Is Bleeding a Necessary Evil?
Aspirin was considered a potentially attractive alternative to warfarin. Its pharmacokinetic profile means that there is little variability in dose–response and there is no need for routine monitoring of antithrombotic effect or dose adjustment. Aspirin exerts its antithrombotic effect by inhibiting cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to prostaglandin – this is converted to bioactive prostanoids including thromboxane A2. Platelets are unable to regenerate COX, so the effect of aspirin can only be overcome by the generation of new platelets, meaning the effect of the aspirin remains in place for approximately 10 days. After oral administration, aspirin is rapidly absorbed from the upper gastrointestinal tract with peak levels occurring at 30–40 min. Higher doses are not associated with an increased antiplatelet effect.
Hart et al. demonstrated that aspirin conferred a non-significant 19% risk reduction in stroke for AF patients. The confidence intervals crossed zero in this meta-analysis and were, in the main, driven by the results of one single positive trial (SPAF-1), where aspirin was given at the higher dose of 325 mg. In the SPAF-1 study, there was significant heterogeneity of the aspirin effect between anticoagulation-eligible and anticoagulation-ineligible patients. Since the trial was stopped early, the effect of aspirin may have been exaggerated. Indeed, latter-day evidence suggests that an increased dose of aspirin is associated with increased bleeding despite no further increase in platelet inhibition.
The ACTIVE-W trials sought to identify whether dual antiplatelet therapy with aspirin and clopidogrel would be an effective alternative to warfarin. The trial was stopped early due to the clear superiority of warfarin. For patients unable to take warfarin, the ACTIVE-A trial showed that dual antiplatelet therapy reduced ischemic stroke by 28% compared with aspirin alone. In both ACTIVE-A and ACTIVE-W, the rates of bleeding encountered with dual antiplatelet therapy were similar to those observed with warfarin, despite markedly reduced efficacy in preventing thromboembolism. One trial comparing aspirin with the oral factor Xa inhibitor apixaban was stopped early due to the superiority of apixaban. Here, the rates of major bleeding were similar for apixaban (1.4% per year) and aspirin (1.2% per year).
These contemporary trials showing equivalent bleeding rates with antiplatelets and anticoagulants are at odds with meta-analyses of earlier trials showing significantly more bleeding with warfarin. This may reflect advancements in care pathways since the original trials with warfarin were conducted, such as quality of INR control and rates of TTR. Also, the original (now historical) trials randomized <10% of the patients screened, and may be unrepresentative of more typical AF populations seen in more contemporary trials or 'real-world' clinical practice.
In view of its weak efficacy, aspirin is now difficult to advocate in stroke prevention, particularly when the risk of major bleeding (including ICH) is not significantly different to that of warfarin, especially in the elderly. Moreover, the emergence of NOACs which have fewer bleeding complications compared with warfarin and overcome many of its limitations means that the role of antiplatelet therapy in stroke prevention in AF is likely to be minimal in the future. Current European Society of Cardiology (ESC) guidelines only recommend the use of antiplatelet therapy (using an aspirin–clopidogrel combination therapy – reflecting the results of the ACTIVE-A trial) or less effectively, aspirin monotherapy in those patients who refuse any form of OAC (whether warfarin or NOACs).
Aspirin and Antiplatelet Therapy
Aspirin was considered a potentially attractive alternative to warfarin. Its pharmacokinetic profile means that there is little variability in dose–response and there is no need for routine monitoring of antithrombotic effect or dose adjustment. Aspirin exerts its antithrombotic effect by inhibiting cyclooxygenase (COX), which catalyzes the conversion of arachidonic acid to prostaglandin – this is converted to bioactive prostanoids including thromboxane A2. Platelets are unable to regenerate COX, so the effect of aspirin can only be overcome by the generation of new platelets, meaning the effect of the aspirin remains in place for approximately 10 days. After oral administration, aspirin is rapidly absorbed from the upper gastrointestinal tract with peak levels occurring at 30–40 min. Higher doses are not associated with an increased antiplatelet effect.
Clinical Trials of Aspirin
Hart et al. demonstrated that aspirin conferred a non-significant 19% risk reduction in stroke for AF patients. The confidence intervals crossed zero in this meta-analysis and were, in the main, driven by the results of one single positive trial (SPAF-1), where aspirin was given at the higher dose of 325 mg. In the SPAF-1 study, there was significant heterogeneity of the aspirin effect between anticoagulation-eligible and anticoagulation-ineligible patients. Since the trial was stopped early, the effect of aspirin may have been exaggerated. Indeed, latter-day evidence suggests that an increased dose of aspirin is associated with increased bleeding despite no further increase in platelet inhibition.
The ACTIVE-W trials sought to identify whether dual antiplatelet therapy with aspirin and clopidogrel would be an effective alternative to warfarin. The trial was stopped early due to the clear superiority of warfarin. For patients unable to take warfarin, the ACTIVE-A trial showed that dual antiplatelet therapy reduced ischemic stroke by 28% compared with aspirin alone. In both ACTIVE-A and ACTIVE-W, the rates of bleeding encountered with dual antiplatelet therapy were similar to those observed with warfarin, despite markedly reduced efficacy in preventing thromboembolism. One trial comparing aspirin with the oral factor Xa inhibitor apixaban was stopped early due to the superiority of apixaban. Here, the rates of major bleeding were similar for apixaban (1.4% per year) and aspirin (1.2% per year).
These contemporary trials showing equivalent bleeding rates with antiplatelets and anticoagulants are at odds with meta-analyses of earlier trials showing significantly more bleeding with warfarin. This may reflect advancements in care pathways since the original trials with warfarin were conducted, such as quality of INR control and rates of TTR. Also, the original (now historical) trials randomized <10% of the patients screened, and may be unrepresentative of more typical AF populations seen in more contemporary trials or 'real-world' clinical practice.
In view of its weak efficacy, aspirin is now difficult to advocate in stroke prevention, particularly when the risk of major bleeding (including ICH) is not significantly different to that of warfarin, especially in the elderly. Moreover, the emergence of NOACs which have fewer bleeding complications compared with warfarin and overcome many of its limitations means that the role of antiplatelet therapy in stroke prevention in AF is likely to be minimal in the future. Current European Society of Cardiology (ESC) guidelines only recommend the use of antiplatelet therapy (using an aspirin–clopidogrel combination therapy – reflecting the results of the ACTIVE-A trial) or less effectively, aspirin monotherapy in those patients who refuse any form of OAC (whether warfarin or NOACs).
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