title: Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial Italian multicenter study on reversible cerebral ischemic attacks: VI--Prognostic factors and follow-up results. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial Long‐term prognosis and quality of life after reversible cerebral ischemic attacks Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. The Care Investigators. Recurrence of bleeding in patients with primary intracerebral hemorrhage. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). ALLHAT Collaborative Research Group. The MRC/BHF Heart Protection Study: preliminary results. Predictors of major vascular events in patients with a transient ischemic attack or minor ischemic stroke and with nonrheumatic atrial fibrillation. European Atrial Fibrillation Trial (EAFT) Study Group. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. Serum lipids after stroke Influence of cholesterol on survival after stroke: retrospective study Rationale and design of a secondary prevention trial of lowering normal plasma cholesterol levels after acute myocardial infarction: the Cholesterol and Recurrent Events trial (CARE) Controlled trial of clofibrate in cerebral vascular disease. Stroke recurrence An evaluation of estrogenic substances in the treatment of cerebral vascular disease. Report of the Veterans Administration Cooperative Study of Atherosclerosis, Neurology Section. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. High-dose atorvastatin after stroke or transient ischemic attack. Design and Baseline Characteristics of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study
abstract: BACKGROUND Patients with transient ischaemic attack ( TIA ) or minor stroke are at high immediate risk of stroke . The optimum early treatment options for these patients are not known . METHODS Within 24 h of symptom onset , we r and omly assigned , in a factorial design , 392 patients with TIA or minor stroke to clopidogrel  ( 300 mg loading dose then 75 mg daily ; 198 patients ) or placebo ( 194 patients ) , and simvastatin ( 40 mg daily ; 199 patients ) or placebo ( 193 patients ) . All patients were also given aspirin and were followed for 90 days . Descriptive analyses were done by intention to treat . The primary outcome was total stroke ( ischaemic and haemorrhagic ) within 90 days . Safety outcomes included haemorrhage related to clopidogrel and myositis related to simvastatin . This study is registered as an International St and ard R and omised Controlled Trial ( number 35624812 ) and with Clinical Trials.gov ( NCT00109382 ) . FINDINGS The median time to stroke outcome was 1 day ( range 0 - 62 days ) . The trial was stopped early due to a failure to recruit patients at the prespecified minimum enrolment rate because of increased use of statins . 14 ( 7.1 % ) patients on clopidogrel had a stroke within 90 days compared with 21 ( 10.8 % ) patients on placebo ( risk ratio 0.7 [ 95 % CI 0.3 - 1.2 ] ; absolute risk reduction -3.8 % [ 95 % CI -9.4 to 1.9 ] ; p=0.19 ) . 21 ( 10.6 % ) patients on simvastatin had a stroke within 90 days compared with 14 ( 7.3 % ) patients on placebo ( risk ratio 1.3 [ 0.7 - 2.4 ] ; absolute risk increase 3.3 % [ -2.3 to 8.9 ] ; p=0.25 ) . The interaction between clopidogrel and simvastatin was not significant ( p=0.64 ) . Two patients on clopidogrel had intracranial haemorrhage compared with none on placebo ( absolute risk increase 1.0 % [ -0.4 to 2.4 ] ; p=0.5 ) . There was no difference between groups for the simvastatin safety outcomes . INTERPRETATION Immediately after TIA or minor stroke , patients are at high risk of stroke , which might be reduced by using clopidogrel in addition to aspirin . The haemorrhagic risks of the combination of aspirin and clopidogrel do not seem to offset this potential benefit . We were unable to provide evidence of benefit of simvastatin in this setting . This aggressive prevention approach merits further study BACKGROUND Although statins reduce coronary and cerebrovascular morbidity and mortality in middle-aged individuals , their efficacy and safety in elderly people is not fully established . Our aim was to test the benefits of pravastatin treatment in an elderly cohort of men and women with , or at high risk of developing , cardiovascular disease and stroke . METHODS We did a r and omised controlled trial in which we assigned 5804 men ( n=2804 ) and women ( n=3000 ) aged 70 - 82 years with a history of , or risk factors for , vascular disease to pravastatin ( 40 mg per day ; n=2891 ) or placebo ( n=2913 ) . Baseline cholesterol concentrations ranged from 4.0 mmol/L to 9.0 mmol/L. Follow-up was 3.2 years on average and our primary endpoint was a composite of coronary death , non-fatal myocardial infa rct ion , and fatal or non-fatal stroke . Analysis was by intention-to-treat . FINDINGS Pravastatin lowered LDL cholesterol concentrations by 34 % and reduced the incidence of the primary endpoint to 408 events compared with 473 on placebo ( hazard ratio 0.85 , 95 % CI 0.74 - 0.97 , p=0.014 ) . Coronary heart disease death and non-fatal myocardial infa rct ion risk was also reduced ( 0.81 , 0.69 - 0.94 , p=0.006 ) . Stroke risk was unaffected ( 1.03 , 0.81 - 1.31 , p=0.8 ) , but the hazard ratio for transient ischaemic attack was 0.75 ( 0.55 - 1.00 , p=0.051 ) . New