HMG Co-A reductase inhibitors (statins) are effective for primary prevention of ischemic stroke in people who have a history of occlusive artery disease, coronary artery disease, or diabetes without history of cerebrovascular disease (strength of recommendation [SOR]: A, based on 1 randomized controlled trial [RCT]). Statins reduce the risk of ischemic stroke in hypertensive patients with multiple cardiovascular risk factors and nonfasting total cholesterol <250 mg/dL (SOR: A, based on RCT). Statins also reduce the risk of ischemic stroke for patients with coronary disease or equivalents (such as diabetes or peripheral artery disease), including patients who have a normal fasting lipid profile (SOR: A, based on RCT). For patients with ischemic stroke who have coronary disease, statins prevent recurrent ischemic stroke; evidence is conflicting about whether this benefit is proportional to initial cholesterol levels (SOR: A, systematic review). Statins do not prevent hemorrhagic stroke (SOR: A, based on RCTs)

Busch, Naomi

Kelsberg, Gary

Kendall, Susan K.

University of Missouri: MOspace

C L I N I C A L  I N Q U I R I E SJULY 2004 / VOL 53, NO 7 · The Journal of Family Practice 575C O N T I N U E D■ CLINICAL COMMENTARY:When warfarin is started, aspirin should be stoppedThe lack of evidence to support the combineduse of aspirin and warfarin creates an excellentopportunity to remove an unnecessary drugfrom a patient’s medication list. Patients whowere taking aspirin for thrombosis prophylaxisoccasionally develop atrial fibrillation. Manypatients who take aspirin for prophylaxis do sobecause they are already at moderate to highrisk for embolic stroke. The onset of atrial fib-rillation in these patients appropriately leads tothe initiation of warfarin. At the time of war-farin initiation, the aspirin should be stopped.By stopping the aspirin at the initiation of thewarfarin, one can reduce the number of med-ications that the patient must take, avoid theinteractions of aspirin and warfarin, and elimi-nate the side the effects of the aspirin.Rick Guthmann, MD, Illinois Masonic Family PracticeResidency, University of Illinois at ChicagoREFERENCES1. Peterson P, Boysen G, Godtfredsen J, et al. Placebo-controlled,randomized trial of warfarin and aspirin for prevention ofthromboembolic complications in chronic atrial fibrillation:the Copenhagen AFASAK Study. Lancet 1989; 1:175–179.2. The Stroke Prevention in Atrial Fibrillation Investigators.The stroke prevention in atrial fibrillation study: finalresults. Circulation 1991; 84:527–539.3. The Boston Area Anticoagulation Trial for AtrialFibrillation Investigators. The effect of low-dose warfarinon the risk of stroke in patients with nonrheumatic atrialfibrillation. N Eng J Med 1990; 323:1505–1511.4. Connolly SJ, Laupacis A, Gent M, et al. Canadian AtrialFibrillation Anticoagulation (CAFA) Study. J Am CollCardiol 1991; 18:349–355.5. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin inthe prevention of stroke associated with nonrheumaticatrial fibrillation: Veterans Affairs Stroke Prevention inNonrheumatic Atrial Fibrillation Investigators. N Eng JMed 1992; 327:1406–1412.6. Atrial Fibrillation Investigators. Risk factors for strokeand efficacy of antithrombotic therapy in atrial fibrillation.Arch Intern Med 1994; 154:1449–1457. 7. Secondary prevention in non-rheumatic atrial fibrillationafter transient ischemic attack or minor stroke: EAFT(European Atrial Fibrillation Trial) study group. Lancet1993; 342:1255–1262.8. Atrial Fibrillation Investigators. The efficacy of aspirin inpatients with atrial fibrillation: analysis of pooled datafrom three randomized trials. Arch Intern Med 1997;157:1237–1240.9. The Stroke Prevention in Atrial Fibrillation Investigators.Adjusted-dose warfarin versus low-intensity, fixed-dosewarfarin plus aspirin for high-risk patients with atrial fib-rillation: Stroke Prevention in Atrial Fibrillation III ran-domized clinical trial. Lancet 1996; 348:633–638.10. Gullov AL, Koefoed BG, Petersen P, et al. Fixed minidose war-farin and aspirin alone and in combination vs adjusted-dosewarfarin for stroke prevention in atrial fibrillation, SecondCopenhagen Atrial Fibrillation, Aspirin, and AnticoagulationStudy. Arch Intern Med 1998; 158:1513–1521.11. Pengo V, Zasso A, Barbero F, et al. Effectiveness of fixed-dose minidose warfarin in the prevention of thromboem-bolism and vascular death in nonrheumatic atrial fibrilla-tion. Am J Cardiol 1998; 82:433–437.12. Hylek EM, Go AS, Chang Y, et al. Effect of intensity of oralanticoagulation on stroke severity and mortality in atrialfibrillation. N Eng J Med 2003; 349:1019–1026.13. Hirsh J, Fuster V, Ansell J, et al. American Heart Association/American College of Cardiology Foundationguide to warfarin therapy. Circulation 2003; 107:1692–1711.14. Albers GW, Dalen JE, Laupacis A, et al. Antithrombotic ther-apy in atrial fibrillation. Chest 2001; 119(Suppl 1):194S.Do statins reduce the risk of stroke?