- Email: [email protected]
Secondary Stroke Prevention
Stroke Rehabilitation
1047-9651/91 $0.00 + .20
Secondary Stroke Prevention
Gary Goldberg, MD, FRCP(C)*
In this article we address the issue of how the risk of stroke recurrence can be reduced in patients with a reference stroke. Although stroke mortality has declined by almost 40% in the past 20 years, there is evidence that this downward trend is beginning to level off. 10 Stroke is the leading serious brain disease that produces chronic neurologic deficit. With improvements in acute medical management, more people are surviving stroke, and long-term survival following stroke has improved dramatically in the past 30 years. It is estimated that there are now approximately 2.1 million stroke survivors living in the United States. Since stroke is a disease with increasing incidence as a function of age, the prevalence of stroke is expected to increase in most Western industrialized countries as the postwar "baby boom" generation enters middle age. It is thus clear that, unless major advances can be made in primary prevention of stroke, the ranks of stroke survivors requiring rehabilitative services for residual disabilities can be expected to swell over the next three to four decades. Although primary prevention of stroke would clearly be the preferred goal of care in at-risk populations, secondary prevention of stroke certainly appears to be equally important in the overall care of the stroke survivor. Primary prevention of stroke in a healthy population should be distinguished from secondary prevention in persons with a previous stroke. In the latter circumstance, the purpose of treatment is to prevent the progression of the illness that has already erupted clinically and is well established. For example, aspirin has been found to be a useful agent in men with transient ischemic attacks but did not reduce the risk of stroke in a healthy cohort of male physicians. 29 In fact, hemorrhagic stroke occurred more frequently in the subjects taking aspirin than in controls. * Stroke Center, Moss Rehabilitation Hospital; and Associate Professor, Departments of Physiology and Physical Medicine and Rehabilitation, Temple University School of Medicine, Philadelphia, Pennsylvania A grant from the Whitaker Foundation is acknowledged with appreciation. Physical Medicine and Rehabilitation Clinics of North America-Vol. 2, No. 3, August 1991
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Besides recurrent stroke, patients with cerebral infarcts due to cerebral artery thrombosis are also at significantly increased risk of other catastrophic vascular events such as acute myocardial infarction and systemic embolism. Patients who survive an atherothrombotic brain infarction (ABI), the most common of cerebrovascular accidents, have established and often fairly advanced atherosclerotic disease involving the cerebral vessels. They are thus at significant risk for having another stroke. Approximately one in four hospital admissions for stroke is precipitated by a recurrence. 23 This risk of a recurrent stroke is increased fivefold over that of a matched population without stroke. 26 On the basis of data collected in the NINDS Stroke Data Bank, patients with ABI involving a large cerebral artery have a 24% rate of recurrence within the first year after the stroke. Patients with strokes due to infarct of undetermined origin had a recurrence rate of 12% within the first year. For patients engaged in stroke rehabilitation, a recurrent stroke most often results in additional disability and presents a major threat to the achievements of the rehabilitation program. Patients and family members are often fearful of the prospect of a recurrence and are motivated to engage in risk-reduction behaviors once the patient has been medically stabilized following the reference event. For health professionals involved in stroke rehabilitation, the issue of secondary prevention clearly needs to be an integral part of the treatment program. In this article we focus primarily on the issue of secondary prevention in patients with ABI. Atherothrombotic brain infarction is thought to be due to an acute and sustained reduction in cerebral blood flow precipitated by the formation of a platelet thrombus at the site of an advanced atheromatous lesion that has ruptured through the endothelium lining the interior wall of cerebral arteries. This thrombus then plugs the remaining lumen of the artery, leading to an abrupt disruption of cerebral blood flow. The unstable platelet, or "white" thrombus, may then spontaneously disintegrate, the result being a short-lived obstruction of flow associated with transient brain ischemia. Alternatively, the platelet thrombus may begin to stabilize within a fibrin network, the result being persisting ischemia leading to brain infarction. This event represents a clinical surfacing of the process of atherogenesis, which is a slow and progressive life-long disease of the arterial tree. 24 The advanced involvement of the cerebral component of the arterial tree is often accompanied by significant atherosclerosis at other sites, particularly the coronary arteries. Thus, the manifestations of coronary artery disease, including angina pectoris and acute myocardial infarction, are frequently associated with ABI. Heart disease is the most common cause of death in stroke patients who survive the initial 30 days. In their consensus statement on the treatment of stroke, the British Panel on Stroke Care 6 gave several suggestions for the improvement of stroke care: organized and well-planned post-stroke care programs, education about stroke care for the family and care-givers, the use of
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aspirin to prevent recurrence in nonhemorrhagic stroke, and the careful, controlled reduction of elevated blood pressure associated with stroke. In the following pages, we examine the causes of long-term mortality in stroke survivors and then look at means for reducing the risk of additional morbidity and mortality in stroke survivors. CAUSES OF MORTALITY AFTER STROKE In order to properly implement preventive programs of care, it is important to have a good understanding of the natural history of a disease. This can be done by following a cohort of stroke patients longitudinally to determine what problems they encounter and what events precipitate death or increased morbidity. Within the first 30 days after the stroke, the most common cause of death is usually secondary to events related to the stroke itself, intervening cardiac events, or respiratory impairment. 4 • 32 In their study, Bamford et al 4 reported that patients with intracerebral or subarachnoid hemorrhage are less likely to survive the first month and are more likely to die of the direct neurologic insult, with over half of the deaths occurring within the first 72 hours following symptom onset. Those patients who do not succumb to the direct neurologic sequelae generally die from complications of prolonged immobility, with most of these deaths occurring beyond the first week. 4 An autopsy-based study reported by Brown and Glassenberg 7 found that all deaths occurring more than 1 week after onset were related to complications of prolonged immobility involving systems other than the nervous system. Early aggressive rehabilitation therapy with the goal of rapid remobilization of the patient whenever possible may be of some value in reducing the complications of immobility in the context of a neurovascular intensive care unit. 11 In an autopsy-verified prospective study of mortality in patients with stroke, Viitanen et al 32 found that the most common primary cause of death between 2 and 4 weeks after a stroke was pulmonary embolism. This was followed by recurrent cerebrovascular disease, cardiac events, and bronchopneumonia. Beyond 3 months after the stroke, these investigators found that the most common cause of death was myocardial infarction, followed by recurrent cerebrovascular accident. These findings have important implications for the medical management of the stroke survivor and suggest that the medical problems precipitating deterioration in stroke survivors vary with the time after onset. During the rehabilitative subacute phase of care, it is important to maintain a high level of suspicion for pulmonary embolism and deep venous thrombosis. Special attention also needs to be given to ventilation and pulmonary care, particularly in patients with brain stem involvement, which may precipitate decreased respiratory drive and dysphagia. It is important to pay special attention to the problem of dysphagia (see the article by Palmer and Du Chane in this volume) and to institute specific management to reduce the risk of aspiration. Be-
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cause the most common cause of late mortality is related to coronary artery disease, it is important to evaluate cardiac status in the stroke survivor and to consider instituting measures to reduce the risk of myocardial infarction. Such measures overlap with those directed to reducing the risk of secondary stroke in patients with stroke due to ABI.