cancer diagnoses were more frequent on pravastatin than on placebo ( 1.25 , 1.04 - 1.51 , p=0.020 ) . However , incorporation of this finding in a meta- analysis of all pravastatin and all statin trials showed no overall increase in risk . Mortality from coronary disease fell by 24 % ( p=0.043 ) in the pravastatin group . Pravastatin had no significant effect on cognitive function or disability . INTERPRETATION Pravastatin given for 3 years reduced the risk of coronary disease in elderly individuals . PROSPER therefore extends to elderly individuals the treatment strategy currently used in middle aged people A total of 462 patients ( mean age 52 years ) affected by reversible focal ischemic attacks ( RIAs ) were followed prospect ively in 8 neurologic institutions in Italy for 4 years . All cases were evaluated with a cerebral angiography and 21 % of angiograms were normal . At the end of the follow-up period the cumulated probability for death , stroke , cardiac event and new RIA was respectively 7 % , 8 % , 3 % and 36 % . The predictive value of the baseline characteristics of this series was evaluated by a multifactorial analysis which showed that RIA and stroke ( specific cerebrovascular risk ) were more likely to develop in patients with a history of more than one RIA and in those in whom multiple vascular territories were involved . Moreover , previous myocardial infa rct ion , intermittent claudication , angina pectoris , time elapsed since the first attack , and duration and severity of the attack itself were independently associated with general cardiovascular risk ( death , stroke and myocardial infa rct ion ) . We conclude that predictive factors , and thus also pathogenetic mechanisms , may be different for general cardiovascular risk and specific cerebrovascular risk in RIA patients BACKGROUND The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome . No study , however , has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease ( CHD ) in hypertensive patients who are not conventionally deemed dyslipidaemic . METHODS Of 19342 hypertensive patients ( aged 40 - 79 years with at least three other cardiovascular risk factors ) r and omised to one of two antihypertensive regimens in the Anglo-Sc and inavian Cardiac Outcomes Trial , 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were r and omly assigned additional atorvastatin 10 mg or placebo .  These patients formed the lipid-lowering arm of the study . We planned follow-up for an average of 5 years , the primary endpoint being non-fatal myocardial infa rct ion and fatal CHD . Data were analysed by intention to treat . FINDINGS Treatment was stopped after a median follow-up of 3.3 years . By that time , 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group ( hazard ratio 0.64 [ 95 % CI 0.50 - 0.83 ] , p=0.0005 ) . This benefit emerged in the first year of follow-up . There was no significant heterogeneity among prespecified subgroups . Fatal and non-fatal stroke ( 89 atorvastatin vs 121 placebo , 0.73 [ 0.56 - 0.96 ] , p=0.024 ) , total cardiovascular events ( 389 vs 486 , 0.79 [ 0.69 - 0.90 ] , p=0.0005 ) , and total coronary events ( 178 vs 247 , 0.71 [ 0.59 - 0.86 ] , p=0.0005 ) were also significantly lowered . There were 185 deaths in the atorvastatin group and 212 in the placebo group ( 0.87 [ 0.71 - 1.06 ] , p=0.16 ) . Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months , and by 1.1 mmol/L after 3 years of follow-up . INTERPRETATION The reductions in major cardiovascular events with atorvastatin are large , given the short follow-up time . These findings may have implication s for future lipid-lowering guidelines ABSTRACT — The long‐term prognosis and quality of life of 201 patients admitted to hospital with reversible ischemic attacks ( RIA ) were estimated in a prospect i ve study . The median follow‐up time was 58 months . Further RIAs were reported by 91 patients ( 45 % ) and 48 ( 24 % ) suffered a stroke . The risk of stroke was markedly higher in the first 6 months after RIA , after which the annual stroke rate was rather constant with an average of 4.8 % , about 8 times higher than expected . The average annual mortality rate for the RIA patients was 5.9 % , which is significantly higher than expected . Cardiovascular deaths accounted for more than half of all deaths , stroke for one fourth . Life‐table analysis of subgroups disclosed a much more favorable prognosis for women under 60 years .  High systolic blood pressure , diabetes , and previous myocardial infa rct ion were identified as risk factors . The occurrence of RIA had significantly influenced the quality of life and occupational status for the majority of the patients , even for those who did not suffer a subsequent stroke . Decreased working capacity , general asthenia and fatigue and impaired memory were the most common complaints . We conclude that RIA may be a more serious vascular event than generally believed . Apart from carrying a substantial risk of stroke and death , even a single RIA can cause permanent psychological dysfunction influencing the quality of life BACKGROUND The role of lipid modification in stroke prevention is controversial , although increasing evidence suggests that HMG-CoA reductase inhibition may reduce cerebrovascular events in patients with prevalent