WHY? AF Increases Stroke Risk by Nearly 500% Disclosures. Terminology. Anticoagulation in Atrial Fibrillation: Why, What, When and for How Long

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1 Anticoagulation in Atrial Fibrillation: Disclosures Why, What, When and for How Long Edward Kersh, MD, FACC Chief of Cardiology, St. Luke s Hospital, SF Clinical Professor of Medicine, UCSF CAPA, September 2011 Speaker s Bureaus: Boeringer Ingelheim, Sanofi Aventis, Novartis, Pfizer, Gilead, Tethys Bioscience Terminology Lone (no heart disease) Paroxysmal (self terminating) Persistent (requires intervention to terminate) Permanent (cannot maintain RSR) NVAF (non-valvular AFib) WHY? AF Increases Stroke Risk by Nearly 500% Risk ratio = 4.8 P < Wolf et al. Stroke. 1991;22:

2 Incidence of AF Increases with Age 8% of 5,000,000 = 400,000 Fuster, V. et al. J Am Coll Cardiol 2011;57:e101-e198 Risk of Stroke in AF Increases with Age Severe Disability Is Increased in Patients With Stroke Due to AF 2x incidence of being bedridden with AFib Stroke rates in relation to age in untreated control groups of randomized trials Fuster, V. et al. J Am Coll Cardiol 2011;57:e101-e198 Lin et al. Stroke. 1996;27:

3 Clinical predictors of stroke in AFIB Hart RG et al, JACC 2000:35: Prior TIA or CVA Prosthetic Valve RHD Hypertension LV dysfunction/chf Age > 75 Cardiomyopathies (restrictive or hypertrophic) Diabetes CAD Thyrotoxicosis Echo Predictors of Emboli LV Dysfunction Mitral Valve Disease, Annular Calcium LA Enlargement Spontaneous Echo Contrast (Smoke) LAA emptying velocity LA thrombus Absence of mitral regurgitation CHADS 2 Score Helps Predict Stroke Risk in AF (non-valvular) Risk Factor Points Congestive heart failure 1 Hypertension 1 Age >75 1 Diabetes 1 Prior stroke/tia 2 TIA, transient ischemic attack Gage et al. JAMA. 2001;285:

4 Thrombus Forms in the Left Atrium (we rarely see it on TTE) LAA Clot LAA Clot by TEE in appendage WHY? Oral Anticoagulation Reduces Stroke in AF (8% to 3%) Warfarin Compared With Placebo The aggregate RRR for all stroke was 62% (95% CI, 48% 72%) AFASAK (n=671) SPAF (n=421) BAATAF (n=420) CAFA (n=378) SPINAF (n=571) EAFT (n=439) All 6 Trials (n=2900) 100% 50% 0-50% -100% RRR=relative risk reduction Adapted from Hart. Ann Intern Med. 1999;131:492; with permission. Warfarin Better Warfarin Worse 4

5 What Parenteral Agents heparin, enoxaparin, Arixtra* Antiplatelet Agents Aspirin clopidigrel Vitamin K antagonists Direct Thrombin Inhibitors Dabigatran Factor XA inhibitors Apixaban Rivaroxaban Appendectomy New Agents The problem with warfarin: The Therapeutic Window Stroke vs intracranial bleeding in relation to intensity of anticoagulation Therapeutic window Fuster, V. et al. J Am Coll Cardiol 2011;57:e101-e198 5

6 WARFARIN Connolly SJ et al. Circ. 2008,118: SPAF, Circulation 1991 What About Aspirin? Red vs White Thrombus Red Thrombus White thrombus Dominated by RBC s Low Pressure systems (veins, LA) Rx anti-thrombin agents Stasis (DVT, AFib) Dominated by platelets High-pressure systems (arteries, bypass) Rx antiplatlet agents Plaque Rupture (ACS) Fuster, V. et al. J Am Coll Cardiol 2011;57:e101-e198 6

7 Aspirin half as effective ASA + PLAVIX less stroke, more bleeding n = 7554 pts unsuitable for warfarin Stroke, MI, Embolism, death SPAF, Circulation 1991 The ACTIVE Investigators. N Engl J Med 2009;360: New Agents Direct Thrombin Inhibitor Dabigatran Factor Xa Inhibitor Rivaroxiban Apixaban 7