RISK FACTORS AND RISK FACTOR MODIFICATION Certain aspects of a person's condition are associated with an increased risk of stroke. These are termed risk factors, and the relative risk ratio is a number that conveys the factor by which the probability of a stroke is increased owing to the presence of the risk factor. For example, the age-adjusted relative risk ratio for ABI in diabetic males is 2.5, indicating that the probability of stroke is about 2.5 times greater in diabetic males than in nondiabetic males of the same age. We focus in this article on those factors that are modifiable during the period of stroke rehabilitation and may be changed so as to reduce the risk of subsequent stroke. 37 The presence of hypertension is clearly the dominant precursor of stroke, with the increase in risk proportional to the elevation of mean arterial pressure in a continuous gradient. Isolated elevation of systolic blood pressure, seen commonly in the elderly, presents as a potentially independent risk factor. 22 Hypertension is a readily treatable condition, although care must be taken not to treat blood pressure too aggressively, particularly in the acute phase. A variety of options are available for the treatment of hypertension and should be carefully selected to suit the needs of the patient. 18 Cardiac comorbidity, including left ventricular hypertrophy, congestive heart failure, angina pectoris, and arrhythmia, also can significantly complicate the management of the stroke survivor. 25 In the Framingham Study, a strong association was found between cardiac comorbidity and recurrent stroke in stroke survivors. 26 It is uncertain to what extent intensive management and optimization of cardiac function may have beneficial effects for the stroke survivor in terms of reducing stroke recurrence . Similarly, risk of ABI is more than doubled in the presence of diabetes mellitus. However, there is little evidence to date to demonstrate that close control of blood glucose can reduce the rate at which atherosclerosis advances and becomes clinically apparent. The relationship between elevated blood lipids and cerebrovascular disease remains less clear for cerebrovascular than for coronary artery disease. 31 However, since coronary artery disease is the most frequent cause oflate mortality in stroke survivors, attention should be paid to the management of an identified hyperlipoproteinemia. The risk of death due to coronary artery disease increases in direct relationship to total serum cholesterol greater than 180 mg/dl. 28 Hyperlipoproteinemia is readily treated with diet and drug therapy and has been shown to be effective in reducing the rate at which lesions of the coronary arteries advance. 16 • 19 However, there has been no similar evidence to date regarding the relationship between the management
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ofhyperlipoproteinemia and the risk of ABI or the regression of significant cerebrovascular lesions. Cigarette smoking is generally accepted as a contributing risk factor for both cerebrovascular and coronary artery disease. Smokers show a 70% increase in risk for death due to coronary heart disease compared to nonsmokers. Smoking appears to be a particularly important risk factor for coronary disease in women. 35 In the Framingham Study, there was a threefold increase of ABI in cigarette smokers compared to nonsmokers. 21 ' 36 An independent increase in risk of stroke was also noted in smokers in a longitudinal study of at-risk Hawaiian-} apanese men. 1 This study also indicated that cessation of smoking during the course of follow-up reduced the risk of subsequent stroke, suggesting that the increased risk of stroke related to smoking may be reversible. A recent study from the Mayo Clinic correlated the presence of significant extracranial carotid artery atherosclerosis as revealed by angiography with cigarette smoking. 33 These investigators found that the duration of cigarette smoking in years was the most significant independent predictor of advanced atherosclerotic lesions. This finding suggests that the benefit of smoking cessation is to limit the cumulative effect of smoking on the development of atherosclerotic plaques in the extracranial anterior circulation. Patients with elevated hemoglobin and hematocrit have an increased risk of cerebral ischemia. When the venous hematocrit exceeds 50%, there is an increased risk of impaired capillary perfusion of cerebral tissues due to increased blood viscosity. 15 The value of decreasing hematocrit for the purpose of reducing the risk of recurrent stroke has not yet been demonstrated. A number of additional factors may be important in the risk of stroke in some patients. These include the presence of hypercoagulable states, hemoglobinopathies, and various vasculitides associated with viral infection and autoimmune illnesses such as systemic lupus erythematosus. Substance abuse, including excessive alcohol intake and the use of vasoactive street drugs such as cocaine, can precipitate stroke and may contribute to recurrence if not recognized and addressed. Patients engaged in intravenous drug abuse are at risk for the development of bacterial endocarditis and septic embolization. In young adults with recurrent stroke, an underlying process, such as an impairment of the coagulation system, should be sought and identified. Sobel et al 27 used a logistic regression model to determine the relative importance of different factors in patients with recurrent cerebral ischemia. They found that history of TIA, myocardial infarction, or some other form of heart disease (e.g., congestive heart failure) was the major factor associated with recurrence. Risk factors can be modified through specific interventions, although relatively few studies have looked at the value of risk factor modification for the secondary prevention of stroke. It is possible to identify patients who are at high risk for cerebral ischemia based upon risk factor assessment. Patients with severe and moderate hypertension clearly benefit by reducing blood pressure to normal levels. Simi-
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larly, patients who smoke cigarettes can benefit through cessation of smoking. It is possible to identify a small segment of the population which is at the highest risk of stroke by identifying a history of smoking, an abnormal electrocardiogram, elevated blood pressure, abnormal fasting blood sugar, and an elevated total cholesterol level. 37 However, there remains a need for prospective controlled clinical trials such as the Multiple Risk Factor Intervention Trial to examine the value of modifying risk factors for secondary prevention in stroke patients.