coronary artery disease . METHODS AND RESULTS To test the hypothesis that cholesterol reduction with pravastatin may reduce stroke incidence after myocardial infa rct ion , we followed 4159 subjects with average total and LDL serum cholesterol levels ( mean , 209 and 139 mg/dL , respectively ) who had sustained an infa rct ion an average of 10 months before study entry and who were r and omized to pravastatin 40 mg/d or placebo in the Cholesterol and Recurrent Events ( CARE ) trial . Using prospect ively defined criteria , we assessed the incidence of stroke , a prespecified secondary end point , and transient ischemic attack ( TIA ) over a median 5-year follow-up period . Patients were well matched for stroke risk factors and the use of antiplatelet agents ( 85 % of subjects in each group ) . Compared with placebo , pravastatin lowered total serum cholesterol by 20 % , LDL cholesterol by 32 % , and triglycerides by 14 % and raised HDL cholesterol by 5 % over the course of the trial . A total of 128 strokes ( 52 on pravastatin , 76 on placebo ) and 216 strokes or TIAs ( 92 on pravastatin , 124 on placebo ) were observed , representing a 32 % reduction ( 95 % CI , 4 % to 52 % , P=0.03 ) in all-cause stroke and 27 % reduction in stroke or TIA ( 95 % CI , 4 % to 44 % , P=0.02 ) . All categories of strokes were reduced , and treatment effect was similar when adjusted for age , sex , history of hypertension , cigarette smoking , diabetes , left ventricular ejection fraction , and baseline total , HDL , and LDL cholesterol and triglyceride levels . There was no increase in hemorrhagic stroke in patients on pravastatin compared with placebo ( 2 versus 6 , respectively ) . CONCLUSIONS Pravastatin significantly reduced stroke and stroke or TIA incidence after myocardial infa rct ion in patients with average serum cholesterol levels despite the high concurrent use of antiplatelet therapy BACKGROUND AND PURPOSE Rebleeding in patients with primary intracerebral hemorrhage is considered uncommon , but there are no precise data to support this opinion . The purpose of this study was to assess the incidence and predictors of recurrent bleeding in survivors of primary intracerebral hemorrhage . METHODS As part of a prospect i ve study , 112 survivors of a first primary intracerebral hemorrhage were followed up for a mean period of 84.1 months after their discharge . To ascertain risk factors that may influence rebleeding , several demographic , medical history , clinical , and laboratory variables were collected and analyzed . RESULTS Twenty-four percent ( 27/112 ) of survivors experienced one or more rebleeding during the follow-up period , in 8 cases ( 30 % ) in the first year of follow-up ; in the others recurrence occurred later , up to 11.5 years . Rebleeding had a high mortality rate : 70 % of patients died as a consequence of their second or third hemorrhage . Univariate and multivariate analyses showed that lobar location of the first hemorrhage was the only significant predictor of rebleeding . Patients with rebleeding were more frequently older , more often had a history of previous transient ischemic attack or ischemic stroke , and less often had hyperlipidemia than patients without rebleeding , although these correlations did not reach statistical significance . During follow-up , poor control of arterial hypertension was found in 7 % of hypertensive patients without rebleeding and in 47 % of hypertensive patients with rebleeding . CONCLUSIONS Our study showed that rebleeding after a first primary intracerebral hemorrhage is not as uncommon as is usually believed . The risk of rebleeding seems to be particularly high after hemorrhage at the junction of the gray and white matter , a site regarded as typical of hemorrhages due to amyloid angiopathy , and when arterial hypertension is poorly controlled CONTEXT Hypertension is associated with a significantly increased risk of morbidity and mortality . Only diuretics and beta-blockers have been shown to reduce this risk in long-term clinical trials . Whether newer antihypertensive agents reduce the incidence of cardiovascular disease ( CVD ) is unknown . OBJECTIVE To compare the effect of doxazosin , an alpha-blocker , with chlorthalidone , a diuretic , on incidence of CVD in patients with hypertension as part of a study of 4 types of antihypertensive drugs : chlorthalidone , doxazosin , amlodipine , and lisinopril . DESIGN R and omized , double-blind , active-controlled clinical trial , the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial , initiated in February 1994 . In January 2000 , after an interim analysis , an independent data review committee recommended discontinuing the doxazosin treatment arm based on comparisons with chlorthalidone . Therefore , outcomes data presented herein reflect follow-up through December 1999 . SETTING A total of 625 centers in the United States and Canada . PARTICIPANTS A total of 24,335 patients ( aged > or = 55 years ) with hypertension and at least 1 other coronary heart disease ( CHD ) risk factor who received either doxazosin or chlorthalidone .  