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1 Mary Bradbury, PharmD, BCPS Clinical Pharmacy Specialist, Cardiac Surgery September 18, 2012 This presentation will discuss unlabeled and investigational use of products The author has no disclosures 1

2 2.5 million Americans live with atrial fibrillation (afib) Afib-associated morbidity and mortality Annual incidence of stroke in patients with afib: 5% Risk of stroke increases with age Reprinted from AF Stat : A Call to Action for Atrial Fibrillation; Accessed via AHA/ASA guidelines for the primary prevention of stroke 2010 AHA/ASA guidelines for prevention of stroke in patients with ischemic stroke or TIA 2012 ACCP evidence-based clinical practice guidelines: antithrombotic therapy for atrial fibrillation and prevention of thrombosis, 9 th Ed AHA/ASA advisory on oral antithrombotic agents for the prevention of stroke in nonvalvular atrial fibrillation 2

3 Which patients with afib need stroke prevention therapy? Risk stratification: CHADS2 Score 2 Risk Factor Points Congestive heart failure 1 Hypertension 1 Age 75 years 1 Diabetes 1 Stroke or TIA 2 CHADS2 score Risk group Recommendation (Level of evidence) Annual absolute risk ASA VKA 0 Low Nothing or ASA only (2B) 0.6% 0.3% 1 Moderate Anticoagulation (1B) 1.7% 0.8% 2 High Anticoagulation (1A) 3.6% 1.7% 3-6 High Anticoagulation (1A) 7.6% 3.6% ASA: Aspirin; VKA: Vitamin K antagonist Antithrombotic therapy and prevention of thrombosis, 9 th Ed: ACCP Guidelines 3

4 4

5 Safety Efficacy 5

6 FDA approved October mg PO BID for CrCL > 30 ml/min 75 mg PO BID for CrCL ml/min (not studied) Unique mechanism of action: direct thrombin inhibitor (argatroban, bivalirudin) 150 mg dose demonstrated superior efficacy and similar bleeding rates vs. warfarin (RELY) Mean CHADS2 score: 2.1 Connolly SJ. N Engl J Med 2009;361(9): Furie KL. Stroke 1012;43:

7 Event Warfarin (INR 2-3) Dabigatran 150 mg BID PValue Stroke Hemorrhagic Ischemic 1.69% 0.38% 1.20% 1.11% 0.10% 0.92% < < Major bleeding Intracranial Life threatening Gastrointestinal 3.36% 0.74% 1.80% 1.02% 3.11% 0.30% 1.45% 1.51% 0.31 < < Dyspepsia 5.8% 11.3% < Myocardial infarction (MI) 0.53% 0.74% All results reported as % per year Connolly SJ. N Engl J Med 2009;361(9): RELY substudy: platelet function test No difference in platelet activation between warfarin and dabigatran groups Meta-analysis supports increase risk of MI Risk of MI/ACS: 1.19% dabigatran vs. 0.79% comparator (P = 0.03) Uchino K. Arch Intern Med 2012;172(5): Ferreira J. Thrombosis 2012 Uchino K. Arch Intern Med

8 ACCP 9 th Ed. (January 2012) For those with atrial fibrillation and risk score favoring anticoagulation, dabigatran recommended rather than VKA therapy (2B) with the exception of patients with the following: Mitral stenosis Active coronary artery disease (CAD) or history of CAD You JJ. Chest 2012;141(2)Suppl:e531s-e575s. AHA/ASA Advisory (August 2012) Dabigatran Is useful as an alterative to warfarin in patients who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure, or advanced liver disease (1B). Furie KL. Stroke 2012;43:

9 Lack of monitoring does not always prove beneficial Renal function must be monitored closely Lack of reversal agent New Zealand experience identifies 4 items likely contributing to bleeding complications: Prescriber error (renal impairment, bridging off warfarin) Acute changes in renal function Patient age and weight, especially > 80 years and < 60 kg Complications secondary to prolonged half-life and lack of reversal Harper P. N Engl J Med 2012;366;9:

10 FDA approved November mg PO daily with meal for CrCL > 50 ml/min 15 mg PO daily with meal for CrCL ml/min Mechanism of action: Inhibitor of factor Xa Similar efficacy and similar bleeding rates vs. warfarin (ROCKET AF) Mean CHADS2 score: 3.5 Patel MR. N Engl J Med 2011;365;10: Event Warfarin (n=7125) Rivaroxaban (n=7111) PValue Stroke Hemorrhagic 2.2% 1.2% 1.7% 0.8% <0.001* 0.02 Major bleeding 5.4% 5.6% 0.31 Myocardial infarction 1.1% 0.9% 0.12 All results reported as % per year *Results reported for per protocol analysis (n=7004 for warfarin and n=6958 for Rivaroxaban) and as non-inferiority Patel MR. N Engl J Med 2011;365;10:

