SPS3

Clinical Question

In patients with recent symptomatic MRI-confirmed lacunar stroke, does adding clopidogrel to aspirin reduce the risk of recurrent stroke compared with aspirin alone?

Inclusion Criteria

• Age ≥30 years.
• Symptomatic lacunar stroke within the preceding 180 days, with randomization occurring at least 2 weeks after the qualifying stroke.
• MRI confirmation: lesion ≤2.0 cm in diameter on diffusion-weighted imaging with corresponding positive apparent-diffusion-coefficient image, or well-delineated area of focal hyperintensity ≤2.0 cm on FLAIR or T2-weighted imaging, in a location consistent with a lacunar syndrome (internal capsule, thalamus, basal ganglia, pons, corona radiata, or centrum semiovale).
• Clinical presentation consistent with a lacunar syndrome (pure motor hemiparesis, pure sensory stroke, sensorimotor stroke, ataxic hemiparesis, or dysarthria-clumsy hand); transient lacunar ischemic attacks required diffusion-weighted MRI evidence.
• Modified Rankin Scale <4 (non-disabling).

Exclusion Criteria

• Disabling stroke (modified Rankin score ≥4).
• Previous nontraumatic intracranial hemorrhage or previous cortical ischemic stroke.
• Surgically amenable ipsilateral carotid artery disease (paper does not specify a stenosis threshold).
• Major-risk cardioembolic source (per protocol; specific list not enumerated in the primary paper).
• MRI evidence of a recent or remote cortical infarct, or a large subcortical infarct (>1.5 cm).

Baseline Characteristics

Arms

Outcomes

Criticisms

• The sample-size calculation assumed a 3-year recurrent-stroke rate of 21% with a 25% relative reduction from DAPT (initial n=2500, upsized midway to 3000 with a 1-year follow-up extension). Observed rates were much lower (2.7%/yr in aspirin-only), so the trial may have been underpowered to detect a modest DAPT benefit.
• All-cause mortality significantly increased with DAPT (HR 1.52, P=0.004) but was NOT fully explained by fatal hemorrhages (HR 2.29, P=0.17) — the unexplained excess deaths raise concern about occult harm from chronic DAPT in this population.
• 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, although the authors cite data suggesting aspirin dose did not modify efficacy of aspirin+clopidogrel in other populations.
• Enrolled patients up to 180 days after the qualifying event — much later than CHANCE (24 h) or POINT (12 h). The acute short-course DAPT benefit seen in those trials may not apply to chronic long-term use, making SPS3 not directly comparable.
• Early termination by DSMB for futility with harm — while ethically necessary, it limited power for secondary endpoints and subgroup analyses.
• No MRI assessment of cerebral microbleeds at baseline — microbleed burden may modify bleeding risk from DAPT in SVD but was not captured in the trial.
• Latin American / Hispanic enrollment (31%) may limit generalizability; CYP2C19 polymorphisms affecting clopidogrel metabolism vary across ethnic groups.
• No comparison of aspirin monotherapy vs. clopidogrel monotherapy — SPS3 only tested adding clopidogrel to aspirin, leaving open whether clopidogrel alone would differ from aspirin alone for lacunar stroke.

Funding

National Institute of Neurological Disorders and Stroke (NINDS; U01 NS38529-04A1) and others. Clopidogrel and matching placebo were donated by Sanofi-Aventis and Bristol-Myers Squibb; neither company had involvement in trial design, execution, analysis, or reporting.