INTERVENTIONS Participants were r and omly assigned to receive chlorthalidone , 12.5 to 25 mg/d ( n=15,268 ) , or doxazosin , 2 to 8 mg/d ( n=9067 ) , for a planned follow-up of 4 to 8 years . MAIN OUTCOME MEASURES The primary outcome measure was fatal CHD or nonfatal myocardial infa rct ion ( MI ) , analyzed by intent to treat ; secondary outcome measures included all-cause mortality , stroke , and combined CVD ( CHD death , nonfatal MI , stroke , angina , coronary revascularization , congestive heart failure [ CHF ] , and peripheral arterial disease ) ; compared by the chlorthalidone group vs the doxazosin group . RESULTS Median follow-up was 3.3 years . A total of 365 patients in the doxazosin group and 608 in the chlorthalidone group had fatal CHD or nonfatal MI , with no difference in risk between the groups ( relative risk [ RR ] , 1.03 ; 95 % confidence interval [ CI ] , 0.90 - 1.17 ; P=.71 ) . Total mortality did not differ between the doxazosin and chlorthalidone arms ( 4-year rates , 9.62 % and 9.08 % , respectively ; RR , 1.03 ; 95 % CI , 0.90 - 1.15 ; P=.56 . ) The doxazosin arm , compared with the chlorthalidone arm , had a higher risk of stroke ( RR , 1.19 ; 95 % CI , 1.01 - 1.40 ; P=.04 ) and combined CVD ( 4-year rates , 25.45 % vs 21.76 % ; RR , 1.25 ; 95 % CI , 1.17 - 1.33 ; P<.001 ) . Considered separately , CHF risk was doubled ( 4-year rates , 8.13 % vs 4.45 % ; RR , 2.04 ; 95 % CI , 1.79 - 2.32 ; P<.001 ) ; RRs for angina , coronary revascularization , and peripheral arterial disease were 1.16 ( P<.001 ) , 1.15 ( P=.05 ) , and 1.07 ( P=.50 ) , respectively . CONCLUSION Our data indicate that compared with doxazosin , chlorthalidone yields essentially equal risk of CHD death/nonfatal MI but significantly reduces the risk of combined CVD events , particularly CHF , in high-risk hypertensive patients The Heart Protection Study ( HPS ) , with over 20,500 subjects , is the largest trial of statin therapy ever conducted . It provides important and definitive new information on women , the elderly , diabetics , and people with low baseline cholesterol pre-treatment and those with prior occlusive non-coronary vascular disease . It is a prospect i ve double blind r and omised controlled trial with a 2 x 2 factorial design investigating prolonged use ( > 5 years ) of simvastatin 40 mg and a cocktail of antioxidant vitamins ( 650 mg vitamin E , 250 mg vitamin C and 20 mg beta-carotene ) . The HPS specifically included patients with high risk for coronary heart disease ( CHD ) but characteristics that excluded them from participation in previous statin trials .  Simvastatin 40 mg treatment showed benefit across all patient groups regardless of age , gender or baseline cholesterol value and proved safe and well tolerated . Results show a 12 % reduction in total mortality , a 17 % reduction in vascular mortality , a 24 % reduction in CHD events , a 27 % reduction in all strokes and a 16 % reduction in non-coronary revascularisations . Among high-risk patients in this western population ( with a minimum total cholesterol [ TC ] > or = 3.5 mmol/l at entry ) there appears to be no threshold cholesterol value below which statin therapy is not associated with benefit ; even among those with pre-treatment cholesterol levels below current national recommended targets . Over the 5.5 year study period patients and their doctors were encouraged to add an active non- study statin to the study regimen if they wished to do so . Thus the trial eventually had only two-thirds complying with the original intention-to-treat design . Nevertheless , results were highly significant for the study statin -- simvastatin 40 mg once daily . Preliminary results of the HPS are negative for the antioxidant vitamin cocktail but provide reassurance that vitamins do no harm BACKGROUND AND PURPOSE The risk of major vascular events after an initial episode of cerebral ischemia in patients with nonrheumatic atrial fibrillation ( NRAF ) varies from 2 % to 15 % in the first year and is approximately 5 % yearly thereafter . Few studies have reported on risk factors that can be used to identify high-risk subgroups within this patient population . METHODS We studied the predictive value of several easily obtainable clinical characteristics in a group of 375 placebo-treated patients with NRAF and a recent episode of transient or nondisabling cerebral ischemia who were entered in a multicenter clinical trial . The mean follow-up was 1.6 years . RESULTS By means of multivariate modeling , six independent variables were identified : history of previous thromboembolism , ischemic heart disease , enlarged cardiothoracic ratio on chest roentgenogram , systolic blood pressure greater than 160 mm Hg at study entry , NRAF for more than 1 year , and presence of an ischemic lesion on CT scan . These variables could also be used to stratify patients in low- , medium- , and high-risk subgroups for the other two arms of the trial , those treated with anticoagulation and aspirin .  