Aspirin in Stroke Prevention in Nonvalvular Atrial Fibrillation and Stable Vascular Disease

An Era of New Anticoagulants

Mohit K Turagam; Poonam Velagapudi; Miguel A Leal; Abraham G Kocheril

Disclosures

Expert Rev Cardiovasc Ther. 2012;10(4):433-439. 

In This Article

Role of Aspirin in AF

As mentioned previously, aspirin is currently recommended for patients with a CHADS2 score or CHA2DS2-VASc score of 0–1, with preference given to anticoagulation in patients with a score of 1 and no treatment in patients with a score of zero. Data from several studies have shown that oral anticoagulation with warfarin is superior to aspirin in ischemic stroke prevention without a significant increased risk of bleeding in patients with a CHADS2 score of 1.[20,21,24,25] A meta-analysis by Hart et al., including 29 trials with 28,044 participants (mean age: 71 years; mean follow-up: 1.5 years) compared adjusted-dose warfarin (six trials, 2900 participants) and antiplatelet agents (eight trials, 4876 participants), and found that they reduced stroke by 64% (95% CI: 49–74%) and 22% (95% CI: 6–35%), respectively.[26] Adjusted-dose warfarin was substantially more efficacious than antiplatelet therapy (RR reduction: 39%; 95% CI: 22–52%; 12 trials; 12,963 participants). Absolute increases in major extracranial hemorrhage were small (≤0.3% per year) on the basis of meta-analysis. In the analysis confined to the aspirin-only trials, stroke risk was reduced by only 19% (95% CI: 1–35%) by aspirin therapy compared with placebo; however, this analysis is considered to be nonsignificant statistically since the CI crossed zero. Furthermore, the reduction in stroke risk seen with aspirin in the meta-analysis was largely driven by positive results from the SPAF1 trial, which reported an overall significant reduction in stroke risk of 42% with aspirin versus placebo.[4] Furthermore, aspirin was ineffective in stroke prevention in those over 75 years of age and did not prevent severe strokes. The only benefit shown in stroke prevention by aspirin was with a dose of 325 mg, as there seems to be no benefit by using lower doses when compared with placebo for stroke prevention in AF, although this can be considered to be a controversial conclusion given the paucity of consistent data. The most common reasons for using aspirin in comparison to anticoagulation is the perceived risk of bleeding, anticoagulation ineligibility and patient preference.

Although aspirin is recommended as an option for stroke prevention in AF, two questions remain: does it really help, and, if yes, is it dose-dependent? Aguilar and Hart[27] performed a meta-analysis of three trials comparing aspirin in dosages ranging from 75 mg to 325 mg per day and 125 mg every other day to placebo (in two trials) or control (in one trial) in 1965 AF patients without prior stroke. Aspirin was associated with nonsignificant lower risks of all stroke (OR: 0.70; 95% CI: 0.47–1.07), ischemic stroke (OR: 0.70; 95% CI: 0.46–1.07), all-disabling or fatal stroke (OR: 0.86; 95% CI: 0.50–1.49) and all-cause death (OR: 0.75; 95% CI: 0.54–1.04). However, the combination of stroke, MI or vascular death was significantly reduced (OR: 0.71; 95% CI: 0.51–0.97), with no increase in intracranial hemorrhage. The study concluded that aspirin appears to reduce stroke in patients with nonvalvular AF similar to its effect in other high-risk patients. However, the results of this analysis were driven by the sensitivity analysis of the fourth trial (SAFT), in which aspirin was combined with warfarin.[27] Similarly, another study by Sato et al. studied the role of aspirin compared with placebo in patients with nonvalvular AF.[28] Subjects were randomized to aspirin (150–200 mg per day) or a control group without antiplatelet or anticoagulant therapy. A total of 426 patients were randomized to the aspirin group and 445 to no treatment. The trial was stopped early because there were 27 primary end point events (3.1% per year; 95% CI: 2.1–4.6% per year) in the aspirin group versus 23 (2.4% per year; 95% CI: 1.5–3.5% per year) in the control group, suggesting a low likelihood of aspirin superiority for prevention of the primary end point. In addition, treatment with aspirin caused a marginally increased risk of major bleeding (1.6%, compared with the control group 0.4%; p = 0.1). The study concluded that aspirin at a dose of 150–200 mg per day does not seem to be effective or safe for prevention of stroke in patients with AF.

