Secondary Prevention of Small Subcortical Strokes - SPS3


Data regarding optimal antiplatelet therapy in patients with subcortical/lacunar infarcts are limited, even though they constitute 25% of all ischemic strokes. The current trial sought to study if the dual antiplatelet therapy (DAPT) with aspirin and clopidogrel daily would be superior to aspirin monotherapy alone in preventing recurrent strokes.

Contribution to the Literature: The SPS trial showed that DAPT is not superior to aspirin monotherapy for secondary prevention in patients with lacunar/subcortical infarcts, with an increase in bleeding risk. Similarly, targeting a systolic blood pressure (SBP) of <130 mm Hg is not beneficial compared with SBP of 130-149 mm Hg, although renal complications may be higher with more intensive control.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Lacunar strokes within 180 days, confirmed by magnetic resonance imaging (MRI)
  • Age ≥30 years
  • Lesion diameter ≤2 cm

    Number of enrollees: 3,020
    Duration of follow-up: 3.5 years
    Mean patient age: 63 years
    Percentage female: 37%


  • Cortical stroke on MRI (recent or remote)
  • Cardioembolic stroke
  • Carotid stenosis
  • Large subcortical infarct (≥1.5 cm)
  • History of or intracranial hemorrhage (except traumatic)
  • Disabling stroke with Rankin score ≥4

Primary Endpoints:

  • All ischemic and hemorrhagic strokes

Secondary Endpoints:

  • Acute myocardial infarction
  • Major vascular complications
  • All-cause mortality
  • All hemorrhages

Drug/Procedures Used:

Eligible patients were randomized in a double-blind fashion to either DAPT with aspirin 325 mg/clopidogrel 75 mg daily or aspirin 325 mg monotherapy. In a 2 x 2 factorial design, patients were also randomized in an open-label fashion to usual BP control (goal SBP 130-149 mm Hg) or tight BP control (goal SBP <130 mm Hg).

Concomitant Medications:

Statin (85%)

Principal Findings:

A total of 3,020 patients were randomized at 82 centers in 8 countries between 2003 and 2011 when the trial was terminated early due to futility. At this point, 1,517 had been randomized to DAPT and 1,503 to aspirin alone. Baseline characteristics were fairly similar between the two arms. About 52% were Caucasian, 17% were black, and 31% Hispanic. About two-thirds of the patients had a Rankin score of 0 or 1, with a mean baseline Mini-Mental Status Examination (MMSE) of 28. About 37% had diabetes mellitus, 10% had prior stroke, 6% prior transient ischemic attack (TIA), and the mean baseline systolic BP was 143 mm Hg. About a third presented with pure motor hemiparesis, 31% had sensorimotor symptoms, and 10% had pure sensory symptoms.

The primary endpoint of incident ischemic or hemorrhagic stroke was similar between the aspirin and DAPT arms at 8 years (2.7%/patient-year vs. 2.5%/patient-year, hazard ratio 0.92, 95% confidence interval 0.72-1.16, p = 0.48). Individual components including ischemic stroke (2.4%/patient-year vs. 2.1%/patient-year, p = 0.21) and hemorrhagic stroke (0.25%/patient-year vs. 0.42%/patient-year, p = 0.15) were also similar between the two arms.

Other endpoints including major vascular complications (3.4%/patient-year vs. 3.1%/patient-year, p = 0.28) and myocardial infarction (0.71%/patient-year vs. 0.59%/patient-year, p = 0.47) were also similar; all-cause mortality was lower in the aspirin arm (1.4%/patient-year vs. 2.1%/patient-year, p = 0.004). This seemed to be driven by a reduction in probable vascular deaths (0.11%/patient-year vs. 0.34%/patient-year, p = 0.02); cerebral deaths were similar (0.17%/patient-year vs. 0.19%/patient-year, p = 0.79). All hemorrhages were lower in the aspirin arm as well (1.1%/patient-year vs. 2.1%/patient-year, p < 0.0001); rates of intracerebral hemorrhage (ICH) were similar (0.15%/patient-year vs. 0.28%/patient-year; p = 0.18). Extracranial bleeding, especially GI bleeding, was also higher in the DAPT arm (p < 0.001).

Compared with higher target SBP, lower target SBP had a faster decline in estimated glomerular filtration rate (eGFR) by 0.5 ml/min/1.73 m2. Rates were particularly higher in the first year (2.1 ml/min/1.73 m2). Rapid renal function decline (eGFR decline >30%) was more common in the low target SBP arm (24% vs. 19%, p < 0.05).


The results of this trial indicate that DAPT with full-dose aspirin and clopidogrel is not superior to full-dose aspirin monotherapy for secondary prevention in patients with lacunar/subcortical infarcts. The combination is also associated with an increased risk of bleeding complications, and possibly increased mortality. Moreover, renal function decline was greater in the low-target SBP arm, particularly in the first year.

A number of clinical trials have tested antiplatelet combination therapy versus monotherapy before. In the CHARISMA trial, patients at high-risk for cardiovascular disease (including prior ischemic stroke) were randomized to low-dose aspirin + clopidogrel versus low-dose aspirin alone. Although the overall results for the primary endpoint were not significant, the combination of aspirin and clopidogrel was associated with a significant reduction in ischemic events compared with aspirin monotherapy in the subgroup of patients with ischemic cerebrovascular accident (CVA), but with an increase in the risk of moderate bleeding. On the other hand, in the MATCH trial, patients with TIA or recent ischemic stroke were randomized to low-dose aspirin + clopidogrel versus clopidogrel alone. No significant difference in the primary endpoint was noted, and life-threatening bleeding (including ICH) was increased with DAPT.

Taken together, these results indicate that antiplatelet monotherapy is probably the appropriate first choice for patients with ischemic CVA (cortical or subcortical). The choice of aspirin versus clopidogrel is debatable, although subgroup analysis of the CAPRIE trial seemed to suggest that clopidogrel may be preferable. Data from east Asia also suggest that cilostazol monotherapy may be a viable alternative. If DAPT is necessary, it is preferred to use low-dose aspirin, and evaluate patients carefully for increased bleeding risk.


Peralta CA, McClure LA, Scherzer R, et al. The Effect of Intensive vs. Usual Blood Pressure Control on Kidney Function Among Persons With Prior Lacunar Stroke: A Post-Hoc Analysis of the SPS3 Randomized Trial. Circulation 2016;Jan 13:[Epub ahead of print].

The SPS3 Investigators. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med 2012;367:817-25.

Presented by Dr. Oscar Benavente at the American Stroke Association’s International Stroke Conference, February 2012.

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