Patients older than 75 years with three or more risk factors seemingly benefited less from both aspirin and anticoagulant treatment . CONCLUSIONS Easily obtainable patient characteristics are helpful in estimating the potential effect of adequate secondary prevention in patients with NRAF who recently suffered a transient ischemic attack or minor ischemic stroke BACKGROUND In patients with high cholesterol levels , lowering the cholesterol level reduces the risk of coronary events , but the effect of lowering cholesterol levels in the majority of patients with coronary disease , who have average levels , is less clear . METHODS In a double-blind trial lasting five years we administered either 40 mg of pravastatin per day or placebo to 4159 patients ( 3583 men and 576 women ) with myocardial infa rct ion who had plasma total cholesterol levels below 240 mg per deciliter ( mean , 209 ) and low-density lipoprotein ( LDL ) cholesterol levels of 115 to 174 mg per deciliter ( mean , 139 ) . The primary end point was a fatal coronary event or a nonfatal myocardial infa rct ion . RESULTS The frequency of the primary end point was 10.2 percent in the pravastatin group and 13.2 percent in the placebo group , an absolute difference of 3 percentage points and a 24 percent reduction in risk ( 95 percent confidence interval , 9 to 36 percent ; P = 0.003 ) . Coronary bypass surgery was needed in 7.5 percent of the patients in the pravastatin group and 10 percent of those in the placebo group , a 26 percent reduction ( P=0.005 ) , and coronary angioplasty was needed in 8.3 percent of the pravastatin group and 10.5 percent of the placebo group , a 23 percent reduction ( P=0.01 ) . The frequency of stroke was reduced by 31 percent ( P=0.03 ) . There were no significant differences in overall mortality or mortality from noncardiovascular causes . Pravastatin lowered the rate of coronary events more among women than among men . The reduction in coronary events was also greater in patients with higher pretreatment levels of LDL cholesterol . CONCLUSIONS These results demonstrate that the benefit of cholesterol-lowering therapy extends to the majority of patients with coronary disease who have average cholesterol levels To ascertain the appropriate time for detecting lipid abnormalities for prophylaxis , serial analyses of fasting serum lipoproteins were undertaken prospect ively in men with cerebral infa rct ion or transient ischemic attacks .  Serum total cholesterol ( T CHOL ) and low density lipoprotein cholesterol ( LDL CHOL ) in cerebral infa rct ion patients aged 50 to 69 were lowest on day 7 , intermediate on day 1 , and highest at 3 months , whereas very low density lipoprotein and high density lipoprotein cholesterol ( HDL CHOL ) changed little . The day 1 mean fasting serum HDL CHOL of cerebral infa rct patients was significantly lower in subjects aged 50 to 59 than in those aged 60 to 69 ( 23 ± 3 versus 42 ± 5 mg/dl ) , and there was a corresponding higher ratio of T CHOL : HDL CHOL ( 12.7 ± 4.5 versus 4.7 ± 0.4 , p < 0.01 ) . Mean HDL CHOL levels were low normal to low in patients aged 50 to 69 with transient ischemic attacks . Both serum cholesterol and triglyceride levels are initially decreased in patients aged 50 to 69 with cerebral infa rct ion , whereas only cholesterol is decreased in patients 60 to 69 with transient ischemic attacks . Important lipoprotein abnormalities may be missed in the acute phase Abstract Objective : To investigate the association between serum cholesterol concentration and cerebrovascular disease . Design : Retrospective study . Setting : Acute stroke unit of inner city general hospital . Subjects : 977 patients with acute stroke . Main outcome measures : Serum total cholesterol concentration , type of stroke investigated by computed tomography or magnetic resonance imaging  , three month outcome ( good ( alive at home ) or bad ( dead or in care ) ) , long term mortality . Results : After adjustment for known prognostic factors , higher serum cholesterol concentrations were associated with reduced long term mortality after stroke ( relative hazard 0.91 ( 95 % confidence interval 0.84 to 0.98 ) per mmol/l increase in cholesterol ) independently of stroke type , vascular territory and extent , age , and hyperglycaemia . Three month outcome was also influenced independently by serum cholesterol ( P=0.024 ) . Conclusions : Our data suggest an association between poor stroke outcome and lower serum cholesterol concentration . Until a prospect i ve controlled study has confirmed the benefits of lowering cholesterol concentration in elderly subjects , the application of cholesterol lowering guidelines can not be justified as secondary prevention of acute stroke . Key messages Although the link between cholesterol and stroke is controversial , the balance of evidence suggests higher cholesterol is associated with an increased risk of atherothrombotic stroke but a reduced risk of intracerebral haemorrhage Trials of lipid lowering drugs have concentrated on middle aged patients with a relatively low incidence of stroke events We investigated the association between serum cholesterol and cerebrovascular disease in 977 patients hospitalised with acute stroke and found that higher serum total cholesterol concentrations were associated with a reduction in long term mortality after stroke This relation was independent of the type or extent of the stroke , vascular territory , age , and hyperglycaemia – all factors known to influence survival independently after stroke Until conclusive benefit is shown in elderly patients with cerebrovascular disease , the routine application of lipid lowering treatment after stroke can not be Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol decreases the incidence of coronary heart disease in patients with elevated