SPS3 Trial: DAPT in Lacunar Stroke
In patients with MRI-confirmed symptomatic lacunar infarction, does long-term dual antiplatelet therapy (aspirin plus clopidogrel) reduce recurrent stroke compared with aspirin monotherapy?
SPS3 Investigators (NEJM 2012) · 3,020 patients
Population
Included
- MRI-confirmed symptomatic lacunar infarction within the prior 6 months
- No significant ipsilateral large-artery disease or cardioembolic source
- Modified Rankin Scale 3 or less at entry
- Able to tolerate aspirin and clopidogrel
Eligible patients
- 30 years of age or older
- A symptomatic lacunar stroke within the preceding 180 days
- No surgically amenable ipsilateral carotid-artery disease and no major risk factors for cardioembolic sources of stroke
- Patients with a clinical lacunar syndrome were required to meet MRI criteria: a lesion 2.0 cm or less in diameter on diffusion-weighted imaging corresponding to a positive apparent-diffusion-coefficient image, or a lesion with a well-delineated area of focal hyperintensity 2.0 cm or less in diameter on FLAIR or T2-weighted imaging corresponding to the clinical syndrome
- Patients with transient lacunar ischemic attacks were included only if there was evidence of the attacks on diffusion-weighted MRI
- Randomization did not take place for at least 2 weeks after the qualifying stroke (to avoid lowering of blood pressure during the acute period)
Excluded
- Cortical infarct or infarct larger than 1.5 cm on MRI (non-lacunar mechanism)
- Significant carotid or intracranial stenosis as likely cause
- Cardioembolic source requiring anticoagulation
- Prior intracranial hemorrhage or high bleeding risk
Infarct type / imaging
- MRI evidence of a recent or remote cortical infarct
- A large subcortical infarct (measuring more than 1.5 cm in diameter)
Hemorrhage / prior stroke
- A history of intracerebral hemorrhage (with the exception of traumatic hemorrhage)
- Previous cortical ischemic stroke
Disability
- Disabling stroke, defined as a modified Rankin scale score of 4 or more (scale of 0 to 6, with higher scores indicating more severe disability)
Source: SPS3 Investigators (Benavente OR et al.), N Engl J Med 2012· Retrieved 2026-06-09
Primary Outcome
Negligible absolute difference
Stroke-free (annual rate per year)
Study Arms
- Agent
- Aspirin plus clopidogrel
- Dose
- Aspirin 325 mg daily plus clopidogrel 75 mg daily
- Route
- Oral
- Frequency
- Once daily
- Duration
- Long-term (mean follow-up 3.4 years)
- Co-interventions
- All participants received open-label aspirin 325 mg (enteric-coated) daily as background therapy; antiplatelet assignment ran inside a 2x2 factorial alongside a separate blood-pressure-target intervention (SBP under 130 vs 130 to 149 mm Hg)
This entry encodes the ANTIPLATELET comparison. The antiplatelet component was stopped early by the data and safety monitoring board for lack of efficacy combined with evidence of harm: no reduction in recurrent stroke (HR 0.92, 95% CI 0.72 to 1.16) and increased all-cause mortality (HR 1.52, 95% CI 1.14 to 2.04, P=0.004) and major hemorrhage (HR 1.97, 95% CI 1.41 to 2.71, P less than 0.001) versus aspirin alone
- Agent
- Aspirin plus placebo clopidogrel
- Dose
- Aspirin 325 mg daily plus a matching clopidogrel placebo once daily
- Route
- Oral
- Frequency
- Once daily
- Duration
- Long-term (mean follow-up 3.4 years)
- Co-interventions
- All participants received open-label aspirin 325 mg (enteric-coated) daily as background therapy; assignment ran inside the same 2x2 factorial alongside the blood-pressure-target intervention
Double-blind, placebo-controlled for the clopidogrel comparison; adherence measured by quarterly pill counts
Safety
All-cause mortality (DAPT arm higher, HR 1.52, P=0.004)
2.1%
1.4%
Mortality was significantly higher in the DAPT arm. This finding triggered early stopping. /* claimId: sps3-mortality-harm | source: SPS3 Investigators NEJM 2012 Table 3 */
Major bleeding (DAPT vs Aspirin)
2.1%
1.1%
Major hemorrhage nearly doubled in the DAPT arm. /* claimId: sps3-bleeding-harm | source: SPS3 Investigators NEJM 2012 Table 3 */
Trial Design
Type
- Randomized double-blind multicenter trial
- Stopped early due to harm
- 1:1 allocation (DAPT vs. Aspirin)
Timeline
Enrolled 2003-2011 (stopped early)
N
3,020
Enrollment
3,020 of 3,600 planned patients enrolled. Stopped early by DSMB for harm (increased mortality in DAPT arm). Enrolled 2003 to 2011.
ClinicalTrials.gov
NCT00059306Bedside Pearl
SPS3 is a HARM signal trial: long-term DAPT in lacunar stroke increases mortality and bleeding with no stroke reduction. This is the opposite of CHANCE/POINT, which show short-term DAPT benefit in acute presentations. The practical rule: DAPT is for the first 21 days after TIA or minor stroke, not for chronic secondary prevention in lacunar disease. Aspirin monotherapy remains the long-term standard in this population.
See also