Treating people who experience a mild stroke or high-risk transient ischemic attack (TIA) within 24 hours and for 21 days with dual antiplatelet therapy with clopidogrel and aspirin resulted in a net benefit vs aspirin alone when balancing the risks of a recurrent stroke against a hemorrhagic event, pooled data from two randomized, double-blind studies suggests.
The analysis used individual patient-level data on more than 10,000 participants in the previously reported CHANCE and POINT trials, both comparing a combination of clopidogrel and aspirin with aspirin alone.
"Patients with minor acute ischemic stroke and high-risk TIA benefit from treatment with clopidogrel–aspirin," study author Claiborne Johnston, MD, PhD, dean and vice president for medical affairs at the Dell Medical School of the University of Texas at Austin, told Medscape Medical News.
"This secondary analysis suggests 21 days may be the optimal duration of treatment to maximize benefit in reduction of ischemic events and minimize risk of hemorrhage," he added.
The study was published online August 19 in JAMA Neurology.
These same researchers conducted the individual trials included in the latest report. The Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) study showed a 32% lower risk of stroke recurrence among Chinese people treated within 24 hours with a combination of clopidogrel and aspirin vs aspirin alone. The study also showed no increase in the risk of hemorrhagic complications, as previously reported by Medscape Medical News.
A second study, the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial, also favored clopidogrel plus aspirin vs aspirin alone in an international patient population. "However, an increase in major hemorrhage observed in the POINT trial led to concerns about bleeding risks in dual antiplatelet therapy," the researchers note.
"Uncertainties remained about the risks and benefits of dual antiplatelet therapy and the optimal duration of dual antiplatelet therapy for minor stroke or TIA," they add. "Moreover, the two trials were each moderate in size, whereas pooled-data analysis can provide more precise estimates of treatment outcomes."
Significant Differences Emerge
From a total of 10,051 participants, 5016 were randomly assigned in the two trials to clopidogrel–aspirin and another 5035 to aspirin alone. Almost 61% were men and the median age was 63 years. Approximately 65% experienced a minor stroke and 35% had a TIA.
At 90 days, 6.5% of the dual treatment group vs 9.1% of the aspirin only group experienced a new ischemic or hemorrhagic stroke (adjusted hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.61 - 0.81; P < .001).
These findings remained similar when the investigators controlled for treatment with lipid-lowering drugs or antihypertensive drugs (HR, 0.70; 95% CI, 0.60 - 0.82; P < .001).
A total of 0.6% participants experienced major hemorrhage in the dual antiplatelet group vs 0.4% in the aspirin monotherapy group (adjusted HR, 1.59; 95% CI, 0.88 - 2.86). The difference was not statistically significant (P = .12).
The rate of minor hemorrhage at 90 days was likewise higher in the clopidogrel–aspirin patients, 1.9% compared to 0.9% of the aspirin-only group (adjusted HR, 2.01; 95% CI, 1.41 - 2.86; P < .001).
There were no significant differences between the two groups in the rates of hemorrhagic stroke or death from any cause.
Timing of the Essence?
"The absolute numbers of major ischemic events prevented by clopidogrel–aspirin exceeded the increase in major hemorrhages, particularly within the first 3 weeks of treatment," the researchers note.
For example, within the first 21 days, those receiving clopidogrel–aspirin treatment experienced a significantly lower rate of major ischemic events, 5.2%, compared with 7.8% among others receiving aspirin alone (adjusted HR, 0.66; 95% CI, 0.56 - 0.77; P < .001).
In analyses of "net clinical benefit," the combination treatment had a positive net benefit in the total 90-day study period, as well as the first 21 days after randomization. In contrast, they found a negligible net benefit between day 22 and 90, regardless of whether they chose the weight of a major hemorrhage to be between 0.5-fold to 1.2-fold that of a major ischemic event.
A strength of the study was inclusion of patients from different settings and populations, the authors note. In addition, the consistency of results between the CHANCE and POINT trials, the researchers add, suggest that the findings "are generalizable to a broad range of patients with minor stroke or TIA."
Johnston said he and colleagues plan to continue this line of research. "We are currently testing other antiplatelet agents in this setting. We know the risk of subsequent stroke is so high in the days to weeks after an ischemic stroke or TIA, and we think there is room for improvement in terms of reducing this risk."
"This patient-level meta-analysis comparing clopidogrel plus aspirin vs aspirin alone for acute minor ischemic stroke or high risk transient ischemic attack included the two largest randomized trials in the field, which were at low risk of bias," Rustam Al-Shahi Salman, MB BChir, PhD, professor of clinical neurology at the University of Edinburgh, United Kingdom, told Medscape Medical News when asked to comment. "The trials were similar, although their durations of dual antiplatelet therapy and outcome event definitions differed."
"It is unclear," Al-Shahi Salman noted, "why the authors did not use all of the available data by including the third trial addressing this question in 396 patients, the FASTER trial."
The findings of this pooled analysis of two trials are "clinically relevant," said Al-Shahi Salman, who was not involved with the current study. They also confirm the findings of a systematic review and meta-analysis of all three trials. Together, this evidence indicates that "the beneficial reduction in ischemic events from dual antiplatelet therapy with clopidogrel and aspirin given within 24 hours after high risk TIA or minor ischemic stroke occurs within the first 10 to 21 days, and probably not later," he added.
"Together, these findings will influence guidelines for everyday clinical practice around the world," he said.
The study was supported by the Ministry of Science and Technology of the People’s Republic of China, Beijing Municipal Commission of Health and Family Planning, Beijing Municipal Science & Technology Commission, the National Institute of Neurological Disorders and Stroke (NINDS), and Sanofi. Johnston reports grants from the National Institutes of Health/NINDS, with Sanofi providing drug and matching placebo for 85% of the patients enrolled in the trial, nonfinancial support from Sanofi, and grants from AstraZeneca during the conduct of the study. Al-Shahi Salman has disclosed no relevant financial relationships.
JAMA Neurol. Published online August 19, 2019. Abstract
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Cite this: Optimal Dual Antiplatelet Duration After Minor Stroke or TIA? - Medscape - Aug 29, 2019.