Prevention of stroke
Authors: Philip A Wolf
Journal: The Lancet (1998)

Although therapies to reduce brain injury from acute stroke are being developed, prevention will continue to be the most effective strategy for reducing the health consequences and costs of stroke. Host and environmental factors predisposing to stroke, and the relative impact of each, have been identified through prospective epidemiological study. These observational studies, taken together with randomised clinical trials of risk-factor modification, show the effectiveness of these strategies and of drug and surgical therapies for stroke prevention. There is considerable evidence that host and environmental factors are powerful contributors to stroke incidence (panel).1Sacco RL Benjamin EJ Broderick JP et al.Risk factors, panel.Stroke. 1997; 28: 1507-1517Crossref PubMed Scopus (553) Google Scholar In particular, the remarkable declines in death rates from stroke in most industrialised nations (eg, a 60% reduction in the USA since 1972) offer strong support for the influence of modifiable environmental factors on stroke occurrence. Findings from clinical trials and observational data indicate that stroke can be prevented and risk of stroke recurrence reduced. Preventive measures include control of hypertension; cessation of cigarette smoking; increasing the physical activity levels of sedentary persons; warfarin anticoagulation in most patients with atrial fibrillation; and, platelet-antiaggregant therapy in patients with transient ischaemic attacks and stroke survivors to reduce stroke and stroke recurrences. Recently, treatment with inhibitors of 3–hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase reduced stroke incidence by 31% in persons with clinical evidence of coronary-artery disease and average total cholesterol concentrations.2Sacks FM Pfeffer MA Moye LA et al.The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.N Engl J Med. 1996; 335 (Cholesterol and Recurrent Events Trial Investigators): 1001-1009Crossref PubMed Scopus (7125) Google Scholar It is possible that reduction of raised plasma homocysteine and improved control of blood glucose in diabetics may also reduce stroke incidence but data are lacking. Prevention and treatment of predisposing cardiac diseases—coronary-heart disease (CHD), congestive heart failure, atrial fibrillation (AF), increased left ventricular mass, and valvular heart disease—will probably help to reduce stroke occurrence.PanelRisk factors for first Ischaemlc stroke Tabled 1Well-documented risk factorsModifiable, value establishedHypertensionCardiac diseaseAtrial fibrillationInfective endocarditisMitral stenosisRecent large myocardial infarctionCigarette smokingSicke-cell diseaseTransient ischaemic attacksAsymptomatic carotid stenosisPotentially modifiableDiabetes mellitusHyperhomocysteinaemiaLeft ventricular hypertrophyNon-modifiableAgeSexHereditary/familial factorsRace/ethnicityGeographic locationLess well-documented risk factorsPotentially modifiableRaised blood cholesterol and lipidsCardiac diseaseCardiomyopathySegmental wall-motion abnormalitiesNon-bacterial endocarditisMitral annular calcificationMitral-valve prolapseValve strandsSpontaneous echocardiographic contrastAortic stenosisPatent foramen ovaleAtrial septal aneurysmUse of oral contraceptivesConsumption of alcoholUse of illicit drugsPhysical inactivityObesityRaised packed-cell volumeDietary factorsHyperinsulinaemia and insulin resistanceAcute triggers (stress)MigraineHypercoagulability and inflammationFibrin formation and fibrinolysisFibrinogenAnticardiolipin antibodiesGenetic and acquired causesSubclinical diseasesIncreased intimal-medial thicknessAortic atheromaLowered ankle-brachial blood-pressure ratioInfarct-like lesions on magnetic resonance imagingSocioeconomic featuresNon-modifiableSeason and climateFrom 1Sacco RL Benjamin EJ Broderick JP et al.Risk factors, panel.Stroke. 1997; 28: 1507-1517Crossref PubMed Scopus (553) Google Scholar. with permission Open table in a new tab Tabled 1Well-documented risk factorsModifiable, value establishedHypertensionCardiac diseaseAtrial fibrillationInfective endocarditisMitral stenosisRecent large myocardial infarctionCigarette smokingSicke-cell diseaseTransient ischaemic attacksAsymptomatic carotid stenosisPotentially modifiableDiabetes mellitusHyperhomocysteinaemiaLeft ventricular hypertrophyNon-modifiableAgeSexHereditary/familial factorsRace/ethnicityGeographic locationLess well-documented risk factorsPotentially modifiableRaised blood cholesterol and lipidsCardiac diseaseCardiomyopathySegmental wall-motion abnormalitiesNon-bacterial endocarditisMitral annular calcificationMitral-valve prolapseValve strandsSpontaneous echocardiographic contrastAortic stenosisPatent foramen ovaleAtrial septal aneurysmUse of oral contraceptivesConsumption of alcoholUse of illicit drugsPhysical inactivityObesityRaised packed-cell volumeDietary factorsHyperinsulinaemia and insulin resistanceAcute triggers (stress)MigraineHypercoagulability and inflammationFibrin formation and fibrinolysisFibrinogenAnticardiolipin antibodiesGenetic and acquired causesSubclinical diseasesIncreased intimal-medial thicknessAortic atheromaLowered ankle-brachial blood-pressure ratioInfarct-like lesions on magnetic resonance imagingSocioeconomic featuresNon-modifiableSeason and climateFrom 1Sacco RL Benjamin EJ Broderick JP et al.Risk factors, panel.Stroke. 