MEDICAL INTERVENTIONS Antiplatelet Agents Medications that impede platelet aggregation have been used to reduce the risk of stroke under a variety of conditions. There are no data to support the value of sulfinpyrazone or suloctidil in the prevention of cerebral ischemia. Similarly, the use of dipyridamole, either alone or together with aspirin, has not been proven effective in reducing the risk of atherothrombotic brain infarction. The most widely available medication is aspirin, which has been shown to prevent progression to ABI from transient ischemic attacks in males. The reason for this gender-specific effect remains unclear but may be an artifact of the methodology used in performing the randomized controlled trials. The optimal dose of aspirin remains under study. Patients who show evidence of cerebral ischemia or who are at high risk are recommended to take one to four 325-mg tablets of aspirin daily depending on gastrointestinal tolerance. Because of the technical considerations in judging the clinical trial outcomes, it has been recommended that both sexes follow this suggestion. 34 In the Harvard study of 22,000 healthy male physicians, the dosage employed was 325 mg of aspirin on alternate days.29 This treatment significantly reduced the risk of myocardial infarction without reducing the risk of stroke. Ticlopidine hydrochloride (250 mg twice daily) has been evaluated in two major clinical trials-one in which ticlopidine was compared to aspirin in patients with TIA or minor cerebral ischemia (the ticlopidine-aspirin stroke study-TASS) 20 and one in which ticlopidine was compared to placebo for prevention of recurrent stroke (the Canadian-American ticlopidine study-CATS) . 13 , 14 Ticlopidine demonstrated a significant advantage over aspirin in preventing the progression from transient ischemic attack to ABI in both men and women. Patients receiving ticlopidine had a 21 % reduction in their risk of nonfatal stroke or stroke-related death as compared to the group receiving aspirin. In the CATS study, the risk of recurrent stroke, myocardial infarction, or sudden vascular death was reduced by over 30% in patients on ticlopidine as compared to placebo. Ticlopidine was found to have a significant profile of side effects, including neutropenia (< 1% ), diarrhea, and rash. All these problems were found to
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be reversible when the drug was stopped. Most of the significant problems were encountered within the first 3 months after the medication was started. During this period, patients need to be checked regularly to allow early detection ofleukopenia. Overall, however, the risk of serious side effects with ticlopidine is comparable to that encountered with aspirin and the benefits appear to be substantially better and apply equally well to both men and women. The relative efficacy of ticlopidine and aspirin as well as the indications for the use of these medications needs to be carefully worked out. The availability of ticlopidine as a choice in stroke prevention adds significant options from which to choose. Ticlopidine is certainly available as an option whenever aspirin therapy is not tolerated and may be the drug of choice for women. Both medications need to be carefully monitored for significant side effects. Anticoagulation
Whenever cerebral ischemia may result from embolization of a red thrombus in the proximal part of the circulation, usually in the heart, full anticoagulation with heparin or warfarin should be considered. This treatment, of course, carries a significant risk of hemorrhage and should be used only in patients who have no previous history of hemorrhage or coagulopathy. Anticoagulants should be used with extra caution in elderly patients, who may be prone to injury due to falls.17 Anticoagulation for a period of 3 months is indicated to reduce the risk of stroke after an acute myocardial infarction, particularly if the infarct is transmural and there is evidence of a mural thrombus on echocardiography or if the area of the infarct involves the anterior or septal walls of the ventricle. Anticoagulation should also be considered if there has been evidence of congestive heart failure. The case of nonvalvular atrial fibrillation is considered separately. In patients with rheumatic heart disease, particularly in the presence of mitral stenosis, long-term anticoagulation should be considered as a preventive measure and is required if there has been any evidence of embolization to the retinal or cerebral circulation. Patients with prosthetic heart valves may or may not require long-term anticoagulation depending upon the type of valve and its thrombogenic potential and whether the aortic or the mitral valve has been replaced. 34 Certain patients who present with recurrent episodes of cerebral ischemia related to a hypercoagulable state may require longterm anticoagulation, depending upon the nature of the underlying pathology. Two recent studies have clearly documented the value of anticoagulation with warfarin in patients with nonvalvular atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation5 showed an 86% reduction in the risk of stroke as well as a reduction in the risk of death in patients with nonvalvular atrial fibrillation (NVAF) who were treated with low-dose warfarin and followed for an average of2.2 years. The target prothrombin time ratio was 1.2 to 1.5. The control group was not given warfarin but could choose to be on aspirin. These
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authors concluded that "long-term low-dose warfarin therapy is highly effective in preventing stroke" in patients with NVAF. Furthermore, they found that, with appropriate monitoring, this could be done quite safely. Similar results were obtained in the Stroke Prevention in Atrial Fibrillation Study. 3 • 30 In this controlled clinical study, patients with NVAF were treated with warfarin or aspirin and compared to patients on placebo in terms of the reduction in risk of either cerebral or systemic embolism. The placebo arm was terminated owing to the demonstration of efficacy of either treatment as compared to the placebo control. 30 The study is now continuing in order to compare the relative efficacy of warfarin versus aspirin in preventing cerebral or systemic embolism. The study was unable to demonstrate clear benefit of aspirin in patients who were over 75 years of age. The recommendations from these studies indicate that patients with NV AF should be placed on low-dose warfarin whenever possible and that aspirin (325 mg daily) may be effective in younger patients for whom anticoagulation is contraindicated. In patients over the age of 75 years, low-dose warfarin therapy that can be adequately monitored appears to be effective, whereas aspirin therapy does not appear to be of benefit. The relative benefits and risks of aspirin versus warfarin therapy are being investigated further in order to determine whether there are specific subpopulations in which one agent has significant advantage over the other. In elderly patients who are at risk of falling, treatment with low-dose warfarin needs to be weighed against the risk of hemorrhage associated with a fall. As Chesebro et al 9 note, "the challenge . . . is to choose appropriate therapy, and if the treatment is warfarin, to maintain the prothrombin time consistently in the therapeutic range . . . to prevent emboli and avoid bleeding." Clinical trials have demonstrated the relative safety of closely monitored low-dose warfarin therapy in most patients without specific contraindication to anticoagulation.
