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POINT

Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA

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Year of Publication: 2018

Authors: S. Claiborne Johnston, M.D., Ph.D., ..., and Yuko Y. Palesch

Journal: The New England Journal of Medicine

Citation: N Engl J Med 2018;379:215-25.

Link: https://doi.org/10.1056/NEJMoa1800410

PDF: https://www.nejm.org/doi/pdf/10.1056/NEJMoa1800410

Clinical Question

In patients with a recent minor ischemic stroke or a high-risk transient ischemic attack (TIA), does treatment with clopidogrel plus aspirin, as compared with aspirin alone, reduce the risk of major ischemic events at 90 days?

Study Overview

Objective

To evaluate whether dual antiplatelet therapy (clopidogrel + aspirin) for 90 days reduces recurrent major ischemic events compared with aspirin alone in patients with minor ischemic stroke (NIHSS ≤3) or high-risk TIA (ABCD2 ≥4) when started within 12 hours of onset.

Study Summary

Primary major ischemic events at 90 days (ischemic stroke, MI, or ischemic vascular death): 5.0% DAPT vs 6.5% aspirin (HR 0.75, 95% CI 0.59–0.95, P=0.02; NNT≈65).
Ischemic stroke alone: 4.6% vs 6.3% (HR 0.72, 0.56–0.92, P=0.01).
Major hemorrhage: 0.9% vs 0.4% (HR 2.32, 1.10–4.87, P=0.02; NNH≈200).
Most of the ischemic benefit occurred in the first 7 days (HR ~0.65) while bleeding accrued steadily across all 90 days — supporting a 21-day DAPT duration (later operationalized by CHANCE-2 and guideline updates).
Trial stopped early for both efficacy AND safety — rare dual-signal termination.

Intervention

Clopidogrel 600 mg load → 75 mg daily × 90 days + aspirin 50–325 mg daily vs aspirin alone. Initiated within 12 h of symptom onset.

Patients per Arm

DAPT n=2432 vs Aspirin n=2449 (total 4881)

Bottom Line

In patients with minor ischemic stroke or high-risk TIA treated within 12 hours, the combination of clopidogrel and aspirin for 90 days resulted in a lower risk of major ischemic events but a higher risk of major hemorrhage compared to aspirin alone. The authors estimate that for every 1000 patients treated, combination therapy would prevent approximately 15 ischemic events and cause 5 major hemorrhages.

        Major Points
        Companion trial to CHANCE — together they established DAPT as the standard of care for minor stroke/TIA. POINT was the Western (predominantly US) counterpart to the Chinese CHANCE trial.
4,881 patients randomized across 269 sites in 10 countries (North America, Europe, Australia, New Zealand; 82.8% enrolled in the United States). Double-blind, placebo-controlled — higher-quality design than the open-label CHANCE trial.
Primary efficacy outcome: major ischemic events (ischemic stroke, MI, or ischemic vascular death) at 90 days: 5.0% DAPT vs 6.5% aspirin alone (HR 0.75, 95% CI 0.59–0.95, p=0.02). NNT ≈ 65 over 90 days.
Primary safety outcome: major hemorrhage was significantly higher with DAPT (0.9% vs 0.4%, HR 2.32, 95% CI 1.10–4.87, p=0.02). NNH ≈ 200 over 90 days.
Critical timing insight: benefit of DAPT was greater in the first 7 days and first 30 days than at 90 days (P=0.04 for days 0–7 vs 8–90; P=0.02 for days 0–30 vs 31–90), while hemorrhage risk was greater in days 8–90 than in the first 7 days (P=0.04) — forming the basis for the '21-day DAPT' practice now standard.
Key difference from CHANCE: POINT used 90-day DAPT (clopidogrel 600 mg load → 75 mg/day × 90 days), while CHANCE used 21-day DAPT then clopidogrel monotherapy. POINT's longer DAPT duration likely explains the higher bleeding rate.
Stopped early for both efficacy AND safety — a rare 'dual signal' termination that made the benefit-risk balance complex and led to the AHA/ASA compromise recommendation of 21-day DAPT (combining CHANCE timing with POINT efficacy data).
57% of qualifying events were ischemic stroke (NIHSS ≤3), 43% were high-risk TIA (ABCD2 ≥4). Both subgroups benefited similarly.
Predominantly White (75%) and US (83%) population — complementing CHANCE's exclusively Chinese population, allowing cross-ethnic generalization.
The clopidogrel loading dose of 600 mg was higher than CHANCE's 300 mg — potentially contributing to faster platelet inhibition but also higher early bleeding.

