Clopidogrel, Aspirin Combination Lowers Ischemic Event Risk, Slightly Ups Hemorrhage Risk

S Claiborne Johnston, MD, PhD, dean of the Dell Medical School at the University of Texas

S. Claiborne Johnston, MD, PhD

A combination of clopidogrel and aspirin, when utilized in patients with minor ischemic stroke or high-risk transient ischemic attack (TIA), can lower the risk for major ischemic events compared to aspirin alone at 90 days but leads to a higher risk of major hemorrhage.

Previous research, in the CHANCE trial, with a Chinese patient population, has revealed that treating patients with this combination regimen within 24 hours of symptom onset did not increase their risk of hemorrhage more so than aspirin alone (hazard ratio, 0.68; 95% CI, 0.57 to 0.81; P <.001).¹ It has been believed that the combination treatment could reduce the rate of recurrent stroke in the first 3 months post-TIA or ischemic stroke—a risk that normally runs between 3% and 15%.

This new data, from the phase III POINT trial, led by S. Claiborne Johnston, MD, PhD, dean of the Dell Medical School at the University of Texas, assessed the regimen in an international population and found an incidence of major hemorrhage of 0.9% (n = 23) for those in the dual-therapy group compared to 0.4% (n = 10) in the aspirin alone group (hazard ratio, 2.32; 95% CI, 1.10 to 4.87; P = .02).²

“It is not possible to make direct comparisons between clinical and safety outcomes because disability due to each of the outcomes cannot be ascertained, but we estimate that for every 1000 patients who are treated with clopidogrel plus aspirin during a period of 90 days, such treatment would prevent approximately 15 ischemic events and would cause 5 major hemorrhages,” Johnston and colleagues wrote.

"[This data] gives [physicians] some pretty solid evidence that they can use the combination of clopidogrel-aspirin and reduce the stroke risk in these high-risk patients," Johnston told NeurologyLive. "Yes, there is a risk of hemorrhage, but it is relatively small. The duration data is really important and couldn’t be emphasized in the initial paper. The benefits are primarily early but the risks extend throughout the treatment period. That is going to be important to physicians."

The prospective, randomized, double-blind, multicenter trial included 4881 patients from 269 sites. In total, 4557 (93.4%) patients completed the 90-day trial assessment period, while 4782 (98.0%) were followed for ≥7 days. Enrollment was halted at 84% of the target amount due to a determination from the data and safety monitoring board regarding the exceeding of the prespecified boundary for major hemorrhage.

Patients were randomized to receive either a loading dose of 600-mg clopidogrel on day 1, followed by 75 mg per day, plus a dose of 50-325-mg aspirin (n = 2432); or aspirin alone in the same dosing range (n = 2449).

During the first week after their initial event, 5.0% (n = 121) of patients in the dual-therapy group experienced major ischemic events, compared to 6.5% (n = 160) of those treated with solely aspirin (hazard ratio, 0.75; 95% CI, 0.59 to 0.95; P = .02). The secondary endpoint of ischemic stroke occurred in 4.6% (n = 112) of those in the clopidogrel plus aspirin group compared to 6.3% (n = 155) of those in the aspirin only group (hazard ratio, 0.72; 95% CI, 0.56 to 0.92; P = .01).

Aside from stroke, the composite primary efficacy outcome of ischemic stroke, myocardial infarction, or death from ischemic vascular causes did not reveal significant differences between groups. That composite occurred in 5.8% (n = 141) of those in the clopidogrel plus aspirin group versus 6.8% (n = 167) of those administered only aspirin (hazard ratio, 0.84; 95% CI, 0.67 to 1.05; P = .13).

Johnston and colleagues noted that no significant treatment-by-subgroup interactions were significant in prespecified subgroups. However, they also acknowledged that the number of patients with available data limited the power to establish these interactions. The treatment effect, according to the main daily aspirin dose received during the trial period, was no different among groups.

Secondary analysis of the treatment effect revealed that the benefit of clopidogrel plus aspirin was greater within the first 7 and 30 days than it was at 90 days (P = .04 for days 0 to 7; P = .02 for days 0 to 30), whereas the risk of hemorrhage with the dual-therapy regimen compared to aspirin alone was greater from day 8 to day 90 than it was during the first 7 days (P = .04 for days 8 to 90; P = .34 for days 0 to 7).

Adverse events (AEs) were similar and had no significant differences between groups aside from general disorders and administration site conditions (P = .004). No AEs, excluding the components of the primary outcomes, occurred at a rate ≥5% in either group. Nervous system disorders, occurring at a rate of 4.6% (n = 113) in the dual-therapy group and 4.7% (n = 115) in the aspirin-only group.

"Pretty much all the groups in the trial benefited from the treatment and we haven’t been able to identify folks who clearly shouldn’t have been treated within the entry criteria of the trial," Johnston said. "Duration is another question. The benefit seems to be greatest in the first few weeks, and we’re doing more analysis on that now."

In an accompanying editorial, James C. Grotta, MD, noted that while these results might suggest no benefit on a surface level, but there were several notable points.³ “First, most of the prevented events were ischemic strokes—the most common and arguably most important of the outcomes after a TIA or minor stroke. Second, most of the bleeding complications were systemic, nonfatal, nonintracranial hemorrhages and not the most feared event of intracranial bleeding. Third, and most salient, is the timing of these outcomes.”

Grotta wrote that the take-home message for the clinician that the evidence from this trial, combined with that of the CHANCE and SAMMPRIS studies, shows that this combination regimen reduces the chance of recurrent stroke during the high-risk period post-TIA or ischemic stroke. “However, to conform to the results of the POINT trial, if dual therapy is used, it should be confined to the first 3 weeks after a TIA or minor stroke and then transitioned to monotherapy,” he noted.

The therapy should not be utilized, according to Grotta, in patients with non-reliable adherence, those with an uncertain diagnosis of TIA, or those at an increased risk of bleeding.

REFERENCES

1. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369(1):11—9. Epub 2013 Jun 26

2. Johnston SC, Easton DJ, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379:215-225.

doi

: 10.1056/NEJMoa1800410.

3. Grotta JC. Antiplatelet therapy after ischemic stroke or TIA. N Engl J Med. 2018;379:291-292.

doi

: 10.1056/NEJMe1806043.