David Putney, PharmD, BCPS Cardiology Specialist II The Methodist Hospital Houston, TX Stroke Prevention with Atrial Fibrillation Objectives • Review trials on antiplatelet and anticoagulation in atrial fibrillation • Apply literature to case based discussion • Describe the pharmacokinetic properties of newer oral anticoagulants 2 Atrial Fibrillation Atrial Fibrillation http://heartstrong.files.wordpress.com/2009/06/atrial-fibrillation-lg.jpg 4 Atrial Fibrillation Prevalence • Affects nearly 2.5 million people in the US – Uncommon among individuals < 50 years of age (risk < 0.5%) – Nearly 10% in those > 80 years of age – Men > women – Lifetime risk of AF for an individual at 40 years of age is 25% Singer D, et al. Chest. 2008;133:546S-592S. Gage BF, et al. Circulation. 2004;110:2287-92. 5 2010 US Census 25,000,000 20,000,000 15,000,000 10,000,000 5,000,000 0 http://www.census.gov/population/www/socdemo/age/age _sex_older.html. Last accessed 3/8/2012. 6 Atrial Fibrillation Atrial electrical remodeling • “Atrial fibrillation begets atrial fibrillation” • Repeated episodes of induced atrial tachycardia – Marked shortening of atrial refractory period • Normal function occurs 2 to 4 weeks after normalization of sinus rhythm (SR) Camm AJ, et al. Eur Heart J. 2010;31:2369-2439. Singer D, et al. Chest. 2008;133:546S-592S. 7 Stroke Risk Go SA. N Engl J Med. 2009;360: 2127-29. 8 Atrial Fibrillation Stroke Risk • Loss of coordinated atrial contractions – Predisposition for thrombus formation within the atria • Flow abnormalities – Reduced left atrial appendage flow velocity • Endocardial abnormalities – Progressive atrial dilation and edematous/fibrolastic infiltration of extracellular matrix • Abnormalities of blood constituents – Hemostatic and platelet activation – Inflammation and growth factor abnormalities Camm AJ, et al. Eur Heart J. 2010;31:2369-2439. Rockson S, et al. J Am Coll Cardiol. 2004;43:929-35. 9 Case • CC: “fluttering heart” • HPI: AJ is a 60 yo female who presents with a 2 day history of fluttering feeling in chest. No SOB, syncope, or chest pain noted. • PMH: HTN x 20 yrs (well controlled) • Medication: HCTZ 25 mg daily and Ramipril 10 mg daily • ECG: Atrial fibrillation with a ventricular response of 128 BPM • Significant Events: Pt spontaneously cardioverted back into NSR 10 What to do? • Do we anticoagulate? • What if pt has had previous TIA/CVA? • What if pt has hx of CAD and is taking ASA and clopidogrel? • What if pt has ESRD? 11 Stroke Risk CHADS2 CHADS2 Risk Criteria Score Congestive Heart Failure 1 HTN 1 Age >75y 1 DM 1 Prior stroke or TIA 2 Singer D, et al. Chest. 2008;133:546S-592S. 12 CHA2DS2-VASc Camm AJ, et al. Eur Heart J. 2010;31:2369-2439. 13 HAS BLED Scale Pisters R, et al. Chest 2010;138;1093-1100. 14 Guideline Recommendations CHEST Guidelines • CHADS2 score 0 – No therapy or long-term aspirin 75-325mg daily • CHADS2 score 1 – Long-term antithrombotic therapy • CHADS2 score ≥ 2 – Long-term antithrombotic therapy You J, et al. Chest. 2012;141:531S-575S. 15 Guideline Recommendations European Society of Cardiology (ESC) Guidelines Camm AJ, et al. Eur Heart J. 2010;31:2369-2439. 16 Coagulation Cascade Accessed 8 October 2010. URL: http://picasaweb.google.com/lh/photo/GCMu-PcRpUhwQS9538eKYw New Agents 18 Weitz J, et al. Chest. 2012;141:120S-151S. RCTs Drug Interactions Special Populations Reversibility 19 Adverse Effects in the Elderly Agents Utilized 60% 50% 40% 30% 20% 10% Hospitalization ED Encounter 0% Budnitz D, et al. NEJM. 2012;365:2002-12. 20 Latest Trial Information SPAF III Hart R, et al. Stroke. 1999;30:1223-1229. 