AHA/ASA Guideline Guidelines for the Prevention of Stroke in ...

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Furie et al Prevention of Stroke in Patients With Stroke and TIA 245forms of native valvular heart disease and in patients withmechanical and biological heart valve prostheses must bebalanced against the risk of bleeding.Rheumatic Mitral Valve DiseaseRecurrent embolism occurs in 30% to 65% of patients withrheumatic mitral valve disease who have a history of aprevious embolic event. 256–259 Between 60% and 65% ofthese recurrences develop within the first year, 256,257 mostwithin 6 months. Mitral valvuloplasty does not seem toeliminate the risk of thromboembolism 260,261 ; therefore, successfulvalvuloplasty does not eliminate the need for anticoagulationin patients requiring long-term anticoagulationpreoperatively. Although not evaluated in randomized trials,multiple observational studies have reported that long-termanticoagulant therapy effectively reduces the risk of systemicembolism in patients with rheumatic mitral valve disease. 262–265Long-term anticoagulant therapy in patients with mitralstenosis who had left atrial thrombus identified by TEE hasbeen shown to result in the disappearance of the left atrialthrombus. 266 The ACC/AHA Task Force on Practice Guidelineshas published guidelines for the management of patientswith valvular heart disease. 267The safety and efficacy of combining antiplatelet andanticoagulant therapy have not been evaluated in patientswith rheumatic valve disease. On the basis of extrapolationfrom similar patient populations, it is clear that combinationtherapy increases bleeding risk. 268,269Mitral Valve ProlapseMitral valve prolapse (MVP) is the most common form ofvalve disease in adults. 270 Although generally innocuous, it issometimes symptomatic, and thromboembolic phenomenahave been reported in patients with MVP in whom no othersource could be found. 271–275 However, more recentpopulation-based prospective studies, such as the FraminghamHeart Study, have failed to clearly identify an increasedrisk of stroke. 276,277No randomized trials have addressed the efficacy ofantithrombotic therapies for this specific subgroup of strokeor TIA patients.Mitral Annular CalcificationMAC, 278 which is predominantly found in women, is sometimesassociated with significant mitral regurgitation and isan uncommon nonrheumatic cause of mitral stenosis. Althoughthe incidence of systemic and cerebral embolism isnot clear, 279–284 thrombus has been found at autopsy onheavily calcified annular tissue, and echogenic densities havebeen identified in the LV outflow tract in patients with MACwho experience cerebral ischemic events. 280,282 Aside fromthe risk of thromboembolism, spicules of fibrocalcific materialmay embolize from the calcified mitral annulus. 279,281,283The relative frequencies of calcific and thrombotic embolismare unknown. 279,284There has been uncertainty whether MAC is an independentrisk factor for stroke. In a recent cohort study of AmericanIndians, MAC was found to be a strong risk factor for stroke,even after adjustment for other risk factors. 273 A cross-sectionalstudy of patients referred for TEE for evaluation of cerebralischemia found that MAC was significantly associated withproximal and distal complex aortic atheroma. 285There are no relevant data comparing the safety andefficacy of anticoagulant therapy versus antiplatelet therapyin patients with TIA or stroke.Aortic Valve DiseaseClinically detectable systemic embolism in isolated aorticvalve disease is increasingly recognized as due to microthrombior calcific emboli. 