Reduced risk of ischemic events but higher risk of hemorrhages with DAPT after ischemic stroke or TIA
Clopidogrel and aspirin in acute ischemic stroke and high-risk TIAS.
Literature - Johnston C, Easton JD, Farrant M et al. - N Engl J Med 2018; 379:215-225 DOI: 10.1056/NEJMoa180041Introduction and methods
Aspirin has been shown to lower risk of recurrent stroke by approximately 20% in several trials [1-5], but the combination with clopidogrel is more effective in reducing the risk of ischemic events in patients with acute coronary syndromes (ACS) [6]. In the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, Chinese patients with ischemic stroke or transient ischemic attack (TIA) had a 32% reduced risk of recurrent stroke, without an increase in risk of hemorrhagic complications, after treatment with clopidogrel and aspirin, compared with only aspirin [7]. The effect of dual antiplatelet therapy (DAPT) remains unknown in an international population and this treatment has therefore not been recommended in guidelines for the treatment of stroke [1,5].
The Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial therefore investigated the effect of DAPT with clopidogrel and aspirin in an international population with patients aged >18 years with minor ischemic stroke or TIA (N=4557), in comparison with only aspirin.
In this international, double-blind, placebo-controlled trial (May 2010- December 2017) patients were randomly assigned to either clopidogrel (600 mg on day 1, followed by 75 mg on day 2-90) plus aspirin (50-325 mg per day) or only aspirin (50-325 mg per day). The primary efficacy outcome was the risk of ischemic events; a composite of ischemic stroke, myocardial infarction (MI) or death due to ischemic vascular events after 90 days. Furthermore, the primary safety outcome was major hemorrhages after 90 days.
Main results
Efficacy outcomes
- DAPT with clopidogrel and aspirin resulted in reduced risk of ischemic events (5%), compared to aspirin alone (6.5%) (HR: 0.75, 95%CI: 0.59-0.95, P=0.02).
- DAPT resulted in decreased risk of hemorrhagic stroke (4.6%), compared to aspirin (6.3%) (HR: 0.72, 95%CI: 0.56-0.92, P=0.01).
- The advantages of DAPT were greater within the first 7 and 30 days, compared to a period of 90 days (P=0.04 and P=0.02 respectively).
- The risk of hemorrhage was greater from day 8 to 90, compared to the first 7 days after treatment with DAPT compared to aspirin alone (P=0.04 and P=0.34 respectively).
- The primary composite outcome was observed in 5.8% of patients treated DAPT, compared to 6.8% of patients treated with aspirin (HR: 0.84, 95%CI: 0.67-1.05, P=0.13).
Safety outcomes
- Major hemorrhages were observed in 23 patients (0.9%) after treatment DAPT, compared to 10 patients (0.4%) treated with aspirin (HR: 2.32, 95%CI: 1.10-4.87, P=0.02).
- Increased risk of the secondary safety endpoint of minor hemorrhages was found after DAPT (1.6%), compared to aspirin (0.5%) (HR: 3.12, 95%CI: 1.67-5.83, P=0.002).
- Treatment with DAPT resulted in more adverse effects included in the Medical Dictionary for Regulatory Activities, compared to aspirin (P=0.004).
- More major ischemic events and major hemorrhages were observed after DAPT in the analyses, compared to aspirin (HR: 0.73, 95%CI: 0.56-0.94, P=0.01; HR: 3.57, 95%CI: 1.44-8.85, P=0.003, respectively).
Conclusion
Dual antiplatelet therapy with clopidogrel and aspirin reduced the risk of ischemic events, but increased the risk of hemorrhages, after a period of 90 days in patients with minor ischemic stroke or high-risk TIA, compared to treatment with aspirin.
Editorial comment
In the editorial article [8], James Grotta discusses the results of the POINT trial, which are consistent with other trials in which bleeding complications offset the lower rates of ischemic events. However, a higher rate of bleeding was observed with DAPT in this trial, compared to the CHANCE trial, possibly due to different durations of combined treatment and differences in the metabolism of clopidogrel in Asian versus non-Asian individuals. The author finished with the take-home message for the clinician: ‘The evidence from the SAMMPRIS, CHANCE, and POINT trials is that the combination of aspirin plus clopidogrel reduces the chance of recurrent ischemic stroke during the high-risk period in the first few weeks after a TIA or non-cardioembolic 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.’ In certain situations, he thinks dual therapy should perhaps not be considered, for instance if patient follow-up and adherence to therapy are not reliable. Moreover, it may also not be advisable in patients with an uncertain diagnosis of TIA, as these patients have been excluded from the trial or did not benefit. Patients who are at increased risk for bleeding, such as those with cerebral microbleeding or a history of brain or systemic bleeding, were also excluded from this trial. Grotta concluded by stating that ‘The POINT trial has provided useful data to help us further personalize our efforts in preventing recurrent stroke.’
References
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8 Grotta JC. Antiplatelet Therapy after Ischemic Stroke or TIA. N Engl J Med 2018; DOI: 10.1056/NEJMe1806043
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