plasma cholesterol . However , it is not known whether patients with established coronary artery disease and normal plasma cholesterol can be benefited . Several previous prevention trials review ed in this report found that patients who had plasma cholesterol levels at baseline in the upper portion of the eligibility range ( e.g. , greater than 240 mg/dl ) received greater benefit from hypolipidemic diet or drug therapy than patients who had lower plasma cholesterol levels at baseline . The recent availability of drugs that are more potent and less prone to cause adverse reactions than previous regimens permits this important question to be addressed . The Cholesterol and Recurrent Events trial is testing whether pravastatin , a hydroxymethylglutaryl coenzyme A reductase inhibitor , will decrease the sum of fatal coronary heart disease and nonfatal myocardial infa rct ion ( MI ) in patients who have recovered from a MI and who have normal total cholesterol levels .  Fatal cardiovascular disease and total mortality are important secondary end points . The trial is enrolling 4,000 men and women from 80 centers throughout North America , age 21 to 75 years , who have survived MI for 3 to 20 months , who have plasma total cholesterol less than 240 mg/dl ( 6.2 mmol/liter ) and low-density cholesterol of 115 to 174 mg/dl ( 3.0 to 4.5 mmol/liter ) , and who are representative of the general population of patients with MI . Patients are r and omized to either active or inactive drug therapy . Active therapy consists of pravastatin , 40 mg/day , design ed to achieve an average decrease in low-density lipoprotein cholesterol of approximately 30 % , and an increase in high-density lipoprotein of 5 % . The average duration of follow-up will be greater than or equal to 5 years . To protect against a lower than expected rate of recurrent events , the trial will be continued until a predetermined fixed number of coronary heart disease events occurs in the entire cohort so that the original sensitivity of the trial will be maintained Abstract A controlled trial of Clofibrate in 95 patients with established cerebral vascular disease is described . The level of serum cholesterol is significantly lowered in patients on treatment compared with control patients . There is no evidence to indicate that lowering the level of serum cholesterol in patients with established cerebral vascular disease has affected either the incidence of further episodes of cerebral ischaemia or the mortality rate We compared stroke severity , risk factors , and prognosis in patients with recurrent versus first-ever stroke . In the Copenhagen Stroke Study , we prospect ively studied 1,138 unselected patients with acute stroke . Stroke was recurrent in 265 ( 23 % ) despite most of these patients being given prophylactic treatment prior to recurrence . Only 12 % of patients with atrial fibrillation were receiving anticoagulant treatment prior to recurrence . In multivariate analysis , recurrence was more frequently associated with a history of TIA , atrial fibrillation , male gender , and hypertension , but not with age , daily alcohol consumption , smoking , diabetes , ischemic heart disease , serum cholesterol , or hematocrit . Mortality was almost doubled compared with patients with a first-ever stroke . In survivors , however , both neurologic and functional outcomes and the speed of recovery were , in general , similar in the two groups . Despite similar neurologic impairments , patients with recurrence contralateral to their first stroke had markedly more severe functional disability after completed rehabilitation than patients with ipsilateral recurrence , implying that the ability to compensate functionally is decreased in patients with contralateral recurrence . Our findings emphasize the importance of consistent anticoagulant treatment for stroke patients with atrial fibrillation and close blood pressure control in stroke patients with hypertension . Other prophylactic measures are needed in patients in whom ASA fails to prevent recurrence . Patients with recurrent stroke have a markedly higher mortality than patients with a first-ever stroke , but those who survive recover as well and as fast as patients with a first-ever stroke . However , if recurrence is contralateral to the first stroke , functional recovery is poorer A cooperative clinical investigation was undertaken in 17 Veterans Administration Hospitals to determine the effects of long-term therapy with conjugated equine estrogens ( Premarin ) in prevention of recurrent cerebral infa rct ion or death due to atherosclerotic vascular disease . To date , 582 men with cerebral infa rct ion have been assigned on a r and om basis to either the treatment or control groups and observed for periods as long as 34 months . Initial treatment consisted of 1.25 mg . of Premarin daily and was increased to 2.5 mg . after the first year . Estrogenic therapy failed to reduce the incidence of either cerebral or myocardial infa rct ion developing during the period of follow-up observation . There was likewise no significant change in the mortality rate following onset of therapy . Of the 63 deaths in the study , 34 occurred in patients receiving treatment and 29 among those receiving the placebo preparation . Approximately 40 per cent of