1997; 28: 1507-1517Crossref PubMed Scopus (553) Google Scholar. with permission Open table in a new tab From 1Sacco RL Benjamin EJ Broderick JP et al.Risk factors, panel.Stroke. 1997; 28: 1507-1517Crossref PubMed Scopus (553) Google Scholar. with permission A combined analysis of nine major prospective (observational) studies of 420 000 individuals showed a graded relation between diastolic pressure and stroke and CHD. Risk rose steadily as diastolic pressure level rose, even in the normal range. In a meta-analysis of drug treatment for hypertension, incidence of stroke increased by 46% and CHD by 29% for every 7·5 mm Hg increase in diastolic pressure. Importantly, randomised trials have shown that reduction of raised blood pressure prevented stroke. An overview of 14 treatment trials in 37 000 hypertensive patients led to the conclusion that an average blood-pressure reduction of 5·8 mm Hg resulted in a 42% reduction in stroke incidence.3Collins R Peto R MacMahon S et al.Blood pressure, stroke, and coronary heart disease. Part 2, short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context.Lancet. 1990; 335: 827-838Summary PubMed Scopus (3434) Google Scholar These data conclusively put to rest the long-standing notion that reduction of raised blood pressure in hypertensive people would precipitate stroke. These observed reductions in stroke incidence closely approximated that expected from prospective observational studies. Although these studies were of brief duration, averaging 5 years, the striking reduction in stroke incidence suggests that anti-hypertensive treatment prevented stroke by interrupting precipitating factors rather than by retarding or reversing atherosclerosis. Presumably, longer-term blood-pressure control would do both. Although the diastolic component of blood pressure was emphasised in most trials, stroke risk is just as clearly related to levels of systolic pressure. In the elderly, in whom raised systolic blood pressure alone is common, reduction of the raised systolic component has significantly reduced the incidence of stroke without appreciable side-effects. In the Systolic Hypertension in the Elderly Program (SHEP), 4736 persons above age 60, with systolic blood pressure of 160 mm Hg or more and diastolic pressure of under 90 mm Hg were assigned in a randomised manner to treatment or placebo.4SHEP Cooperative Research GroupPrevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP).JAMA. 1991; 265: 3255-3264Crossref PubMed Scopus (4560) Google Scholar In the treated group, stroke incidence was reduced by 36% (and the combined outcome of myocardial infarction and coronary death was reduced by 27%) after 4·5 years of follow-up. These findings were confirmed in the Syst-Eur Trial among 4695 elderly men and women with isolated systolic hypertension.5Staessen J Amery A Birkenhager W et al.Syst-Eur—a multicenter trial on the treatment of isolated systolic hypertension in the elderly: first interim report.J Cardiovasc Pharmacol. 1992; 19: 120-125Crossref PubMed Scopus (26) Google Scholar Since two-thirds of elderly hypertensive people aged 65 to 89 years have isolated systolic hypertension, and most strokes occur in this age group, the findings from these two trials are important. However, only a fraction of the potential benefit of antihypertensive therapy for stroke prevention has been achieved. Optimum blood-pressure control has been achieved in only 21% of the estimated 50 million Americans with raised blood pressure (those with systolic blood pressure of 140 mm Hg or more and/or diastolic blood pressure 90 mm Hg or more, or those taking antihypertensive drugs).6Arch Intern Med. 1997; 157: 2413-2446Crossref PubMed Google Scholar Estimates based on a sample of the US adult population are that 35% of hypertensive people are unaware of their raised blood pressure, and only half are on treatment. Thus, four-fifths of American people with hypertension are unaware of their disorder, not treated for it, or do not have it under control. In a meta-analysis of 32 separate studies, cigarette smoking was a significant independent contributor to stroke incidence, increasing risk by 50%.7Shinton R Beevers G Meta-analysis of relation between cigarette smoking and stroke.BMJ. 1989; 298: 789-794Crossref PubMed Scopus (755) Google Scholar There was a dose-response, with risk rising with increase in numbers of cigarettes smoked daily. This increased risk is reversible, and cessation of smoking is followed by a rapid decline in incidence. In Framingham, within 5 years of cessation of cigarette smoking, risk of stroke returned to that of people who have never smoked.8Wolf PA D'Agostino RB Kannel WB Bonita R Belanger AJ Cigarette