22 ACTIVE A Atrial Fibrillation with At Least One Additional Risk Factors for Stroke Randomized Double-blind N = 7,554 Clopidogrel 75mg daily + ASA 75 – 100mg daily Risk Factors • Prior stroke or TIA, or SE • Age ≥ 75yo • HTN • DM • HF or EF ≤ 35% ASA 75 – 100mg daily + Placebo Primary outcome: Any major vascular event Connolly S, et al. N Engl J Med. 2009;360:2066-78. 23 ACTIVE A Results: Primary and Secondary Outcomes Clopidogrel + ASA ASA P-value Composite of stroke, nonCNS embolus, MI, vascular death 6.8 7.6 0.01 Ischemic stroke 1.9 2.8 <0.05 Total mortality 6.4 6.6 0.69 Major Bleeding 2 1.3 <0.001 Connolly S, et al. N Engl J Med. 2009;360:2066-78. 24 ACTIVE W Atrial Fibrillation with At Least One Additional Risk Factor for Stroke Randomized Blinded N = 6,706 Clopidogrel 75mg daily + ASA 75 – 100mg daily Risk Factors • Prior stroke or TIA, or SE • Age ≥ 75yo • HTN • DM • HF or EF ≤ 35% Warfarin (INR 2 – 3) Primary outcome: First occurrence of stroke, non-CNS systemic embolism, MI, or vascular death Connolly S, et al. Lancet. 2006;367:1903-12. 25 ACTIVE W Results: Primary and Secondary Outcomes Clopidogrel + ASA Warfarin P-value Composite of stroke, nonCNS embolus, MI, vascular death 5.60 3.93 0.0003 Ischemic stroke 2.39 1.40 <0.0001 Total mortality 3.80 3.76 0.91 Major Bleeding 2.42 2.21 0.53 Primary outcome and major bleed 7.56 5.45 <0.0001 Connolly S, et al. Lancet. 2006;367:1903-12. 26 RE-LY Atrial Fibrillation with At Least One Additional Risk Factor for Stroke Risk Factors • Prior stroke or TIA, or SE • Age ≥ 75yo • HTN • DM • HF or EF ≤ 35% Randomized Blinded N = 18,113 Dabigatran 110 or 150mg twice daily Warfarin (INR 2 – 3) Primary outcome: Stroke or systemic embolism Safety outcome: Major hemorrhage Conolly S, et al. N Engl J Med. 2009;361:1139-51. 27 RE-LY RE-LY: Results Conolly S, et al. N Engl J Med. 2009;361:1139-51. 28 RE-LY RE-LY: Adverse Effects • Major bleeding: – Warfarin 3.36% per year – Dabigatran 110mg, 2.71% per year (p = 0.003) – Dabigatran 150mg, 3.11% per year (p = 0.31) • Elevation in LFTs: – Warfarin 2.2% – Dabigatran 110mg, 2.1% and 150mg, 1.9% • Dyspepsia: – Warfarin 5.8% – Dabigatran 110mg, 11.8% and 150mg, 11.3% (p<0.001) Conolly S, et al. N Engl J Med. 2009;361:1139-51. 29 ROCKET AF Atrial Fibrillation with At Least Two Additional Risk Factors for Stroke Randomized Double-blind N = ~14,000 Rivaroxaban 20mg daily (15 mg if CrCL 20 – 49 mL/min) Risk Factors • Prior stroke or TIA, or SE • Age ≥ 75yo • HTN • DM • HF or EF ≤ 35% Warfarin (INR 2 – 3) Primary outcome: Stroke or non-CNS systemic embolism Maffey K, et al. Am Heart J. 2010;159:340–7. ROCKET AF Results Maffey K, et al. Am Heart J. 2010;159:340–7. Patel MR, et al. NEJM 2011;365:883-91. 31 ROCKET AF Safety Rivaroxaban Warfarin P-value Primary Safety Endpoint: Major and nonmajor clinically relevant bleeding 14.9 14.5 0.44 Any Major Bleeding 3.6 3.4 0.58 Intracranial Hemorrhage 0.5 0.7 0.02 Fatal Bleeding 0.2 0.5 0.003 Patel MR, et al. NEJM 2011;365:883-91. 32 AVERROES Atrial Fibrillation with At Least One Additional Risk Factor for Stroke Risk Factors • Prior stroke or TIA, or SE • Age ≥ 75yo • HTN • DM • HF or EF ≤ 40% Randomized Double-blind N = 5,599 Apixaban 5mg twice daily (2.5 mg if 2 or more of the following were present: Age > 80, ABW < 60kg or Scr > 1.5 mg/dL) Aspirin (81-325 mg) daily Primary outcome: Stroke or systemic embolism Safety outcome: Major hemorrhage Connolly SJ , et al. N Engl J Med. 2011;364:806-17. 33 AVERROES Connolly SJ , et al. N Engl J Med. 2011;364:806-17. 34 AVERROES Apixaban Aspirin P-value Primary Safety Endpoint: Major Bleeding 1.4 % 1.2 % 0.57 Fatal Bleeding 0.1 % 0.2 % 0.53 Intracranial Hemorrhage 0.4 % 0.4 % 0.69 Gastrointestinal 0.4 % 0.4 % 0.71 Connolly SJ , et al. N Engl J Med. 2011;364:806-17. 