What Antiplatelet Therapy Should We Use in Patients with Stroke/TIA? Interesting Results for the POINT Trial

Courtesy of Dr. Alejandro Lakowsky, MTSAC (Full Member of the Argentine Society of Cardiology)

The New England Journal of Medicine (NEJM) recently published an article about the POINT trial (simultaneously presented at the European Stroke Organisation Conference), a long-awaited randomized clinical trial to assess the efficacy and safety of dual antiplatelet therapy (DAPT) with aspirin and clopidogrel in patients with recent transient ischemic attack (TIA) or ischemic stroke.

Background history

Up to 2013, the superiority of dual antiplatelet therapy over aspirin monotherapy in patients with stroke had not been demonstrated yet. The MATCH study (Lancet 2004) had explored that hypothesis, but its result had been negative.

In 2011, the SAMMPRIS study randomly compared the usefulness of angioplasty plus optimal medical treatment (OMT) vs. OMT alone in patients with stroke or TIA secondary to severe atherosclerotic intracranial arterial lesions. SAMMPRIS had to be terminated prematurely due to a higher rate of events (recurrent stroke and/or death) for the angioplasty group, plus a rate of events lower than expected for the OMT alone group. In this work, optimal medical treatment consisted in dual antiplatelet therapy with aspirin (325 mg/day) plus clopidogrel (75 mg/day) for 3 months, and aggressive control of risk factors and changes in patient lifestyle. However, dual antiplatelet therapy was not compared with antiplatelet monotherapy.

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In 2013, NEJM published the CHANCE trial, a study carried out in China with over 5000 patients enrolled. This was the first study to prove that dual antiplatelet therapy with aspirin plus clopidogrel for three weeks was superior to aspirin monotherapy in patients with stroke or TIA. The key to this Chinese study was the enrollment of patients who were in the most acute stage within 24 hours from the event, something that had not been done before. One of the limitations of the CHANCE trial was that it only included patients from Asian origin, whose genotype, body mass index (BMI), demographic characteristics, and response to pharmacological treatment are all considered to be particular. In consequence, the conclusions of this study could not be generalized and applied to other populations.

The POINT study is the “Western version” of this Chinese study: its design is very similar and it seeks to answer the same questions. A subtle difference is that it enrolls patients in an even more acute stage, within 12 hours from symptom onset.

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The results of the CHANCE trial plus the publication of the design and rationale behind POINT, also in 2013, were the basis for the design of the SOCRATES trial with ticagrelor, comparing both ticagrelor and aspirin as monotherapy (without dual antiplatelet therapy) in patients with stroke or TIA within 24 hours from symptom onset. This trial, published in NEJM in 2016, showed a trend towards benefit with ticagrelor regarding a reduction in ischemic events that lacked statistical significance (p = 0.07). The rate of major bleeding was the same for both ticagrelor and aspirin.

POINT

The POINT trial randomized 4881 patients to dual antiplatelet therapy with clopidogrel (a loading dose of 600 mg, followed by 75 mg/day) plus aspirin (50-325 mg/day) for 3 months versus aspirin alone (50-325 mg/day) in patients with ischemic stroke or high-risk TIA within 12 hours from symptom onset. Due to a rate of events that was lower than expected in the aspirin alone control arm, which reflected the inclusion of a relatively low-risk population, sample size was increased from 4150 initial patients to 5840 patients in order to maintain a statistical power of 80%, so as to detect differences in the primary endpoint (vascular death, acute myocardial infarction, or ischemic stroke at 90 days).

The study was terminated prematurely following the recommendation of the Committee for Safety and Monitoring after 84% of the anticipated number of patients had been enrolled, due to two findings:

1. a) a significant reduction in the risk of major ischemic events with dual antiplatelet therapy compared with aspirin alone (5% vs. 6.5%; hazard ratio [HR]: 0.75; 95% confidence interval [CI]: 0.59-0.95; p = 0.02).
2. b) a significant increase in the risk of major bleeding with DAPT compared with aspirin (0.9% vs. 0.4%; HR: 2.32; 95% CI: 1.1-4.87; p = 0.02).

Most of the reduction in ischemic events was verified during the first weeks after the initial event, particularly during the first 7 days, as a decrease in the rate of ischemic stroke with no difference as regards infarction or vascular death. Additionally, the increase in the risk of major hemorrhages was constant during the whole study. It should be noted that non-fatal and non-intracranial major hemorrhages (considered by some as more severe than fatal bleeding) accounted for this increase in the risk of bleeding. In the assessment of net clinical benefit (vascular death, acute myocardial infarction, stroke, or major bleeding), there was a slightly favorable trend towards DAPT that did not reach statistical significance (5.8% vs. 6.8%; HR: 0.84; 95% CI: 0.67-1.05; p = 0.13).

Read also: REDUCE Trial: Patients with PFO and cryptogenic stroke at lower risk of recurrent stoke when treated with APT and closure device.

In a global analysis of results of the CHANCE and POINT trials, the best risk/benefit balance seems to lay in restricting DAPT to the first 3-4 weeks after the initial TIA or stroke, followed by aspirin monotherapy (in CHANCE, DAPT lasted only 21 days; in POINT, it lasted 3 months, but most of the benefit was obtained in the first 30 days).

Currently, there is a second ongoing randomized study with ticagrelor in patients with stroke or TIA, THALES, which will assess dual antiplatelet therapy with ticagrelor plus aspirin compared with aspirin alone (similarly to CHANCE or POINT, but replacing clopidogrel by ticagrelor).

Courtesy of Dr. Alejandro Lakowsky, MTSAC (Full Member of the Argentine Society of Cardiology)

Original title: Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA.

Reference: Johnston SC et al. N Engl J Med. 2018 May 16. [Epub ahead of print].

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