Two small trials performed during the late 1970s and early 1980s failed to show the superiority of DP-ASA dual therapy over aspirin monotherapy.21,22 Four subsequent large randomized trials have tested the efficacy of DP-ASA in patients with stroke or TIA.

The European Stroke Prevention Study (ESPS), the first large trial enrolling 2500 patients with TIA, reversible ischemic neurologic deficit, or stroke within 3 months of onset, showed that after 2 years, the DP-ASA group (75 mg of immediate-release dipyridamole plus 325 mg of aspirin three times daily) had lower rates of the primary endpoint of stroke or death (15.2% vs. 22.6%; RRR=33%, p<0.001), recurrent stroke (9.1% vs. 14.7%; RRR=35%, p<0.001), and mortality (8.6% vs. 12.5%, p<0.01) compared to the placebo group.23

The second large trial was the ESPS-2 study, which randomly assigned 6602 patients with TIA or ischemic stroke within 3 months of onset to one of four groups: ERDP-ASA dual therapy (200 mg of ERDP plus 25 mg of aspirin twice daily), ERDP monotherapy (200 mg twice daily), aspirin monotherapy (25 mg twice daily), and placebo. ERDP-ASA dual therapy reduced recurrent stroke with RRRs of 23.1% (p=0.006), 24.7% (p=0.002), and 37.0% (p<0.001) compared with aspirin, ERDP, and placebo, respectively. For the composite endpoint of stroke or all-cause deaths, the dual therapy was superior to placebo (RRR=24.4%, p<0.001), and trended toward a reduction compared to aspirin (RRR=12.9%, p=0.056) and ERDP (RRR=10.7%, p=0.073). The rates of recurrent stroke and the composite endpoint were reduced for both the aspirin and ERDP monotherapies compared to placebo. Bleeding from any site (from mild to fatal bleeding) occurred in 4.5%, 4.7%, 8.2%, and 8.7% of subjects in the placebo, ERDP monotherapy group, aspirin monotherapy, and ERDP-ASA groups, respectively, suggesting that aspirin is associated with an increased bleeding risk whereas ERDP is not.24 Headache resulting in discontinuation of study medication was more frequent with ERDP monotherapy (8.0%) and ERDP-ASA (8.1%) than with aspirin monotherapy (1.9%) or placebo (2.4%; treatment groups overall comparison, p<0.001). However, even after the ESPS-2 study, the benefit of DP-ASA dual therapy over aspirin monotherapy was not widely accepted because 1) it was demonstrated by only one trial, 2) the ESPS-2 trial used a relatively low dose of aspirin (25 mg twice daily), 3) there was no reduction in the risks of MI and vascular death despite the more potent antiplatelet activity of dual therapy, and 4) in a meta-analysis of 11 trials, DP-ASA dual therapy was associated with a marginal reduction of vascular events compared to aspirin monotherapy, a finding that was largely driven by the ESPS-2 data [relative risk (RR)=0.90, 95% CI=0.80-1.00] and was not associated with a reduction in the rate of vascular death (RR=1.03, 95% CI=0.87-1.22).25

The uncertainty about the superior efficacy of the dual therapy with dipyridamole plus aspirin over aspirin monotherapy led to a third large trial, the European/Australasian Stroke Prevention in Reversible Ischemia Trial (ESPRIT), which used a PROBE design, in which DP-ASA [fixed-dose combination of 200 mg of ERPD plus 25 mg of aspirin twice daily or as a free combination of 200 mg of dipyridamole twice daily plus aspirin (30-325 mg/day)] was compared with aspirin monotherapy (30-325 mg/day) in 2763 patients with ischemic stroke or TIA of presumed arterial origin within 6 months of onset. The primary endpoint of the composite of vascular death, nonfatal stroke, nonfatal MI, or major bleeding complication was significantly reduced with dual therapy versus aspirin monotherapy (13% vs. 16%; HR=0.80, 95% CI=0.66-0.98; ARR=1.0%/year, 95% CI=0.1-1.8). The rates of the major vascular events of vascular death, nonfatal stroke, and nonfatal MI (excluding major bleeding events) were also significantly lower with dual therapy (HR=0.78, 95% CI=0.63-0.97). Dual therapy was associated with a trend toward a reduction in ischemic stroke (HR=0.84, 95% CI=0.64-1.10) and major ischemic events including nonhemorrhagic vascular death, nonfatal ischemic stroke, and nonfatal MI (HR=0.81, 95% CI=0.65-1.01). The dual therapy group more frequently discontinued the trial medication compared to the aspirin monotherapy group, and at least 25% of the discontinuations were attributed to headache. An accompanying updated meta-analysis found that DP-ASA dual therapy versus aspirin monotherapy was more effective for preventing the major vascular events of vascular death, nonfatal stroke, and nonfatal MI (HR=0.82, 95% CI=0.74-0.91).26

