Findings from two randomized trials—Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) and Clopidogrel for the Reduction of Events During Observation (CREDO)—have shown sustained benefits of clopidogrel for combined endpoints of MI, stroke, and vascular death.11-12 The incidence of stroke was very small and the risk of serious bleeding was significantly increased.
These trials provided the rationale to undertake the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent Transient Ischemic Attack or Ischemic Stroke study (MATCH).13 This study was designed to determine whether the addition of ASA to clopidogrel would further reduce the risk of recurrent ischemic attacks in high-risk patients after recent IS or TIA, as was observed with coronary manifestations of atherothrombosis in the CURE and CREDO trials.
MATCH, a randomized, double-blind, placebo-controlled trial, involved 7,599 patients and compared clopidogrel with low-dose ASA plus clopidogrel. During an 18-month follow-up, no significant benefit was observed for ASA plus clopidogrel versus clopidogrel monotherapy; however, there was a significant increase in the risk of life-threatening bleeding in the group receiving combined therapy (2.6% versus 1.3%, respectively). Therefore, ASA plus clopidogrel is not a recommended option for prevention of secondary stroke in cerebrovascular patients.
ASA Plus Extended-Release Dipyridamole
The Second European Stroke Prevention Study (ESPS-2), a randomized trial with 2,500 patients, was conducted to compare the efficacy of ASA plus dipyridamole versus placebo. Dipyridamole is a pyrimidopyrimidine derivative from the papaverine family with antithrombotic properties and vasodilatory effects on cells and vasculature.14 It inhibits phosphodiesterases, resulting in increased concentration of cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP), which inhibits platelet activation and adhesion.14
ESPS-2 results showed a 38% relative reduction in risk of stroke for the combination versus placebo. The study did not include an ASA-only group. Results prompted reformulation of dipyridamole into a high-dose extended-release capsule combined with low-dose ASA. The higher dose and slower release of dipyridamole combined with ASA provides a more consistent plasma level and is less affected by stomach acidity or concomitant medications.
This combination was tested versus ASA alone in the ESPS-2 trial.15 ESPS-2, a randomized, double-blind, multicenter study, enrolled 6,602 patients with prior stroke or TIA. During the two-year follow-up ASA plus extended-release dipyridamole reduced the risk of recurrent stroke by 37% compared with placebo, and by 22% compared with ASA or dipyridamole alone. Adverse events associated with this combination are similar to those observed with low-dose ASA.
These results were further substantiated by a recent post hoc analysis conducted using data from the ESPS-2 trial. ASA plus extended-release dipyridamole had greater efficacy in preventing stroke than ASA; this difference in efficacy was more pronounced in high-risk patients.16
We need further studies that include direct comparisons to verify the most effective and safe antiplatelet agent for secondary stroke prevention. The Prospective Regimen for Effectively Avoiding Second Strokes (PRoFESS) is a head-to-head trial designed to compare the combination of ASA plus extended-release dipyridamole to clopidogrel in terms of efficacy and safety. This study includes 15,500 patients in more than 20 countries at approximately 600 sites.17