Many patients with AF have associated vascular disease, and adding aspirin to warfarin or even aspirin to clopidogrel has not been shown to reduce cardiovascular events in patients with AF, but substantially increased the risk of bleeding.[29,30] Aspirin–clopidogrel therapy was compared with aspirin monotherapy in the ACTIVE A trial, which included patients with AF who were deemed unsuitable for warfarin or had previously refused warfarin. This randomized controlled trial showed that adding clopidogrel to aspirin therapy prevented 0.57 ischemic stroke equivalents (95% CI: 0.12–1.24) per 100 patient-years of treatment when weighted by hazard for death after ischemia or hemorrhage, and 0.67 ischemic stroke equivalent events (95% CI: 0.03–1.18) when weighted by death or disability after ischemia or hemorrhage.[31] Warfarin was compared with aspirin–clopidogrel combination therapy for stroke prevention in the ACTIVE W trial, which was stopped early because of the clear superiority of warfarin over the aspirin–clopidogrel combination.[32]

Based on the results of the RE-LY,[18] ROCKET-AF[19] and ARISTOTLE[20] trials, given the significant reduction of intracerebral bleeding events compared with patients taking vitamin K antagonists, the newer anticoagulants might theoretically be a valid alternative for patients with nonvalvular AF and increased risk of stroke (CHADS2 score of at least 2). The question remains if the results of these studies should be extended to elderly patients with low risk of stroke (CHA2DS2-VASc score of 1). A recent analysis by Olesen et al. reported that the thromboembolic rates after 1 year of follow-up in the low-risk category (score = 0) were 1.67 (95% CI: 1.47–1.89) for CHADS2 and 0.78 (95% CI: 0.58–1.04) for CHA2DS2-VASc.[16] In the intermediate-risk category (score = 1), the rate of thromboembolism per 100 person-years was 4.75 (95% CI: 4.45–5.07) for CHADS2 and 2.01 (95% CI: 1.70–2.36) for CHA2DS2-VASc. This risk pattern was generally sustained at 5 and 10 years of follow-up; patients classified as being at intermediate risk by CHADS2 had a higher rate of thromboembolism than did those classified as being at intermediate risk by CHA2DS2-VASc (3.6 vs 1.5). The study also reported that it was unfair to consider all the risk factors in the CHADS2 and CHA2DS2-VASc scores regarding stroke risk equally. In the CHADS2 score, the risk factor associated with the highest risk at 1 year follow-up was age ≥75 years (HR: 3.52; 95% CI: 3.05–4.07), whereas hypertension was associated with the lowest thromboembolism risk (1.45; 95% CI: 1.17–1.79). Similarly, for a CHA2DS2-VASc score for patients with a CHA2DS2-VASc score of 1, diabetes was associated with the highest thromboembolism rate (3.47; 95% CI: 1.65–7.27), and age 65–74 years had the second highest rate (2.88; 95% CI: 2.29–3.62) at 1 year of follow-up. The study also reported that with a CHA2DS2-VASc score of 0, the risk was 'truly low' and no reduction in thromboembolic rate occurred with vitamin K antagonist treatment, whereas the thromboembolic rate was reduced in vitamin K-antagonist treated patients with CHADS2 scores 0–1 and a CHA2DS2-VASc score of 1. Use of CHA2DS2-VASc could theoretically simplify thromboprophylaxis, with a CHA2DS2-VASc score of 0 identifying patients at truly low risk, for whom no anti-thrombotic treatment may be considered. With a CHA2DS2-VASc score of 1, oral anticoagulation may be used, given the limited evidence for the efficacy of aspirin. Further discussion on the pros and cons of both CHADS2 and CHA2DS2-VASc scores in stroke risk stratification of AF is beyond the scope of this paper. Even though there are no randomized studies supporting this hypothesis, results from the AVERROES trial[11] have shown that major bleeding risk with aspirin is not significantly different from apixaban (1.2% for aspirin and 1.4% for apixaban; p = 0.33), especially in elderly individuals. Finally, the decision to anticoagulate is based not only on thromboembolism risk but also on the risk of bleeding.

This article suggests the need to reconsider the benefits of using aspirin in stroke prevention, especially in low-risk patients or patients not suitable for warfarin therapy. Further trials comparing aspirin with newer anticoagulants (dabigatran, apixaban and rivaroxaban) are necessary to assess the role of each agent in stroke prevention in patients with AF.

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