The ESPRIT results have been the subject of some debate. First, some of the findings cannot be explained by dual-therapy-enhanced antiplatelet activity. The dual therapy group had fewer major bleeding events compared to the monotherapy group, and the difference was more prominent for on-treatment analysis (statistically significant) than for intention-to-treat analysis (statistically nonsignificant). According to the Kaplan-Meier curves for the composite ischemic vascular events, there was no difference in the first 2.5 years, but a difference emerged thereafter. If the benefit of dual therapy was related to an enhanced antiplatelet effect, the Kaplan-Meier curves would have diverged earlier. Second, the ESPRIT used a PROBE design, which carries a risk of event reporting bias. In addition, the ESPRIT investigators did not provide information on risk factor control during the follow-up, which is particularly important for an unblinded study.

Since earlier trials and a network meta-analysis suggested that DP-ASA dual therapy had a greater vascular protection effect than did clopidogrel monotherapy and both regimens were more effective than aspirin monotherapy,26,27,28,29 the Prevention Regimen for Effectively Avoiding Second Strokes study was conducted to compare ERDP-ASA dual therapy (200 mg of ERDP plus 25 mg of aspirin twice daily) and clopidogrel monotherapy (75 mg once daily) among 20332 patients with ischemic stroke within 3 months of onset with a mean follow-up of 2.5 years.30 At its inception, the trial aimed to compare ERDP-ASA and clopidogrel plus aspirin, but after the results of the Management of Atherothrombosis with Clopidogrel in High-Risk Patients with Recent TIA or Ischemic Stroke (MATCH) trial,31 the design was modified to compare ERDPASA and clopidogrel monotherapy after enrolling 2027 patients. In addition, the planned statistical analysis was changed from a superiority test to a noninferiority test because of lower-than-expected event rates observed during the trial. The primary endpoint of recurrent stroke did not differ between the ERDP-ASA and clopidogrel groups (9.0% vs. 8.8%; HR=1.01, 95% CI=0.92-1.11), but the trial failed to demonstrate the noninferiority of ERDP-ASA to clopidogrel monotherapy because the upper limit of the confidence interval crossed the predetermined noninferiority margin of 1.075 (indicating a 7.5% noninferiority difference). The ERDP-ASA group appeared to have fewer ischemic strokes, although the difference was not statistically significant (7.7% vs. 7.9%; HR=0.97, 95% CI=0.88-1.07), but had significantly more intracranial hemorrhages (1.4% vs. 1.0%; HR=1.42, 95% CI=1.11-1.83). The rates of major vascular events including stroke, MI, and vascular death did not differ between the two groups (13.1% vs. 13.1%; HR=0.99, 95% CI=0.92-1.07), but the ERDP-ASA group had a higher rate of major bleeding events (4.1% vs. 3.6%; HR=1.15, 95% CI=1.00-1.32). However, the rate of treatment adherence was lower for patients receiving ERDP-ASA than for those receiving clopidogrel, which was due to more frequent discontinuation of the study drug, largely due to headache and gastrointestinal adverse effects, and lower medication compliance (defined as taking the study medication for >75% of the time). The imbalanced adherence to treatment might have affected the trial results. Whatever the reasons, clopidogrel monotherapy and ERDP-ASA dual therapy were found to be equally efficacious for secondary stroke prevention.

