From Wiki Journal Club
Jump to: navigation, search
Halkes PH, et al. "Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): Randomized controlled trial". The Lancet. 2006. 367(9523):1665-1673.
PubMedFull textPDF

Clinical Question

In patients with TIAs or minor ischemic strokes, does combination aspirin/dipyridamole reduce rates of vascular mortality, non-fatal stroke, non-fatal MI, or non-fatal major bleeding when compared to aspirin alone?

Bottom Line

In patients with TIAs or minor ischemic strokes, combination aspirin/dipyridamole was associated with lower rates of vascular mortality, non-fatal stroke, non-fatal MI, and non-fatal major bleeding when compared to aspirin alone.

Major Points

Prior studies demonstrated the efficacy of single-agent aspirin or single-agent dipyridamole for secondary stroke prevention, but studies of combination aspirin/dipyridamole therapy yielded conflicting results. The most promising study to date had been ESPS-2 (1996),[1] which suggested a modest benefit to combination therapy, but its results had not been confirmed.

The 2006 European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) randomized 2,739 patients with TIA or minor ischemic stroke to combination aspirin/dipyridamole or aspirin alone in an unblinded fashion. Patient with likely cardioembolic strokes were excluded. With a mean follow-up of 3.5 years, combination aspirin/dipyridamole was associated with an absolute risk reduction of 1% per year for the composite primary outcome of vascular mortality, non-fatal stroke, non-fatal MI, or major bleeding (13% vs. 16%; NNT 33). Bleeding rates were similar between the two groups. Combination aspirin/dipyridamole was discontinued secondary to headaches 8.8% of patients.

The Cochrane group updated their review in 2007 and concluded that combination aspirin/dipyridamole reduces the risk of future vascular events in patients with prior TIA or ischemic stroke. However, they note that combination therapy does not reduce the rate of vascular death.[2]

Of note, the 2008 PRoFESS trial found no difference between combination aspirin/dipyridamole and single-agent clopidogrel in a similar population for secondary stroke prevention.


AHA/ASA Stroke prevention for those with stroke or TIA (2011, adapted)[3]

  • Antiplatelets rather than anticoagulation for prophylaxis in patients with noncardioembolic ischemic stroke or TIA to reduce recurrent stroke and other CV events (class I, level A) with:
    • Aspirin 50-325 mg PO daily (class I, level A)
    • Aspirin 25 mg and extended-release dipyridamole 200 mg PO twice daily (class I, level B)
    • Clopidogrel 75 mg PO daily (class IIa, level B)
  • Dual therapy with aspirin and clopidogrel is not recommended as it increases risk of hemorrhage (class III, level A)
  • In patients with a stroke while on aspirin:
    • There is no evidence demonstrating that increasing the dose provides additional benefit (class IIb, level C)
    • Providers often consider alternative antiplatelet medications though no single or combination medication has been studied in this regard (class IIb, level C)


  • Multicenter, randomized, controlled, open label trial
  • N=2,739
    • Aspirin/dipyridamole (n=1,363)
    • Aspirin (n=1,376)
  • Setting: 79 hospitals in 14 countries
  • Enrollment: 1997-2005
  • Mean follow-up: 3.5 years
  • Analysis: Intention-to-treat
  • Primary outcome: Composite of vascular mortality, non-fatal stroke, non-fatal MI, or major bleeding


Inclusion Criteria

  • TIA (including transient monocular blindness) or minor ischemic stroke (modified Rankin score ?3) thought to be arterial in origin
  • Qualifying event within prior 6 months

Exclusion Criteria

  • Possible cardiac source of embolism, defined by any of the following:
    • AF on EKG
    • Valvular heart disease
    • Recent MI
  • Planned carotid intervention for high-grade stenosis associated with cerebral ischemia
  • Coagulopathy
  • Contraindication for aspirin or dipyridamole
  • Limited life expectancy

Baseline Characteristics

From the aspirin/dipyridamole group.

