Secondary Stroke Prevention Trials Research Articles

Editorial Comment—Female Sex: A Questionable Risk Factor for Carotid Endarterectomy

The misconception that clinical manifestations of cardiovascular disease are a much more significant problem among male patients is hard to eliminate, supported by the higher incidence of cardiac, cerebrovascular, and peripheral arterial diseases in men than in women.1 Our understanding of cerebrovascular disease in women is hampered by a paucity of studies including an adequate number of female patients. Most studies are heavily biased toward the male sex. The efficacy of aspirin in primary and secondary stroke prevention trials has been demonstrated almost exclusively in men.2 Men were also the majority of the population recruited in the major clinical trials on symptomatic (North American Symptomatic Carotid Endarterectomy Trial [NASCET] and European Carotid Surgery Trial [ECST])3,4 and asymptomatic (Asymptomatic Carotid Atherosclerosis Study [ACAS]) carotid stenoses,5 and no women were enrolled in the Veteran Administration trials.6,7 Unfortunately, neither the original report from the NASCET nor the one from ECST analyzed data specifically by sex. Although the superiority of carotid endarterectomy (CEA) over the best medical management in protecting against stroke for selected symptomatic and asymptomatic patients with carotid lesions was well demonstrated,3–7 post-hoc analyses,8,9 along with several reviews and large single-center studies, have prompted a reevaluation of the role of CEA in women.10–14 The NASCET results did not distinguish, …

Stroke prevention in patients without coronary heart disease: A link with antihypertensive treatment effect on angiotensin and sympathetic systems ?

HOPE trial has shown that in patients with a high prevalence of coronary heart disease (CHD = 80 %) an angiotensin converting enzyme inhibitor (ACEI) decreases the risk of stroke beyond what is expected from the BP-reduction. The objective of this study is to see whether suppression of the renin-angiotensin and/or sympathetic systems (RA/SS) by antihypertensive drugs also gives such a protection in primary or secondary stroke prevention trials in which patients have a low initial prevalence (<30 %) of CHD. All the large randomized primary prevention trials in mild hypertension published since 1985 as well as the 2 recent large secondary stroke prevention trials (PATS and PROGRESS) were reviewed. The BP-independent stroke risk change was calculated by substracting, from the stroke risk change observed in the trial, the risk change expected from the BP change. This latter was calculated from the log-linear relation between stroke risk and diastolic BP established by MacMahon in cohort studies of individuals without initial cardiovascular complications and from the relation established by Rodgers et al in the patients of the UKTIA trial showing that 10 mmHg SBP decrease is expected to reduce the stroke recurrence risk by 28 %. The trials were then classified as giving RA/SS-stimulation if diuretics or calcium antagonists were compared to placebo, betablockers or ACEI (which decrease angiotensin II formation) or to alpha 1 blockers (which are neutral). When the reverse comparison was made the trial was considered as RASS-suppressing. Trials comparing associations of 2 drugs with opposite effect on RASS to placebo or to similar associations were considered as having a neutral effect on RASS. In hypertension primary prevention trials, median of DBP-independent stroke risk change was significantly higher in trials with RASS-suppression (+18%;p=0.006) or with neutral effect on RASS (+10%;p=0.02) than in trials with RASS stimulation (−16 %). In secondary stroke prevention trials the SBP-independent stroke risk change was significantly higher with perindopril alone (+9 %; p=0.01), or with the combination perindopril + indapamide (−9 %; p<0.05) than with indapamide alone (−15 %). In patients without high prevalence of CHD, stroke prevention is worse when RASS are not activated by the antihypertensive treatment.