35 ARISTOTLE Atrial Fibrillation with At Least One Additional Risk Factor for Stroke Risk Factors • Prior stroke or TIA, or SE • Age ≥ 75yo • HTN • DM • HF or EF ≤ 40% Randomized Double-blind N = 18,201 Apixaban 5mg twice daily (2.5 mg if 2 or more of the following were present: Age > 80, ABW < 60kg or Scr > 1.5 mg/dL) Warfarin (INR 2 – 3) Primary outcome: Stroke or systemic embolism Safety outcome: Major hemorrhage Granger C, et al. N Engl J Med. 2011;365:981-992. 36 ARISTOTLE Granger C, et al. N Engl J Med. 2011;365:981-992. 37 ARISTOTLE Apixaban Warfarin P-value Primary Safety Endpoint: ISTH major bleeding 2.13 3.09 <0.001 Any Major Bleeding 4.07 6.01 <0.001 Intracranial Hemorrhage 0.33 0.8 <0.001 Gastrointestinal 0.76 0.86 0.37 ISTH=International Society on Thrombosis and Haemostasis Granger C, et al. N Engl J Med. 2011;365:981-992. 38 Summary Agent Studied Stroke or Systemic Embolism Primary Safety Endpoint Aspirin Aspirin & Clopidogrel Warfarin 7.6 % 6.8 % 5.6 % 1.3 % 2.0 % 2.2 % Dabigatran 110 Dabigatran 150 Warfarin 1.54 % 1.11 % 1.71 % 2.87 % 3.32 % 3.57 % ROCKET AF Rivaroxaban Warfarin 1.7 % 2.2 % 14.9 % 14.5% AVERROES Apixiban Aspirin 1.6 % 3.7 % 1.4 % 1.2 % ARISTOTLE Apixiban Warfarin 1.27 % 1.6 % 2.13 % 3.09 % Trial Acronym ACTIVE RE-LY 39 Patient Specific Factors Warfarin Control Across Trials RE-LY ROCKET AF ARISTOTLE Time in Therapeutic INR 64 % 55 % 66 % Subtherapeutic 23 % NA NA Supratherapeutic 2% NA NA Conolly S, et al. N Engl J Med. 2009;361:1139-51. Patel MR, et al. NEJM 2011;365:883-91. Granger C, et al. N Engl J Med. 2011;365:981-992. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/dru gs/cardiovascularandrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12 41 RE-LY Analysis 42 Wallentin L, et al. Lancet 2010;376:975-83. RE-LY Analysis Time in Therapeutic Target (%) Dabigatran 110 Dabigatran 150 Warfarin < 57.1 1.91 1.10 1.92 57.1 - 65.5 1.67 1.04 2.06 65.5 – 72.6 1.34 1.04 1.51 > 72.6 1.23 1.27 1.34 Improved time within therapeutic range was associated with a decrease in stroke and systemic embolism 43 Wallentin L, et al. Lancet 2010;376:975-83. RE-LY Analysis Time in Therapeutic Target (%) Dabigatran 110 Dabigatran 150 Warfarin < 57.1 2.36 2.54 3.59 57.1 - 65.5 3.38 3.33 4.13 65.5 – 72.6 2.82 3.80 3.40 > 72.6 2.81 3.60 3.11 Major bleeding was associated with poorer control of warfarin therapy 44 Wallentin L, et al. Lancet 2010;376:975-83. Dabigatran Steady State • Mean concentration of dabigatran 150 mg twice daily in patients with normal renal function http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovasculara ndrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12 45 Effects of Renal Dysfunction http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovasculara ndrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12 46 75 mg Twice Daily Dosing http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovasculara ndrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12 47 Dabigatran Drug Interactions Dabigatran Concentration 48 http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovasculara ndrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12 Renal Function Update • When to assess renal function: – Prior to starting therapy – Annually in patients greater than 75 years old and those with a creatinine clearance (CrCl) less than 50 mL per minute • Recommended dosing guidelines in renal impairment CrCl (mL per minute) Dose Greater than 30 150mg twice daily 15-30 75mg twice daily Less than 15 Use not recommended Dabigatran [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc; 2011. Connolly SJ, et al. N Engl J Med. 2009;361:1139-51. 