(Stroke. 1997;28:1498-1500.)
© 1997 American Heart Association, Inc.
Articles |
American Heart Association Prevention Conference IV: Prevention and Rehabilitation of Stroke
Introduction
Key Words: AHA Medical/Scientific Statements • stroke • prevention
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Introduction |
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The fourth American Heart Association Prevention Conference was held May 1-2, 1996, in Tucson, Ariz. This report of the conference presents the state of knowledge on stroke epidemiology, etiologic basis, treatment, and rehabilitation. Since the conference, enthusiasm for and activity in acute stroke treatment has increased, spurred by the encouraging and successful National Institutes of Health trial of tissue plasminogen activator (TPA).
This document attests to the large variety of conditions that contribute to stroke. The challenge for the future will be to forge a better understanding of the interaction of pathogenic risk factors, causes, and physiology. Evidence-based medicine should provide a scientific framework that can be used in the prevention and treatment of stroke in individual patients.
The untimely death of Dr Mike Pessin, who chaired the Acute Interventions panel, has deeply saddened all of us. His presence and contributions will be sorely missed.
We thank the section chairs and panel members who contributed many hours and their expertise to the preparation of this paper. We are indebted to the American Heart Association, which contributes to the dominant and driving force in stroke research and treatment.
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Keynote Address: Properly Designed Trials and Identification of Risk Factors |
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TopIntroductionKeynote Address: Properly...References |
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Mark L. Dyken, MD
The best treatment for stroke is prevention. If stroke cannot be prevented, the next best treatment is to prevent permanent deficit. AHA Prevention ConferenceIV is dedicated to the prevention and rehabilitation of stroke, with an emphasis on risk factors, etiology, acute intervention, and rehabilitation. Leaders in the field will define where we are and where we need to go. To put this in perspective, the evolution of properly designed studies, the recognition of risk factors, and the evidence that risk factors can be altered must be reviewed.
No matter how sophisticated the design and statistical techniques, all studies must have the same fundamentals: There must be a testable hypothesis, an experiment designed to exclude bias, and the probability of the results occurring by chance to be so low that they are unacceptable. For clinical trials, this requires that the study be prospective, the treatment determined randomly and in a double-blinded manner, the numbers large enough to avoid type II error, and statistical tests determined at the beginning of the study.
Although for many years most studies were anecdotal, today the stroke research community is very sophisticated. Unfortunately, good studies are still being improperly interpreted, and conclusions are drawn that are not warranted by the experimental design. Two examples are the controversy concerning aspirin dosage in the secondary prevention of stroke1 2 and the Asymptomatic Carotid Atherosclerosis Study (ACAS).3
Although no study has adequately compared high-dose aspirin (900 to 1300 mg/d) with low-dose aspirin (325 mg/d or less), by extrapolating from theory and meta-analysis of primarily cardiac trials, many have concluded that these doses are equivalent.4 5 In the only direct comparison of 300 mg/d versus 1200 mg/d, there was no statistical difference between the two doses, but this was also true when each aspirin dose was compared with placebo.6 Yet differences in effect in favor of a higher dose have been noted in retrospective studies. A comparison of the results with studies of transient ischemic attack (TIA) and mild stroke that have shown a benefit suggests that high-dose aspirin might be two to three times more effective.2 In the North American Symptomatic Carotid Endarterectomy Trial (NASCET),1 ipsilateral stroke occurred in 11% of those taking 325 mg of aspirin each day and in only 4% of those taking 1300 mg/d. In Israel, in patients who had a recurrent stroke, the average time from the first to second stroke was 11.7 months for those taking 325 mg of aspirin or less per day and 24.1 months for those taking 500 mg/d.7 Only 25.6% of those who had a second stroke were taking 500 mg/d, compared with 38.0% of the control subjects. In the Physicians' Health Study, those taking 325 mg of aspirin every other day when compared with placebo had a very significant decrease in myocardial infarction but not stroke.8 Because 217 strokes occurred, it was expected that the results would be similar if the mechanisms for the heart and brain were the same. A large number of responses other than platelet aggregation have been established as dose related. Among these are variable strength of agonist or collagen, increased hydrolysis of aspirin, inhibition of shear stress, hyperactivity to shear stress, disaggregation response, variability of response, decreased platelet membrane fluidity, generation of thrombin, inhibition of smooth muscle cell growth, and inhibition of megakaryocyte cyclo-oxgenase.1 2
The assumption that low-dose aspirin is equivalent to high-dose aspirin could have important consequences in evaluating the results of trials in which the benefit of an experimental therapy is compared with 325 mg of aspirin per day. Twofold to threefold differences might be accounted for by too low a dose of aspirin and not the therapy being investigated.
Very likely the ACAS study3 is under fire because of conclusions made by some that are not warranted by the design. In contrast, the results of two similar large prospective randomized studies for symptomatic patients are widely accepted with little controversy.9 10 Yet the ACAS is as well designed as possible for a treatment that cannot be double-blinded. By design, all patients with asymptomatic carotid artery stenosis of 60% to 99% were studied, and the results can only be applied to this group in general. There was a significant decrease in aggregate risk at 5 years for ipsilateral or perioperative stroke or death for patients who had undergone endarterectomy (5.1% versus 11.0%). The study was not large enough or was not designed to address the differences between subgroups with different degrees of stenosis, for major stroke and death, between women and men, for surgeons outside the trial with higher complications, and whether the results would have been the same if three to four aspirins a day had been used instead of one. Thus, the results of this study cannot be applied to any of these special circumstances.
