PRoFESS

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Sacco RL, et al. "Aspirin and Extended-Release Dipyridamole versus Clopidogrel for Recurrent Stroke". The New England Journal of Medicine. 2008. 359(12):1238-1251.
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Clinical Question

Among patients with a recent ischemic stroke, how does combination aspirin-dipyridamole compare to clopidogrel in preventing recurrent stroke?

Bottom Line

Among patients with a recent ischemic stroke, there was no difference between aspirin-dipyridamole and clopidogrel in preventing recurrence of ischemic stroke.

Major Points

Aspirin's efficacy in the secondary prevention of ischemic stroke was best demonstrated in the 2002 Antithrombotic Trialists' Collaboration meta-analysis.[1] Randomized trials of other antiplatelet agents, namely clopidogrel and combination aspirin-dipyridamole, showed that perhaps greater benefits would be seen with alternative agents. For example, CAPRIE demonstrated clopidogrel's superiority over aspirin at reducing cardiovascular events, and ESPS-2 and ESPRIT demonstrated that combination aspirin-dipyridamole outperformed aspirin in secondary prevention of ischemic stroke. PRoFESS sought to determine whether these alternative antiplatelet therapies would perform similarly in reducing recurrent ischemic strokes.

The Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial randomized 20,332 patients with a noncardioembolic ischemic stroke within the previous 90-120 days to either aspirin-dipyridamole or clopidogrel. At a mean follow-up of 2.5 years, there was no difference in the primary outcome of any recurrent stroke (9.0% vs. 8.8%) or the composite secondary outcome of stroke, MI, or CV death. Compared with clopidogrel, aspirin-dipyridamole was associated with less heart failure but more major hemorrhages including intracranial hemorrhages, and more discontinuation of treatment due to adverse events, mainly headaches, the most common side effect of dipyridamole.

Of note, the trial's initial objective sought to compare combination aspirin-dipyridamole to combination aspirin-clopidogrel. However, after MATCH (2004) demonstrated that the addition of aspirin to clopidogrel had increased the risk of major bleeding complications without significantly reducing the risk of recurrent ischemic stroke, the PRoFESS protocol was subsequently modified. As a result, the 2,027 patients initially randomized to receive aspirin-clopidogrel were taken off aspirin, and all the following patients randomized to that arm were administered clopidogrel monotherapy.

Guidelines

The 2011 AHA/ASA guidelines recommend aspirin (level IA), aspirin-dipyridamole (level IB), or clopidogrel (level IIB) as initial therapy following noncardioembolic ischemic stroke. The combination of aspirin-clopidogrel is advised against due to excessive bleeding (level IIIA).

Design

  • Multicenter, double-blind, randomized, placebo-controlled trial
  • N=20,332 patients with recent noncardioembolic ischemic stroke
    • Aspirin-dipyridamole (n=10,181)
    • Clopidogrel (n=10,151)
  • Setting: 695 centers in 35 countries
  • Enrollment: 2003-2008
  • Mean follow-up: 2.5 years
  • Analysis: Intention-to-treat, noninferiority
  • Primary end point: Recurrent stroke

Population

Inclusion Criteria

  • Age ≥50 years
  • Ischemic stroke in prior 90-120 days

Exclusion Criteria

  • Contraindication to antiplatelet therapy

Baseline Characteristics

  • Age: 66 years
  • Female: 36%
  • White: 57.5%
  • Chinese: 18%
  • South Asian: 8.4%
  • African: 4%
  • BMI: 26.8 (25.7% obese)
  • Smoking: 42.7% never, 21.2% currently, 36.2% previously
  • TOAST classification of qualifying stroke
    • Small-artery (lacunar): 52%
    • Large-artery: 28.6%
    • Cardioembolic: 2%
    • Etiology unknown: 15.5%
  • Median time from stroke to randomization: 15 days
  • Modified Rankin score:
    • 0: 14.0%
    • 1: 37.3%
    • 2: 25.0%
    • 3-5: 23.7%
  • Baseline NIHSS score:
    • 0-1: 39.8%
    • 2-3: 29.5%
    • 4-5: 16.5%
    • 6-14: 13.6%
    • >14: 0.8%
  • Previous stroke or TIA: 24.6%
  • Atherosclerosis: 19.4%
  • HF: 2.6%
  • HTN: 74%
  • DM: 28.3%
  • HL: 46.6%
  • AF: 2.7%

Interventions

  • Randomized to either aspirin 25mg plus extended-release dipyridamole 200mg twice daily or clopidogrel 75mg daily.
  • Follow-up within 1 week of discharge, months 1, 3, and 6, and every 6 months thereafter

Outcomes

Comparisons are aspirin-dipyridamole vs. clopidogrel.

Primary Outcomes

Recurrent stroke
9.0% vs. 8.8% (HR 1.01; 95% CI 0.92-1.11)

Secondary Outcomes

Composite of stroke, MI, or CV mortality
13.1% vs. 13.1% (HR 0.99; 95% CI 0.92-1.07)
MI
1.7% vs. 1.9% (HR 0.90; 95% CI 0..73-1.10)
CV mortality
4.3% vs. 4.5% (HR 0.94; 95% CI 0.82-1.07)
All-cause mortality
7.3% vs. 7.4% (HR 0.97; 95% CI 0.87-1.07)
New or worsening CHF
1.4% vs. 1.8% (HR 0.78; 95% CI 0.62-0.96)
Premature discontinuation
29.1% vs. 22.6% (P<0.001)
Compliance
69.6% vs. 76.8%

Adverse Events

Major hemorrhage
4.1% vs. 3.6% (HR 1.15; 95% CI 1.00-1.32)
Intracranial hemorrhage
1.4% vs. 1.0% (HR 1.42; 95% CI 1.11-1.83; P=0.006)
Adverse event leading to treatment discontinuation
16.4% vs. 10.6% (mainly headache: 5.9% vs. 0.9%)

Criticisms

  • The clopidogrel arm was changed during the study from aspirin plus clopidogrel to clopidogrel alone.
  • Even though event rates for the primary and secondary outcomes were nearly identical, the trial failed to achieve prespecified noninferiority criteria for aspirin-dipyridamole

Funding

Funding by Boehringer Ingelheim which manufactures Aggrenox, combination of aspirin-dipyridamole.

Further Reading

  1. "Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients". BMJ 324 (7329): 71–86. January 2002.