POINT

Published

Johnston SC, et al. "Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA". The New England Journal of Medicine. 2018. 379(3):215-225.
PubMed • Full text • PDF

Clinical Question

Among patients with acute TIA or minor ischemic stroke, does the early administration of aspirin/clopidogrel reduce rates of subsequent strokes when compared to aspirin monotherapy?

Bottom Line

Among patients with acute TIA or minor ischemic stroke, starting aspirin/clopidogrel within 12h of symptom onset reduces the 90-day stroke incidence at the cost of increasing bleeding rates, when compared to aspirin monotherapy.

Major Points

Aspirin and other antiplatelet agents are the mainstays of therapy in patients with non-thromboembolic ischemic stroke and TIA, and there has been interest in combining antiplatelet agents to improve efficacy. Prior studies in which patients received long-term treatment with aspirin/clopidogrel in CHARISMA, MATCH, and SPS3 suggested that dual antiplatelet therapy increases bleeding risk without significantly reducing the risk of stroke. However, since the risk of stroke recurrence after TIA or minor stroke is front-loaded, there continued to be interest in investigating the efficacy of a short course of dual antiplatelet therapy immediately following stroke or high-risk TIA. CHANCE demonstrated in a Chinese population that the combination of aspirin/clopidogrel for 21 days followed by clopidogrel monotherapy was superior to single-agent aspirin for reducing stroke recurrence at 90 days, without a difference in bleeding rate between the two groups. Despite these promising results, many European and North American clinicians were reluctant to apply this data to their patients for a variety of reasons. Chinese patients have a larger proportion of undertreated modifiable stroke risk factors (including diabetes and hypertension), a greater burden of intracranial large vessel atherosclerosis who are known to benefit from dual antiplatelet therapy (based on SAMMPRIS), and frequently have polymorphisms in genes regulating clopidogrel metabolism which are less common in Western populations. A randomized study of a broader population was necessary.

The international Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial randomized 4,881 patients to either aspirin/clopidogrel or to aspirin/placebo within 12 hours of a minor stroke or high-risk TIA, and excluded patients eligible for thrombolysis, those with atrial fibrillation, or those with significant atherosclerotic disease in whom endarterectomy or stenting is indicated. Patients received 90 days of study treatment and then aspirin monotherapy, and were followed for the primary composite outcome of ischemic stroke, MI, or ischemic vascular death. The study was halted after 83.6% of planned enrollment when a safety signal for excess major hemorrhage was noted in the aspirin/clopidogrel group. Among patients in the aspirin/clopidogrel group, fewer primary efficacy outcome events occurred (5.0% vs. 6.5%; P=0.02; NNT=66), but with more major bleeding (0.9% vs. 0.4%; P=0.02; NNH=200).

POINT demonstrates that 90 days of DAPT reduces the rate of recurrent stroke and increases rates of major bleeding among patients with minor ischemic stroke and high-risk TIA. Further analysis suggests that 90 days of DAPT is unnecessarily long. The majority of efficacy events occurred during the first 7 days, and 80-90% occurred within the first 30 days, while the bleeding rate was roughly stable during the 90-day follow-up. Until further guidelines are available it seems reasonable to limit DAPT to the 30 days following minor ischemic stroke or high-risk TIA. The ongoing THALES trial is studying a 30-day course of aspirin/ticagrelor vs. aspirin monotherapy for secondary stroke prevention in this same patient population.

Guidelines

As of August 2018, no guidelines have been published that reflect the results of this trial.

Design

• Multicenter, randomized, double-blind, placebo-controlled trial
• N=4,881 patients with acute ischemic stroke or high-risk TIA
  • Aspirin (n=2,432)
  • Aspirin/clopidogrel (n=2,449)
• Setting: 269 centers in North America, Europe, Australia, and New Zealand
• Enrollment: 2010-2017
• Follow-up: 90 days
• Analysis: Intention-to-treat
• Primary outcome: Composite of ischemic stroke, MI, or ischemic vascular death

Population

Inclusion Criteria

• Age ≥18 years
• Either of the following:
  • Minor ischemic stroke (NIHSS score ≤3)
  • High-risk TIA (ABCD² score ≥4)
• Ability to be randomized ≤12 hours of symptom onset
• CT/MRI brain to rule out hemorrhage, vascular malformations, tumor, abscess that could explain symptoms or contraindicate therapy

Exclusion Criteria

• Isolated sensory symptoms, visual changes, dizziness or vertigo without evidence of acute infarction
• Candidacy for thrombolysis, endarterectomy, or endovascular intervention (unless subject declines both endarterectomy and endovascular intervention)
• Receipt of tPA in prior week
• GI bleeding or major surgery in prior 3 months
• History of non-traumatic intracranial hemorrhage
• Qualifying event induced by angiography or surgery
• Life expectancy <3 months
• Other need for anticoagulation including AF
• Unavailable to follow up
• Pre-event Rankin score >2
• Contraindication to aspirin or clopidogrel
• Anticoagulation therapy in prior 10 days
• Females with child-bearing capacity not on contraception without a negative pregnancy test
• Indication for long-term (>7 day) non-study antiplatelet drugs (eg, dipyridamole, clopidogrel, ticlopidine), or NSAID affecting platelet function (eg, prior vascular stent or arthritis)

Baseline Characteristics

From the aspirin/clopidogrel group.