patients developed mild side reactions to the estrogenic agent , usually consisting of breast tenderness or enlargement , or both . These preliminary observations failed to demonstrate that treatment with conjugated equine estrogenic hormones in small and moderate dosages for an average period of 16.7 months had any value in lowering the recurrence of cerebral infa rct ion or reducing the mortality rate subsequent to this disorder CONTEXT Studies have demonstrated that statins administered to individuals with risk factors for coronary heart disease ( CHD ) reduce CHD events . However , many of these studies were too small to assess all-cause mortality or outcomes in important subgroups . OBJECTIVE To determine whether pravastatin compared with usual care reduces all-cause mortality in older , moderately hypercholesterolemic , hypertensive participants with at least 1 additional CHD risk factor . DESIGN AND SETTING Multicenter ( 513 primarily community-based North American clinical centers ) , r and omized , nonblinded trial conducted from 1994 through March 2002 in a subset of participants from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial ( ALLHAT ) . PARTICIPANTS Ambulatory persons ( n = 10 355 ) , aged 55 years or older , with low-density lipoprotein cholesterol ( LDL-C ) of 120 to 189 mg/dL ( 100 to 129 mg/dL if known CHD ) and triglycerides lower than 350 mg/dL , were r and omized to  pravastatin  ( n = 5170 ) or to  usual care  ( n = 5185 ) . Baseline mean total cholesterol was 224 mg/dL ; LDL-C , 146 mg/dL ; high-density lipoprotein cholesterol , 48 mg/dL ; and triglycerides , 152 mg/dL. Mean age was 66 years , 49 % were women , 38 % black and 23 % Hispanic , 14 % had a history of CHD , and 35 % had type 2 diabetes . INTERVENTION Pravastatin , 40 mg/d , vs usual care . MAIN OUTCOME MEASURES The primary outcome was all-cause mortality , with follow-up for up to 8 years . Secondary outcomes included nonfatal myocardial infa rct ion or fatal CHD ( CHD events ) combined , cause-specific mortality , and cancer . RESULTS Mean follow-up was 4.8 years . During the trial , 32 % of usual care participants with and 29 % without CHD started taking lipid-lowering drugs . At year 4 , total cholesterol levels were reduced by 17 % with pravastatin vs 8 % with usual care ; among the r and om sample who had LDL-C levels assessed , levels were reduced by 28 % with pravastatin vs 11 % with usual care .  All-cause mortality was similar for the 2 groups ( relative risk [ RR ] , 0.99 ; 95 % confidence interval [ CI ] , 0.89 - 1.11 ; P = .88 ) , with 6-year mortality rates of 14.9 % for pravastatin vs 15.3 % with usual care .  CHD event rates were not significantly different between the groups ( RR , 0.91 ; 95 % CI , 0.79 - 1.04 ; P = .16 ) , with 6-year CHD event rates of 9.3 % for pravastatin and 10.4 % for usual care . CONCLUSIONS Pravastatin did not reduce either all-cause mortality or CHD significantly when compared with usual care in older participants with well-controlled hypertension and moderately elevated LDL-C. The results may be due to the modest differential in total cholesterol ( 9.6 % ) and LDL-C ( 16.7 % ) between pravastatin and usual care compared with prior statin trials supporting cardiovascular disease prevention BACKGROUND Lower blood cholesterol concentrations have consistently been found to be strongly associated with lower risks of coronary disease but not with lower risks of stroke . Despite this observation , previous r and omised trials had indicated that cholesterol-lowering statin therapy reduces the risk of stroke , but large-scale prospect i ve confirmation has been needed . METHODS 3280 adults with cerebrovascular disease , and an additional 17256 with other occlusive arterial disease or diabetes , were r and omly allocated 40 mg simvastatin daily or matching placebo . Subgroup analyses were prespecified of first " major vascular event " ( ie , non-fatal myocardial infa rct ion or coronary death , stroke of any type , or any revascularisation procedure ) in prior disease subcategories . Subsidiary outcomes included any stroke , and stroke sub-type . Comparisons are of all simvastatin-allocated versus all placebo-allocated participants ( ie , " intention-to-treat " ) , which yielded an average difference in LDL cholesterol of 1.0 mmol/L ( 39 mg/dL ) during the 5-year treatment period . FINDINGS Overall , there was a highly significant 25 % ( 95 % CI 15 - 34 ) proportional reduction in the first event rate for stroke ( 444 [ 4.3 % ] simvastatin vs 585 [ 5.7 % ] placebo ; p<0.0001 ) , reflecting a definite 28 % ( 19 - 37 ) reduction in presumed ischaemic strokes ( p<0.0001 ) and no apparent difference in strokes attributed to haemorrhage ( 51 [ 0.5 % ] vs 53 [ 0.5 % ] ; rate ratio 0.95 [ 0.65 - 1.40 ] ; p=0.8 ) . In addition , simvastatin reduced the numbers having transient cerebral ischaemic attacks alone ( 2.0 % vs 2.4 % ; p=0.02 ) or requiring carotid endarterectomy or angioplasty ( 0.4 % vs 0.8 % ; p=0.0003 ) . The reduction in stroke was not significant during the first year , but was already significant ( p=0.0004 ) by the end of the second year . Among patients with pre-existing cerebrovascular disease there was no apparent reduction in the stroke rate , but there was a highly significant 20 % ( 8 - 29 ) reduction