The first trial to show benefit with ASA-ERDP was ESPS2 (European Stroke Prevention Study 2), which demonstrated superiority of the combination over placebo in reducing recurrent stroke when treatment was added within 3 months of an index stroke.19 A few studies have evaluated ASA-ERDP compared to aspirin monotherapy; however, most of these studies were small and did not show any difference in outcomes.20 Only ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial)21 carried significant weight in a 2013 meta-analysis, which showed a significant reduction in recurrent events with the combination product compared to aspirin monotherapy.20
Both the ESPS2 and ESPRIT trials had significant limitations.19,21 Patients in both studies had vascular comorbidities including atherosclerotic cardiovascular disease (ASCVD); however, pharmacotherapies designated to treat these diseases were not mentioned in the demographic data, nor were these medications taken into consideration to limit potential bias.19,21 Retrospectively, a significant proportion of aspirin doses utilized as a control in ESPRIT were inferior to the guideline-recommended dosing with 42% to 46% of patients receiving 30 mg/d.21 Despite these controversies, ASA-ERDP is still considered an alternative to aspirin monotherapy in the guidelines.7
The timing of ASA-ERDP initiation appears to be inversely related to the efficacy of the combination over therapeutic alternatives. Studies in which the therapy was initiated 3 to 6 months from the index stroke indicated favorable outcomes for the combination when compared to ASA or ERDP monotherapy.19,21 Studies utilizing early initiation (ie, within 24 or 48 hours of the index event) or even within 3 weeks showed no difference in outcomes; however, this may be due in part to the use of clopidogrel or other combination antiplatelet therapy as active comparators.22-24
Early initiation of ASA-ERDP also demonstrated a higher risk of major and intracranial bleeding compared to clopidogrel.22 Additionally, use of triple therapy with ASA-ERDP plus clopidogrel increased bleeding events without improving efficacy.24 More recent studies of ASA-ERDP are focusing on earlier initiation of therapy; it is unknown whether the benefits of late initiation will be confirmed in future studies. Highlights of the major RCTs evaluating the safety and efficacy of ASA-ERDP are detailed in TABLE 219,21-24.
The takeaway. Methodological issues and potential confounding factors in many of the key trials for ASA-ERDP make it challenging to fully discern the role that ASA-ERDP may play in the secondary prevention of stroke. Further evidence utilizing appropriate controls, timing, and assessment of confounders is needed. Additionally, ASA-ERDP is plagued by tolerability issues such as headache, nausea, and vomiting, leading to higher rates of discontinuation than its comparators in clinical trials. Accordingly, the maintenance use of ASA-ERDP for secondary stroke prevention may be considered less preferred than other recommended alternatives such as aspirin or clopidogrel monotherapies.
Robert S. Helmer, PharmD, BCPS, Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, 650 Clinic Drive, Suite 2100, Mobile, AL 36688; [email protected].