• Age: 65 years (median)
• Female: 45.1%
• Region: US center 82.8%
• Race: White 75.2%, Black 20%, Asian 3.3%, others 1.5%; Hispanic ethnic group 6.2%
• PMH: HTN 69.9%, DM 28.0%, CAD 10.6%
• Medication at presentation:
  • Aspirin 58.3%
  • Clopidogrel 2%
• Mean time to randomization: 7.4 hours
  • Symptom onset <6h: 31.1%
• Qualifying event:
  • TIA 43.4%, median ABCD² score 5 (IQR 4.0-6.0)
  • Minor stroke 56.6%, median NIHSS score 2 (IQR 1.0-2.0)

Interventions

• Randomization to one of two groups:
  • Aspirin group received aspirin 50-325 mg/d (recommended 150-200 mg/d for 5 days followed by 75-100 mg/d) plus matching placebo
  • Aspirin/clopidogrel group received same aspirin dose as above, with clopidogrel 600-mg loading dose followed by 75 mg/d through day 90
• Thrombolytics were disallowed

Outcomes

Comparisons are aspirin/clopidogrel vs. aspirin group. All outcomes are at 90 days.

Primary Outcome

Composite of ischemic stroke, myocardial infarction, or death from ischemic vascular causes

5.0% vs. 6.5% (HR 0.75; 95% CI 0.59-0.95; P=0.02)

Secondary Outcomes

Ischemic stroke

4.6% vs. 6.3% (HR 0.72; 95% CI 0.56-0.92; P=0.01)

Myocardial infarction

0.4% vs. 0.3% (HR 1.44; 95% CI 0.55-3.78; P=0.46)

Death from ischemic vascular causes

0.2% vs. 0.2% (HR 1.51; 95% CI 0.43-5.35; P=0.52)

Ischemic or hemorrhagic stroke

4.8% vs. 6.4% (HR 0.74; 95% CI 0.58-0.94; P=0.01)

Composite of ischemic stroke, myocardial infarction, death from ischemic vascular causes, or major hemorrhage

5.8% vs. 6.8% (HR 0.84; 95% CI 0.67-1.05; P=0.13)

Subgroup Analysis

There was no interaction for the primary endpoint for age, sex, race, geographic region of recruitment, stroke vs. TIA, time to randomization, new infarct on CT or MRI, baseline NIHSS or ABCD² scores, HTN, previous statin or aspirin use and dose of aspirin.

Adverse Events

Major hemorrhage

0.9% vs. 0.4% (HR 2.32; 95% CI 1.10-4.87; P=0.02)

Hemorrhagic stroke

0.2% vs. 0.1% (HR 1.68; 95% CI 0.40-7.03; P=0.47)

Symptomatic intracerebral hemorrhage

0.1% vs. 0.1% (HR 1.01; 95% CI 0.14-7.14; P=0.99)

Other symptomatic intracranial hemorrhage

0.1% vs. 0%

Major hemorrhage other than intracranial hemorrhage

0.7% vs. 0.3% (HR 2.45; 95% CI 1.01-5.90; P=0.04)

Minor hemorrhage

1.6% vs. 0.5% (HR 3.12; 95% CI 1.67-5.83; P<0.001)

Death from any cause

0.7% vs. 0.5% (HR 1.51; 95% CI 0.73-3.13; P=0.27)

Criticisms

• Compared to CHANCE, in addition to the longer duration of dual anti-platelet therapy (90 vs. 30 days), the loading dose for clopidogrel used here is higher (600 mg vs. 300 mg). It is unclear what effect this had on the increased bleeding rates here compared to CHANCE.
• Information on stroke etiology was not captured and it is unclear if dual anti-platelet therapy would benefit TIA and minor strokes from etiologies similarly
• Although discontinuation rates are similar in the two groups, a trial drug was discontinued permanently in 29% of the patients before the follow up period was complete

Funding

Funded by the National Institute of Neurological Disorders and Stroke. Multiple authors reported support from pharmaceutical companies including AstraZeneca and Boehringer Ingelheim. Sanofi provided clopidogrel and placebo to 75% of study patients.