      

Design

Study Type: Randomized, double-blind, placebo-controlled trial.

Randomization: 1

Blinding: Double-blind.

Enrollment Period: May 28, 2010, to December 19, 2017.

Follow-up Duration: 90 days (with a window of ±14 days) after randomization.

Centers: 269

Countries: 10 countries in North America (majority United States, 82.8%), Europe, Australia, and New Zealand

Sample Size: 4881

Analysis: Intention-to-treat.

Inclusion Criteria

Age ≥18 years.
Randomization within 12 hours after symptom onset.
Acute ischemic stroke with a National Institutes of Health Stroke Scale (NIHSS) score of 3 or less.
High-risk transient ischemic attack (TIA) with an ABCD² score of 4 or more.
Imaging to rule out intracranial hemorrhage or other explanatory conditions.

Exclusion Criteria

TIA symptoms limited to isolated numbness, isolated visual changes, or isolated dizziness or vertigo.
Received any thrombolytic therapy within 1 week before the event.
Candidate for thrombolysis, endovascular therapy, or endarterectomy.
Planned use of antiplatelet therapy (other than aspirin) or anticoagulation therapy.
Contraindication to aspirin or clopidogrel.
Anticipated use of a nonsteroidal antiinflammatory drug for more than 7 days.

Baseline Characteristics

Characteristic	Control	Active
Median age (IQR)-yr	65.0 (56.0-74.0)	65.0 (55.0-74.0)
Female sex-no. (%)	1098 (44.8)	1097 (45.1)
Race (White)-no./total no. (%)	1781/2378 (74.9)	1774/2360 (75.2)
Race (Black)-no./total no. (%)	493/2378 (20.7)	473/2360 (20.0)
Hispanic ethnic group-no./total no. (%)	146/2328 (6.3)	144/2320 (6.2)
Region (United States)-no. (%)	2029 (82.9)	2014 (82.8)
Ischemic heart disease-no./total no. (%)	240/2443 (9.8)	257/2426 (10.6)
Hypertension-no./total no. (%)	1680/2437 (68.9)	1693/2423 (69.9)
Diabetes mellitus-no./total no. (%)	662/2447 (27.1)	678/2425 (28.0)
Medication use at presentation (Aspirin)-no. (%)	1397 (57.0)	1417 (58.3)
Time from presentation to randomization (<6 hr)-no./total no. (%)	789/2449 (32.2)	755/2431 (31.1)
Qualifying event (TIA)-no. (%)	1052 (43.0)	1056 (43.4)
Qualifying event (Ischemic stroke)-no. (%)	1397 (57.0)	1376 (56.6)
Median ABCD2 for TIA (IQR)	5.0 (4.0-5.0)	5.0 (4.0-6.0)
Median NIHSS for ischemic stroke (IQR)	2.0 (1.0-2.0)	2.0 (1.0-2.0)

Arms

Field	Control	Clopidogrel + Aspirin (DAPT)
Intervention	Open-label aspirin at 50–325 mg/day (dose selected by treating physician; most common dose was 81 mg or 325 mg) plus clopidogrel-matched placebo. A dose of 162 mg daily for 5 days followed by 81 mg daily was recommended, consistent with guidelines. No loading dose of aspirin was specified. Aspirin was started immediately after enrollment (within 12h of symptom onset).	Clopidogrel 600 mg loading dose on day 1 (double the standard 300 mg loading dose used in CHANCE), followed by clopidogrel 75 mg/day for 90 days, plus open-label aspirin 50–325 mg/day (recommended aspirin schedule: 162 mg daily for 5 days followed by 81 mg daily). The higher loading dose aimed for faster platelet inhibition. DAPT was maintained for the full 90-day duration (unlike CHANCE which stopped clopidogrel + aspirin at day 21).
Duration	90 days	90 days