■ EVIDENCE-BASED ANSWERHMG Co-A reductase inhibitors (statins) are effec-tive for primary prevention of ischemic stroke inpeople who have a history of occlusive artery dis-ease, coronary artery disease, or diabetes withouthistory of cerebrovascular disease (strength ofrecommendation [SOR]: A, based on 1 random-ized controlled trial [RCT]).Statins reduce the risk of ischemic stroke inhypertensive patients with multiple cardiovascu-lar risk factors and nonfasting total cholesterol<250 mg/dL (SOR: A, based on RCT). Statins alsoreduce the risk of ischemic stroke for patientswith coronary disease or equivalents (such as dia-betes or peripheral artery disease), includingpatients who have a normal fasting lipid profile(SOR: A, based on RCT). For patients withischemic stroke who have coronary disease,statins prevent recurrent ischemic stroke; evi-dence is conflicting about whether this benefit isproportional to initial cholesterol levels (SOR: A,systematic review). Statins do not prevent hemor-rhagic stroke (SOR: A, based on RCTs).C L I N I C A L  I N Q U I R I E S576 JULY 2004 / VOL 53, NO 7 · The Journal of Family PracticeC O N T I N U E D■ EVIDENCE SUMMARYWe found no studies evaluating statins for the pri-mary prevention of stroke. An observational studyof 433 patients with ischemic stroke found thatpatients who were taking statins before hospitaladmission more often had better outcomes (51%)than those who were not taking statins (38%).However, the groups differed in many respects.1Many coronary event prevention and treatmenttrials using statins include the risk of primary andrecurrent ischemic stroke as secondary endpointsfor patients with high cardiac risk. Primary prevention of stroke in vascular disease. The Heart Protection Study followed20,536 patients in the United Kingdom (aged40–80 years), 3280 with a history of cerebrovas-cular disease (defined as nondisabling stroke,transient cerebral ischemic attack, or carotidendarterectomy or angioplasty) and 17,256 withother occlusive arterial disease, coronary arterydisease, or diabetes. Patients were randomized toreceive either simvastatin 40 mg or placebo for anaverage of 5 years. The endpoint was major vas-cular events: myocardial infarction, stroke of anytype, and revascularization procedure. Simvastatin reduced the combined risk of non-fatal or fatal ischemic stroke for patients with nohistory of cerebrovascular disease (3.2% for sim-vastatin vs 4.8% with placebo; relative risk reduc-tion=33%, number needed to treat [NNT]=63;P=.0001).2 As noted in other well-done studies, theHeart Protection Study showed no difference in thenumber of hemorrhagic strokes between treatmentand placebo groups. There were 3500 subjects withpretreatment low-density lipoprotein (LDL) choles-terol <100 mg/dL; lowering LDL to 65 mg/dLreduced major vascular event risk by about 25%.3Hypertension with multiple cardiovascularrisk factors and cholesterol <250 mg/dL. TheASCOT-LLA study compared atorvastatin withplacebo in 10,305 hypertensive Caucasianpatients with multiple cardiovascular risk fac-tors and a total nonfasting cholesterol of 250mg/dL (6.5 mmol/L) or less. Patients were aged40 to 79 years and had at least 3 other cardio-vascular risk factors (left ventricular hypertro-phy, abnormal electrocardiogram, type 2 dia-betes, peripheral artery disease, stroke or tran-sient ischemic attack, male sex, age >55 years,proteinuria or microalbuminuria, smoking, fam-ily history of premature coronary heart disease).The study was stopped early at a median of 3.3years because atorvastatin significantly reducedcardiac events. Atorvastatin also significantlyreduced ischemic strokes when compared withplacebo (relative risk [RR]=0.73, 95% confi-dence interval [CI], 0.56–0.96; P=.024). Thisstudy did not differentiate between first or sec-ond stroke. The NNT was 155.4Ischemic stroke and coronary disease. TheLIPID trial randomized 9014 patients with ahistory of acute coronary syndromes and totalcholesterol of 150 to 270 mg/dL (4 to 7 mmol/L)to either pravastatin or placebo and followedthem for 6 years. Among the 350 patients withprior ischemic stroke, there were 388 newischemic stokes over the course of the study.When adjusted for risk factors (atrial fibrilla-tion, history of cerebrovascular accident, dia-betes, hypertension, cigarette smoking, bodymass index, and male sex), pravastatin reducedrecurrent ischemic stroke by 21% relative toplacebo (P=.024). The reduction was not modi-fied by baseline lipid level.5A meta-analysis of 15 randomized placebo-controlled trials using various statins (32,684participants) assessed the risk of strokes forpatients with a history of coronary disease.Among patients who had cerebrovascular dis-ease, statins significantly reduced recurrentischemic stroke (RR=0.74; 95% CI, 0.64–0.86).One recurrence of ischemic stroke would be