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

242 Stroke January 2011prevention in AF patients who are allergic to aspirin. 230 TheAtrial Fibrillation Clopidogrel Trial with Irbesartan for Preventionof Vascular Events (ACTIVE W) evaluated the safetyand efficacy of the combination of clopidogrel and aspirinversus warfarin in AF patients with at least 1 risk factor forstroke. This study was stopped prematurely by the safetymonitoring committee after 3371 patients were enrolledbecause of the clear superiority of warfarin (INR 2.0 to 3.0)over the antiplatelet combination (RR, 1.44; 95% CI 1.18 to1.76; P0.0003). 231An additional arm of this study (ACTIVE A) comparedaspirin versus clopidogrel plus aspirin in AF patients whowere considered “unsuitable for vitamin K antagonist therapy”and reported a reduction in the rate of stroke withclopidogrel plus aspirin. Stroke occurred in 296 patientsreceiving clopidogrel plus aspirin (2.4% per year) and 408patients receiving aspirin monotherapy (3.3% per year; RR,0.72; 95% CI, 0.62 to 0.83; P0.001). Major bleedingoccurred in 251 patients receiving clopidogrel plus aspirin(2.0% per year) and in 162 patients receiving aspirin alone(1.3% per year; RR, 1.57; 95% CI, 1.29 to 1.92; P0.001). 232An analysis of major vascular events combined with majorhemorrhage showed no difference between the 2 treatmentoptions (RR, 0.97; 95% CI, 0.89 to 1.06; P0.54). Themajority of patients enrolled in this study were deemed to beunsuitable for warfarin based on physician judgment orpatient preference; only 23% had increased bleeding risk orinability to comply with monitoring as the reason for enrollment.Therefore, on the basis of uncertainty of how toidentify patients who are “unsuitable” for anticoagulation, aswell as the lack of benefit in the analysis of vascular eventsplus major hemorrhage, aspirin remains the treatment ofchoice for AF patients who have a clear contraindication tovitamin K antagonist therapy but are able to tolerate antiplatelettherapy.The superior efficacy of anticoagulation over aspirin forstroke prevention in patients with AF and a recent TIA orminor stroke was demonstrated in the European Atrial FibrillationTrial (EAFT). 233 Therefore, unless a clear contraindicationexists, AF patients with a recent stroke or TIA shouldreceive long-term anticoagulation rather than antiplatelettherapy. There is no evidence that combining anticoagulationwith an antiplatelet agent reduces the risk of stroke or MIcompared with anticoagulant therapy alone in AF patients,but there is clear evidence of increased bleeding risk. 234Therefore, in general, addition of aspirin to anticoagulationtherapy should be avoided in AF patients.The narrow therapeutic margin of warfarin in conjunctionwith numerous associated food and drug interactions requiresfrequent INR testing and dose adjustments. These liabilitiescontribute to significant underutilization of warfarin even inhigh-risk patients. Therefore, alternative therapies that areeasier to use are needed. A number of recent and ongoingtrials are evaluating alternative antithrombotic strategies inAF patients, including direct thrombin inhibitors and factorXa inhibitors. To date, the most successful alternative anticoagulantevaluated is the oral antithrombin dabigatran,which was tested in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) study. 235 RE-LY, arandomized open-label trial of 18 000 AF patients, demonstratedthat at a dose of 150 mg twice daily, dabigatran wasassociated with lower rates of stroke or systemic embolismand rates of major hemorrhage similar to those of doseadjustedwarfarin. The absolute reduction in stroke or systemicembolism was small (1.69% in the warfarin groupversus 1.11% in the dabigatran 150 mg twice-daily group;RR, 0.66 [0.53 to 0.82]; P0.001). No significant safetyconcerns were noted with dabigatran other than a small butstatistically significant increase in MI (0.74% per year versus0.53% per year). No recommendation will be provided fordabigatran in the current version of these guidelines becauseregulatory evaluation and approval has not yet occurred.However, the availability of a highly effective oral agentwithout significant drug or food interactions that does notrequire coagulation monitoring would represent a majoradvance for this patient population.An alternative strategy for preventing stroke in AF patientsis percutaneous implantation of a device to occlude the leftatrial appendage. The PROTECT AF (WATCHMAN LeftAtrial Appendage System for Embolic Protection in Patientswith Atrial Fibrillation) study demonstrated that use of anocclusion device is feasible in AF patients and has thepotential to reduce stroke risk. 236 In this open-label trial, 707warfarin-eligible AF patients were randomly assigned toreceive either the WATCHMAN left atrial appendage occlusiondevice (n463) or dose-adjusted warfarin (n244).Forty-five days after successful device implantation, warfarinwas discontinued. The primary efficacy rate (combination ofstroke, cardiovascular or unexplained death, or systemicembolism) was low in both the device versus the warfaringroup and satisfied the noninferiority criteria established forthe study. The most common periprocedural complicationwas serious pericardial effusion in 22 patients (5%; 15 weretreated with pericardiocentesis and 7 with surgery). Fivepatients (1%) had a procedure-related ischemic stroke and 3had embolization of the device. This approach is likely tohave greatest clinical utility for AF patients at high stroke riskwho are poor candidates for oral anticoagulation; however,more data are required in these patient populations before arecommendation can be made.Available data do not show greater efficacy of the acuteadministration of anticoagulants over antiplatelet agents inthe setting of cardioembolic stroke. 237 More studies arerequired to clarify whether certain subgroups of patients whoare perceived to be at high risk of recurrent embolism maybenefit from urgent anticoagulation (eg, AF patients forwhom transesophageal echocardiography [TEE] shows a leftatrial appendage thrombus).No data are available to address the question of optimaltiming for initiation of oral anticoagulation in a patient withAF after a stroke or TIA. In the EAFT trial, 233 oral anticoagulationwas initiated within 14 days of symptom onset inabout one half of patients. Patients in this trial had minorstrokes or TIAs and AF. However, for patients with largeinfarcts, extensive hemorrhagic transformation, or uncontrolledhypertension, further delays may be appropriate.For patients with AF who suffer an ischemic stroke or TIAdespite therapeutic anticoagulation, there are no data toDownloaded from stroke.ahajournals.org by on March 8, 2011