Elsevier

The Lancet Neurology

Volume 7, Issue 10, October 2008, Pages 875-884
The Lancet Neurology

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Effects of aspirin plus extended-release dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study

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Summary

Background

The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful, and whether these compounds can be used to reduce disability after recurrent stroke is unknown. The putative neuroprotective effects of antiplatelet compounds and the angiotensin II receptor antagonist telmisartan were investigated in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.

Methods

Patients who had had an ischaemic stroke were randomly assigned in a two by two factorial design to receive either 25 mg aspirin (ASA) and 200 mg extended-release dipyridamole (ER-DP) twice a day or 75 mg clopidogrel once a day, and either 80 mg telmisartan or placebo once per day. The predefined endpoints for this substudy were disability after a recurrent stroke, assessed with the modified Rankin scale (mRS) and Barthel index at 3 months, and cognitive function, assessed with the mini-mental state examination (MMSE) score at 4 weeks after randomisation and at the penultimate visit. Analysis was by intention to treat. The study was registered with ClinicalTrials.gov, number NTC00153062.

Findings

20 332 patients (mean age 66 years) were randomised and followed-up for a median of 2·4 years. Recurrent strokes occurred in 916 (9%) patients randomly assigned to ASA with ER-DP and 898 (9%) patients randomly assigned to clopidogrel; 880 (9%) patients randomly assigned to telmisartan and 934 (9%) patients given placebo had recurrent strokes. mRS scores were not statistically different in patients with recurrent stroke who were treated with ASA and ER-DP versus clopidogrel (p=0·38), or with telmisartan versus placebo (p=0·61). There was no significant difference in the proportion of patients with recurrent stroke with a good outcome, as measured with the Barthel index, across all treatment groups. Additionally, there was no significant difference in the median MMSE scores, the percentage of patients with an MMSE score of 24 points or less, the percentage of patients with a drop in MMSE score of 3 points or more between 1 month and the penultimate visit, and the number of patients with dementia among the treatment groups. There were no significant differences in the proportion of patients with cognitive impairment or dementia among the treatment groups.

Interpretation

Disability due to recurrent stroke and cognitive decline in patients with ischaemic stroke were not different between the two antiplatelet regimens and were not affected by the preventive use of telmisartan.

Funding

Boehringer Ingelheim; Bayer-Schering Pharma (in selected countries); GlaxoSmithKline (in selected countries).

Introduction

The treatment of ischaemic stroke with neuroprotective drugs has been unsuccessful,1, 2, 3 possibly because of the delay in giving these drugs after stroke. Whether neuroprotective drugs are effective when they are given before a recurrent stroke has not been investigated in a large sample. There are conflicting data between experiments in animals4, 5 and in human beings6 that aspirin (acetylsalicylic acid, ASA) might be neuroprotective in acute ischaemic stroke. Dipyridamole used with aspirin had neuroprotective properties in cell cultures of neurons7, 8 and in models of embolic stroke in rats9 but not in a secondary prevention study in human beings.10 There is no evidence that clopidogrel, another antiplatelet drug used to prevent stroke, has neuroprotective properties.11 Therefore, we compared the efficacy of prophylactic treatment with ASA and extended-release dipyridamole (ER-DP) with treatment with clopidogrel in the reduction of disability after recurrent strokes in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial.

Hypertension is the most important risk factor for stroke and cerebral small vessel disease, and antihypertensive treatment lowers the risk of first and recurrent strokes.12 Angiotensin II receptor antagonists, such as candesartan, telmisartan, losartan, and olmesartan, can reduce the rate of stroke in hypertensive rats and are neuroprotective in other animal models of stroke.13, 14, 15, 16, 17, 18 Therefore, we hypothesised that telmisartan, in contrast with placebo, would reduce the disability due to recurrent strokes.

Small vessel disease is common in patients who have had a stroke, is associated with decreased cognition, and is a marker of incipient dementia. Vascular changes and vascular risk factors also have a role in Alzheimer's disease and vascular dementia.19, 20, 21, 22, 23, 24 A meta-analysis of the results from four placebo-controlled studies found a non-significant 20% reduction in risk of dementia in favour of antihypertensive therapy.25, 26, 27, 28, 29 This was confirmed by the HYVET-COG trial in elderly patients.30 Therefore, we also collected data on cognitive performance, which enabled us to test the hypothesis that telmisartan could prevent or delay cognitive decline in this population.

Section snippets

Patients

From September, 2003, to July, 2006, patients aged 55 years or older who had had an ischaemic stroke in the previous 90 days were recruited to the PRoFESS trial. In addition, patients aged between 50 and 54 years or patients who presented 90 to 120 days after the qualifying stroke were also included, provided the patient had two of the following additional risk factors: diabetes mellitus, hypertension, was a smoker at the time of the qualifying stroke, obesity (BMI ≥30), previous vascular

Results

Investigators at 695 sites in 35 countries or regions randomised 20 332 patients who had had ischaemic stroke. The baseline characteristics of the study population of the PRoFESS trial are reported elsewhere.40 Mean age was 66·1 years (SD 8·6) and 36% (7319) of the patients were women. The median time from the qualifying event to randomisation was 15 days, with 40% (8133) of patients randomised within 10 days. The median time of follow-up was 2·44 years. In accordance with the Trial of Org

Discussion

PRoFESS is the largest trial so far to investigate in a prespecified manner whether treatment with antiplatelet drugs or angiotensin II receptor antagonists (such as telmisartan) are neuroprotective in patients who have had recurrent stroke. The degree of functional impairment at 3 months poststroke was similar across treatment arms. The most probable explanation is that neither ASA with ER-DP nor clopidogrel are neuroprotective,43 despite indications from experiments in animals that this might

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  • Cited by (0)

    *

    All PRoFESS trial investigators listed at the end of this paper

    These authors contributed equally

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