Duality of angiotensin receptors and opposite link between angiotensin II and stroke risk according to high or low prevalence of coronary disease

The HOPE trial is the only trial in which an angiotensin converting enzyme inhibitor (ACEI) has decreased stroke risk beyond what was expected from blood pressure (BP) lowering. In hypertension primary prevention trials or in secondary stroke prevention trials,stroke prevention is worse when the renin angiotensin and/or sympathetic systems (RASS) are not activated. The main difference between HOPE trial population and those of the other trials is the much higher prevalence of coronary heart disease (CHD) since it was 80% in HOPE and less than 30% in the other trial. We propose the hypothesis that this difference accounts for the opposite links between BP-independent stroke prevention and activation of the RASS in HOPE comparatively to the other trial. Indeed since myocardial infarction and heart failure occurrence greatly increases the risk of stroke and that their occurrence in HOPE trial was overriding that of stroke (1477 and 952 versus 382) it is likely that a large proportion of the 70 strokes prevented by ramipril was accounted by the prevention of 219 cardiac events. This prevention of cardiac events was all the more likely to occur in this trial because twice the usual dose of an ACEI with high affinity for tissular ACE was used and that the cardiac complications are directly related to the vasoconstrictive and proatherothrombotic effects of angiotensin II mediated by the AT1 receptors. The BP-independent stroke risk decrease observed in trials with a low initial prevalence of CHD in which the RASS are stimulated cannot however be explained by lack of manifestation of AT1-receptor mediated deleterious effects in patients with low CHD prevalence. This decrease implies an actual beneficial effect from angiotensin II stimulation. Experimental data in rodent models of acute brain ischemia showing that non-AT1-receptor stimulation triggers protective mechanisms such as recruitment of collateral circulation and increased neuronal resistance to anoxia in ischemic tissues where AT2-receptors are over expressed (Achard Biochem Pharmacol 2001;62:261), we propose that these phenomen account for the BP-independent stroke risk decrease with stimulation of angiotensin II. AT1 receptor antagonist (AT1RA) having the same antiatherothrombotic effect as ACEI, but triggering angiotensin II stimulation,may have a cutting edge over ACEI in preventing stroke. Therefore a trial comparing AT1RA and ACEI for the prevention of stroke is proposed in patients at higher risk of stroke than of CHD ie in elderly hypertensives or in patients with a history of stroke but low prevalence of CHD.

Antiagregación plaquetaria en la prevención secundaria del ictus después del ESPS-2 y del CAPRIE

Antiplatelet therapy is effective for secondary prevention of atherothrombotic stroke. Aspirin, the more frequently used antiplatelet drug, prevents 13 to 17% of ischemic events after stroke. New and more effective antiplatelet therapies are needed. Two large secondary stroke prevention trials have been recently published (CAPRIE and ESPS-2), including more than 25,000 patients. As well TACIP trial designed to assess the efficacy of triflusal, is close to end. The combination of ticlopidine and Aspirin has shown synergistic effect. Clopidogrel, like ticlopidine, increase 9% the relative risk reduction of stroke over Aspirin. Clopidogrel has a better safety profile than ticlopidine. Dipyridamole is an effective antiplatelet drug, but in combination with low doses of Aspirin is more effective. The possible efficacy of clopidogrel-Aspirin combination should be evaluated.

Cerebrovascular disease in African Americans.

It was an honor to be selected as the first lecturer for the American Heart Association (AHA) Presidential Symposium in conjunction with the 23rd International Joint Conference on Stroke and Cerebral Circulation. I wish to thank Dr Martha Hill, the AHA President, for the invitation to participate. Dr Hill has had a longstanding interest in cardiovascular health issues in the African American community. I also wish to thank Drs Edward Cooper and Jacqueline Washington, who served as panel discussants for the symposium. Since 1981, I have been carrying out epidemiological studies of stroke in African Americans. The studies have included both observational ones and clinical trials. At the present time, we are completing a secondary stroke prevention trial: the African American Antiplatelet Stroke Prevention Study (AAASPS). I now provide an overview of cerebrovascular disease in African Americans. I begin my discussion with a brief review of the constructs race and ethnicity. Williams has critically examined the scientific consensus on the conceptualization of race.1 The United States government recognizes four racial groups—white, black, Asian or Pacific Islander, and American Indian or Alaskan Native—and one ethnic category, Hispanic. The distinction between race and ethnicity may be obscured, however, as some Hispanics may prefer to refer to themselves as a racial category.1 In the social science literature, the early definitions of race used the term to capture “physical” or “biological” characteristics that differentiated human populations. The term was then extended to encompass biological and social interaction. More recent definitions of race have discredited the early definition that included physical or biological characteristics because in general, phenotypic characteristics do not correlate well with biochemical or other genetic characteristics, and there may be more genetic variation …