The first large trial was the MATCH study, which was a randomized, double-blind, placebo-controlled trial to compare clopidogrel (75 mg once daily) plus aspirin (75 mg once daily) versus clopidogrel monotherapy in patients who had an ischemic stroke or TIA, within 3 months of onset, and had one or more risk factors of previous ischemic stroke, previous MI, angina pectoris, diabetes mellitus, or symptomatic peripheral arterial disease (PAD). The MATCH trial enrolled 7599 patients, and the mean follow-up was 18 months. The clopidogrel plus aspirin group and the clopidogrel monotherapy group had similar rates for the primary efficacy endpoint of the composite of ischemic stroke, MI, vascular death, or hospitalization for TIA, angina pectoris, or worsening of PAD (15.7% vs. 16.7%; RRR=6.4%, 95% CI=-4.6 to 16.3, p=0.244) as well as for secondary efficacy endpoints of major vascular events of stroke, MI, or vascular death (11.7% vs. 12.4%; RRR=5.9%, 95% CI=-7.1 to 17.3, p=0.360) and recurrent ischemic stroke (10.6% vs. 11.3%; RRR=6.6%, 95% CI=-7.0 to 18.5, p=0.324). However, the dual therapy group had significantly more life-threatening bleeding events compared to the clopidogrel monotherapy group (2.6% vs. 1.3%; ARI=1.26%, 95% CI=0.64-1.88, p<0.0001), and more major bleeding events (1.9% vs. 0.6%; ARI=1.36%, 95% CI=0.86-1.86, p<0.0001).31 Therefore, adding aspirin to clopidogrel provided no further benefit, while increasing the harm.

There are several criticisms of the MATCH trial. First, less than 20% of patients were enrolled within 7 days from stroke onset, and more than 30% were enrolled after 30 days. Therefore, the trial largely missed the period when the risk is high and the treatment effect would be greatest. Second, more than 50% of the patients had an etiologic mechanism of small-vessel occlusion, which has a lower risk of recurrent stroke but a higher risk of subsequent intracerebral hemorrhage than other ischemic stroke subtypes, and thereby increases the risk of major bleeding and decreases the benefit of clopidogrel and aspirin dual therapy.

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial was another large randomized, double-blind, placebo-controlled trial, which compared clopidogrel (75 mg once daily) plus aspirin (75-162 mg once daily) versus aspirin monotherapy in 15603 patients with established cardiovascular disease or with multiple risk factors. The trial revealed no significant benefit of adding clopidogrel to aspirin during the 28-month follow-up for preventing the composite of vascular events in this broad population of patients at high risk for atherothrombotic events.32

When analyzing the data of 9478 patients with established cardiovascular disease (prior MI, stroke, or symptomatic PAD), dual therapy significantly reduced the composite of MI, stroke, or vascular death (7.3% vs. 8.8%; HR=0.83, 95% CI=0.72-0.96, p=0.01) compared to aspirin monotherapy, without increasing the rate of severe bleeding events (1.7% vs. 1.5%; HR=1.12, 95% CI=0.81-1.53, p=0.50).33 However, moderate bleeding events were more frequent with dual therapy in this subgroup of patients (2.0% vs. 1.3%; HR=1.60, 95% CI=1.16-2.20, p=0.004). Another subgroup analysis of 4320 patients with prior ischemic stroke or TIA found that dual therapy tended to reduce the composite of stroke, MI, or vascular death (8.1% vs. 9.6%; HR=0.84, 95% CI=0.69-1.03) and recurrent stroke (4.9% vs. 6.1%; HR=0.80, 95% CI=0.62-1.03) without significantly increasing the rate of severe bleeding events (1.9% vs. 1.7%; HR=1.11, 95% CI=0.71-1.73), but again significantly increased that of moderate bleeding events (2.4% vs. 1.1%; HR=2.15, 95% CI=1.32-3.49).34 However, post-hoc subgroup analysis is associated with high risk of bias related to multiple testing and selective reporting, and thereby should be considered as hypothesis-generating only.