11 ACCP Antithrombotic guidelines: no recommendation to date AHA/ASA In patients with CrCL > 50 ml/min and afib at high risk of stroke (CHADS2 2), rivaroxaban is a reasonable alternative to warfarin (IIa) The safety and efficacy of the renally adjusted dose has not been clearly established (IIb) Lack of monitoring does not always prove beneficial Safety and efficacy with renal and hepatic dysfunction not clearly established Lack of reversal agent Lack of post-marketing surveillance Harper P. N Engl J Med 2012;366;9:

12 Not yet FDA approved Studied as 5 mg PO BID 2.5 mg PO BID suggested in patients with at least two of the following: Age 80 years, weight 60 kg, creatinine 1.5 mg/dl Mechanism of action: Inhibitor of factor Xa Superior efficacy and safetyvs. warfarin (ARISTOTLE) Mean CHADS2 score: 2.1 Granger CB. N Engl J Med 2011;365: Event Warfarin (n=9081) Apixaban (n=9120) PValue Stroke Hemorrhagic Ischemic 1.60% 0.47% 1.05% 1.27% 0.24% 0.97% 0.01 < Major bleeding Intracranial Gastrointestinal 3.09% 0.80% 0.86% 2.13% 0.33% 0.76% <0.001 < Myocardial infarction 0.61% 0.53% 0.37 All-cause mortality 3.94% 3.52% All results reported as % per year Granger CB. N Engl J Med 2011;365:

13 ACCP Antithrombotic guidelines: no recommendation to date AHA/ASA If CHADS2 score 1 and VKA unsuitable, apixaban is reasonable alternative to ASA therapy (I) If CHADS2 score 2, apixaban is reasonable alternative to VKA therapy (I) If either of above is true and patient has > 1 risk factor for decreased drug clearance (age, weight, creatinine), consider lower dose alternative (IIb) Avoid apixaban if CrCL < 25 ml/min (Class III) Never bridge No monitoring Consider all factors that may lead to drug accumulation Route of elimination: renal +/- hepatic Drug interactions due to CYP3A4 or P- glycoprotein Advanced age or low body weight 13

14 Warfarin Class I INR goal 2-3 Dabigatran Class I Dose adjust based on CrCL and drug interactions Level of evidence lower for renally adjusted dose, avoid if CrCL < 15 ml/min Apixaban Class I Dose adjust based on age, weight, creatinine* Level of evidence lower for renally adjusted dose, avoid if CrCL < 25 ml/min Rivaroxaban Class IIa Dose adjust based on CrCL Avoid if CrCL < 15 ml/min or moderate-severe hepatic dysfunction *Drug/dosing not currently FDA approved 14

15 Contraindicated with therapeutic warfarin 2007 Stroke Guidelines recommend INR 1.7 Dabigatran: not recommended Normal aptt and thrombin time suggest complete elimination of dabigatran Rivaroxaban: not recommended Normal PT may suggest complete elimination of rivaroxaban Apixaban: not recommended Adams HP. Stroke 2007;38: MINIMIZE ABSORPTION Activated charcoal if ingestion occurred within 2 hours MAXIMIZE RENAL ELIMINATION Assure adequate hydration & diuresis Hemodialysis: 68% of drug is removed in a 4-hour dialysis session BLOOD PRODUCTS FOR HEMODYNAMIC SUPPORT FFP will not reverse the coagulopathy of dabigatran OTHER AGENTS Non-specific reversal agents? Activated PCC, rfviia Monoclonal antibody PCC: Prothrombin complex concentrate, rfviia: recombinant activated factor VII 15

16 MINIMIZE ABSORPTION Activated charcoal if ingestion occurred within 2 hours BLOOD PRODUCTS FOR HEMODYNAMIC SUPPORT FFP will not reverse the coagulopathy of dabigatran OTHER AGENTS Non-specific reversal agents? Activated PCC, PCC, rfviia PCC: Prothrombin complex concentrate, rfviia: recombinant activated factor VII Mary Bradbury, PharmD, BCPS Clinical Pharmacy Specialist, Cardiac Surgery September 18,