Selecting antithrombotic therapy for patients with atrial fibrillation

RISK-BASED ANTITHROMBOTIC THERAPY IN NONVALVULAR ATRIAL FIBRILLATION

The 2014 atrial fibrillation guidelines¹ state that the decision to give antithrombotic therapy for atrial fibrillation should be individualized, based on the absolute and relative risks of stroke and bleeding, and ought to take into consideration the patient’s preferences. For patients with nonvalvular atrial fibrillation, selection of antithrombotic therapy should take into account the risk of thromboembolism determined by the CHA₂DS₂-VASc score and be irrespective of the pattern of atrial fibrillation (paroxysmal, persistent, or permanent). Antithrombotic therapy is similarly recommended for patients with atrial flutter, according to the same risk profile used for atrial fibrillation.

Studies have consistently shown^24–27 that the risk of ischemic stroke without anticoagulation exceeds the risk of intracranial bleeding with anticoagulation in nearly all patients except those at lowest risk of thromboembolism. The CHA₂DS₂-VASc score better identified those at truly low risk, in whom treatment may offer more risk than benefit.^24–27

The HAS-BLED score²⁸ assigns points as follows:

• Hypertension (systolic blood pressure > 160 mm Hg): 1 point
• Abnormal renal function (dialysis, renal transplantation, or serum creatinine > 2.6 mg/mL) or liver function (cirrhosis, bilirubin more than two times the upper limit, or aminotransferase levels more than three times the upper limit): 1 or 2 points
• Stroke: 1 point
• Bleeding (prior major bleeding event or predisposition to bleeding): 1 point
• Labile international normalized ratio (INR) (supratherapeutic or time in therapeutic range < 60%): 1 point
• Elderly (age > 65): 1 point
• Drugs (antiplatelet, nonsteroidal anti-inflammatory) or alcohol (more than eight drinks per week): 1 or 2 points
• Maximum total: 9 points.

HAS-BLED is a practical and validated approach for estimating bleeding risk and is mentioned in the guidelines, but it is not recommended for use in guiding decisions about antithrombotic therapy. Specifically, it should not be used to exclude patients, but rather to identify those at high risk (score ≥ 3) who may require closer observation and more attentive monitoring of the INR.

ANTITHROMBOTIC THERAPY

Antithrombotic agents available for use in the United States include antiplatelet drugs (eg, aspirin and clopidogrel) and anticoagulants (unfractionated heparin and low-molecular-weight heparin, vitamin K antagonists such as warfarin, and direct thrombin and factor Xa inhibitors). Anticoagulation has been shown in randomized controlled trials to be superior to both placebo and antiplatelet agents used either alone or in combination.²⁹

Aspirin has been downgraded

Aspirin has been compared with placebo in seven randomized controlled trials. Only the original SPAF study, in which aspirin 325 mg/day was used, found that it was beneficial. This result alone accounted for the 19% reduction in relative risk (95% CI 1%–35%, P < .05) in a meta-analysis performed by Hart et al.²⁹ Even when combined with clopidogrel 75 mg/day, aspirin 75 to 100 mg/day is still inferior to warfarin.⁵ While dual antiplatelet therapy resulted in a 28% relative reduction in thromboembolism (95% CI 17%–38%, P < .01) compared with aspirin alone, major bleeding significantly increased by 57% (95% CI 29%–92%, P < .01).

Although aspirin may be beneficial, differences among patients may influence its efficacy. It may be more effective in preventing noncardioembolic stroke, particularly in diabetic and hypertensive patients.^30,31 To date, aspirin has not been shown to be beneficial in low-risk populations.

The 2014 guidelines downgraded the recommendation for aspirin therapy. For patients at low risk and for some at intermediate risk, it is permissible to forgo therapy altogether, including aspirin.¹

ORAL ANTICOAGULANTS

The rest of this paper reviews the oral anticoagulants that are approved for reducing the risk of thromboembolism in atrial fibrillation, focusing on each agent’s mechanism of action, pharmacokinetics, clinical efficacy, and safety.

WARFARIN, A VITAMIN K ANTAGONIST

Warfarin inhibits synthesis of vitamin K-dependent clotting factors (ie, factors II, VII, IX, and X) and proteins C and S by inhibiting the C1 subunit of vitamin K epoxide reductase, thereby interfering with production of vitamin K₁ epoxide and consequent regeneration of vitamin K.

Pharmacokinetics. Warfarin is nearly completely absorbed after oral administration. Its anticoagulant effect can be seen within 24 hours of administration, but its peak effect is typically apparent only after 72 hours. Elimination occurs predominantly through metabolism by cytochrome P450 enzymes, principally CYP2C9. Its effective half-life ranges from 20 to 60 hours, with a mean of 40 hours.³²

Warfarin’s effect, dosage, and bleeding risk are influenced by multiple factors, including vitamin K-containing foods such as green leafy vegetables, medications that either inhibit or induce hepatic cytochrome P450 enzymes, and polymorphisms in the VKORC1 and CYP2C9 genes.³²

Reversal. Warfarin’s anticoagulant effect is reversed with vitamin K, but this reversal may not become apparent for 6 to 24 hours. In contrast, fresh-frozen plasma and prothrombin protein concentrate, which contain clotting factors, reverse warfarin immediately. Currently, a three-factor prothrombin protein concentrate (factors II, IX, and X) and a four-factor concentrate (factors II, VII, IX, and X plus proteins C and S) are available in the United States. Although prothrombin protein concentrate works rapidly and has a lower volume of administration, available data do not indicate it is clinically superior to fresh-frozen plasma.^33,34 The ongoing randomized PROTECT trial (NCT00618098), comparing fresh-frozen plasma and four-factor prothrombin protein concentrate for reversal of vitamin K antagonist therapy, may provide further insight.

Efficacy and safety. Randomized controlled trials in patients with nonvalvular atrial fibrillation have shown that warfarin (in doses adjusted to maintain an INR greater than 2) is highly efficacious in preventing systemic embolism, with a relative risk reduction of 61% (95% CI 47%–71%, P < .05) compared with placebo.^29,35 An INR of 2 to 3 is recommended for patients with nonvalvular atrial fibrillation, and those with atrial fibrillation and either a bioprosthetic valve or rheumatic heart disease. In contrast, an INR of 2.5 to 3.5 is recommended for patients with atrial fibrillation and mechanical valves in the aortic or mitral positions.^1,36

An INR of 2 to 3 offers maximum protection with minimal risk of bleeding

Stroke prevention with warfarin is most effective when the achieved mean time in the therapeutic range is at least 70%. The risk of intracranial hemorrhage increases significantly at INRs higher than 3. An INR of 2 to 3 offers maximum protection with minimal risk of bleeding.^37,38 Systematic follow-up of patients through anticoagulation clinics produces better compliance and control and is encouraged.