ESPRIT

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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.
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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.

Guidelines

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)

Design

  • 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

Population

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%

Interventions

  • 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.

Outcomes

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.

Criticisms

  • 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]

Funding

Various international agencies, no obvious industry funding.

Further Reading

  1. Diener HC, et al. "European Stroke Prevention Study 2. Dipyridamole and acetylsalicyclic acid in secondary prevention of stroke. (ESPS2)" Journal of the Neurological Sciences. 1996;143:1-13.
  2. De Schryver EL, et al. "Dipyridamole for preventing stroke and other vascular events in patients with vascular disease." Cochrane Database Syst Rev. 2007 Jul 18;(3):CD001820.
  3. Furie KL et al. "AHA/ASA guideline: Guidelines for prevention of stroke in patients with stroke or transient ischemic attack." Stroke. 2011;42:227-276.
  4. 4.0 4.1 4.2 Tirschwell D. "Aspirin plus dipyridamole was more effective than aspirin alone for preventing vascular events after minor cerebral ischemia." ACP Journal Club. 2006;145(3)57.