Atrial fibrillation anticoagulation


 * Associate Editor(s)-In-Chief:

Synonyms and related keywords: AF, Afib, fib

Overview
Oral anticoagulation is a mainstay of atrial fibrillation management. For both primary and secondary prevention of stroke, there is a 61% relative  risks reduction in the incidence of all cause stroke (both ischemic and  hemorrhagic) associated with adjusted-dose oral anticoagulation.

Increasing patient age (which is associated with smaller body weight, female  gender and a progressive decline in renal function) and higher INRs or  greater intensity of anticoagulation are both associated with a higher  risk of major bleeding. This is critical in so far as bleeding is in turn associated with non-compliance with pharmacotherapy. Given that many patients with atrial fibrillation are elderly, there is often a narrow therapeutic window in achieving the optimal INR. The optimal INR should obviously maximize efficacy in reducing the risk of  stroke and simultaneously minimize the risk of bleeding. In the setting of atrial fibrillation, an INR of 2 to 3 appears to be optimal. INRs lower than this, such as those in the range of 1.6 to 2.5, are  associated with efficacy that is only 80% of that in the target range.

Based upon the RE-LY study, dabigatran was recently approved for the treatment of non-valvular atrial fibrillation.

Interruption of anticoagulation with coumadin
No mechanical valve, high risk of bleeding with procedure: Coumadin can be discontinued for one week without heparin bridging.

Presence of mechanical valve, patients with AF who are at high risk of  stroke,  or patients in whom Coumadin must be interrupted for over a  week:  These  patients should be administered either unfractionated heparin or low molecular weight heparin.

Investigational antithrombin agents
Warfarin inhibits multiple factors in the anticoagulation cascade, and dabigatran is a direct thrombin (Factor 2) inhibitor. Newer agents that inhibit factor Xa are under investigation for the anticoagulation of patients with non-valvular atrial fibrillation. These agents include apixaban which is being evaluated in the Aristotle trial, edoxaban which is being evaluated in the Engage trial and rivaroxaban which was evaluated in the Rocket AF program. Slides from the Rocket-AF program can be downloaded [[media:ROCKET-AF.ppt|here]]. A comparison of the RE-LY and Rocket AF trials can be found here.

Aspirin Monotherapy
Aspirin monotherapy is associated with only a modest  and inconsistent  reduction in the risk of stroke associated with atrial fibrillation.

Studies suggest that the efficacy of aspirin may be greater in patients with hypertension or diabetes. Aspirin may also be more efficacious in reducing the risk of non cardioembolic stroke as opposed to the more disabling cardioembolic form  of stroke.

Dual Antiplatelet therapy
Among patients who are not deemed candidates for Coumadin therapy (estimated to be approximately 40-50% of patients), dual antiplatelet therapy with both aspirin and clopidogrel (at a maintenance dose of 75 mg/day) was superior to aspirin monotherapy in the ACTIVE A trial. The primary endpoint of the trial was the composite of stroke, myocardial infarction, non–central nervous system systemic embolism, or  death from vascular causes. After a median of 3.6 years of follow-up in 7,554 randomized patients, the addition of clopidogrel to aspirin  alone yielded a reduction in events from 7.6% to 6.8% (relative risk  reduction with clopidogrel, 0.89; 95% confidence interval [CI], 0.81 to  0.98; P=0.01). The addition of clopidogrel to aspirin alone reduced the risk of stroke by 28% (from 3.3% to 2.4%, p<0.001)  and reduced the risk of MI by 22% (from 0.9% per year to 0.7% per year,  p=0.08). The risk of major bleeding among patients treated with aspirin and clopidogrel was 2.0% per year whereas it was 1.3% per year among  patients treated with aspirin alone (relative risk, 1.57; 95% CI, 1.29  to 1.92; P<0.001). If 1000 patients were treated for 3 years, the combination of aspirin plus clopidogrel would prevent 28 strokes (17  disabling or fatal), and 6 myocardial infarctions, at a cost of 20 major  bleeds compared to aspirin alone.