SURGICAL INTERVENTIONS When cerebral ischemia results from an isolated proximal lesion in the internal carotid artery, endarterectomy has been proposed as a definitive procedure for re-establishing blood flow and reducing the risk of cerebral ischemia. The value of the procedure depends on an adequate reduction of the risk of perioperative complications associated with the procedure and angiography. Because of the controversy surrounding this procedure, several randomized clinical trials are currently underway to determine the value of carotid endarterectomy in treating patients who are predisposed to cerebral ischemia, whether or not they are symptomatic. The current status of carotid endarterectomy and relative indications for its application have been recently reviewed. 2 • 8 • 34 Carotid endarterectormy may be of value in patients with transient
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ischemic attacks in whom medical management has failed to prevent recurrent episodes of cerebral ishcemia provided that there is evidence of a high-grade ipsilateral carotid stenosis or a large proximal ulcerative plaque with good distal circulation. The risk of undergoing the surgery must be carefully assessed and weighed against the potential benefit. The statement of the American College of Physicians regarding indications for carotid endarterectomy notes that the risks of the procedure generally exceed the potential benefits for patients with a completed major atherothrombotic brain infarct who have been left with significant neurologic sequelae.2 This tends to rule out most patients who come to a stroke rehabilitation program. Carotid endarterectomy may be considered after waiting 1 month following the stroke if the patient has minor residual deficits but qualifies otherwise for the procedure and is considered to have low to medium risk. 2 At one time, the technique of constructing a bypass graft between the external and internal carotid circulations was employed to improve the flow of blood to cerebral tissues. However, a multicenter randomized clinical trial showed no significant benefit associated with this surgical approach in terms of reducing the risk of subsequent stroke. 12 This procedure generally is not recommended for patients with cerebral ischemia secondary to atherosclerosis. SUMMARY
Secondary prevention should be an integral component of any stroke rehabilitation program. Frequently, it is during the subacute phase after medical stabilization that the issue of preventive health care for the stroke survivor surfaces. The evaluation of the patient for stroke rehabilitation should include a review of risk factors for recurrent stroke and an attempt to modify risk factors whenever possible. With a history of completed ABI, consideration must be given to the need for prophylaxis with antiplatelet agents, including aspirin and ticlopidine. Ticlopidine appears to have beneficial effects in both men and women and is the only agent that has demonstrated efficacy in a trial specifically addressing the issue of secondary stroke prevention. 13 • 14 Aspirin and ticlopidine both have a similar incidence of severe side effects, although they differ somewhat in profile, with ticlopidine more frequently producing diarrhea and neutropenia and aspirin more frequently associated with gastrointestinal bleeding. If there is evidence of cardioembolism or of nonvalvular atrial fibrillation, anticoagulation with warfarin should be considered. CT scans to rule out hemorrhage or hemorrhagic infarction should be completed before initiating anticoagulation. The benefits of reducing disabling stroke recurrence must always be weighed against the risks of therapy or complications associated with the preventive measures chosen. The most common cause of cardioembolic stroke is related to NVAF. Recently completed studies suggest that low-dose warfarin therapy may be of substantial value in preventing stroke in patients
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with NVAF and that younger patients who cannot be anticoagulated may benefit from aspirin therapy (325 mg daily). Complications of treatment with these agents may be minimized through careful clinical monitoring.
REFERENCES l. Abbott RD , Yin Y, Reed DM, Yano K: Risk of stroke in male cigarette smokers. N Engl J Med 315:1717, 1986 2. American College of Physicians : Indications for carotid endarterectomy. Ann Intern Med 111:665, 1989 3. Anderson DC, for the Stroke Prevention in Atrial Fibrillation Study Group: Progress report of the Stroke Prevention in Atrial Fibrillation Study. Stroke 21 (Suppl III): III-12, 1990 4. Bamford J, Dennis M, Sandercock, et al: The frequency, causes and timing of death within 30 days of a first stroke: The Oxfordshire Community Stroke Project. J Neural Neurosurg Psychiatry 53:824, 1990 5. Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators: The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibril lation. N Engl J Med 323:1505, 1990 6. British Panel on Stroke Care: Consensus statement of the treatment of stroke. Br Med J 297:126- 128, 1988 7. Brown M, Glassenberg M: Mortality factors in patients with acute stroke. JAMA 224:1493, 1973 8. Cebu! RD, Whisnant JP: Carotid endarterectomy. Ann Intern Med 111:660, 1989 9. Chesebro JH, Fuster V, Halperin JL: Atrial fibrillation- risk marker for stroke [editorial]. N Engl J Med 323: 1556, 1990 10. Cooper R, Sempos C, Hsieh S-C, Kovar MG: Slowdown in the decline of stroke mortality in the United States, 1978- 1986. Stroke 21:1274- 1279, 1990 11. Drake WE, Hamilton MJ, Blumenkrantz J: Acute stroke management and patient outcome: The value of neurovascular care units (NCU) . Stroke 4:933, 1973 12. EC/IC Bypass Study Group: Failure of extracranial-intracranial arterial bypass to reduce risk of ischemic stroke: Results of an international randomized trial. N Engl J Med 313:1191, 1985 13. Gent M, Blakely JA, Easton JD, et al: Th e Canadian-American ticlopidine study in thromboembolic stroke: D esign, organization and baseline results. Stroke 19: 1203, 1988 14. Gent M, Easton J, Hachinski V, et al : The Canadian-American Ticlopidine Study (CATS) in th romboembolic stroke. Lancet 1:1215, 1989 15. Grotta J, Ackerman R, Correia J, et al: Whole blood viscosity parameters and cerebral blood flow. Stroke 13:296, 1982 16. Grundy SM : Cholesterol and coronary heart disease: A new era. JAMA 256:2849, 1986 17. Gryfe CI, Amies A, Ashley MJ : A longitudinal study of falls in an elderly population. I. Incidence and morbidity. Age Ageing 6:201, 1977 18. Haber E , Slater EE: High blood pressure. In Rubinstein, E, Federman DD (eds): Scientific American Medicine . New York, Scientific American, Inc, 1988, pp l:VIl:l- 30 19. H ancock EW: Coronary artery disease- epidemiology and prevention. In Rubinstein E, Federman DD (eds): Scientific American Medicine. New York, Scientific American, Inc, 1988, pp l:VIIl:l- 9 20. Hass WK, Easton JD, Adams HP, et al: A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients . N Engl J Med 321:501, 1989 21. Kannel WB: Current status of epidemiology of brain infarction associated with occlusive vascular disease. Stroke 2:295, 1971
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22. Kannel WB, Wolf PA, McGee DL, et al: Systolic blood pressure, arterial rigidity, and risk of stroke: Framingham Study. JAMA 245:1225, 1981 23. Robins M, Baum HM: Incidence: National survey of stroke. Stroke 12 (Suppl 1):145157, 1981 24. Ross R: Pathogenesis of atherosclerosis-an update. N Engl J Med 314:488- 500, 1986 25. Roth EJ, Mueller K, Green D: Stroke rehabilitation outcome: Impact of coronary artery disease. Stroke 19:42, 1988 26. Sacco RL, Wolf PA, Kannel WB, McNamara PM: Survival and recurrence following stroke: Framingham Study. Stroke 13:290-295, 1982 27. Sobel E, Alter M, Davanipour A, et al: Stroke in the Lehigh Valley: Combined risk factors for recurrent ischemic stroke. Neurology 39:669, 1989 28. Stamler J, Wentworth D, Neaton JD: Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 256:2823, 1986 29. Steering Committee of the Physician's Health Study Research Group: Preliminary report: Findings from the aspirin component of the ongoing physicians' health study. N Engl J Med 318:262, 1988 30. Stroke Prevention in Atrial Fibrillation Study Group: Preliminary report of the stroke prevention in atrial fibrillation study. N Engl J Med 322:863, 1990 31. Tell GS, Crouse JR, Furberg CD: Relation between blood lipids, lipoproteins and cerebrovascular atherosclerosis. A review. Stroke 19:423, 1988 32. Viitanen M, Winblad B, Asplund K: Autopsy-verified causes of death after stroke. Acta Med Scand 222:401, 1987 33. Whisnant JP, Homer D, lngall TJ, et al: Duration of cigarette smoking is the strongest predictor of severe extracranial carotid artery atherosclerosis. Stroke 21:707, 1990 34. WHO Task Force on Stroke and other Cerebrovascular Disorders: Stroke-1989. Recommendations on stroke prevention, diagnosis and therapy. Stroke 20: 1407, 1989 35. Willett WC, Green A, Stampfer JF, et al: Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J Med 317:1303, 1987 36. Wolf PA, D'Agostino RB, Kannel WB, et al: Cigarette smoking as a risk factor for stroke. The Framingham Study. JAMA 259:1025, 1988 37. Wolf PA, Kannel WB: Reduction of stroke through risk factor modification. Semin Neurol 6:243, 1986
