SPS3 Clopidogrel-ASA

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SPS3 Study Group writers. "Effects of clopidogrel added to aspirin in patients with recent lacunar stroke". New England Journal of Medicine. 2012. 367(9):817-825.
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Clinical Question

Among patients with recent lacunar strokes, does the administration of clopidogrel+ASA reduce rates of subsequent strokes when compared to ASA monotherapy?

Bottom Line

Among patients with recent lacunar strokes, clopidogrel+ASA did not reduce rate of recurrent stroke and led to increases in bleeding risk and death when compared with ASA monotherapy.

Major Points

The efficacy of single-agent antiplatelet therapy for secondary stroke prevention is well established, particularly for ASA in many trials [1][2][3][4][5] (including IST) and for clopidogrel in the subgroup analysis of the CAPRIE trial. However, the role of dual anti-platelet therapy (DAPT) in secondary stroke prevention is currently unclear.

The CHANCE trial found a significant improvement in DAPT vs. ASA alone, leading to a reduction in 90-day stroke incidence without increasing bleeding rates. However, this trial was done in a Chinese population, with striking differences in epidemiology and secondary prevention practices making these results difficult to generalize to a North American population. The POINT trial is currently ongoing to assess this comparison in a more similar population (DAPT vs. ASA for secondary prevention). Several North American trials of DAPT for stroke prevention have been negative, however with important variations in that core comparison. The MATCH trial compared DAPT to clopidogrel (not aspirin monotherapy) for secondary stroke prevention and found increased bleed risk without improved rates of stroke or mortality. The CHARISMA trial compared DAPT vs ASA, however for primary prevention, and also found increased bleed rates without significant benefit. Despite the MATCH trial showing clopidogrel monotherapy to have similar efficacy to DAPT, a major trial of ASA vs. clopidogrel for secondary stroke prevention has not been done.

The SPS3 trial examined the role of DAPT in the setting of lacunar ischemic disease, as these prior trials did not evaluate specifically for benefit of additional antiplatelet effect for small arterial occlusive events. Lacunar strokes are defined as infarcts <20 mm in diameter located in territories supplied by cerebral small vessels (40–200 μm in diameter). The SPS3 trial randomized patients 2 weeks to 6 months after a lacunar ischemic event to ASA/clopidogrel vs. ASA monotherapy. The DAPT arm was terminated early at 3.4 years after an interim analysis found no difference in rates of recurrent stroke between groups, with an increased rate of major hemorrhage. This negative trial suggested another important failure of DAPT, suggesting that it has no long-term benefit in patients with predominantly lacunar disease.


Adapted from 2014 AHA/ASA Secondary Stroke Prevention Guidelines [6]

  • For patients with noncardioembolic ischemic stroke or TIA, the use of antiplatelet agents rather than oral anticoagulation is recommended to reduce the risk of recurrent stroke and other cardiovascular events (Class I; Level of Evidence A).
  • The combination of aspirin and clopidogrel might be considered for initiation within 24 hours of a minor ischemic stroke or TIA and for continuation for 90 days (Class IIb; Level of Evidence B). (New recommendation in 2014 Update)
  • The combination of aspirin and clopidogrel, when initiated days to years after a minor stroke or TIA and continued for 2 to 3 years, increases the risk of hemorrhage relative to either agent alone and is not recommended for routine long-term secondary prevention after ischemic stroke or TIA (Class III; Level of Evidence A).


  • Multicenter, open label, 2x2 factorial, randomized controlled trial
  • N=3,020
    • ASA (n=1,503)
    • Clopidogrel+ASA (n=1,517)
Participants were also randomized to intensive versus regular blood pressure control, which is reported in a separate publication. SPS3-BP
  • Setting: 82 centers in North America, Latin America, and Spain
  • Enrollment: 2003-2011
  • Mean follow-up: 3.4 years (stopped 10 months before planned end date)
  • Analysis: Intention-to-treat
  • Primary outcome: Incident stroke


Inclusion Criteria

Full details are presented elsewhere.[7]

  • Adults ≥30 years with hypertension or normotension
  • ≥1 lacunar stroke clinical syndromes lasting >24 hrs or subcortical TIA with corresponding lesion on DWI in prior 6 months but randomized ≥2 weeks after event
  • MRI evidence of small subcortical stroke (S3; ≤2.0 cm in diameter) corresponding to the qualifying event (required for all brainstem events) OR multiple S3s and absence of cortical stroke and large subcortical stroke (recent or remote)

Exclusion Criteria

  • Disabling stroke (Modified Rankin Scale ≥4)
  • Signs or symptoms of cortical dysfunction (eg, aphasia, apraxia, agnosia, agraphia, homonymous visual field defect)
  • Prior spontaneous ICH or hemorrhagic stroke; high risk of bleeding (eg, recurrent GI or GU bleeding, active peptic ulcer disease, etc)
  • Intolerance or contraindications to aspirin or clopidogrel (eg, thrombocytopenia, prolonged INR)
  • Anticipated requirement for long-term use of anticoagulants (eg, recurrent DVT, AF requiring anticoagulation) or other antiplatelets
  • Ipsilateral cervical carotid stenosis ≥50% if hemispheric lesion or prior ipsilateral carotid endarterectomy or stent
  • Other likely cause of stroke (eg, dissection, vasculitis, prothrombotic diathesis, drug abuse)
  • Prior cortical or retinal stroke or TIA (diagnosed either clinically or by neuroimaging)
  • GFR <40
  • Medical contraindication to MRI
  • Pregnancy or women of child-bearing potential not on contraception
  • An age and education adjusted Folstein MMSE score <24, patients unable or unwilling to provide informed consent, patients unlikely to be compliant with therapy/unwilling to return for frequent clinic visits
  • Patients concurrently participating in another investigational study

Baseline Characteristics

From the ASA only group.

