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Fully Selected Centers in the United States and Canada Were Available for Analysis for the Study Stroke treatment and prevention Five new things t has been almost 15 years since the publica- tion of the landmark National Institute of INeurological Disorders and Stroke tissue plasminogen activator (NINDS-tPA) trial. The findings of the NINDS-tPA trial soon led to Food and Drug Administration (FDA) approval for IV alteplase (tPA) in the treatment of acute ischemic stroke (AIS) that transformed the way neurologists approach this devastating disease. Unfortunately, 15 years removed from the NINDS-tPA trial, IV tPA remains the only FDA-approved drug for the treatment of AIS. Although no major clinical breakthrough has occurred in the AIS treatment front, newer trials have increased the spectrum of patients who can be treated, but failed to find bet- ter lytic drugs or ways to identify treatable patients Tzu-Ching Wu, MD using advanced imaging. Major advancements have transpired in the arena of stroke prevention, especially in James C. Grotta, MD endovascular therapy and management of atrial fibrillation (AF). This article aims to summarize 5 new topics in stroke treatment, prevention, and poststroke care that have or will soon affect clinical treatment of stroke patients, and to offer critiques and commentary on how the results of the trials presented can be applied to the Address correspondence and care of individual stroke patients. reprint requests to Dr. James C. Grotta, Department of Neurology, The University of CAROTID STENTING VS ENDARTERECTOMY The relationship between carotid stenosis and increased Texas–Houston Medical School, stroke risk has been well-established and described. Results of the 3 prospective carotid endarterectomy (CEA) 6431 Fannin Street, Houston, TX 77030 trials, North American Symptomatic Carotid Endarterectomy Trial, European Carotid Surgery Trial, and the [email protected] Veteran’s Affairs Cooperative Study Program, showed that symptomatic patients with high-grade stenosis benefited from surgery1 and established CEA as an effective treatment. In the Asymptomatic Carotid Surgery Neurology® Clinical Practice 2010;75(Suppl 1):S16–S21 Trial, investigators found that CEA also prevented strokes in asymptomatic patients with carotid stenosis greater than 70% and younger than age 75.2 CEA soon became the gold standard secondary stroke prevention treatment for carotid artery atherosclerosis. With the advent of improved angiographic procedures and devices, physicians soon began to seek nonsurgical methods to treat the condition. The Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) was recently completed and published.3 The aim of the trial was to compare outcomes of patients with either symptomatic or asymptom- atic extracranial stenosis who underwent traditional endarterectomy vs carotid artery stenting (CAS) with distal protection. Results of 2,502 patients over 117 carefully selected centers in the United States and Canada were available for analysis for the study. The primary endpoint was the composite of any stroke, myocardial infarc- tion (MI), or death during the periprocedural period or ipsilateral stroke within 4 years after randomization. The results showed that there was no significant difference in the 4-year rate of primary endpoints achieved between the 2 procedures with 7.2% for CAS and 6.8% for CEA (hazard ratio [HR] for stenting 1.11; 95% confidence interval [CI] 0.81–1.51; p ϭ 0.51). Primary endpoints were also similar during the periprocedural period: 5.2% for CAS and 4.5% for CEA (HR for stenting 1.18; 95% CI 0.82–1.68; p ϭ 0.38). Interestingly, the investigators did find that during the periprocedural period, the incidence of MI was more prevalent in the CEA population (2.5% vs 1.1%; p ϭ 0.03) but periprocedural strokes were more common in patients who From the Department of Neurology, University of Texas–Houston Medical School, Houston. Disclosure: Author disclosures are provided at the end of the article. S16 Copyright © 2010 by AAN Enterprises, Inc. underwent CAS (4.1% vs 2.3%; p ϭ 0.01). Second- terectomy trial). We recommend CEA in most other ary analysis aimed to differentiate efficacy by symp- patients. tomatic status, age, and sex. There was no effect of symptomatic status or sex on the primary endpoint, NEW ORAL THERAPY FORATRIAL FIBRILLATION but the data suggest that those younger than 70 years It has been estimated that over 2 million Americans had greater benefit from CAS, with CEA showing are affected by AF and more that 75,000 strokes each greater efficacy in patients older than 70 years of age. year can be attributed to AF.6 Numerous trials have Major advancements have demonstrated the efficacy of warfarin in the treat- ment of AF for stroke prevention and it remains