– Similar major bleeding rates– Elevated rates of GI bleeding

• Both doses showed decreased ICH compared to warfarin (60-70% RRR)

ROCKET-AFResults

Event Rivaroxaban(% per year)

Warfarin(% per year)

HR (95% CI)

Efficacy1˚ Endpoint* 2.1 2.4 0.88 (0.75-1.03)

All stroke 1.65 1.96 0.85 (0.70-1.03)

Ischemic Stroke 1.34 1.42 0.94 (0.75-1.17)

Hemorrhagic Stroke 0.26 0.44 0.59 (0.37-0.93)

MI 0.91 1.12 0.81 (0.63-1.06)

All-cause mortality 1.87 2.21 0.85 (0.70-1.02)

SafetyMajor bleeding 3.6 3.4 1.04 (0.90-1.20)

All bleeding 14.9 14.5 1.03 (0.96-1.11)

Major GI bleeding 3.2 (% overall) 2.2 (% overall) p < 0.001

IC bleeding 0.5 0.7 0.67 (0.47-0.93)

New Engl J Med 2011;365:883-91.*Non-inferiority margin = 1.46

ROCKET-AFSummary

• Rivaroxaban vs. warfarin– Non-Inferior Efficacy– Similar bleeding rates– Lower ICH rates

• High risk patient population (Mean CHADS2 score > 3)

• TTR 55%

New Engl J Med 2011;365:883-91.

ARISTOTLEResults

Event Apixaban(% per year)

Warfarin(% per year)

HR (95% CI)

Efficacy1˚ Endpoint* 1.27 1.60 0.79 (0.66-0.95)

All stroke 1.19 1.51 0.79 (0.65-0.95)

Ischemic Stroke 0.97 1.05 0.92 (0.74-1.13)

Hemorrhagic Stroke 0.24 0.47 0.51 (0.35-0.75)

MI 0.53 0.61 0.88 (0.66-1.17)

All-cause mortality 3.52 3.94 0.89 (0.80-0.998)

SafetyMajor bleeding 4.07 6.01 0.68 (0.61-0.75)

All bleeding 18.1 25.8 0.71 (0.68-0.75)

IC bleeding 0.33 0.80 0.42 (0.30-0.58)

New Engl J Med 2011;365:981-92.

*Non-inferiority margin = 1.38

ARISTOTLE Summary

• Apixaban vs. warfarin– Superior efficacy with apixaban– ↓ overall mortality with apixaban (NNT = 238)– Lower bleeding rates with apixaban– Lower ICH rates

• Apixaban vs. Aspirin– 6,000 high-risk patients (mean CHADS2 = 2)– Not candidates for warfarin– 1 year follow-up– Superior efficacy to aspirin– Similar bleeding (including ICH) rates

New Engl J Med 2011;365:981-92. New Engl J Med 2011;364:806-17.

Summary of Afib Data

Apixaban(ARISTOTLE)

Dabigatran(RE-LY)

Rivaroxaban (ROCKET – AF)

# Patients > 18,000 > 18,000 > 14,000

Mean CHADS2 ≈ 2 ≈ 2 ≈ 3.5

TTR 62% 64% 55%

Efficacy vs. VKA Superior Superior1 Non-Inferior

Bleeding2 vs. VKA Decreased Similar Similar

Elimination CYP3A4/P-gp Renal CYP3A4/P-gp/Renal

1Dabigatran 150 mg BID group. 2Major bleeding per study design.

Use of Concomitant Antiplatelet Agents

AntiplateletAgents

ARISTOTLE(Apixaban)

RELY(Dabigatran)

ROCKET-AF(Rivaroxaban)

ASA < 165 mg/day Yes < 100 mg/day

Clopidogrel Yes Yes Yes

Combination No Yes No

Aspirin Use (%) 31% 40% 36%

New Engl J Med 2009;361:1139-51. New Engl J Med 2011;365:883-91. New Engl J Med 2011;365:981-92.