Address reprint requests to Gary Goldberg, MD, FRCP(C) Stroke Center Moss Rehabilitation Hospital 1200 West Tabor Road Philadelphia, PA 19141-3099
1047-9651/91 $0.00 + .20
Secondary Stroke Prevention
Gary Goldberg, MD, FRCP(C)*
In this article we address the issue of how the risk of stroke recurrence can be reduced in patients with a reference stroke. Although stroke mortality has declined by almost 40% in the past 20 years, there is evidence that this downward trend is beginning to level off. 10 Stroke is the leading serious brain disease that produces chronic neurologic deficit. With improvements in acute medical management, more people are surviving stroke, and long-term survival following stroke has improved dramatically in the past 30 years. It is estimated that there are now approximately 2.1 million stroke survivors living in the United States. Since stroke is a disease with increasing incidence as a function of age, the prevalence of stroke is expected to increase in most Western industrialized countries as the postwar "baby boom" generation enters middle age. It is thus clear that, unless major advances can be made in primary prevention of stroke, the ranks of stroke survivors requiring rehabilitative services for residual disabilities can be expected to swell over the next three to four decades. Although primary prevention of stroke would clearly be the preferred goal of care in at-risk populations, secondary prevention of stroke certainly appears to be equally important in the overall care of the stroke survivor. Primary prevention of stroke in a healthy population should be distinguished from secondary prevention in persons with a previous stroke. In the latter circumstance, the purpose of treatment is to prevent the progression of the illness that has already erupted clinically and is well established. For example, aspirin has been found to be a useful agent in men with transient ischemic attacks but did not reduce the risk of stroke in a healthy cohort of male physicians. 29 In fact, hemorrhagic stroke occurred more frequently in the subjects taking aspirin than in controls. * Stroke Center, Moss Rehabilitation Hospital; and Associate Professor, Departments of Physiology and Physical Medicine and Rehabilitation, Temple University School of Medicine, Philadelphia, Pennsylvania A grant from the Whitaker Foundation is acknowledged with appreciation. Physical Medicine and Rehabilitation Clinics of North America-Vol. 2, No. 3, August 1991
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Besides recurrent stroke, patients with cerebral infarcts due to cerebral artery thrombosis are also at significantly increased risk of other catastrophic vascular events such as acute myocardial infarction and systemic embolism. Patients who survive an atherothrombotic brain infarction (ABI), the most common of cerebrovascular accidents, have established and often fairly advanced atherosclerotic disease involving the cerebral vessels. They are thus at significant risk for having another stroke. Approximately one in four hospital admissions for stroke is precipitated by a recurrence. 23 This risk of a recurrent stroke is increased fivefold over that of a matched population without stroke. 26 On the basis of data collected in the NINDS Stroke Data Bank, patients with ABI involving a large cerebral artery have a 24% rate of recurrence within the first year after the stroke. Patients with strokes due to infarct of undetermined origin had a recurrence rate of 12% within the first year. For patients engaged in stroke rehabilitation, a recurrent stroke most often results in additional disability and presents a major threat to the achievements of the rehabilitation program. Patients and family members are often fearful of the prospect of a recurrence and are motivated to engage in risk-reduction behaviors once the patient has been medically stabilized following the reference event. For health professionals involved in stroke rehabilitation, the issue of secondary prevention clearly needs to be an integral part of the treatment program. In this article we focus primarily on the issue of secondary prevention in patients with ABI. Atherothrombotic brain infarction is thought to be due to an acute and sustained reduction in cerebral blood flow precipitated by the formation of a platelet thrombus at the site of an advanced atheromatous lesion that has ruptured through the endothelium lining the interior wall of cerebral arteries. This thrombus then plugs the remaining lumen of the artery, leading to an abrupt disruption of cerebral blood flow. The unstable platelet, or "white" thrombus, may then spontaneously disintegrate, the result being a short-lived obstruction of flow associated with transient brain ischemia. Alternatively, the platelet thrombus may begin to stabilize within a fibrin network, the result being persisting ischemia leading to brain infarction. This event represents a clinical surfacing of the process of atherogenesis, which is a slow and progressive life-long disease of the arterial tree. 24 The advanced involvement of the cerebral component of the arterial tree is often accompanied by significant atherosclerosis at other sites, particularly the coronary arteries. Thus, the manifestations of coronary artery disease, including angina pectoris and acute myocardial infarction, are frequently associated with ABI. Heart disease is the most common cause of death in stroke patients who survive the initial 30 days. In their consensus statement on the treatment of stroke, the British Panel on Stroke Care 6 gave several suggestions for the improvement of stroke care: organized and well-planned post-stroke care programs, education about stroke care for the family and care-givers, the use of
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aspirin to prevent recurrence in nonhemorrhagic stroke, and the careful, controlled reduction of elevated blood pressure associated with stroke. In the following pages, we examine the causes of long-term mortality in stroke survivors and then look at means for reducing the risk of additional morbidity and mortality in stroke survivors. CAUSES OF MORTALITY AFTER STROKE In order to properly implement preventive programs of care, it is important to have a good understanding of the natural history of a disease. This can be done by following a cohort of stroke patients longitudinally to determine what problems they encounter and what events precipitate death or increased morbidity. Within the first 30 days after the stroke, the most common cause of death is usually secondary to events related to the stroke itself, intervening cardiac events, or respiratory impairment. 