smoking as a risk factor for stroke: the Framingham Study.JAMA. 1988; 259: 1025-1029Crossref PubMed Scopus (645) Google Scholar This rapid risk reduction is similar to that observed with CHD risk—falling by approximately 50% within 1 year of cessation of smoking and reaching the level for those who had not smoked within 5 years. There was no interaction with age or duration of smoking, reinforcing the notion that a key mechanism by which cigarette smoking acted was by precipitating stroke. Increased levels of physical activity have been linked to lower incidence of stroke (and of CHD). Exercise exerts a beneficial influence on risk factors for stroke by reducing raised blood pressure; promoting weight loss; raising the HDL-cholesterol and lowering the LDL-cholesterol; improving glucose tolerance; and promoting a lifestyle conducive to favourably changing detrimental health habits such as cigarette smoking. Among the men in Framingham, moderate physical activity was associated with significantly reduced relative risk of stroke (RR 0·41, p=0·0007) after potential confounders had been accounted for. No protective effect was seen among women. Moderate activity conferred as much benefit as did heavy physical activity. Other studies have found a graded benefit from increasing exercise levels. In the NHANES I Epidemiologic Follow-up Study, low levels of physical activity were associated with increased risk of stroke among women as well as among men, and among both blacks and whites.9Gillum RF Mussolino ME Ingram DD Physical activity and stroke incidence in women and men; the NHANES I Epidemiologic Follow-up Study.Am J Epidemiol. 1996; 143: 860-869Crossref PubMed Scopus (162) Google Scholar Moderate activity provided an intermediate level of protection. Atrial fibrillation is one of the most powerful independent risk factors for stroke, increasing stroke incidence fivefold at rates of approximately 5% per year for initial stroke and 12% per year for recurrent stroke events. Clinical trials have shown the efficacy of warfarin anticoagulation (68 to 81% risk reduction) in primary and recurrent stroke prevention.10Atrial Fibrillation InvestigatorsRisk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation.Arch Intern Med. 1994; 154: 1449-1457Crossref PubMed Scopus (2906) Google Scholar Warfarin anticoagulation at an international normalised ratio (INR) intensity of 2·0 to 3·0 (some suggest a target of INR 3·0) is an optimum and safe level. Warfarin is indicated in all patients with atrial fibrillation, with the possible exception of those below age 65 with no history of hypertension, diabetes, transient ischaemic attack, or stroke, who are free of structural heart disease. Patients in whom anticoagulation is contraindicated may be placed on aspirin 325 mg/day. In patients with a past stroke or transient ischaemic attack, aspirin has reduced the relative odds of a composite outcome of ischaemic stroke, myocardial infarction, or vascular death by 27%.11Antiplatelet Trialists CollaborationCollaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients.BJM. 1994; 308: 81-106Crossref PubMed Scopus (670) Google Scholar Ticlopidine, and more recently clopidogrel, have shown a level of protection 8 to 10 % above that of aspirin in large clinical trials12Hass WK Easton JD Adams Jr, HP et al.A randomised trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients: Ticlopidine Aspirin Stroke Study Group.N Engl J Med. 1989; 321: 501-507Crossref PubMed Scopus (1147) Google Scholar, 13CAPRIE Steering Committee A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE).Lancet. 1996; 348: 1329-1339Summary Full Text Full Text PDF PubMed Scopus (5990) Google Scholar Evidence for primary prevention of stroke with aspirin is lacking; observational studies have either shown no benefit or an adverse effect on ischaemic stroke14Kronmal RA Hart RG Manoloi TA et al.Aspirin used and incident stroke in the cardiovascular health study.Stroke. 1998; 29: 887-894Crossref PubMed Google Scholar. Endarterectomy for symptomatic patients with substantial extracranial carotid stenosis (50–99% with North American Symptomatic Carotid Endarterectomy Trial [NASCET] methods or >75–99% with European Carotid Surgery Trial [EST] criteria), in capable surgical hands, clearly prevents ipsilateral stroke.11Antiplatelet Trialists CollaborationCollaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients.BJM. 1994; 308: 81-106Crossref PubMed Scopus (670) Google Scholar, 15North American Symptomatic Carotid Endarterectomy Trial CollaboratorsBeneficial effect of carotid endarterectomy in symptomatic patient with high-grade carotid stenosis.N Engl J Med. 1991; 325: 445-453Crossref PubMed Scopus (7709) Google Scholar, 16European Carotid Surgery Trialists' Collaborative GroupRandomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).Lancet. 