Antiplatelet Agents in Acute Stroke and TIA

Humans

To the Editor

The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke) trial conducted by Johnston et al. (July 19 issue)1 showed that the combination of clopidogrel and aspirin was superior to aspirin alone and led to a lower risk of major ischemic events in the first 90 days among patients with minor ischemic stroke or high-risk transient ischemic attack (TIA). According to the eligibility criteria, the trial did not exclude patients who were receiving antiplatelet therapy (Table 1 of the article shows that more than half the patients were using aspirin at presentation). Thus, patients who had an ischemic event while taking antiplatelet therapy (which implies the failure of antiplatelet therapy) could be included in the trial. We wonder whether there was a difference in outcomes among patients who had received antiplatelet therapy before enrollment in the trial and those who had not. Patients with a history of unsuccessful antiplatelet therapy might have had a more pronounced clinical benefit from dual antiplatelet therapy than from single-agent antiplatelet therapy.

Lu Jia, M.D.
Hongming Ji, M.D.
Rongshan Li, M.D.
Shanxi Provincial People’s Hospital, Taiyuan, China

No potential conflict of interest relevant to this letter was reported.

  1. 1. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med 2018;379:215225.

To the Editor

The POINT trial was halted early because there was a higher incidence of major hemorrhage in the combined antiplatelet group than in the aspirin group. In comparing the CHANCE (Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events) trial1 with the POINT trial, the authors attributed the higher risk of hemorrhage in the POINT trial to a longer duration of combined antiplatelet treatment (21 days vs. 90 days), a higher loading dose of clopidogrel (300 mg vs. 600 mg), and common CYP2C19 polymorphisms in Asians. The editorialist2 also mentioned the differences in treatment duration and clopidogrel dose.

However, because the risk of hemorrhage was greater during the period from 8 to 90 days than during the first 7 days, the higher loading dose would seem to be an unlikely explanation for the increased bleeding risk in the later part of the trial.2 Although the prevalences of carriage of the CYP2C19 loss-of-function allele differ between Asians and non-Asians,3 the effect of the treatment assignment on bleeding did not differ significantly among patients with loss-of-function alleles and those without (2.3% and 2.5%, respectively, in the clopidogrel–aspirin group and 1.4% and 1.7%, respectively, in the aspirin-only group; P=0.78 for interaction).4 Therefore, the difference in hemorrhage rates between the trials could have been due to the duration of combined therapy with clopidogrel plus aspirin. It would be instructive for the authors to conduct a time-course analysis to determine whether there is a point of net clinical benefit from the dual antiplatelet therapy.

Xiaoliang Yin, M.D.
Daming Wang, M.D.
Beijing Hospital, Beijing, China

No potential conflict of interest relevant to this letter was reported.

  1. 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;369:1119.

  2. 2. Grotta JC. Antiplatelet therapy after ischemic stroke or TIA. N Engl J Med 2018;379:291292.

  3. 3. Man M, Farmen M, Dumaual C, et al. Genetic variation in metabolizing enzyme and transporter genes: comprehensive assessment in 3 major East Asian subpopulations with comparison to Caucasians and Africans. J Clin Pharmacol 2010;50:929940.

  4. 4. Wang Y, Zhao X, Lin J, et al. Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack. JAMA 2016;316:7078.

Response

The authors reply: Although the concept of antiplatelet-therapy failure is controversial, platelet aggregation varies among patients treated with aspirin and those treated with clopidogrel.1 In the POINT trial, we collected information on whether antiplatelet agents were taken in the month before randomization, including in the emergency department. We suspect that most of these patients would have taken their medications within 1 or 2 days before presentation. As shown in Figure 3 of our article, event rates tended to be greater in both treatment groups among patients with previous aspirin therapy than among those who had not received aspirin before randomization, but there was no evidence of a greater treatment effect with clopidogrel plus aspirin than with aspirin alone among patients who had taken aspirin within 1 month before randomization (P=0.71 for interaction). Only 35 patients were taking an antiplatelet agent other than aspirin (i.e., clopidogrel, dipyridamole, or ticlopidine) during the month before randomization. Therefore, the results were similar for the effect of previous receipt of any antiplatelet agent (hazard ratio with clopidogrel–aspirin vs. aspirin, 0.73 among patients with previous antiplatelet therapy; 95% confidence interval [CI], 0.54 to 0.98; hazard ratio, 0.79 among patients without previous antiplatelet therapy; 95% CI, 0.55 to 1.16; P=0.72 for interaction). Thus, we cannot confirm that patients who were taking an antiplatelet agent at the time of the qualifying stroke or TIA were more likely to benefit from treatment with clopidogrel plus aspirin than from aspirin alone.

The rates of major hemorrhage were low in the two treatment groups in the POINT trial, so there are few events for analysis. In general, the risk of hemorrhage remained fairly constant in the trial, although the curves diverged more sharply in the first 2 days of treatment (Fig. 2B of our article). Although other explanations cannot be ruled out, we agree that the most likely reason that our trial showed an elevated risk of major hemorrhage and the CHANCE trial did not was the duration of dual antiplatelet therapy — 90 days in the POINT trial, as compared with 21 days in the CHANCE trial.2 An analysis of data at 7 days and at 30 days that was included in our article showed that efficacy was established and that the risk of hemorrhage was lower at these durations of treatment than at 90-day follow-up.

S. Claiborne Johnston, M.D., Ph.D.
University of Texas, Austin, TX

J. Donald Easton, M.D.
University of California, San Francisco, San Francisco, CA

Jordan J. Elm, Ph.D.
Medical University of South Carolina, Charleston, SC

Since publication of their article, the authors report no further potential conflict of interest.

  1. 1. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014;45:21602236.

  2. 2. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013;369:1119.

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