PDF: SPS3
(2012)Objective
To determine whether dual antiplatelet therapy (aspirin + clopidogrel) and lower systolic blood pressure targets reduce the risk of recurrent stroke in patients with recent lacunar stroke.
Study Summary
• Dual antiplatelet therapy increased the risk of major bleeding and mortality without reducing recurrent stroke compared to aspirin alone. • Lower blood pressure target showed a non-significant trend toward reduced stroke risk.
Intervention
2x2 factorial design: (1) Aspirin + clopidogrel vs. aspirin alone; and (2) systolic blood pressure target <130 mm Hg vs. 130–149 mm Hg in patients with MRI-confirmed recent lacunar stroke.
Inclusion Criteria
Patients ≥30 years with recent symptomatic lacunar stroke confirmed by MRI within the past 180 days, no major atherosclerosis or cardioembolic source.
Study Design
Arms: 1) Antiplatelet: Aspirin + clopidogrel vs. aspirin alone; 2) Blood pressure: Target <130 mm Hg vs. 130–149 mm Hg.
Patients per Arm: Antiplatelet: 1503 dual vs. 1516 aspirin alone; BP: 1491 lower target vs. 1528 higher target.
Outcome
• Stroke recurrence: no significant difference between dual and single antiplatelet (HR 0.92, 95% CI 0.72–1.16); • Major hemorrhage: higher with dual therapy (HR 1.97, P=0.001); • All-cause mortality: higher with dual therapy (HR 1.52, P=0.005); • BP arm: recurrent stroke 2.25%/yr in lower BP group vs. 2.77%/yr in higher BP group (HR 0.81, 95% CI 0.64–1.03, P=0.08).
Bottom Line
Among patients with recent lacunar strokes, adding clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke but did significantly increase the risk of major bleeding and all-cause mortality. These findings do not support the use of dual antiplatelet therapy for secondary prevention in this population.
Major Points
- Largest trial of secondary prevention specifically in lacunar stroke. 2x2 factorial design testing: (1) aspirin + clopidogrel vs aspirin alone (antiplatelet arm, published 2012), and (2) intensive BP control (SBP <130 mmHg) vs standard BP control (SBP 130–149 mmHg) (BP arm, published 2013).
- 3,020 patients with MRI-confirmed lacunar stroke (≤2.0 cm subcortical infarct) within 180 days randomized at 82 centers across North America, Latin America, and Spain.
- Antiplatelet arm: Primary outcome (any recurrent stroke) not reduced with DAPT — 2.5% vs 2.7% per year (HR 0.92, 95% CI 0.72–1.16, P=0.48).
- DAPT HARM: major hemorrhage nearly doubled (2.1% vs 1.1%/yr, HR 1.97, P<0.001). All-cause mortality significantly increased (2.1% vs 1.4%/yr, HR 1.52, P=0.004). Antiplatelet arm stopped early for harm.
- BP arm (2013): Intensive BP target (<130 mmHg) vs standard (130–149 mmHg). Non-significant trend favoring intensive (HR 0.81, 95% CI 0.64–1.03, P=0.08). Mean achieved SBP: 127 vs 138 mmHg.
- Key conclusion: DAPT is harmful for long-term secondary prevention after lacunar stroke, unlike its benefit in acute minor stroke/TIA (CHANCE, POINT where DAPT is used for 21 days only).
- Aspirin dose was 325 mg — higher than the 75–81 mg typically used in combination with clopidogrel in CHANCE/POINT.
- Two separate publications: Antiplatelet arm (NEJM 2012) and BP arm (Lancet 2013). The 2×2 factorial design allowed simultaneous testing of both interventions — no interaction between antiplatelet and BP randomizations.
- MRI-confirmed lacunar infarcts ≤2.0 cm required for enrollment — one of the strictest imaging-verified small vessel disease populations ever studied, distinguishing it from trials using clinical lacunar syndromes alone.
- Death signal (HR 1.52, p=0.004) led to DSMB stopping the antiplatelet arm early. The excess mortality was NOT fully explained by fatal hemorrhages (HR 2.29, p=0.17) — raising concern about unknown DAPT toxicity in this population, possibly related to microbleeds in SVD.
Study Design
- Study Type
- Double-blind, multicenter, randomized trial with a 2x2 factorial design.
- Randomization
- Yes
- Blinding
- Double-blind.
- Sample Size
- 3020
- Follow-up
- Mean of 3.4 years.
- Centers
- 82
- Countries
- North America, Latin America, Spain
Primary Outcome
Definition: Any recurrent stroke, including ischemic stroke and intracranial hemorrhage.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 2.7% per year (138 strokes) | 2.5% per year (125 strokes) | 0.92 (0.72 to 1.16) | 0.48 |
Limitations & Criticisms
- Recurrent stroke rate in aspirin-only group was 2.7%/year — far lower than the 4%/year anticipated in power calculations — leaving the trial potentially underpowered to detect a small DAPT benefit.
- All-cause mortality significantly increased with DAPT (HR 1.52, p=0.004) but NOT fully explained by fatal hemorrhages — the unexplained excess deaths raise concern about occult harm from chronic DAPT in SVD, possibly related to cerebral microbleeds.
- Aspirin dose of 325 mg was higher than the 75–100 mg used in CHANCE, POINT, and most modern DAPT regimens — critics argue higher aspirin may have increased bleeding and confounded the safety signal.
- Enrolled patients up to 180 days after qualifying event — much later than CHANCE (24h) or POINT (12h). The acute DAPT benefit seen in those trials may not apply to chronic use, making SPS3 not directly comparable.
- Early termination by DSMB for harm — while ethically necessary, it limited power for secondary endpoints and subgroup analyses, leaving uncertainty about whether specific subgroups might benefit.
- No MRI assessment of cerebral microbleeds at baseline — microbleed burden may have modified the bleeding risk from DAPT, but this was not captured in the trial design.
- BP arm result (HR 0.81, p=0.08) was borderline — stopping the antiplatelet arm may have indirectly limited enrollment and follow-up for the BP arm, contributing to its non-significant result.
- Latin American enrollment (31% Hispanic) may limit generalizability to other populations — different genetic polymorphisms (CYP2C19) affect clopidogrel metabolism differently across ethnic groups.
- No comparison of aspirin monotherapy vs clopidogrel monotherapy — SPS3 only tested adding clopidogrel to aspirin, leaving open whether clopidogrel alone might be superior to aspirin alone for lacunar stroke.
Citation
N Engl J Med 2012;367:817-25.