Atrial fibrillation anticoagulation
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
Antithrombotic Strategies for Prevention of Ischemic Stroke and Systemic Embolism
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.[1]
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. [1][2][3] [1][4] 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.[5][6] [7][8]
Based upon the RE-LY study, dabigatran was recently approved for the treatment of non-valvular atrial fibrillation.
ACC / AHA Guidelines- Preventing Thromboembolism (DO NOT EDIT) [9]
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Class I1. 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 IIa1. For primary prevention of thromboembolism in patients with non valvular 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) 2. For patients with non valvular 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 (i.e., 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 week 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 IIb1. 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 week 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 (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) 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 month after implantation of a bare metal stent, at least 3 months for a sirolimus-eluting stent, at least 6 months for a paclitaxel-eluting stent, and 12 months 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 III1. 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. (Level of Evidence:C) |
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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
Newer agents that inhibit factor Xa are under investigation for the management of atrial fibrillation. These agents include apixabin and rivaroxaban.
Antiplatelet therapy for atrial fibrillation
Aspirin Monotherapy
Aspirin monotherapy is associated with only a modest and inconsistent reduction in the risk of stroke associated with atrial fibrillation. [8] [8]
[10] 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. [11][12]
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[13]. 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)[14].
REFERENCES
- ↑ 1.0 1.1 1.2 Hart RG, Benavente O, McBride R, Pearce LA (1999). "Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis". Ann. Intern. Med. 131 (7): 492–501. Unknown parameter
|month=ignored (help) - ↑ Gorter JW (1999). "Major bleeding during anticoagulation after cerebral ischemia: patterns and risk factors. Stroke Prevention In Reversible Ischemia Trial (SPIRIT). European Atrial Fibrillation Trial (EAFT) study groups". Neurology. 53 (6): 1319–27. PMID 10522891. Unknown parameter
|month=ignored (help) - ↑ Hylek EM, Singer DE (1994). "Risk factors for intracranial hemorrhage in outpatients taking warfarin". Ann. Intern. Med. 120 (11): 897–902. PMID 8172435. Unknown parameter
|month=ignored (help) - ↑ Hart RG, Halperin JL (1999). "Atrial fibrillation and thromboembolism: a decade of progress in stroke prevention". Ann. Intern. Med. 131 (9): 688–95. PMID 10577332. Unknown parameter
|month=ignored (help) - ↑ Hylek EM, Skates SJ, Sheehan MA, Singer DE (1996). "An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation". N. Engl. J. Med. 335 (8): 540–6. PMID 8678931. Unknown parameter
|month=ignored (help) - ↑ "Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial". Lancet. 348 (9028): 633–8. 1996. PMID 8782752. Unknown parameter
|month=ignored (help) - ↑ "Optimal oral anticoagulant therapy in patients with nonrheumatic atrial fibrillation and recent cerebral ischemia. The European Atrial Fibrillation Trial Study Group". N. Engl. J. Med. 333 (1): 5–10. 1995. PMID 7776995. Unknown parameter
|month=ignored (help) - ↑ 8.0 8.1 8.2 Hart RG (1998). "Intensity of anticoagulation to prevent stroke in patients with atrial fibrillation". Ann. Intern. Med. 128 (5): 408. PMID 9490603. Unknown parameter
|month=ignored (help) - ↑ Fuster V, Ryden LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, Halperin JL, Le Heuzey JY, Kay GN, Lowe JE, Olsson SB, Prystowsky EN, Tamargo JL, Wann S. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation- Executive Summary: executive summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidlines for the Management of Patients With Atrial Fibrillation): Developed in Collaboration With the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006; 114: 700-752. PMID 16908781
- ↑ "The efficacy of aspirin in patients with atrial fibrillation. Analysis of pooled data from 3 randomized trials. The Atrial Fibrillation Investigators". Arch. Intern. Med. 157 (11): 1237–40. 1997. PMID 9183235. Unknown parameter
|month=ignored (help) - ↑ Miller VT, Rothrock JF, Pearce LA, Feinberg WM, Hart RG, Anderson DC (1993). "Ischemic stroke in patients with atrial fibrillation: effect of aspirin according to stroke mechanism. Stroke Prevention in Atrial Fibrillation Investigators". Neurology. 43 (1): 32–6. PMID 8423907. Unknown parameter
|month=ignored (help) - ↑ Hart RG, Pearce LA, Miller VT; et al. (2000). "Cardioembolic vs. noncardioembolic strokes in atrial fibrillation: frequency and effect of antithrombotic agents in the stroke prevention in atrial fibrillation studies". Cerebrovasc. Dis. 10 (1): 39–43. PMID 10629345.
- ↑ The ACTIVE Writing Group on behalf of the ACTIVE Investigators. Lancet 2006;367:1903-12.
- ↑ The ACTIVE Writing Group on behalf of the ACTIVE Investigators. Lancet 2006;367:1903-12.