Adjusted-dose warfarin (international normalized ratio [INR]=2.0-3.0) remains the most efficacious antithrombotic regimen for the primary and secondary prevention of cardioembolic stroke in high-risk patients with nonvalvular atrial fibrillation (NVAF) (strength of recommendation [SOR]: A, based on randomized controlled trials). Aspirin therapy at a dose of 75 to 325 mg reduces the risk of stroke to a lesser degree and may be useful for low-risk patients with NVAF or patients at high risk for bleeding (SOR: A, based on randomized controlled trials). Combination therapy with low, fixed-dose warfarin (1-2 mg) and aspirin has not been shown to be superior to aspirin therapy alone. Moreover, this combination appears to be inferior to adjusted-dose warfarin (SOR: A, based on randomized controlled trials). To date, no clinical trials have investigated the efficacy and safety of combining adjusted-dose warfarin and aspirin for the prevention of stroke from NVAF

Mayer, Jill Byerly

Robertson, Sandy L.

University of Missouri: MOspace

C L I N I C A L  I N Q U I R I E S570 JULY 2004 / VOL 53, NO 7 · The Journal of Family PracticeC O N T I N U E DDoes combining aspirin andwarfarin decrease the risk ofstroke for patients withnonvalvular atrial fibrillation?■ EVIDENCE-BASED ANSWERAdjusted-dose warfarin (international normal-ized ratio [INR]=2.0–3.0) remains the most efficacious antithrombotic regimen for the primary and secondary prevention of cardio-embolic stroke in high-risk patients with nonvalvular atrial fibrillation (NVAF) (strengthof recommendation [SOR]: A, based on random-ized controlled trials). Aspirin therapy at a dose of 75 to 325 mgreduces the risk of stroke to a lesser degree andmay be useful for low-risk patients with NVAFor patients at high risk for bleeding (SOR: A,based on randomized controlled trials). Combination therapy with low, fixed-dosewarfarin (1–2 mg) and aspirin has not beenshown to be superior to aspirin therapy alone.Moreover, this combination appears to be inferi-or to adjusted-dose warfarin (SOR: A, based on randomized controlled trials). To date, noclinical trials have investigated the efficacy and safety of combining adjusted-dose warfarinand aspirin for the prevention of stroke fromNVAF. ■ EVIDENCE SUMMARYThromboprophylaxis with warfarin for patientswith NVAF has been studied in 5 major clinicaltrials.1–5 Pooled analysis with more than 2900patients revealed an annual stroke risk of 4.5%for control patients and 1.4% for patientsreceiving adjusted-dose warfarin (number need-ed to treat [NNT] for 1 year=32).6 Studies com-paring aspirin with placebo for treatment ofNVAF are less robust and have heterogeneousresults. Combined data from the AtrialFibrillation Aspirin Anticoagulation Study(AFASAK-1),1 the European Atrial FibrillationTrial,7 and the Stroke Prevention in AtrialFibrillation (SPAF) I studies2 revealed a smallbut statistically significant reduction in strokerates (relative risk reduction [RRR]=21%;8.1% vs 6.3% annual stroke rate; NNT=55),with no increase in major bleeding risk.8The SPAF III investigators further com-pared adjusted-dose warfarin with low-intensi-ty, fixed-dose warfarin plus aspirin in high-riskpatients with NVAF.9 An interim analysis at 1.1years revealed superiority in the reduction ofischemic strokes and systemic embolisms withadjusted-dose warfarin (7.9% vs 1.9% per year,respectively; NNT=16), which led to the trial’stermination. Rates of major hemorrhage didnot differ between treatment groups (2.4% peryear with combination vs 2.1% per year withwarfarin). Two similar studies published in 1998 wereterminated early, in light of the SPAF IIIresults. The Second Copenhagen AtrialFibrillation, Aspirin, and AnticoagulationStudy10 (AFASAK-2) completed 3 of the sched-uled 6 years; it compared warfarin 1.25 mg/d,warfarin 1.25 mg/d plus aspirin 300 mg,aspirin 300 mg alone, and adjusted-dose war-farin (INR=2.0–3.0) to treat NVAF for patientswith a median age of 74 years (range, 44–89).The cumulative stroke event rate after 1 yearwas 5.8% on fixed-dose warfarin, 7.2% on com-bination, 3.6% on aspirin, and 2.8% on adjust-ed-dose warfarin. The researchers concludedthat while the difference was not statisticallysignificant, adjusted-dose warfarin seemedsuperior to other treatments after 1 year.In a similar fashion, Pengo et al11 random-ized patients with NVAF aged >60 years tofixed-dose (1.25 mg/d) or adjusted-dose war-farin (INR=2.0–3.0) to evaluate ischemicstroke rates and major bleeding. This trialenrolled 303 patients who were followed up for14.5 months before discontinuation of the trial.The rate of ischemic stroke was significantlyhigher in the fixed-dose warfarin group com-pared with the adjusted warfarin group (3.7%C L I N I C A L  I N Q U I R I E S572 JULY 2004 / VOL 53, NO 7 · The Journal of Family PracticeC O N T I N U E Dvs 0% per year; NNT=27). Major bleeds weremore frequent in the adjusted warfarin group(2.6% vs 1% per year, number needed toharm=63). While the combined primary end-point did not show a significant benefit foradjusted-dose warfarin, this study suggests thatfixed-dose warfarin does not protect againstischemic stroke in NVAF patients. The intensity of warfarin therapy and strokeseverity has recently been studied for patientswith NVAF.12 A subtherapeutic INR (<2.0) on the day of admission was independently associ-ated with severe stroke (odds ratio=1.9; 95%confidence interval [CI], 1.1–3.4), and risk ofdeath at 30 days (hazard ratio, 3.4; 95% CI,1.1–10.1) compared with an INR of 2.0 orgreater. Furthermore, an admission INR of1.5–1.9 had a similar mortality rate (18%) as anINR of <1.5 (15%), and for those patients onaspirin (15%). These findings further support the impor-tance of achieving therapeutic INR goals forpatients with NVAF.■ RECOMMENDATIONS FROM OTHERSThe American Heart Association, the AmericanCollege of Cardiology,13 and the AmericanCollege of Chest Physicians (ACCP)14 recom-mend adjusted-dose warfarin for nonvalvularatrial fibrillation patients at high risk forischemic stroke. Risk stratification is a keycomponent in order to maximize efficacy whileminimizing bleeding risk. The Table summarizes the ACCP guidelines forprevention of ischemic stroke based on patientrisk factors. Sandy L. Robertson, PharmD, Cabarrus FamilyMedicine Residency Program, Northeast Medical Center,Concord, NC; Jill Byerly Mayer, MLIS, AHIP, HealthSciences Library, University of North Carolina–Chapel HillAppliACCP Stroke Prevention Guidelines 2001Atrial fibrillation stroke profile Risk factors Treatment guidelinesHigh risk One or more of the following: Warfarin (INR=2.5; range, 2–3)Age 75 yearsHistory of hypertensionCerebrovascular accident/transient ischemic attackArterial thromboembolismPoor left ventricular systolic dysfunction (ejection fraction <40%)Rheumatic mitral valve disease or prosthetic heart valve2 or more moderate risk factorsModerate risk No high risk factors and 1 of the following: Warfarin (INR=2.5, range, 2–3) orAge 65–74 years Aspirin 325 mg/dDiabetesCoronary artery diseaseLow risk No high or moderate risk factors and: Aspirin 325 mg/dAge <65 yearsINR, international normalized ratioTA B L EC 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).

Does combining aspirin and warfarin decrease the risk of stroke for patients with nonvalvular atrial fibrillation?

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