Oral Anticoagulation (Coumadin) versus Dual Antiplatelet Therapy (ASA/Clopidogrel)
In the ACTIVE W trial, dual antiplatelet therapy with aspirin(75-100 mg per day) and clopidogrel (75 mg per day) was found to be statistically inferior to coumadin therapy (target INR 2.0 to 3.0) in the management of patients with atrial fibrillation who had one or more risk factors for stroke. The primary endpoint of ACTIVE W was the first occurrence of stroke, non-CNS systemic embolus, myocardial infarction, or vascular death. The annual risk in the coumadin group was 3.93% per year, and in the Aspirin/Clopidogrel group it was 5.60% per year yielding a relative risk of 1.44  (1.18-1.76; p=0.0003). The efficacy was not as great among patients who were coumadin naive, although the p-value for the interaction was  negative. There was no excess bleeding among patients treated with coumadin, and in fact there was an excess of minor bleeds among patients treated with ASA and clopidogrel (13.6% / yr vs 11.5% year, p=0.0009).

When examining the data from atrial fibrillation trials, it is critical to  evaluate the results in patients who were previously treated with coumadin  separate from those patients who were naive to coumadin. Patients previously treated with coumadin are likely to be those patients who  best tolerate coumadin and have passed their "bleeding stress test" and  have a lower rate of bleeding on coumadin. Those patients who bleed while on coumadin  have already been culled out from the population. When the data in ACTIVE W were evaluated including only those patients previously treated  with coumadin(again  a population to be anticipated to be at low risk of bleeding), the risk  of major bleeding was indeed statistically significantly lower among  patients previously treated with coumadin (p=0.03) than patients not  previously treated.

The majority of the reduction in events was due to a reduction in stroke and non-CNS emolization associated with coumadin therapy. The  pathophysiology of stroke among patients with atrial fibrillation is  thought to be embolization from clot in the [[left atrium.  The data from ACTIVE W suggest that platelet activation and its  treatment may not play a pivotal role in the treatment of mural thrombus  and embolization in atrial fibrillation.  Coumadin was more effective  in the reduction of non-disabling stroke rather than disabling stroke.  There were more fatal hemorrhagic strokes (which may more often be  fatal), and this may explain in part why coumadin was not associated  with a reduction in mortality in the study.

While clopidogrel plus aspirin has been found to reduce the risk of recurrent myocardial infarction among patients with presumed plaque rupture and acute coronary syndromes, it is notable in ACTIVE W that the risk of myocardial infarction tended to be higher among patients treated with aspirin plus clopidogrel versus coumadin (0.86% vs 0.55%,p=0.09).

==ACCF/AHA/HRS 2011 Guidelines- Preventing Thromboembolism (DO NOT EDIT) == {{cquote|

Class I
1. Antithrombotic therapy to prevent thromboembolism is recommended for all patients with AF, except those with lone AF or contraindications. (Level of Evidence: A)

2. 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)

3. 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)

4. 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)

5. INR should be determined at least weekly during initiation of therapy and monthly when anticoagulation is stable. (Level of Evidence: A)

6. Aspirin, 81–325 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)

7. 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)

8. Antithrombotic therapy is recommended for patients with atrial flutter as for those with AF. (Level of Evidence: C)

Class IIa
1. For primary prevention of thromboembolism in patients with nonvalvular AF who have just 1 of the following validated risk factors, anti-thrombotic 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, heart failure, impaired LV function, or diabetes mellitus. (Level of Evidence: A)

2. 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)

3. It is reasonable to select antithrombotic therapy using the same criteria irrespective of the pattern (ie, paroxysmal, persistent, or permanent) of AF. (Level of Evidence: B)

4. 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)

5. It is reasonable to reevaluate the need for anticoagulation at regular intervals. (Level of Evidence: C)

Class IIb
1. 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)

2. 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)

3. Following percutaneous coronary intervention or revascularization surgery in patients with AF, low-dose aspirin (less than 100 mg per d) and/or clopidogrel (75mg 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)

4. 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)

5. 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)

6. 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)

Class III
1. Long-term anticoagulation with a vitamin K antagonist is not recommended for primary prevention of stroke in patients below the age of 60 y without heart disease (lone AF) or any risk factors for thromboembolism. (Level of Evidence: C)}}

Vote on and Suggest Revisions to the Current Guidelines

 * The AF Living Guidelines: Vote on current recommendations and suggest revisions to the guidelines

Guideline Resources

 * ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation


 * 2011 ACCF/AHA/HRS Focused Updates Incorporated Into the ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation


 * ACC/AHA/Physician Consortium 2008 clinical performance measures for adults with nonvalvular atrial fibrillation or atrial flutter