8 RELY - RESULTS 35% reduction in stroke and emboli with D 150 Connolly SJ et al. N Engl J Med 2009;361: Efficacy and Major Safety Outcomes in RE-LY Beasley BN et al. N Engl J Med DOI: /NEJMp

9 Treating Bleeding with Pradaxa on Board Wait short half life compared to warfarin Maintain renal perfusion PRBC Fluids Diuretic (?) Drive Thrombin production FFP Vitamin K (?) Prothrombin Complex Concentrates Dialysis Antibody? Pradaxa Summary Points Onset of action in 1-2 hours No need to bridge with heparin (shorter LOS) Less time off therapy Works on clot bound and free thrombin Decreased emboli/decreased bleeding No dose titration/no INR s Fewer drug interactions Increased GI symptoms and GI Bleeds Less ICH The Competition Factor Xa inhibitors Rivaroxiban: Rocket AF Trial Mechanism of Action of Factor Xa Inhibitors 21% reduction in stroke and emboli Factor Xa Inhibitors Patel MR et al. N Engl J Med DOI: /NEJMoa

10 Rocket AF - Primary End Point of Stroke or Systemic Embolism. Rocket AF: But, Increased Rate of Bleeding Events Patel MR et al. N Engl J Med DOI: /NEJMoa Patel MR et al. N Engl J Med DOI: /NEJMoa Apixaban: Averoes Trial Apixaban vs Aspirin n=5599 ARISTOTLE Apixaban vs Warfarin n = End point APX ASA Hazard P value Ratio Stroke or Emboli < %/yr Mortality %/yr Major Bleed %/yr ICH (n) st Hosp < % reduction in stroke and emboli Granger CB et al. N Engl J Med DOI: % reduction in major bleeding 10

11 Aristotle Apixaban vs Warfarin n=18000 COMPARISON Drug Trial (chads2) Dose TTR % Stroke Reduction % ICH %/yr RR Mortality (p value) Major Bleed Dabig DTI RELY (2.1) 150 bid 64 35% (0.051) 7% Rivaro Xa Rocket AF (3.5) 20 qd 55 21% (0.15) 6% Apixa Xa Aristotle (2.1) 5 bid 62 24% (0.047) 31% Granger CB et al. N Engl J Med DOI: 1056 Efficacy (stroke) vs Side Effect (bleeding) Appendectomy Surgical Interventional Maisel W. N Engl J Med 2009;360:

12 When and For How Long Classes of Recommendations Use the Guidelines, Luke I IIa IIb III Intervention is useful and effective Evidence conflicts/opinions differ but lean toward efficacy Evidence conflicts/opinions differ but lean against efficacy Intervention is not useful/effective and may be harmful Braunwald E, et al Class I Benefit >>> Risk Procedure/ Treatment SHOULD be performed/ administered should is recommended is indicated is useful/effective/ beneficial Applying Classification of Recommendations Class IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment is reasonable can be useful/effective/ beneficial is probably recommended or indicated Class IIb Benefit Risk Additional studies with broad objectives needed; Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED may/might be considered may/might be reasonable usefulness/effectiveness is unknown /unclear/uncertain or not well established Class III Risk Benefit No additional studies needed Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL is not recommended is not indicated should not is not useful/effective/beneficial may be harmful Weighing the Evidence Weight of evidence grades: = Data from many large, randomized trials = Data from fewer, smaller randomized trials, careful analyses of nonrandomized studies, observational registries = Expert consensus Braunwald E, et al