the transpired in the arena of mainstay therapy for this disease. Although effica- stroke prevention, especially cious, warfarin nevertheless has disadvantages that in endovascular therapy and often limit its use in AF patients. Notably, warfarin causes major bleeding in 1.3% annually1 and with management of atrial the multitude of drug and food interactions and nar- fibrillation row therapeutic window, continuous close INR monitoring is required. Not surprisingly, the issue of CEA vs CAS and The Randomized Evaluation of Long-Term Anti- the interpretation of the CREST results are still de- coagulation Therapy trial6 was a noninferiority trial bated within the neurovascular community. Al- that aimed to determine the incidence of systemic though the results showed that there were no embolism in patients treated with warfarin or the differences between the procedures in achieving the new oral thrombin inhibitor, dabigatran. AF patients primary outcome (any stroke, MI, death), it is im- with risks for stroke were randomized to either 110 portant to highlight that stroke, which one can argue mg or 150 mg of dabigatran twice daily or adjusted has a stronger effect on quality of life than a nonfatal dose warfarin (target INR 2.0 to 3.0). The primary MI, was more likely after CAS. The increased risk of clinical outcome was stroke or systemic embolism ischemic events with CAS was also observed in the and the primary safety outcome was major bleeding International Carotid Stenting Study trial: 7.7% for defined as a reduction in the hemoglobin level of at CAS and 4.1% for CEA (HR for stenting 1.92; 95% least 20 g/L, transfusion of at least 2 units of blood, CI 1.27–2.89; p ϭ 0.002)4 and a substudy of the or symptomatic bleeding in a critical area or organ.6 International Carotid Stenting Study trial using In total, 18,113 patients were enrolled with a MRI-DWI showed 3 times more patients in the CAS mean age of 71 years and the median follow-up was 2 group than in the CEA group had new ischemic le- years. Results showed that the primary clinical out- sions on posttreatment MRI scans.5 come was achieved in 1.53%/year of patients receiv- While the CREST trial has shown that both pro- ing 110 mg of dabigatran, 1.11%/year for 150 mg of cedures can be done safely and are durable, at least up to 4 years, it is important to underscore that the pro- dabigatran, and 1.69%/year for warfarin, with both cedures in the trial were performed by highly quali- doses of dabigatran demonstrating noninferiority to Ͻ fied interventionists or surgeons, which may not be warfarin (p 0.001). High-dose dabigatran proved available at all centers. In addition, there are other to be superior to warfarin (RR 0.66; 95% CI 0.74– Ͻ factors that may also influence treatment selection, 0.82; p 0.001) in regards to the primary endpoint. such as location of the stenotic lesion and vessel ac- The occurrence of hemorrhagic stroke was rare in all cessibility. CREST has reinforced the robust utility 3 groups but the rates were lower in the dabigatran of CEA and has also armed clinicians with another group, which achieved statistical significance option to treat carotid disease, but we still need to (0.38%/year warfarin, 0.12%/year 110 mg dabigat- individualize therapy to balance all risks and benefits. ran, 0.10%/year 150 mg dabigatran). Clinicians have to take into account a multitude of Major bleeding was observed in 3.36%/year of clinical factors and also be familiar with the technical warfarin-treated patients, as compared to 2.71%/year expertise of the local surgeon or interventionist in (RR 0.80; 95% CI 0.69–0.93; p ϭ 0.003) in those order to develop the best treatment strategy for each treated with 110 mg dabigatran and 3.11%/year (RR patient. At present, we tend to favor CAS in younger 0.93; 95% CI 0.81–1.7; p ϭ 0.31) in the 150 mg patients without extensive atherosclerosis and non- dabigatran group. Overall, the combined outcome compliant vessels, and also in high surgical risk pa- including major vascular events, major bleeding, tients with bilateral disease (who are currently and death was 7.64%/year in the warfarin group, candidates for the ongoing Stenting and Angioplasty 7.09%/year (RR 0.92; 95% CI 0.84–1.02; p ϭ with Protection in Patients at High Risk for Endar- 0.10) with 110 mg of dabigatran, and 6.91%/year Neurology: Clinical Practice 75(Suppl 1) November 2, 2010 S17 (RR 0.91; 95% CI 0.82–1.00; p ϭ 0.04) with 150 The primary endpoint was 90-day disability mea- mg of dabigatran. sured by the modified Rankin score (mRS), dichoto- Clinical outcomes were comparable between all mized as favorable outcome (0 or 1) or unfavorable doses of dabigatran and warfarin, with the high-dose outcome (2 to 6). Secondary endpoint was a global dabigatran outperforming warfarin.
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