The most recent trial was the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, which was a randomized, double-blind, placebo-controlled trial that compared clopidogrel (75 mg once daily) plus aspirin (325 mg once daily) versus aspirin monotherapy in 3020 patients who had a symptomatic lacunar infarction confirmed by magnetic resonance imaging within 6 months of onset, with a mean follow-up of 3.4 years. The rate of primary endpoint of recurrent stroke (ischemic or hemorrhagic stroke) did not differ between the clopidogrel plus aspirin group and the aspirin monotherapy groups (2.5%/year vs. 2.7%/year; HR=0.92, 95% CI=0.72-1.16, p=0.48). There were no differences between dual therapy and aspirin monotherapy in the rate of ischemic stroke (2.0%/year vs. 2.4%/year; HR=0.82, 95% CI=0.63-1.09, p=0.13) or disabling or fatal stroke (0.84%/year vs. 0.78%/year; HR=1.06, 95% CI=0.69-1.64, p=0.79). However, the dual therapy group had a higher major bleeding rate than the aspirin monotherapy group (2.1%/year vs. 1.1%/year; HR=1.97, 95% CI=1.41-2.71, p<0.001) and had numerically more cases of intracranial hemorrhage (0.42%/year vs. 0.25%/year; HR=1.65, 95% CI 0.83-3.31, p=0.15). The rate of all-cause deaths was higher in the dual therapy group than the monotherapy group (2.1%/year vs. 1.4%/year; HR=1.52, 95% CI=1.14-2.04, p=0.004); these deaths were largely attributed to the increase in definite and probable vascular deaths.35 The SPS3 trial clearly showed that the addition of clopidogrel to aspirin for long-term therapy should be contraindicated in patients with lacunar infarction.

A recent meta-analysis of 7 trials involving 39574 patients with ischemic stroke or TIA compared long-term (range=1.3-3.5 years) dual antiplatelet therapy and antiplatelet monotherapy for risk of intracranial hemorrhage and benefit of preventing recurrent stroke: 2 trials with clopidogrel plus aspirin versus aspirin, 1 trial with clopidogrel plus aspirin versus clopidogrel, 2 trials with DP-ASA versus aspirin, 1 trial with DP-ASA versus clopidogrel, and 1 trial with ticlopidine plus aspirin versus ticlopidine. Dual antiplatelet therapy was associated with a trend toward a reduction in recurrent stroke risk compared to aspirin monotherapy (RR=0.89, 95% CI=0.78 to 1.01), but had no increase in the intracranial hemorrhage risk (RR=0.99, 95% CI=0.70 to 1.42). Compared to clopidogrel monotherapy, dual therapy had a comparable risk reduction for recurrent stroke (RR=1.01, 95% CI=0.93-1.08), but incurred a higher risk of intracranial hemorrhage (RR=1.46, 95% CI=1.17-1.82), resulting in an average of 4 more intracranial hemorrhages per 1000 patients treated (95% CI=1-7).36 The magnitude of the risk increase was not substantial. However, given that dual therapy conferred no further benefit with respect to preventing recurrent stroke, and the greater disabling and fatal health impacts of intracranial hemorrhage compared with ischemic stroke, dual therapy cannot be recommended over clopidogrel monotherapy as a long-term therapy.

In summary, dual antiplatelet therapy initiated early after ischemic stroke or TIA might further reduce recurrent stroke and major vascular events compared to antiplatelet monotherapy, with no significant increase in major bleeding events. In contrast, for the long-term therapy usually administered after a high-risk period, dual antiplatelet therapy is likely to increase the harm caused by major bleeding, including intracranial hemorrhage, and its benefit of further preventing recurrent stroke as well as major ischemic events remains controversial. The risk of recurrent stroke is highest during the early period after ischemic stroke or TIA, but this risk decreases with time. Accordingly, the benefit of dual antiplatelet therapy more potently blocking platelet activation pathways might outweigh the bleeding risk for short-term use, but might be outweighed by the bleeding risk for long-term use. Further research is therefore needed to establish the best candidates for dual antiplatelet therapy. Currently, Korean, American, and European stroke guidelines are not recommending long-term dual antiplatelet therapy except for ERDP-ASA dual therapy.37,38,39