  • Demographics: Male 66%, age 63 years
  • PMH: Stroke 12%, angina 10%, MI 7%, claudication 6%, any vascular intervention 6%, DM 19%, HTN 60%, HLD 47%, active smoker 36%
  • BP: 152/86 mmHg
  • Qualifying event: CVA 66%, TIA 30%, transient monocular blindness 5%
  • Time from event to randomization:
    • <1 week: 11%
    • 1 week to 1 month: 23%
    • 1-6 months: 66%
  • Modified Rankin score:
    • 0: 43%
    • 1: 33%
    • 2: 18%
    • 3: 6%
  • Imaging studies:
    • CT or MRI of brain: 96%
      • Any infarct: 48%
      • Infarct relevant to index event: 36%
    • Carotid US: 90%
      • Stenosis >50%: 11%
  • Vessel involved: Large 30%, small 50%, unspecified 20%
  • Antithrombotic use at time of event: Aspirin 23%, oral anticoagulant <1%, other 1%, none 75%


  • Randomized to a group:
    • Aspirin/dipyridamole - Aspirin 30-325mg PO daily plus dipyridamole 200mg PO BID (either as fixed-dose single pill or as free combination)
    • Aspirin - Aspirin 30-325mg PO daily
A third anticoagulation arm was also studied but was not reported with the primary ESPRIT results.


Comparisons are aspirin/dipyridamole vs. aspirin alone. P-values were not given by the authors.

Primary Outcomes

Vascular mortality, non-fatal stroke, non-fatal MI, or non-fatal major bleeding
12.7% vs. 15.7% (HR 0.80; 95% CI 0.66-0.98; NNT=33)

Secondary Outcomes

All-cause mortality
6.8% vs. 7.8% (HR 0.88; 95% CI 0.67-1.17)
Vascular mortality
3.2% vs. 4.4% (HR 0.75; 95% CI 0.51-1.10)
Vascular mortality or non-fatal stroke
9.7% vs. 12.4% (HR 0.78; 95% CI 0.62-0.97)
Major bleeding
2.6% vs. 3.9% (HR 0.67; 95% CI 0.44-1.03)
Non-fatal extracranial: 1.5% vs. 2.3%
Fatal extracranial: <1% vs. 0
Non-fatal intracranial: 0.7% vs. 1.2%
Fatal intracranial: 0.2% vs. 0.3%
Major ischemic events, non-hemorrhagic vascular mortality, non-fatal ischemic stroke, or non-fatal MI
10.3% vs. 12.6% (HR 0.81; 95% CI 0.65-1.01)
Vascular mortality, non-fatal stroke, non-fatal MI
10.9% vs. 13.9% (HR 0.78; 95% CI 0.63-0.97)
First ischemic stroke
7.0% vs. 8.4% (HR 0.84; 95% CI 0.64-1.10)
First cardiac event
3.1% vs. 4.4% (HR 0.73; 95% CI 0.49-1.08)

Additional Analyses

Dose of aspirin
30 mg: 42% vs. 46%
40 mg: <1% vs. <1%
50 mg: 8% vs. <1%
75 mg: 15% vs. 15%
80 mg: 4% vs. 7%
100 mg: 23% vs. 25%
150 mg: 2% vs. 2%
160 mg: <1% vs. <1%
250 mg: <1% vs. <1%
300 mg: 4% vs. 5%
325 mg: <1% vs. <1%

Subgroup Analysis

There was no difference in the primary outcome for comparisons by cortical vs. small deep vessel, sex, age ≤ or >65 years, ischemic heart disease, Asian vs. non-Asian country, dose of aspirin, or time until randomization.

Adverse Events

Minor bleeding
171 vs. 168 patients (RR 1.03; 95% CI 0.84-1.25)
Discontinuation of medication
34% vs. 13% (RR 2.6)
Headache was the most common reason (26%) for aspirin/dipyridamole discontinuations.


  • Unblinded study
  • High NNT, with 104 to prevent one primary outcome event at one year, suggests minor benefit and questionable cost effectiveness[4]
  • Cannot be generalized to patients with cardioembolic strokes[4]
  • Most patients were randomized 1-6 months after their qualifying event so this does not inform best therapy for acute stroke[4]


Various international agencies, no obvious industry funding.

Further Reading