49 Package Insert Update • Dabigatran is a substrate of the P-glycoprotein (P-gP) metabolism pathway • P-gP inhibitors – Dronedarone (antiarrhythmic) – Ketoconazole (antifungal) • Recommended dosing adjustments Concomitant Medication CrCl (mL per minute) Dose (dabigatran) Dronedarone 30-50 75mg twice daily Ketoconazole 30-50 75 mg twice daily Dronedarone 15-30 Use not recommended Ketoconazole 15-30 Use not recommended Dabigatran [package insert]. Ridgefield, CT. Boehringer Ingelheim Pharmaceuticals, Inc; 2011. 50 Dabigatran Monitoring? http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovasculara ndrenaldrugsadvisorycommittee/ucm226009.pdf. Last accessed 3/12/12 51 Stroke Reduction vs. Bleeding 52 Real World Effects • New Zealand Data • European Data • FDA warnings Dabigatran: Australia issues Dabigatran: 260 fatal bleeds bleeding warning since approval worldwide October 7, 2011 November 17, 2011 http://www.theheart.org/article/1291757.doc. Last accessed 3/12/12 53 Rivaroxaban Effect on PT http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/drugs/Cardiova scularandRenalDrugsAdvisoryCommittee/ucm270796.pdf. Last accessed 3/12/12 54 Rivaroxaban Major Bleeding http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/drugs/Cardiova scularandRenalDrugsAdvisoryCommittee/ucm270796.pdf. Last accessed 3/12/12 55 Kinetic Profiles Dabigatran Rivaroxaban Apixaban 12 – 18 hours 5 – 9 hours 12 hours CYP 450 Substrate No Yes (3A4/3A5 & 2J2) Yes (3A4/3A5) Renal Elimination 80 % 66% 30% Twice Daily Once Daily Twice Daily < 30 mLs/min < 25 mLs/min or Scr > 2.5 mg/dL Half Life Dosing Minimum Renal Function During Major Trial < 30 mLs/min 56 Acute Reversal Eerenberg, ES, et al. Circulation. ePub online Sept. 2011. 57 Cardioversion • Electrical or pharmacological • Systemic embolism is the most serious complication • “Atrial stunning” – Further depression of left atrial appendage ejection velocities – Increased left atrial spontaneous echocardiographic contrast – New thrombus formation You J, et al. Chest. 2012;141:531S-575S. 58 Guideline recommendations CHEST Guidelines • AF duration ≥ 48 hours or unknown – Warfarin (INR 2-3) for 3 weeks before and at least 4 weeks after cardioversion • AF duration known <48 hours – Cardioversion may be performed without prolonged anticoagulation • Emergency cardioversion – Immediate IV UFH (PTT 50-60) or LMWH (full treatment dose) – Follow with 4 weeks of therapeutic anticoagulation You J, et al. Chest. 2012;141:531S-575S. 59 Transesophageal Echocardiography (TEE) Guided Cardioversion • Biplane and multiplane TEE used to detect thrombi • Offers opportunity to perform early cardioversion if no thrombi observed You J, et al. Chest. 2012;141:531S-575S. http://www.yale.edu/imaging/techniques/echo_tee/graphics/unlabelled.gif 60 Case • CC: “fluttering heart” • HPI: AJ is a 60 yo female who presents with a 2 day history of fluttering feeling in chest. No SOB, syncope, or chest pain noted. • PMH: HTN x 20 yrs (well controlled) • Medication: HCTZ 25 mg daily and Ramipril 10 mg daily • ECG: Atrial fibrillation with a ventricular response of 128 BPM • Significant Events: Pt spontaneously cardioverted back into NSR 61 What to do? • Do we anticoagulate? • What if pt has had previous TIA/CVA? • What if pt has hx of CAD and is taking ASA and clopidogrel? • What if pt has ESRD? 62 In Summary • Atrial fibrillation and stroke prevention is an increasing epidemic • Newer oral anticoagulants offer alternatives to traditional warfarin therapy • Tailoring regiments to specific factors helps to minimize the risk of major bleeding events 63 Suggested Readings • CHEST Guidelines on antithrombotic therapy for atrial fibrillation You JJ, et al. Chest. 2012;141:531S-575S. 65