4 • 32 In their study, Bamford et al 4 reported that patients with intracerebral or subarachnoid hemorrhage are less likely to survive the first month and are more likely to die of the direct neurologic insult, with over half of the deaths occurring within the first 72 hours following symptom onset. Those patients who do not succumb to the direct neurologic sequelae generally die from complications of prolonged immobility, with most of these deaths occurring beyond the first week. 4 An autopsy-based study reported by Brown and Glassenberg 7 found that all deaths occurring more than 1 week after onset were related to complications of prolonged immobility involving systems other than the nervous system. Early aggressive rehabilitation therapy with the goal of rapid remobilization of the patient whenever possible may be of some value in reducing the complications of immobility in the context of a neurovascular intensive care unit. 11 In an autopsy-verified prospective study of mortality in patients with stroke, Viitanen et al 32 found that the most common primary cause of death between 2 and 4 weeks after a stroke was pulmonary embolism. This was followed by recurrent cerebrovascular disease, cardiac events, and bronchopneumonia. Beyond 3 months after the stroke, these investigators found that the most common cause of death was myocardial infarction, followed by recurrent cerebrovascular accident. These findings have important implications for the medical management of the stroke survivor and suggest that the medical problems precipitating deterioration in stroke survivors vary with the time after onset. During the rehabilitative subacute phase of care, it is important to maintain a high level of suspicion for pulmonary embolism and deep venous thrombosis. Special attention also needs to be given to ventilation and pulmonary care, particularly in patients with brain stem involvement, which may precipitate decreased respiratory drive and dysphagia. It is important to pay special attention to the problem of dysphagia (see the article by Palmer and Du Chane in this volume) and to institute specific management to reduce the risk of aspiration. Be-
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cause the most common cause of late mortality is related to coronary artery disease, it is important to evaluate cardiac status in the stroke survivor and to consider instituting measures to reduce the risk of myocardial infarction. Such measures overlap with those directed to reducing the risk of secondary stroke in patients with stroke due to ABI.
RISK FACTORS AND RISK FACTOR MODIFICATION Certain aspects of a person's condition are associated with an increased risk of stroke. These are termed risk factors, and the relative risk ratio is a number that conveys the factor by which the probability of a stroke is increased owing to the presence of the risk factor. For example, the age-adjusted relative risk ratio for ABI in diabetic males is 2.5, indicating that the probability of stroke is about 2.5 times greater in diabetic males than in nondiabetic males of the same age. We focus in this article on those factors that are modifiable during the period of stroke rehabilitation and may be changed so as to reduce the risk of subsequent stroke. 37 The presence of hypertension is clearly the dominant precursor of stroke, with the increase in risk proportional to the elevation of mean arterial pressure in a continuous gradient. Isolated elevation of systolic blood pressure, seen commonly in the elderly, presents as a potentially independent risk factor. 22 Hypertension is a readily treatable condition, although care must be taken not to treat blood pressure too aggressively, particularly in the acute phase. A variety of options are available for the treatment of hypertension and should be carefully selected to suit the needs of the patient. 18 Cardiac comorbidity, including left ventricular hypertrophy, congestive heart failure, angina pectoris, and arrhythmia, also can significantly complicate the management of the stroke survivor. 25 In the Framingham Study, a strong association was found between cardiac comorbidity and recurrent stroke in stroke survivors. 26 It is uncertain to what extent intensive management and optimization of cardiac function may have beneficial effects for the stroke survivor in terms of reducing stroke recurrence . Similarly, risk of ABI is more than doubled in the presence of diabetes mellitus. However, there is little evidence to date to demonstrate that close control of blood glucose can reduce the rate at which atherosclerosis advances and becomes clinically apparent. The relationship between elevated blood lipids and cerebrovascular disease remains less clear for cerebrovascular than for coronary artery disease. 31 However, since coronary artery disease is the most frequent cause oflate mortality in stroke survivors, attention should be paid to the management of an identified hyperlipoproteinemia. The risk of death due to coronary artery disease increases in direct relationship to total serum cholesterol greater than 180 mg/dl. 28 Hyperlipoproteinemia is readily treated with diet and drug therapy and has been shown to be effective in reducing the rate at which lesions of the coronary arteries advance. 16 • 19 However, there has been no similar evidence to date regarding the relationship between the management
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ofhyperlipoproteinemia and the risk of ABI or the regression of significant cerebrovascular lesions. Cigarette smoking is generally accepted as a contributing risk factor for both cerebrovascular and coronary artery disease. Smokers show a 70% increase in risk for death due to coronary heart disease compared to nonsmokers. Smoking appears to be a particularly important risk factor for coronary disease in women. 35 In the Framingham Study, there was a threefold increase of ABI in cigarette smokers compared to nonsmokers. 21 ' 36 An independent increase in risk of stroke was also noted in smokers in a longitudinal study of at-risk Hawaiian-} apanese men. 1 This study also indicated that cessation of smoking during the course of follow-up reduced the risk of subsequent stroke, suggesting that the increased risk of stroke related to smoking may be reversible. A recent study from the Mayo Clinic correlated the presence of significant extracranial carotid artery atherosclerosis as revealed by angiography with cigarette smoking. 33 These investigators found that the duration of cigarette smoking in years was the most significant independent predictor of advanced atherosclerotic lesions. This finding suggests that the benefit of smoking cessation is to limit the cumulative effect of smoking on the development of atherosclerotic plaques in the extracranial anterior circulation. Patients with elevated hemoglobin and hematocrit have an increased risk of cerebral ischemia. When the venous hematocrit exceeds 50%, there is an increased risk of impaired capillary perfusion of cerebral tissues due to increased blood viscosity. 15 The value of decreasing hematocrit for the purpose of reducing the risk of recurrent stroke has not yet been demonstrated. A number of additional factors may be important in the risk of stroke in some patients. These include the presence of hypercoagulable states, hemoglobinopathies, and various vasculitides associated with viral infection and autoimmune illnesses such as systemic lupus erythematosus. Substance abuse, including excessive alcohol intake and the use of vasoactive street drugs such as cocaine, can precipitate stroke and may contribute to recurrence if not recognized and addressed. Patients engaged in intravenous drug abuse are at risk for the development of bacterial endocarditis and septic embolization. In young adults with recurrent stroke, an underlying process, such as an impairment of the coagulation system, should be sought and identified. Sobel et al 27 used a logistic regression model to determine the relative importance of different factors in patients with recurrent cerebral ischemia. They found that history of TIA, myocardial infarction, or some other form of heart disease (e.g., congestive heart failure) was the major factor associated with recurrence. Risk factors can be modified through specific interventions, although relatively few studies have looked at the value of risk factor modification for the secondary prevention of stroke. It is possible to identify patients who are at high risk for cerebral ischemia based upon risk factor assessment. Patients with severe and moderate hypertension clearly benefit by reducing blood pressure to normal levels. Simi-
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larly, patients who smoke cigarettes can benefit through cessation of smoking. It is possible to identify a small segment of the population which is at the highest risk of stroke by identifying a history of smoking, an abnormal electrocardiogram, elevated blood pressure, abnormal fasting blood sugar, and an elevated total cholesterol level. 37 However, there remains a need for prospective controlled clinical trials such as the Multiple Risk Factor Intervention Trial to examine the value of modifying risk factors for secondary prevention in stroke patients.