  • Demographics: Mean age 63 years, male 64%
  • Ethic group: White 52%, Hispanic 31%, Black 17%
  • Mean baseline blood pressure: 143/78
  • Past medical history: Diabetes 38%, HTN 74%, other prevention stroke of TIA 15%, ischemic heart disease 11%, current smoker 21%
  • Qualifying event: TIA 3%, minor stroke 97%
  • Lacunar syndrome: Pure motor hemiparesis 35%, pure sensory stroke 10%, sensorimotor stroke 30%, Other 25%
  • Use of ASA at time of qualifying event: 28%
  • Statin at any follow-up: 85%


  • Randomization to one of two groups at least 2 weeks after index event:
    • ASA - Received enteric coated aspirin 325 MG plus placebo every day after randomization
    • Clopidogrel+ASA - Received enteric coated aspirin 325 MG plus 75 MG of clopidogrel every day after randomization


Comparisons are ASA vs. clopidogrel+ASA.

Primary Outcome

Any stroke (ischemic and hemorrhagic)
2.7 vs. 2.5%/yr (HR 0.92; 95% CI 0.72-1.16; P=0.48)
Ischemic stroke: 2.4 vs. 2.0%/yr (HR 0.82; 95% CI 0.63–1.09; P=0.13)
Disabling or fatal stroke: 0.78 vs. 0.84%/yr (HR 1.06; 95% CI 0.69–1.64; P=0.79)
TIA without stroke: 0.78 vs. 0.57%/yr (HR 0.73; 95% CI 0.45–1.18; P=0.19)

Secondary Outcomes

0.71 vs. 0.59%/yr (HR 0.84; CI 0.52–1.35; P=0.47)
Other thromboembolic events
0.22 vs. 0.40%/yr (HR 1.81; CI 0.89–3.68; P=0.10)
Major vascular event
Stroke, MI, or death from vascular event.
3.4 vs. 3.1%/yr (HR 0.89; CI 0.72–1.11; P=0.29)
All-cause mortality
1.4 vs. 2.1%/yr (HR 1.52; CI 1.14–2.04; P=0.004)
Vascular causes: 0.35 vs. 0.51%/yr (HR 1.46; CI 0.81–2.64; P=0.20)
Cerebral: 0.17 vs. 0.19%/yr (HR 1.13; CI 0.46-2.78; P=0.79)
Non-cerebral: 0.18 vs. 0.32%/yr (HR 1.77; CI 0.81-3.87; P=0.15)
Probable vascular causes: 0.11 vs. 0.34%/yr (HR 3.09; CI 1.23–7.80, P=0.02)
Nonvascular causes: 0.57 vs. 0.73%/yr (HR 1.31; CI 0.82–2.10; P=0.26)
Uncertain: 0.39 vs. 0.55%/yr (HR 1.41; CI 0.82–2.52; P=0.21)

Subgroup Analysis

There were no significant interaction for the primary endpoint for age, sex, history of diabetes, ASA at time of qualifying event, race/ethnic group, or region of residence.

Adverse Events

Major hemorrhages
1.1 vs. 2.1%/yr (HR 1.97; CI 1.41–2.71; P<0.001)
Intracranial hemorrhages: 0.28 vs. 0.42%/yr (HR 1.52; CI 0.79–2.93; P=0.21)
Intracerebral hemorrhage: 0.15 vs. 0.28%/yr (HR 1.92; CI 0.82–4.54; P=0.14)
Subdural or epidural: 0.11 vs. 0.13%/yr (HR 1.23; CI 0.41–3.64; P=0.72)
Other: 0.07 vs. 0.04%/yr (HR 0.53; CI 0.10–2.89; P=0.46)
Extracranial bleeding: 0.79 vs. 1.7%/yr (HR 2.15; CI 1.49–3.11; P<0.001)
Gastrointestinal: 0.52 vs. 1.1%/yr (HR 2.14; CI 1.36–3.36; P<0.001)
Fatal hemorrhages: 0.07 vs. 0.17%/yr (HR 2.29; CI 0.70–7.42; P=0.17)
Intracranial: 0.07 vs. 0.13%/yr (HR 1.78; CI 0.52–6.07; P=0.36)
Extracranial: 0 vs. 0.04%/yr


  • Dose of ASA used is higher than currently used in clinical practice (80-81MG) as there is evidence to show equal efficacy for recurrent stroke prevention with ASA doses of 50-1500MG, with higher bleeding risk associated with higher doses of ASA.
  • Patient population in SPS3 is younger than many other stroke trials (mean age 63) which may limit its generalization


National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS)

Further Reading

  1. Farrell B et al. The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J. Neurol. Neurosurg. Psychiatr. 1991. 54:1044-54.
  2. A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. The Dutch TIA Trial Study Group. N. Engl. J. Med. 1991. 325:1261-6.
  3. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. The Canadian Cooperative Study Group. N. Engl. J. Med. 1978. 299:53-9.
  4. Collaborative overview of randomised trials of antiplatelet therapy--I: Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Antiplatelet Trialists' Collaboration. BMJ 1994. 308:81-106.
  5. The International Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both, or neither among 19435 patients with acute ischaemic stroke. International Stroke Trial Collaborative Group. Lancet 1997. 349:1569-81.
  6. Kernan WN et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2014. 45:2160-236.
  7. Benavente OR et al. The Secondary Prevention of Small Subcortical Strokes (SPS3) study. Int J Stroke 2011. 6:164-75.