286 In the absence of associatedmitral valve disease or AF, systemic embolism in patientswith aortic valve disease is uncommon. No randomized trialsof selected patients with stroke and aortic valve disease exist,so recommendations are based on the evidence from largerantiplatelet trials of stroke and TIA patients.Recommendations1. For patients with ischemic stroke or TIA who haverheumatic mitral valve disease, whether or not AF ispresent, long-term warfarin therapy is reasonablewith an INR target range of 2.5 (range, 2.0 to 3.0)(Class IIa; Level of Evidence C).2. To avoid additional bleeding risk, antiplatelet agentsshould not be routinely added to warfarin (Class III;Level of Evidence C).3. For patients with ischemic stroke or TIA and nativeaortic or nonrheumatic mitral valve disease who donot have AF, antiplatelet therapy may be reasonable(Class IIb; Level of Evidence C).4. For patients with ischemic stroke or TIA and mitralannular calcification, antiplatelet therapy may beconsidered (Class IIb; Level of Evidence C).5. For patients with MVP who have ischemic stroke orTIAs, long-term antiplatelet therapy may be considered(Class IIb; Level of Evidence C) (Table 8).E. Prosthetic Heart ValvesEvidence that oral anticoagulants are effective in preventingthromboembolism in patients with prosthetic heart valvescomes from a trial that randomized patients to either 6 monthswith warfarin of uncertain intensity versus 2 different aspirincontainingplatelet-inhibitor drug regimens. 287 Thromboemboliccomplications occurred significantly more frequently inthe antiplatelet groups than in the anticoagulation group(event rates were 8% to 10% per patient-year in the antiplateletgroups versus 2% per year in the anticoagulation group).The incidence of bleeding was higher in the warfarin group.Other studies yielded variable results depending on the typeand location of the prosthesis, the intensity of anticoagulation,and the addition of platelet inhibitor medication; nonespecifically addressed secondary stroke prevention.In 2 randomized studies, concurrent treatment with dipyridamoleand warfarin reduced the incidence of systemicembolism in patients with prosthetic heart valves. 288,289 Anothertrial showed that the addition of aspirin 100 mg/d towarfarin (INR 3.0 to 4.5) improved efficacy compared withwarfarin alone. 290 This combination of low-dose aspirin andhigh-intensity warfarin was associated with a reduced allcausemortality, cardiovascular mortality, and stroke at theexpense of increased minor bleeding; the difference in majorDownloaded from stroke.ahajournals.org by on March 8, 2011
246 Stroke January 2011bleeding, including cerebral hemorrhage, did not reach statisticalsignificance.Bioprosthetic valves are associated with a lower rate ofthromboembolism than mechanical valves. In patients withbioprosthetic valves who have an otherwise unexplainedischemic stroke or TIA, oral anticoagulation (INR 2.0 to 3.0)is suggested.Recommendations1. For patients with ischemic stroke or TIA who havemechanical prosthetic heart valves, warfarin is recommendedwith an INR target of 3.0 (range, 2.5 to3.5) (Class I; Level of Evidence B).2. For patients with mechanical prosthetic heart valveswho have an ischemic stroke or systemic embolismdespite adequate therapy with oral anticoagulants,aspirin 75 mg/d to 100 mg/d in addition to oralanticoagulants and maintenance of the INR at atarget of 3.0 (range, 2.5 to 3.5) is reasonable if thepatient is not at high bleeding risk (eg, history ofhemorrhage, varices, or other known vascularanomalies conveying increased risk of hemorrhage,coagulopathy) (Class IIa; Level of Evidence B).3. For patients with ischemic stroke or TIA who havebioprosthetic heart valves with no other source ofthromboembolism, anticoagulation with warfarin(INR 2.0 to 3.0) may be considered (Class IIb; Levelof Evidence C) (Table 8).IV. Antithrombotic Therapy forNoncardioembolic Stroke or TIA (Specifically,Atherosclerotic, Lacunar, orCryptogenic Infarcts)A. Antiplatelet AgentsFour antiplatelet drugs have been approved by the FDA forprevention of vascular events among patients with a stroke orTIA: aspirin, combination aspirin/dipyridamole, clopidogrel,and ticlopidine. On average, these agents reduce the relativerisk of stroke, MI, or death by about 22%, 291 but importantdifferences exist between agents that have direct implicationsfor therapeutic selection.AspirinAspirin prevents stroke among patients with a recent stroke orTIA. 