13 Case Study: A 60 year old male presents to the ER with chest pain and ST depression on EKG. After responding to slntg, he requests discharge home with a prescription for a Viagra. You would: Class 1 Recommendations A) Administer Viagra (IIIB) B) Give him your phone number (IIbC) C) Admit to Cardiology (IA) Anticoagulation with a vitamin K antagonist is recommended for patients with more than 1 moderate risk factor. Such factors include age 75 y or greater, hypertension, HF, impaired LV systolic function (ejection fraction 35% or less or fractional shortening less than 25%), and diabetes mellitus. (Level of Evidence: A) Class 1 Recommendations Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except those with lone AF or contraindications. (Level of Evidence: A) For patients with AF of 48-h duration or longer, or when the duration of AF is unknown, anticoagulation (INR 2.0 to 3.0) is recommended for at least 3 wk prior to and 4 wk after cardioversion. (Level of Evidence: B) The selection of the antithrombotic agent should be based upon the absolute risks of stroke and bleeding and the relative risk and benefit for a given patient. (Level of Evidence: A) Dabigatran is useful as an alternative to warfarin for the prevention of stroke in patients who do not have a prosthetic heart valve or hemodynamically significant valve disease, severe renal failure (creatinine clearance <15 ml/min) (Level of Evidence: B) Class 1 Recommendations For patients with AF of less than 48-h duration associated with hemodynamic instability (angina pectoris, MI, shock, or pulmonary edema), cardioversion should be performed immediately without delay for prior initiation of anticoagulation. (Level of Evidence: C) For patients without mechanical heart valves at high risk of stroke, chronic oral anticoagulant therapy with a vitamin K antagonist is recommended in a dose adjusted to achieve the target intensity INR of 2.0 to 3.0, unless contraindicated. Factors associated with highest risk for stroke in patients with AF are prior thromboembolism (stroke, TIA, or systemic embolism) and rheumatic mitral stenosis. (Level of Evidence: A) Anticoagulation with a vitamin K antagonist is recommended for patients with more than 1 moderate risk factor. Such factors include age 75 y or greater, hypertension, HF, impaired LV systolic function (ejection fraction 35% or less or fractional shortening less than 25%), and diabetes mellitus. (Level of Evidence: A) 13

14 Class 1 Recommendations When and for how long in new onset afib INR should be determined at least weekly during initiation of therapy and monthly when anticoagulation is stable. (Level of Evidence: A) Aspirin, mg daily, is recommended as an alternative to vitamin K antagonists in low-risk patients or in those with contraindications to oral anticoagulation. (Level of Evidence: A) For patients with AF who have mechanical heart valves, the target intensity of anticoagulation should be based on the type of prosthesis, maintaining an INR of at least 2.5. (Level of Evidence: B) Antithrombotic therapy is recommended for patients with atrial flutter as for those with AF. (Level of Evidence: C) Anticoagulate and rate control everyone initially Decide on cardioversion or rate control 4 weeks after cardioversion, decide on the need for long term anticoagulation ACC/AHA Guidelines 2011: Determine the Risk ACC/AHA Guidelines 2011: Therapy Based on Risk Less Validated or Weaker Risk Factors Moderate-Risk Factors High-Risk Factors Risk Category Recommended Therapy Female gender Age greater than or equal to 75 y Previous stroke, TIA or embolism Age 65 to 74 y Hypertension Mitral stenosis Coronary artery disease Heart failure Prosthetic heart valve * Thyrotoxicosis LV ejection fraction 35% or less Diabetes mellitus No risk factors One moderate-risk factor Any high-risk factor or more than 1 moderate-risk factor (CHADS2) Aspirin, 81 to 325 mg daily Aspirin or warfarin Warfarin (INR 2.0 to 3.0, target 2.5) * * If mechanical valve, target international normalized ratio (INR) greater than 2.5. Fuster, V. et al. J Am Coll Cardiol 2011;57:e101-e198 Fuster, V. et al. J Am Coll Cardiol 2011;57:e101-e198 14

