PDF: POINT
(2018)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
• 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.
Inclusion Criteria
Adults with minor ischemic stroke (NIHSS ≤3) OR high-risk TIA (ABCD2 ≥4), randomized within 12 h of symptom onset. Excluded patients eligible for thrombolysis, needing anticoagulation, with planned carotid procedures, or with contraindications to antiplatelet therapy. 269 centers, 10 countries (83% USA, 75% White) — Western counterpart to the Chinese CHANCE trial.
Study Design
Arms: Clopidogrel + Aspirin (DAPT) vs Aspirin alone
Patients per Arm: DAPT n=2432 vs Aspirin n=2449 (total 4881)
Outcome
• Ischemic stroke: 4.6% vs 6.3%, HR 0.72 (0.56–0.92), P=0.01.
• Any stroke (ischemic or hemorrhagic): 4.8% vs 6.4%, HR 0.74 (0.58–0.94), P=0.01.
• Major hemorrhage: 0.9% vs 0.4%, HR 2.32 (1.10–4.87), P=0.02. NNH≈200.
• Minor hemorrhage: 1.6% vs 0.5%, HR 3.12 (1.67–5.83), P<0.001.
• Time-window analysis: benefit concentrated in days 1–7 (HR ~0.65); bleeding hazard constant throughout 90 days — basis for the 21-day DAPT duration now used in practice.
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 centers in 10 countries. 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 = 67 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: most of the ischemic benefit occurred in the first 7 days (HR 0.65 for days 1–7), while bleeding risk accumulated steadily over 90 days — 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.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled trial.
- Randomization
- Yes
- Blinding
- Double-blind.
- Sample Size
- 4881
- Follow-up
- 90 days.
- Centers
- 269
- Countries
- United States, Canada, Europe, Australia, New Zealand
Primary Outcome
Definition: A composite of major ischemic events, defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event, at 90 days.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 6.5% (160/2449) | 5.0% (121/2432) | 0.75 (0.59 to 0.95 ) | 0.02 |
Limitations & 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 (~5% vs projected ~9%) — trial was underpowered for subgroup analyses and required early termination.
- No comparison with ticagrelor, which was later tested in THALES — leaving the question of optimal P2Y12 inhibitor unanswered.
Citation
N Engl J Med 2018;379:215-25.