MEDICAL INTERVENTIONS Antiplatelet Agents Medications that impede platelet aggregation have been used to reduce the risk of stroke under a variety of conditions. There are no data to support the value of sulfinpyrazone or suloctidil in the prevention of cerebral ischemia. Similarly, the use of dipyridamole, either alone or together with aspirin, has not been proven effective in reducing the risk of atherothrombotic brain infarction. The most widely available medication is aspirin, which has been shown to prevent progression to ABI from transient ischemic attacks in males. The reason for this gender-specific effect remains unclear but may be an artifact of the methodology used in performing the randomized controlled trials. The optimal dose of aspirin remains under study. Patients who show evidence of cerebral ischemia or who are at high risk are recommended to take one to four 325-mg tablets of aspirin daily depending on gastrointestinal tolerance. Because of the technical considerations in judging the clinical trial outcomes, it has been recommended that both sexes follow this suggestion. 34 In the Harvard study of 22,000 healthy male physicians, the dosage employed was 325 mg of aspirin on alternate days.29 This treatment significantly reduced the risk of myocardial infarction without reducing the risk of stroke. Ticlopidine hydrochloride (250 mg twice daily) has been evaluated in two major clinical trials-one in which ticlopidine was compared to aspirin in patients with TIA or minor cerebral ischemia (the ticlopidine-aspirin stroke study-TASS) 20 and one in which ticlopidine was compared to placebo for prevention of recurrent stroke (the Canadian-American ticlopidine study-CATS) . 13 , 14 Ticlopidine demonstrated a significant advantage over aspirin in preventing the progression from transient ischemic attack to ABI in both men and women. Patients receiving ticlopidine had a 21 % reduction in their risk of nonfatal stroke or stroke-related death as compared to the group receiving aspirin. In the CATS study, the risk of recurrent stroke, myocardial infarction, or sudden vascular death was reduced by over 30% in patients on ticlopidine as compared to placebo. Ticlopidine was found to have a significant profile of side effects, including neutropenia (< 1% ), diarrhea, and rash. All these problems were found to
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be reversible when the drug was stopped. Most of the significant problems were encountered within the first 3 months after the medication was started. During this period, patients need to be checked regularly to allow early detection ofleukopenia. Overall, however, the risk of serious side effects with ticlopidine is comparable to that encountered with aspirin and the benefits appear to be substantially better and apply equally well to both men and women. The relative efficacy of ticlopidine and aspirin as well as the indications for the use of these medications needs to be carefully worked out. The availability of ticlopidine as a choice in stroke prevention adds significant options from which to choose. Ticlopidine is certainly available as an option whenever aspirin therapy is not tolerated and may be the drug of choice for women. Both medications need to be carefully monitored for significant side effects. Anticoagulation
Whenever cerebral ischemia may result from embolization of a red thrombus in the proximal part of the circulation, usually in the heart, full anticoagulation with heparin or warfarin should be considered. This treatment, of course, carries a significant risk of hemorrhage and should be used only in patients who have no previous history of hemorrhage or coagulopathy. Anticoagulants should be used with extra caution in elderly patients, who may be prone to injury due to falls.17 Anticoagulation for a period of 3 months is indicated to reduce the risk of stroke after an acute myocardial infarction, particularly if the infarct is transmural and there is evidence of a mural thrombus on echocardiography or if the area of the infarct involves the anterior or septal walls of the ventricle. Anticoagulation should also be considered if there has been evidence of congestive heart failure. The case of nonvalvular atrial fibrillation is considered separately. In patients with rheumatic heart disease, particularly in the presence of mitral stenosis, long-term anticoagulation should be considered as a preventive measure and is required if there has been any evidence of embolization to the retinal or cerebral circulation. Patients with prosthetic heart valves may or may not require long-term anticoagulation depending upon the type of valve and its thrombogenic potential and whether the aortic or the mitral valve has been replaced. 34 Certain patients who present with recurrent episodes of cerebral ischemia related to a hypercoagulable state may require longterm anticoagulation, depending upon the nature of the underlying pathology. Two recent studies have clearly documented the value of anticoagulation with warfarin in patients with nonvalvular atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation5 showed an 86% reduction in the risk of stroke as well as a reduction in the risk of death in patients with nonvalvular atrial fibrillation (NVAF) who were treated with low-dose warfarin and followed for an average of2.2 years. The target prothrombin time ratio was 1.2 to 1.5. The control group was not given warfarin but could choose to be on aspirin. These
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authors concluded that "long-term low-dose warfarin therapy is highly effective in preventing stroke" in patients with NVAF. Furthermore, they found that, with appropriate monitoring, this could be done quite safely. Similar results were obtained in the Stroke Prevention in Atrial Fibrillation Study. 3 • 30 In this controlled clinical study, patients with NVAF were treated with warfarin or aspirin and compared to patients on placebo in terms of the reduction in risk of either cerebral or systemic embolism. The placebo arm was terminated owing to the demonstration of efficacy of either treatment as compared to the placebo control. 30 The study is now continuing in order to compare the relative efficacy of warfarin versus aspirin in preventing cerebral or systemic embolism. The study was unable to demonstrate clear benefit of aspirin in patients who were over 75 years of age. The recommendations from these studies indicate that patients with NV AF should be placed on low-dose warfarin whenever possible and that aspirin (325 mg daily) may be effective in younger patients for whom anticoagulation is contraindicated. In patients over the age of 75 years, low-dose warfarin therapy that can be adequately monitored appears to be effective, whereas aspirin therapy does not appear to be of benefit. The relative benefits and risks of aspirin versus warfarin therapy are being investigated further in order to determine whether there are specific subpopulations in which one agent has significant advantage over the other. In elderly patients who are at risk of falling, treatment with low-dose warfarin needs to be weighed against the risk of hemorrhage associated with a fall. As Chesebro et al 9 note, "the challenge . . . is to choose appropriate therapy, and if the treatment is warfarin, to maintain the prothrombin time consistently in the therapeutic range . . . to prevent emboli and avoid bleeding." Clinical trials have demonstrated the relative safety of closely monitored low-dose warfarin therapy in most patients without specific contraindication to anticoagulation.