15 CHADS 2 Score Risk of Stroke CHADS Score Annual Stroke Risk 0 1.9% 1 2.8% 2 4.0% 3 5.9% 4 8.5% % % Balancing the Risk of Stroke and Risk of Bleeding CHADS-vasc CHF (1) Hypertension (1) Age >75 (2) Diabetes (1) Stroke (2) Vascular Disease: (1) Age (1) SC = Sex Category Female (1) HAS-BLED CHF Hypertension Age > 75 Diabetes Stroke Bleeding History Labile INR Abnormal Renal or Liver Function Drugs/Alcohol Concomitantly CHADS= CHF, BP, Age, Diabetes, Stroke (2) Class IIa Recommendations Class IIa Recommendations For primary prevention of thromboembolism in patients with nonvalvular AF who have just 1 of the following validated risk factors, antithrombotic therapy with either aspirin or a vitamin K antagonist is reasonable, based upon an assessment of the risk of bleeding complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences: age greater than or equal to 75 y (especially in female patients), hypertension, HF, impaired LV function, or diabetes mellitus. (Level of Evidence: A) For patients with nonvalvular AF who have 1 or more of the following less well-validated risk factors, antithrombotic therapy with either aspirin or a vitamin K antagonist is reasonable for prevention of thromboembolism: age 65 to 74 y, female gender, or CAD. The choice of agent should be based upon the risk of bleeding complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences. (Level of Evidence: B) It is reasonable to select antithrombotic therapy using the same criteria irrespective of the pattern (i.e., paroxysmal, persistent, or permanent) of AF. (Level of Evidence: B) In patients with AF who do not have mechanical prosthetic heart valves, it is reasonable to interrupt anticoagulation for up to 1 wk without substituting heparin for surgical or diagnostic procedures that carry a risk of bleeding. (Level of Evidence: C) Low Risk Patients can be treated with aspirin or warfarin Paroxysmal vs Persistent doesn t make a difference Anticoagulation may be stopped for 1 week Re-evaluate the need for anticoagulalants periodically It is reasonable to reevaluate the need for anticoagulation at regular intervals. (Level of Evidence: C) 15

16 Class IIb Recommendations Class IIb Recommendations In patients 75 y of age and older at increased risk of bleeding but without frank contraindications to oral anticoagulant therapy, and in other patients with moderate risk factors for thromboembolism who are unable to safely tolerate anticoagulation at the standard intensity of INR 2.0 to 3.0, a lower INR target of 2.0 (range 1.6 to 2.5) may be considered for primary prevention of ischemic stroke and systemic embolism. (Level of Evidence: C) When surgical procedures require interruption of oral anticoagulant therapy for longer than 1 wk in high-risk patients, unfractionated heparin may be administered or low-molecular-weight heparin given by subcutaneous injection, although the efficacy of these alternatives in this situation is uncertain. (Level of Evidence: C) Following percutaneous coronary intervention or revascularization surgery in patients with AF, low-dose aspirin (less than 100 mg per d) and/or clopidogrel (75 mg per d) may be given concurrently with anticoagulation to prevent myocardial ischemic events, but these strategies have not been thoroughly evaluated and are associated with an increased risk of bleeding. (Level of Evidence: C) In patients undergoing percutaneous coronary intervention, anticoagulation may be interrupted to prevent bleeding at the site of peripheral arterial puncture, but the vitamin K antagonist should be resumed as soon as possible after the procedure and the dose adjusted to achieve an INR in the therapeutic range. Aspirin may be given temporarily during the hiatus, but the maintenance regimen should then consist of the combination of clopidogrel, 75 mg daily, plus warfarin (INR 2.0 to 3.0). Clopidogrel should be given for a minimum of 1 mo after implantation of a bare metal stent, at least 3 mo for a sirolimus-eluting stent, at least 6 mo for a paclitaxel-eluting stent, and 12 mo or longer in selected patients, following which warfarin may be continued as monotherapy in the absence of a subsequent coronary event. When warfarin is given in combination with clopidogrel or low-dose aspirin, the dose intensity must be carefully regulated. (Level of Evidence: C) In patients with AF younger than 60 y without heart disease or risk factors for thromboembolism (lone AF), the risk of thromboembolism is low without treatment and the effectiveness of aspirin for primary prevention of stroke relative to the risk of bleeding has not been established. (Level of Evidence: C) In patients with AF who sustain ischemic stroke or systemic embolism during treatment with low-intensity anticoagulation (INR 2.0 to 3.0), rather than add an antiplatelet agent, it may be reasonable to raise the intensity of anticoagulation to a maximum target INR of 3.0 to 3.5. (Level of Evidence: C) During the first 48 h after onset of AF, the need for anticoagulation before and after cardioversion may be based on the patient's risk of thromboembolism. (Level of Evidence: C) As an alternative to anticoagulation prior to cardioversion of AF, it is reasonable to perform TEE in search of thrombus in the LA or LAA. (Level of Evidence: B) For patients with no identifiable thrombus, cardioversion is reasonable immediately after anticoagulation with unfractionated heparin (e.g., initiate by intravenous bolus injection and an infusion continued at a dose adjusted to prolong the activated partial thromboplastin time to 1.5 to 2 times the control value until oral anticoagulation has been established with a vitamin K antagonist (e.g., warfarin), as evidenced by an INR equal to or greater than 2.0.). (Level of Evidence: B) Thereafter, oral anticoagulation (INR 2.0 to 3.0) is reasonable for a total anticoagulation period of at least 4 wk, as for patients undergoing elective cardioversion. (Level of Evidence: B) Limited data are available to support the subcutaneous administration of a low-molecular-weight heparin in this indication. (Level of Evidence: C) For patients in whom thrombus is identified by TEE, oral anticoagulation (INR 2.0 to 3.0) is reasonable for at least 3 wk prior to and 4 wk after restoration of sinus rhythm, and a longer period of anticoagulation may be appropriate even after apparently successful cardioversion, because the risk of thromboembolism often remains elevated in such cases. (Level of Evidence: C) For patients with atrial flutter undergoing cardioversion, anticoagulation can be beneficial according to the recommendations as for patients with AF. (Level of Evidence: C) Class IIb Recommendations If you can t tolerate full dose, try low dose If you can't tolerate warfarin, ASA + clopidogrel is an option If you need to stop warfarin for more than 1 week, use heparin Post PCI warfarin, clopidogrel and low dose aspirin are OK Warfarin may be temporarily stopped for elective PCI If a stroke occurs on low intensity AC, raise the intensity (+) In the first 48 hours, AC should be based on risk In the first 48 hours, TEE cardioversion is an alternative to AC Low risk TEE (-) patients may be treated with AC for 4 weeks TEE (+) when cardioverting patients are high risk Class III Recommedation Long-term anticoagulation with a vitamin K antagonist is not recommended for primary prevention of stroke in patients below the age of 60 without heart disease (lone AF) or any risk factors for thromboembolism. (Level of Evidence: C) 16