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
A composite of major ischemic events, defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days.	Primary	6.5% (160/2449)	5.0% (121/2432)	0.75	0.02
Ischemic stroke	Secondary	6.3% (155/2449)	4.6% (112/2432)	HR 0.72 (95% CI, 0.56-0.92)	0.01
Myocardial infarction	Secondary	0.3% (7/2449)	0.4% (10/2432)	HR 1.44 (95% CI, 0.55-3.78)	0.46
Death from ischemic vascular causes	Secondary	0.2% (4/2449)	0.2% (6/2432)	HR 1.51 (95% CI, 0.43-5.35)	0.52
Ischemic or hemorrhagic stroke	Secondary	6.4% (156/2449)	4.8% (116/2432)	HR 0.74 (95% CI, 0.58-0.94)	0.01
Composite of ischemic stroke, MI, death from ischemic vascular causes, or major hemorrhage	Secondary	6.8% (167/2449)	5.8% (141/2432)	HR 0.84 (95% CI, 0.67-1.05)	0.13
Major hemorrhage	Adverse	0.4% (10/2449)	0.9% (23/2432)	HR 2.32 (95% CI, 1.10-4.87)	0.02
Hemorrhagic stroke	Adverse	0.1% (3/2449)	0.2% (5/2432)	HR 1.68 (95% CI, 0.40-7.03)	0.47
Symptomatic intracerebral hemorrhage	Adverse	0.1% (2/2449)	0.1% (2/2432)	HR 1.01 (95% CI, 0.14-7.14)	0.99
Other symptomatic intracranial hemorrhage	Adverse	0 (0/2449)	0.1% (2/2432)	not estimable	0.16
Major hemorrhage other than intracranial hemorrhage	Adverse	0.3% (7/2449)	0.7% (17/2432)	HR 2.45 (95% CI, 1.01-5.90)	0.04
Minor hemorrhage	Adverse	0.5% (13/2449)	1.6% (40/2432)	HR 3.12 (95% CI, 1.67-5.83)	<0.001
Death from any cause	Adverse	0.5% (12/2449)	0.7% (18/2432)	HR 1.51 (95% CI, 0.73-3.13)	0.27

Subgroup Analysis

No significant treatment-by-subgroup interactions across prespecified subgroups: qualifying event type (minor stroke vs TIA), age (<65 vs ≥65), sex, race, region (US vs non-US), hypertension, previous aspirin therapy, previous statin therapy, time from symptom onset to randomization (<6h vs ≥6h), baseline NIHSS, ABCD2 score, new infarct on CT/MRI, and predominant daily aspirin dose. Time-stratified secondary analysis (the most clinically important finding): the benefit of clopidogrel plus aspirin was greater in the first 7 days and in the first 30 days than at 90 days (P=0.04 for days 0–7 vs days 8–90; P=0.02 for days 0–30 vs days 31–90), whereas the risk of hemorrhage with clopidogrel plus aspirin versus aspirin alone was greater during days 8–90 than during the first 7 days (P=0.04 for days 8–90; P=0.34 for days 0–7) — directly informing the AHA/ASA 21-day DAPT recommendation.

Criticisms

90-day DAPT duration was longer than the now-standard 21 days — the increased bleeding risk beyond 21 days is what prompted the shorter duration recommendation, but POINT itself tested only the 90-day regimen.
29% drug discontinuation rate before study completion — among the highest in stroke prevention trials, limiting the per-protocol analysis.
Cannot be generalized to moderate-severe stroke (NIHSS >3), cardioembolic stroke, or patients eligible for thrombolysis/thrombectomy — all were excluded.
Variable aspirin dose (50–325 mg/day) at investigator discretion — dose-dependent interaction with clopidogrel efficacy and bleeding risk is possible.
Predominantly US/White population (75% White, 83% US) — different CYP2C19 polymorphism prevalence than East Asian populations (CHANCE), potentially affecting clopidogrel metabolism and efficacy.
No CYP2C19 genotyping was performed — approximately 2–5% of White patients are poor metabolizers who do not activate clopidogrel, potentially diluting the treatment effect.
Clopidogrel 600 mg loading dose was chosen without dose-finding study — the higher load may contribute to more early bleeding vs CHANCE's 300 mg load.
Event rates were lower than expected — trial was powered assuming a 15% event rate in the aspirin-only group, but observed primary outcome was 6.5% aspirin vs 5.0% DAPT, contributing to early termination and limited power for subgroup analyses.
No comparison with ticagrelor, which was later tested in THALES — leaving the question of optimal P2Y12 inhibitor unanswered.

Funding

Supported by grants (U01 NS062835, U01 NS056975, and U01 NS059041) from the National Institute of Neurological Disorders and Stroke (NINDS). Sanofi provided clopidogrel and matching placebo for 75% of the patients enrolled in the trial and provided comments on an earlier version of the manuscript; there was no other industry involvement and no confidentiality agreement between the authors and Sanofi.

Based on: POINT (The New England Journal of Medicine, 2018)