in the rate of any major vascular event ( 406 [ 24.7 % ] vs 488 [ 29.8 % ] ; p=0.001 ) . The proportional reductions in stroke were about one-quarter in each of the other subcategories of participant studied , including : those with coronary disease or diabetes ; those aged under or over 70 years at entry ; and those presenting with different levels of blood pressure or lipids ( even when the pretreatment LDL cholesterol was below 3.0 mmol/L [ 116 mg/dL ] ) . INTERPRETATION Much larger numbers of people in the present study suffered a stroke than in any previous cholesterol-lowering trial . The results demonstrate that statin therapy rapidly reduces the incidence not only of coronary events but also of ischaemic strokes , with no apparent effect on cerebral haemorrhage , even among individuals who do not have high cholesterol concentrations . Allocation to 40 mg simvastatin daily reduced the rate of ischaemic strokes by about one-quarter and so , after making allowance for non-compliance in the trial , actual use of this regimen would probably reduce the stroke rate by about a third . HPS also provides definitive evidence that statin therapy is beneficial for people with pre-existing cerebrovascular disease , even if they do not already have manifest coronary disease BACKGROUND Statins reduce the incidence of strokes among patients at increased risk for cardiovascular disease ; whether they reduce the risk of stroke after a recent stroke or transient ischemic attack ( TIA ) remains to be established . METHODS We r and omly assigned 4731 patients who had had a stroke or TIA within one to six months before study entry , had low-density lipoprotein ( LDL ) cholesterol levels of 100 to 190 mg per deciliter ( 2.6 to 4.9 mmol per liter ) , and had no known coronary heart disease to double-blind treatment with 80 mg of atorvastatin per day or placebo .  The primary end point was a first nonfatal or fatal stroke . RESULTS The mean LDL cholesterol level during the trial was 73 mg per deciliter ( 1.9 mmol per liter ) among patients receiving atorvastatin and 129 mg per deciliter ( 3.3 mmol per liter ) among patients receiving placebo . During a median follow-up of 4.9 years , 265 patients ( 11.2 percent ) receiving atorvastatin and 311 patients ( 13.1 percent ) receiving placebo had a fatal or nonfatal stroke ( 5-year absolute reduction in risk , 2.2 percent ; adjusted hazard ratio , 0.84 ; 95 percent confidence interval , 0.71 to 0.99 ; P=0.03 ; unadjusted P=0.05 ) . The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes , whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes . The five-year absolute reduction in the risk of major cardiovascular events was 3.5 percent ( hazard ratio , 0.80 ; 95 percent confidence interval , 0.69 to 0.92 ; P=0.002 ) . The overall mortality rate was similar , with 216 deaths in the atorvastatin group and 211 deaths in the placebo group ( P=0.98 ) , as were the rates of serious adverse events . Elevated liver enzyme values were more common in patients taking atorvastatin . CONCLUSIONS In patients with recent stroke or TIA and without known coronary heart disease , 80 mg of atorvastatin per day reduced the overall incidence of strokes and of cardiovascular events , despite a small increase in the incidence of hemorrhagic stroke . ( Clinical Trials.gov number , NCT00147602 [ Clinical Trials.gov ] . ) Evidence suggests that statin therapy reduces the risk of stroke in patients with coronary heart disease ( CHD ) , but its benefit for patients with cerebrovascular disease and no history of CHD remains uncertain . The Stroke Prevention by Aggressive Reduction in Cholesterol Levels ( SPARCL ) Study is a prospect i ve , multi-centre , double-blind , r and omised , placebo-controlled trial design ed to evaluate the effects of atorvastatin 80 mg/day in patients who previously experienced a stroke or transient ischaemic attack , but who have no known CHD . A total of 4,732 patients have been enrolled , and the data collection phase of the study is expected to be completed by October 2004 . SPARCL is the first study primarily design ed to prospect ively evaluate the effect of statin treatment  in secondary stroke prevention
target: There is evidence that statin therapy in patients with a history of ischaemic stroke or TIA significantly reduces subsequent major coronary events but only marginally reduces the risk of stroke recurrence .
  There is no clear evidence of beneficial effect from statins in those with previous haemorrhagic stroke and it is unclear whether statins should be started immediately post stroke or later .
background: BACKGROUND Studies have shown that interventions which reduce total and low-density lipoprotein cholesterol levels also reduce coronary heart disease ( CHD ) and stroke events in those with a history of CHD .
  However , it is uncertain whether treatment to alter cholesterol levels can prevent recurrence of either stroke or subsequent cardiovascular events and whether differences in outcomes exist between classes of lipid-lowering therapy .
  This is an up date of a Cochrane review first published in 2002 .
  OBJECTIVES To investigate the effect of altering serum lipids pharmacologically for preventing subsequent cardiovascular disease and stroke recurrence in patients with a history of stroke .