17 AFFECT Registry 1461 patients with lone paroxysmal AF Cardiologists trained in guidelines Strategy - Rhythm Control 64% - Rate Control 36% 83% received anticoagulants - warfarin 64% - aspirin 32% AFFECT Registry: % on AC by risk and strategy CHADS Score Rhythm Strategy Rate Strategy >2 66% 73% <2 49% 60% AFFIRM: Patients Require Anticoagulation Despite Successful Rhythm-Control Therapy Atrial Fibrillation Follow-up Investigation of Rhythm Management Compliance Can Be Improved Only 15% to 44% of eligible AF patients receive warfarin. Don t make promises The very elderly are at highest risk of stroke, but are least likely to receive therapy. Survey of 142 internists: - Physician estimates of intra-cerebral bleeding rates for a given patient overestimated by >10-times those reported in clinical trials. - Some physicians doubt that the high efficacy and low bleeding rates obtained in clinical trials can be achieved in routine practice. AFFIRM Investigators. N Engl J Med. 2002;347: Bungard et al. Arch Intern Med. 2000;160: Wolf et al. Arch Intern Med. 1987;147: White et al. Am J Med. 1999;106:

18 Summary Why Reduce the risk of Stroke What Warfarin will be a thing of the past When At time of presentation if possible For How Long? CHADS > 2 forever CHADS < 2 1 month or aspirin forever Don t make promises References Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation Patel M.R., Mahaffey K.W., Garg J., et al. N Engl J Med 2011; 365: New Options in Anticoagulation for Atrial Fibrillation del Zoppo G.J. and Eliasziw M. N Engl J Med 2011; 365: Apixaban versus Warfarin in Patients with Atrial Fibrillation Granger C.B., Alexander J.H., McMurray J.J.V., et al /NEJMoa Anticoagulant Options Why the FDA Approved a Higher but Not a Lower Dose of Dabigatran Beasley B.N., Unger E.F., Temple R. N Engl J Med 2011; 364: Dabigatran versus Warfarin in Patients with Atrial Fibrillation Connolly S.J., Ezekowitz M.D., Yusuf S., et al. N Engl J Med 2009; 361: Left Atrial Appendage Occlusion Closure or Just the Beginning? Maisel W.H. N Engl J Med 2009; 360: A Comparison of Rate Control and Rhythm Control in Patients with Atrial FibrillationThe Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators N Engl J Med 2002; 347: