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 247was designed as a noninferiority study. Among 20 332patients with ischemic stroke who were followed for a meanof 2.5 years, recurrent stroke occurred among 9.0% ofparticipants assigned to aspirin/dipyridamole compared with8.8% assigned to clopidogrel (HR, 1.01; 95% CI, 0.92 to1.11). Because the upper bound of the confidence intervalcrossed the noninferiority margin (HR, 1.075), the investigatorsconcluded that the results failed to show that aspirin/dipyridamolewas not inferior to clopidogrel.Overall the safety of clopidogrel is comparable to that ofaspirin with only minor differences. 298 As with ticlopidine,diarrhea and rash are more frequent than with aspirin, butaside from diarrhea, gastrointestinal symptoms and hemorrhagesare less frequent. Neutropenia did not occur morefrequently among patients assigned to clopidogrel, comparedwith aspirin or placebo, in published trials, 298,306 but a fewcases of thrombotic thrombocytopenic purpura have beendescribed. 303 Recently, evidence has emerged that protonpump inhibitors (PPIs), such as esomeprazole, reduce theeffectiveness of clopidogrel. 307 Coadministration of clopidogrelwith a PPI may lead to increased risk for majorcardiovascular events, including stroke and MI. When antacidtherapy is required in a patient on clopidogrel, an H2 blockermay be preferable to a PPI if the PPI is metabolized at theCYP2C19 P-450 cytochrome site. 308 In addition, functionalgenetic variants in CYP genes can affect the effectiveness ofplatelet inhibition in patients taking clopidogrel. Carriers of atleast 1 CYP2C19 reduced-function allele had a relativereduction of 32% in plasma exposure to the active metaboliteof clopidogrel compared with noncarriers (P0.001). 309Dipyridamole and AspirinDipyridamole inhibits phosphodiesterase and augmentsprostacyclin-related platelet aggregation inhibition. The effectof dipyridamole combined with aspirin among patientswith TIA or stroke has been examined in 4 large randomizedclinical trials. Together these trials indicate that the combinationis at least as effective as aspirin alone for secondarystroke prevention but less well tolerated by patients.The first of the large trials was the European StrokePrevention Study (ESPS-1), 310 which randomly assigned2500 patients to placebo or the combination of 325 mg aspirinplus 75 mg immediate-release dipyridamole 3 times a day.After 24 months the rate of stroke or death was 16% amongpatients assigned to aspirin/dipyridamole compared with 25%among patients assigned to placebo (RRR, 33%; P0.001).The next large study was ESPS-2, which randomized 6602patients with prior stroke or TIA in a factorial design to 4groups: (1) aspirin 25 mg twice a day plus extended-releasedipyridamole 200 mg twice a day, (2) aspirin 25 mg twicedaily, (3) extended-release dipyridamole alone, and (4) placebo.311 Compared with placebo, risk of stroke was reducedby 18% with aspirin (P0.013), 16% with dipyridamole(P0.039), and 37% with the combination (P0.001). Comparedwith aspirin alone, combination therapy reduced therisk of stroke by 23% (P0.006) and stroke or death by 13%(P0.056). Bleeding was not significantly increased bydipyridamole, but headache and gastrointestinal symptomswere more common among the combination group. Theinterpretation of this study was complicated by problems indata quality reported by the investigators, a relatively lowdose of aspirin, and the choice of a placebo at a time whenaspirin was standard therapy in many countries.The third large trial, European/Australasian Stroke Preventionin Reversible Ischemia Trial (ESPRIT), used a prospective,randomized, open-label, blinded end point evaluationdesign to compare aspirin alone with aspirin plus dipyridamolefor prevention of stroke, MI, vascular death, or majorbleeding among men and women with a TIA or ischemicstroke within 6 months. 312 Although the dose of aspirin couldvary at the discretion of the treating physician from 30 mg to325 mg daily, the mean dose in each group was 75 mg.Among patients assigned to dipyridamole, 83% took theextended-release form and the rest took the immediatereleaseform. After 3.5 years the primary end point wasobserved in 13% of patients assigned to combination therapycompared with 16% among those assigned to aspirin alone(HR, 0.80; 95% CI, 0.66 to 0.98; absolute risk reduction[ARR], 1.0% per year; 95% CI, 0.1 to 1.8). In this open-labeltrial, bias in reporting of potential outcome events might haveoccurred if either patients or field researchers differentiallyreported potential vascular events to the coordinating center.The unexpected finding of a reduced rate of major bleeding inthe combination group (35 compared with 53 events) may bean indication of this bias. Finally, the investigators did notreport postrandomization risk factor management, which, ifdifferential, could partially explain differing outcome rates.The fourth trial was the PRoFESS study describedabove, 304 which showed no difference in stroke recurrencerates among patients assigned to clopidogrel compared withpatients assigned to combination dipyridamole and aspirin.Major hemorrhagic events were more common among patientsassigned to aspirin and extended-release dipyridamole(4.1% compared with 3.6%) but did not meet statisticalsignificance. Adverse events leading to drug discontinuation(16.4% compared with 10.6%) were more common amongpatients assigned to aspirin and extended-release dipyridamole.The combination therapy was shown to be less welltolerated than single antiplatelet therapy.Combination of Clopidogrel and AspirinThe effectiveness of clopidogrel 75 mg plus aspirin 75 mg,compared with clopidogrel 75 mg alone for prevention ofvascular events among patients with a recent TIA or ischemicstroke, was examined in the Management of Atherothrombosiswith Clopidogrel in High-Risk Patients with RecentTransient Ischemic Attacks or Ischemic Stroke (MATCH)trial. 313 A total of 7599 patients were followed for 3.5 yearsfor the occurrence of the primary composite outcome ofischemic stroke, MI, vascular death, or rehospitalization forany central or peripheral ischemic event. There was nosignificant benefit of combination therapy compared withclopidogrel alone in reducing the primary outcome or any ofthe secondary outcomes. The risk of major hemorrhage wassignificantly increased in the combination group comparedwith clopidogrel alone, with a 1.3% absolute increase inlife-threatening bleeding. Although clopidogrel plus aspirin isrecommended over aspirin for acute coronary syndromes, theDownloaded from stroke.ahajournals.org by on March 8, 2011
248 Stroke January 2011results of MATCH do not suggest a similar risk-benefit ratiofor patients with stroke and TIA who start therapy beyond theacute period.Combination clopidogrel and aspirin has been comparedwith aspirin alone in 2 secondary prevention trials: 1 small 314and 1 large. 315 Neither demonstrated a benefit from combinationtherapy. The Clopidogrel for High AtherothromboticRisk and Ischemic Stabilization, Management, and Avoidance(CHARISMA) trial 315 enrolled 15 603 patients withclinically evident cardiovascular disease or multiple riskfactors. After a median of 28 months the primary outcome(MI, stroke, or death due to cardiovascular causes) wasobserved in 6.8% of patients assigned to combination therapycompared with 7.3% assigned to aspirin (RR, 0.93; 95% CI,0.83 to 1.05; P0.22). An analysis among the subgroup ofpatients who entered after a stroke showed increased bleedingrisk but no statistically significant benefit of combinationtherapy compared with aspirin alone. The Fast Assessment ofStroke and Transient ischemic attack to prevent Early Recurrence(FASTER) trial 314 was designed to test the effectivenessof combination therapy compared with aspirin alone forpreventing stroke among patients with a TIA or minor strokewithin the previous 24 hours. The trial was stopped earlybecause of slow recruitment. Results were inconclusive.Selection of Oral Antiplatelet TherapyThe evidence described above indicates that aspirin, ticlopidine,and the combination of aspirin and dipyridamole areeach effective for secondary stroke prevention. No studieshave compared clopidogrel with placebo, and studies comparingit with other antiplatelet agents have not clearlyestablished that it is superior to or even equivalent to any oneof them. Observation of the survival curves from CAPRIEand PRoFESS indicate that it is probably as effective asaspirin and combination aspirin/dipyridamole, respectively.Selection among these 4 agents should be based on relativeeffectiveness, safety, cost, patient characteristics, and patientpreference. The combination of aspirin and dipyridamole maybe more effective than aspirin alone for prevention ofrecurrent stroke 311 and the combination of stroke, MI, death,or major bleeding. 312 On average, compared with aspirinalone, the combination may prevent 1 event among 100patients treated for 1 year. 312 Ticlopidine may be moreeffective than aspirin for secondary prevention, 301 but safetyconcerns limit its clinical value.Risk for gastrointestinal hemorrhage or other major hemorrhagemay be greater for aspirin or combination aspirin/dipyridamolethan for clopidogrel. 298,304 The difference issmall, however, amounting to 1 major hemorrhage event per500 patient-years. 304 The risk appears to be similar for aspirinat doses of 50 mg to 75 mg compared with the combinationof aspirin/dipyridamole. However, the combination of aspirin/dipyridamoleis less well tolerated than either aspirin orclopidogrel, primarily because of headache. Ticlopidine isassociated with thrombotic thrombocytopenic purpura andshould be used only cautiously in patients who cannot tolerateother agents.In terms of cost, aspirin is by far the least expensive agent.The cost of aspirin at acquisition is at least 20 times less thanany of the other 3 options.Patient characteristics that may affect choice of agentinclude tolerance of specific agents and comorbid illness. Forpatients who cannot tolerate aspirin because of allergy orgastrointestinal side effects, clopidogrel is an appropriatechoice. For patients who do not tolerate dipyridamole becauseof headache, either aspirin or clopidogrel is appropriate. Thecombination of aspirin and clopidogrel may be appropriatefor patients with acute coronary syndromes 306 or recentvascular stenting. 306,316Selection of Antiplatelet Agents for Patients WhoExperience a Stroke While on TherapyPatients who present with a first or recurrent stroke arecommonly already on antiplatelet therapy. Unfortunately,there have been no clinical trials to indicate that switchingantiplatelet agents reduces the risk for subsequent events.B. Oral AnticoagulantsRandomized trials have addressed the use of oral anticoagulantsto prevent recurrent stroke among patients with noncardioembolicstroke, including strokes caused by large-arteryextracranial or intracranial atherosclerosis, small penetratingartery disease, and cryptogenic infarcts. The Stroke Preventionin Reversible Ischemia Trial (SPIRIT) was stopped earlybecause of increased bleeding among those treated withhigh-intensity oral anticoagulation (INR 3.0 to 4.5) comparedwith aspirin (30 mg/d) in 1316 patients. 317,318 The trial wasthen reformulated as ESPRIT, using a medium-intensitywarfarin dose (INR 2.0 to 3.0) compared with either aspirinalone (30 mg to 325 mg daily) or aspirin plus extendedreleasedipyridamole 200 mg twice daily. The trial was againended early due to the superiority demonstrated by thecombination of aspirin and dipyridamole over aspirinalone. 312 Mean follow-up was 4.6 years and mean INRachieved was 2.57. Patients treated with warfarin experienceda significantly higher rate of major bleeding (HR, 2.56; 95%CI, 1.48 to 4.43) but lower rate, albeit not statisticallysignificant, in ischemic events (HR, 0.73; 95% CI, 0.52 to1.01) 319 compared with aspirin alone.The ESPRIT results confirmed those reported earlier by theWarfarin Aspirin Recurrent Stroke Study (WARSS), in whichwarfarin (INR 1.4 to 2.8) was compared with aspirin (325 mgdaily) among 2206 patients with a noncardioembolic stroke. 320This randomized, double-blind, multicenter trial found nosignificant difference between treatments for prevention ofrecurrent stroke or death (warfarin, 17.8%; aspirin, 16.0%). Incontrast to ESPRIT, rates of major bleeding were not significantlydifferent between the warfarin and aspirin groups(2.2% and 1.5% per year, respectively). A variety of subgroupswere evaluated, with no clear evidence of efficacyobserved across baseline stroke subtypes, including largearteryatherosclerotic and cryptogenic categories. The aforementionedWASID trial compared warfarin with aspirin inpatients with intracranial stenoses and found no significantbenefit and a higher risk of hemorrhage with warfarin therapy(see “Intracranial Atherosclerosis”).The role of anticoagulation for specific stroke etiologies isdescribed elsewhere in this document.Downloaded from stroke.ahajournals.org by on March 8, 2011
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