1998; 351: 1379-1387Summary Full Text Full Text PDF PubMed Scopus (2877) Google Scholar, 17Asymptomatic Carotid Athersclerosis Study Executive Committee Endarterectomy for Asymptomatic Carotid Artery Stenosis.JAMA. 1995; 273: 1421-1428Crossref PubMed Scopus (5064) Google Scholar A benefit of surgery in symptom-free individuals with carotid stenosis 60–99% was found among men in the Asymptomatic Carotid Atherosclerosis Study (ACAS), but not among women. However, the results depended on the extremely low surgical complication rate of less than 3% in ACAS, which may be difficult to match in non-trial surgical practice. For this reason, some critics believe that the risk of complications does not warrant the 1% annual reduction in absolute risk of stroke.18Barnett HJM Eliasziw M Meldrum HE Taylor DW Do the facts and figures warrant a 10-fold increase in the performance of carotid endarterectomy on astmptomatic patients?.Neurology. 1996; 46: 603-608Crossref PubMed Scopus (130) Google Scholar In two recently completed randomised clinical trials, the HMG-CoA-reductase inhibitor pravastatin given to patients with CHD with total and LDL-cholesterol concentrations in the average range reduced stroke incidence by 31%.2Sacks FM Pfeffer MA Moye LA et al.The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels.N Engl J Med. 1996; 335 (Cholesterol and Recurrent Events Trial Investigators): 1001-1009Crossref PubMed Scopus (7125) Google Scholar A secondary analysis of data from a large trial of simvastatin on stroke and transient ischaemic attack in persons with much higher total and LDL-cholesterol concentrations also significantly reduced stroke incidence.19Scandinavian Simvastatin Survival Study GroupRandomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).Lancet. 1994; 344: 1383-1389Summary PubMed Scopus (11161) Google Scholar This effect may be somewhat surprising since abnormal blood lipids are not universally believed to be a significant risk factor for ischaemic stroke. In addition, the rapid benefit from pravastatin on stroke incidence suggests that, in addition to reduction in LDL-cholesterol, HMG-CoA-reductase inhibitors prevent precipitation of clinical events by stabilising the atherosclerotic plaque, improving endothelial function, and exerting beneficial effects on clotting.20Vaughan CJ Murphy MB Buckley BM Statins do more than just lower cholesterol.Lancet. 1996; 348: 1079-1082Summary Full Text Full Text PDF PubMed Scopus (673) Google Scholar Several case-control studies have related raised total plasma homocysteine (tHcy) to incidence of CHD and stroke.21Boushey CJ Beresford SAA Omenn GS Motulsky AG A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes.JAMA. 1995; 274: 1049-1057Crossref PubMed Scopus (3480) Google Scholar The concentration of tHcy may be reduced by folic acid and pyridoxine, with possibly a reduction in risk of stroke or cardiovascular disease. In the British Regional Heart Study cohort, stroke patients had higher non-fasting tHcy concentrations than did controls, with a graded increase in risk with increasing concentrations of tHcy22Perry IJ Refsum H Morris RW Ebrahim SB Ueland PM Shaper AG Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged British men.Lancet. 1995; 346: 1395-1398PubMed Scopus (846) Google Scholar. However, in other large population studies no statistically significant relation was found. Every physician can identify those patients at increased risk of stroke. Hypertensive individuals need to have blood pressures reduced to under 140 mm Hg systolic and under 90 mm Hg diastolic. Cessation of cigarette smoking, weight reduction in obese patients, and a programme of moderate physical activity may be generally recommended. It is likely that vitamin supplementation with folic acid and vitamins B6 and B12 and reduction of raised total and LDL-cholesterol with pravastatin or simvastatin may soon be advocated for stroke-prone patients. The probability of stroke may be quantified by use of a profile such as the Framingham stroke-risk profile.23Wolf PA D'Agostino RB Belanger AJ Kannel WB Probability of stroke: a risk profile from the Framingham Study.Stroke. 1991; 22: 312-318Crossref PubMed Scopus (1383) Google Scholar Using medical history and physical examination findings (and the electrocardiograph), probability of stroke in 10 years may be computed by use of a point system based on: age; systolic blood-pressure; antihypertensive therapy; presence of diabetes; cigarette smoking; history of cardiovascular disease (CHD or congestive heart failure); and electrocardiographic abnormalities (left ventricular hypertrophy or atrial fibrillation). Risk of stroke in 10 years may then be compared with that for an average man or woman of the same age (figure). This quantitative assessment of risk is particularly helpful in guiding the patient, and the physician, in deciding how vigorously to reduce risk factors for stroke, especially in the patient with multiple borderline risk-factor abnormalities. Supported in part by grants 2–RO1–NS-17950–17 (National Institute of Neurological Disorders and Stroke), RO1–HL40423 (National Institute on Aging, National Heart, Lung, and Blood Institute), and Contract NIH-NO1–HC-38038 (National Heart, Lung, and Blood Institute).