novel oral anticoagulant agents: an update in pharmacotherapy david stewart, pharmd, bcps associate...
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Novel Oral Anticoagulant Agents: An Update in Pharmacotherapy
David Stewart, PharmD, BCPSAssociate Professor of Pharmacy Practice
East Tennessee State UniversityBill Gatton College of Pharmacy
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
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 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.
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
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.