233,292–294 In a meta-regression analysis of placebocontrolledtrials of aspirin therapy for secondary strokeprevention, the relative risk reduction for any type of stroke(hemorrhagic or ischemic) was estimated at 15% (95% CI,6% to 23%). 295 The magnitude of the benefit is similar fordoses ranging from 50 mg to 1500 mg, 233,291,292,294–296 althoughthe data for doses 75 mg are limited. 291 In contrast,toxicity does vary by dose; the principal toxicity of aspirin isgastrointestinal hemorrhage, and higher doses of aspirin areassociated with greater risk. 292,294 For patients who uselow-dose aspirin (325 mg) for prolonged intervals, theannual risk of serious gastrointestinal hemorrhage is about0.4%, which is 2.5 times the risk for nonusers. 292,294,297,298Aspirin therapy is associated with an increased risk ofhemorrhagic stroke that is smaller than the risk for ischemicstroke, resulting in a net benefit. 299TiclopidineTiclopidine is a platelet adenosine diphosphate (ADP) receptorantagonist that has been evaluated in 3 randomized trialsof patients with cerebrovascular disease. 300–302 The CanadianAmerican Ticlopidine Study (CATS) compared ticlopidine(250 mg twice a day) with placebo for prevention of stroke,MI, or vascular death in 1053 patients with ischemicstroke. 302 After a mean follow-up duration of 2 years, patientsassigned to ticlopidine therapy had fewer outcomes per year(11.3% compared with 14.8%; relative risk reduction [RRR],23%; 95% CI, 1% to 41%). The Ticlopidine Aspirin StrokeStudy (TASS) compared ticlopidine 250 mg twice a day withaspirin 650 mg twice a day in 3069 patients with recent minorstroke or TIA. 301 After 3 years, patients assigned to ticlopidinehad a lower rate for the primary outcome of stroke ordeath (17% compared with 19%; RRR, 12%; 95% CI, 2% to26%; P0.048 by Kaplan-Meier estimates). Finally, theAfrican American Antiplatelet Stroke Prevention Study enrolled1809 black patients with recent noncardioembolicischemic stroke who were allocated to receive ticlopidine 250mg twice a day or aspirin 325 mg twice a day. 300 The studyfound no difference in risk of the combination of stroke, MI,or vascular death at 2 years. Side effects of ticlopidine includediarrhea and rash. Rates of gastrointestinal bleeding arecomparable or less than with aspirin. Neutropenia occurred in2% of patients treated with ticlopidine in CATS and TASS;however, it was severe in about 1% and was almost alwaysreversible with discontinuation. Thrombotic thrombocytopenicpurpura has also been described. 303ClopidogrelAnother platelet ADP receptor antagonist, clopidogrel, becameavailable after aspirin, combination aspirin/dipyridamole,and ticlopidine were each shown to be effective forsecondary stroke prevention. As a single agent, clopidogrelhas been tested for secondary stroke prevention in 2 trials,one comparing it with aspirin 298 alone and one comparing itwith combination aspirin/dipyridamole. 304 In each trial, ratesof primary outcomes were similar between the treatmentgroups. Clopidogrel has not been compared with placebo forsecondary stroke prevention. 305Clopidogrel was compared with aspirin alone in the Clopidogrelversus Aspirin in Patients at Risk of Ischemic Events(CAPRIE) trial. 298 More than 19 000 patients with stroke, MI,or peripheral vascular disease were randomly assigned toaspirin 325 mg/d or clopidogrel 75 mg/d. The annual rate ofischemic stroke, MI, or vascular death was 5.32% amongpatients assigned to clopidogrel compared with 5.83% amongpatients assigned to aspirin (RRR, 8.7%; 95% CI, 0.3 to 16.5;P0.043). Notably, in a subgroup analysis of patients whoentered CAPRIE after a stroke, the effect of clopidogrel wassmaller and did not reach statistical significance. In thissubgroup the annual rate of stroke, MI, or vascular death was7.15% in the clopidogrel group compared with 7.71% in theaspirin group (RRR, 7.3%; 95% CI, 6% to 19%; P0.26).CAPRIE was not designed to determine if clopidogrel wasequivalent to aspirin among stroke patients.Clopidogrel was compared with combination aspirin andextended-release dipyridamole in the PRoFESS trial, whichDownloaded from stroke.ahajournals.org by on March 8, 2011
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