SURGICAL INTERVENTIONS When cerebral ischemia results from an isolated proximal lesion in the internal carotid artery, endarterectomy has been proposed as a definitive procedure for re-establishing blood flow and reducing the risk of cerebral ischemia. The value of the procedure depends on an adequate reduction of the risk of perioperative complications associated with the procedure and angiography. Because of the controversy surrounding this procedure, several randomized clinical trials are currently underway to determine the value of carotid endarterectomy in treating patients who are predisposed to cerebral ischemia, whether or not they are symptomatic. The current status of carotid endarterectomy and relative indications for its application have been recently reviewed. 2 • 8 • 34 Carotid endarterectormy may be of value in patients with transient
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ischemic attacks in whom medical management has failed to prevent recurrent episodes of cerebral ishcemia provided that there is evidence of a high-grade ipsilateral carotid stenosis or a large proximal ulcerative plaque with good distal circulation. The risk of undergoing the surgery must be carefully assessed and weighed against the potential benefit. The statement of the American College of Physicians regarding indications for carotid endarterectomy notes that the risks of the procedure generally exceed the potential benefits for patients with a completed major atherothrombotic brain infarct who have been left with significant neurologic sequelae.2 This tends to rule out most patients who come to a stroke rehabilitation program. Carotid endarterectomy may be considered after waiting 1 month following the stroke if the patient has minor residual deficits but qualifies otherwise for the procedure and is considered to have low to medium risk. 2 At one time, the technique of constructing a bypass graft between the external and internal carotid circulations was employed to improve the flow of blood to cerebral tissues. However, a multicenter randomized clinical trial showed no significant benefit associated with this surgical approach in terms of reducing the risk of subsequent stroke. 12 This procedure generally is not recommended for patients with cerebral ischemia secondary to atherosclerosis. SUMMARY
Secondary prevention should be an integral component of any stroke rehabilitation program. Frequently, it is during the subacute phase after medical stabilization that the issue of preventive health care for the stroke survivor surfaces. The evaluation of the patient for stroke rehabilitation should include a review of risk factors for recurrent stroke and an attempt to modify risk factors whenever possible. With a history of completed ABI, consideration must be given to the need for prophylaxis with antiplatelet agents, including aspirin and ticlopidine. Ticlopidine appears to have beneficial effects in both men and women and is the only agent that has demonstrated efficacy in a trial specifically addressing the issue of secondary stroke prevention. 13 • 14 Aspirin and ticlopidine both have a similar incidence of severe side effects, although they differ somewhat in profile, with ticlopidine more frequently producing diarrhea and neutropenia and aspirin more frequently associated with gastrointestinal bleeding. If there is evidence of cardioembolism or of nonvalvular atrial fibrillation, anticoagulation with warfarin should be considered. CT scans to rule out hemorrhage or hemorrhagic infarction should be completed before initiating anticoagulation. The benefits of reducing disabling stroke recurrence must always be weighed against the risks of therapy or complications associated with the preventive measures chosen. The most common cause of cardioembolic stroke is related to NVAF. Recently completed studies suggest that low-dose warfarin therapy may be of substantial value in preventing stroke in patients
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with NVAF and that younger patients who cannot be anticoagulated may benefit from aspirin therapy (325 mg daily). Complications of treatment with these agents may be minimized through careful clinical monitoring.
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22. Kannel WB, Wolf PA, McGee DL, et al: Systolic blood pressure, arterial rigidity, and risk of stroke: Framingham Study. JAMA 245:1225, 1981 23. Robins M, Baum HM: Incidence: National survey of stroke. Stroke 12 (Suppl 1):145157, 1981 24. Ross R: Pathogenesis of atherosclerosis-an update. N Engl J Med 314:488- 500, 1986 25. Roth EJ, Mueller K, Green D: Stroke rehabilitation outcome: Impact of coronary artery disease. Stroke 19:42, 1988 26. Sacco RL, Wolf PA, Kannel WB, McNamara PM: Survival and recurrence following stroke: Framingham Study. Stroke 13:290-295, 1982 27. Sobel E, Alter M, Davanipour A, et al: Stroke in the Lehigh Valley: Combined risk factors for recurrent ischemic stroke. Neurology 39:669, 1989 28. Stamler J, Wentworth D, Neaton JD: Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA 256:2823, 1986 29. Steering Committee of the Physician's Health Study Research Group: Preliminary report: Findings from the aspirin component of the ongoing physicians' health study. N Engl J Med 318:262, 1988 30. Stroke Prevention in Atrial Fibrillation Study Group: Preliminary report of the stroke prevention in atrial fibrillation study. N Engl J Med 322:863, 1990 31. Tell GS, Crouse JR, Furberg CD: Relation between blood lipids, lipoproteins and cerebrovascular atherosclerosis. A review. Stroke 19:423, 1988 32. Viitanen M, Winblad B, Asplund K: Autopsy-verified causes of death after stroke. Acta Med Scand 222:401, 1987 33. Whisnant JP, Homer D, lngall TJ, et al: Duration of cigarette smoking is the strongest predictor of severe extracranial carotid artery atherosclerosis. Stroke 21:707, 1990 34. WHO Task Force on Stroke and other Cerebrovascular Disorders: Stroke-1989. Recommendations on stroke prevention, diagnosis and therapy. Stroke 20: 1407, 1989 35. Willett WC, Green A, Stampfer JF, et al: Relative and absolute excess risks of coronary heart disease among women who smoke cigarettes. N Engl J Med 317:1303, 1987 36. Wolf PA, D'Agostino RB, Kannel WB, et al: Cigarette smoking as a risk factor for stroke. The Framingham Study. JAMA 259:1025, 1988 37. Wolf PA, Kannel WB: Reduction of stroke through risk factor modification. Semin Neurol 6:243, 1986
Address reprint requests to Gary Goldberg, MD, FRCP(C) Stroke Center Moss Rehabilitation Hospital 1200 West Tabor Road Philadelphia, PA 19141-3099