pre-vented for every 110 coronary disease patientstreated with a statin. Achieving final total cho-lesterol <232 mg/dL correlated with reducedStatins reduce the risk of ischemicstroke for patients with coronarydisease or equivalentsC L I N I C A L  I N Q U I R I E SJULY 2004 / VOL 53, NO 7 · The Journal of Family Practice 577C O N T I N U E Drisk of recurrent stroke.6 Three of the studiesevaluated primary prevention of stroke and didnot show a significant risk reduction (RR=0.85;P=.4). Statins did not reduce the rate of hemor-rhagic stroke or fatal strokes. Risks of statins. In 1 study involving 35,000participants and 158,000 person-years of observa-tion, there were 8 cases of rhabdomyolysis in thetreatment groups vs 5 in the placebo groups.7Forty-three deaths attributed to statin therapyhave been reported to the Food and DrugAdministration from 1987 to 2001, or 1 per mil-lion person-years of use. The Heart ProtectionStudy found simvastatin and placebo users report-ed myopathy or muscle pain at the same annualrate of 0.01%.■ RECOMMENDATIONS FROM OTHERSWe found no recommendations specificallyregarding the use of statins to prevent stroke.However, the Third Report of the NationalCholesterol Education Program, Adult TreatmentPanel III (NCEP-ATP III) describes symptomaticcarotid artery disease as a coronary heart diseaserisk equivalent and recommends therapy toreduce the LDL below 100 mg/dL.8Naomi Busch, MD, Gary Kelsberg, MD,Valley Family Medicine, Renton, WA; Susan K. Kendall,PhD, MSLIS, Michigan State UniversityREFERENCES1. Yoon SS, Dambrosia J, Chalela J, Ezzeddine M, Warach S,Haymore J, Davis L, Baird AE. Rising statin use and effecton ischemic stroke outcome. BMC Med 2004; 2:4.Available at: www.biomedcentral.com/1741-7015/2/4.Accessed on April 8, 2004.2. Collins R, Armitage J, Parish S, Sleight P, Peto R, HeartProtection Study Collaborative Group. Effects of choles-terol-lowering with simvastatin on stroke and other majorvascular events in 20,536 people with cerebrovasculardisease or other high-risk conditions. Lancet 2004;363:757–767.3. Heart Protection Study Collaborative Group. MRC/BHFHeart Protection Study of cholesterol lowering with sim-vastatin in 20,536 high-risk individuals: a randomisedplacebo-controlled trial. Lancet 2002; 360:7–22.4. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G,Caulfield M et al. Prevention of coronary and strokeevents with atorvastatin in hypertensive patients whohave average or lower-than-average cholesterol concen-trations, in the Anglo-Scandinavian Cardiac OutcomesTrial – Lipid Lowering Arm (ASCOT-LLA): a multicentrerandomised controlled trial. Lancet 2003; 361:1149–1158.5. West MJ, White HD, Simes RJ, Kirby A, Watson JD,Anderson NE et al. Risk factors for non-haemorrhagicstroke in patients with coronary heart disease and theeffect of lipid-modifying therapy with pravastatin. J Hypertens 2002; 20:2513–2517.6. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P,Lechat P. Differential effects of lipid-lowering therapies onstroke prevention: a meta-analysis of randomized trials.Arch Intern Med 2003; 163:669–676.7. Law MR, Wald NJ, Rudnicka AR. Quantifying effect ofstatins on low-density lipoprotein cholesterol, ischaemicheart disease, and stroke: systematic review and meta-analysis. BMJ 2003; 326:1423–1427.8. National Cholesterol Education Program. Third Report ofthe Expert Panel on Detection, Evaluation, and Treatment ofHigh Blood Cholesterol in Adults. NIH Pub. No. 02-5215.Bethesda, Md: National Heart, Lung, and Blood Institute;2002.9. Corvol JC, Bouzamondo A, Sirol M, Hulot JS, Sanchez P,Lechat P. Differential effects of lipid-lowering therapies onstroke prevention: a meta-analysis of randomized trials.Arch Intern Med 2003; 163:669–676.■ CLINICAL COMMENTARY:Statins prevent cerebrovascular accidentsand have low adverse event ratesStatins are effective for primary and tertiarycardiovascular disease prevention. For thosewith vascular disease or significant risks,statins prevent cerebrovascular accidents andhave low adverse event rates. While no evidence is available about pri-mary prevention of cerebrovascular accidents forthose at lower risk, in practice statins are oftenappropriately initiated. NCEP-ATP III,8 the keyguideline on when to start statins, is basedmore on cardiac benefits. Most studies evaluat-ing statins use a triple outcome of mortality,myocardial infarction, or cerebrovascular acci-dent. Since myocardial infarction is more com-mon than the other adverse endpoints, there isa greater demonstrated cardioprotective effect(prevention of myocardial infarction: NNT=95;prevention of cerebrovascular accidents:NNT=735).9 However, regardless of whetherthe benefits are cardiac or cerebrovascular,statins will prevent disease for many patients.Alex Krist, MD, Fairfax Family Practice Residency,Virginia Commonwealth University, Fairfax

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