The recommendations of this conference must be based on the results of properly designed and interpreted studies. Using these principles, exciting new therapies are emerging. The AHA guidelines11 published in 1994 are already outdated. Using strict rules of evidence, the AHA writing group concluded that no specific therapy for acute stroke was established to be of value. In the last few months low-molecular-weight heparin12 and thrombolytic agents13 were found to decrease the severity of dysfunction after acute stroke at 6 months and at 3 months, respectively.
A review of the identification and treatment of risk factors is critical. Although special conferences devoted to stroke have been held since 1954, when the Princeton Conferences were established, it was not until the fifth Princeton Conference in 1966 that epidemiology or risk factors were even mentioned.14 At that time, data from the Framingham Study indicated that the most clear-cut risk factors for stroke were hypertension, heart disease, and diabetes.
A special subcommittee of the AHA Council on Cerebrovascular Disease prepared the first formal consensus statement on stroke in 1971.15 The subcommittee was convened in 1968 but after a year was unable to reach a consensus because of a reluctance to set a policy statement until every loophole was plugged, the recognized need for prospective studies of large population groups, and the fear that recognition of a risk factor would imply that eliminating or minimizing it would automatically reduce the risk. A tentative consensus was finally reached, and hypertension, heart disease, and diabetes were agreed upon as established major risk factors. The possible implications of high serum cholesterol and cigarette smoking were noted but with qualifications.
One year later the Epidemiological Subcommittee of the Joint Committee for Stroke Facilities concluded, "The major factors known to be associated with stroke include increasing age, hypertension, cardiovascular disease, and diabetes. However, many additional data are required to substantiate the role of other risk factors."16
In 1984 a new subcommittee of the AHA Stroke Council issued a second statement.17 Hypertension, cardiac disease, TIAs, elevated hematocrit, and, to some extent, sickle cell disease were identified as single well-documented treatable factors. Cigarette smoking, alcohol consumption, use of oral contraceptives, and blood lipids were not considered treatable but not well established. By then it was recognized that single factors in combination could result in a risk much higher than their sum. Thus, a smaller segment of the population at very high risk could be identified.
By 1990 additional studies had established that cigarette smoking, excessive alcohol consumption, and drug abuse are lifestyle risk factors for stroke that can be altered (National Institutes of Neurological Disorders and Stroke Classification III).18 Although not well established before, cigarette smoking is now considered one of the most important of the treatable factors. In addition to the diseases and disease markers of hypertension and cardiac disease, TIA was added as a treatable factor. Potentially treatable factors still under study include oral contraceptives, socioeconomic status, diet, physical activity, personality type, obesity, geographic location, abnormal lipids, diabetes mellitus, and climate.
Although age, gender, race, and familial factors are in themselves not treatable, risk changes in racial groups and by sex indicate risk may be altered. The risk for stroke in Japanese is different in Japan, Honolulu, and the mainland United States. In the National Health and Nutrition Study, the unadjusted rate ratio of mortality for blacks versus whites was 2.3 but when simultaneously adjusted for six factors, of which five are alterable, it was reduced to 1.9.19 Although Hispanics are a very heterogeneous group, in a New Mexico study stroke mortality was less for Hispanics than non-Hispanic whites during the 25-year period from 1958 to 1987 but became higher during the 5-year period from 1988 to 1992.20 Although this change is for the worse, it suggests that risk for stroke can be altered. Once the reasons for these changes are better understood, what appears to be an unalterable state may be favorably altered.
The steady decrease in stroke death rates since the 1960s has leveled off, and it is estimated that in 1993 and 1994 the rate increased slightly.21 In addition, stroke is extremely expensive. The total cost for stroke has been estimated to be at least $30 billion per year.22 These factors indicate a need for an increase in properly designed prospective studies to answer the many unanswered questions concerning recognition and treatment of risk factors and ideal medical therapy and rehabilitation. The relatively low financial support given stroke as compared with other diseases must be corrected. The AHA reported that dollars spent by the US government Health and Human Services division for each death was lowest for stroke.23 In 1994 only $765 was spent per stroke death, compared with $1056 for heart disease, $3776 for cancer, $5449 for diabetes mellitus, and $39 172 for AIDS.
Although a keynote address should conclude with where we are today and where we will be tomorrow, the proceedings of this conference will do this with data and not opinion.
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Footnotes |
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An executive summary of this report will appear in the July 15, 1997 issue of Circulation. A single reprint of the executive summary and this report will be available after July 15, 1997, by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Avenue, Dallas, TX 75231-4596. Ask for reprint No. 71-0126. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or To make photocopies for personal or educational use, call the Copyright Clearance Center, 508-750-8400.
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References |
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TopIntroductionKeynote Address: Properly...References |
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2.
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