Stroke Alert: A Review of Current Clinical Stroke Literature

By Matthew E. Fink, MD, Interim Chair and Neurologist-in-Chief, Director, Division of Stroke & Critical Care Neurology, Weill Cornell Medical College and New York Presbyterian Hospital.

Direct Thrombin Inhibitors Soon Available to Prevent Stroke in Atrial Fibrillation Patients

Sources: Patel MR, et. al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation (ROCKET AF). N Engl J Med 2011;365:883-891. Granger CB, et. al. Apixaban versus warfarin in patients with atrial fibrillation (ARISTOTLE). N Engl J Med 2011;365:981-992.

Two recent clinical trials, rocket af and aristotle, have added two new direct thrombin inhibitors, in addition to dabigatran (RE-LY), to our armamentarium to prevent stroke in patients with atrial fibrillation.

ROCKET AF was designed to test rivaroxaban 20 mg/day in a "non-inferiority" double-blind trial against warfarin (adjusted to INR) in 14,264 patients with nonvalvular atrial fibrillation who were at an increased risk for stroke. The primary endpoints were stroke or systemic embolism, and they occurred in 188 patients (1.7% per year) in the rivaroxaban group and in 241 (2.2% per year) in the warfarin group (hazard ratio [HR] = 0.79; 95% confidence interval [CI] 0.66 to 0.96; P < 0.001 for noninferiority). Major and non-major bleeding occurred in 1475 patients in the rivaroxaban group (14.9% per year) and in 1449 patients in the warfarin group (14.5% per year) (HR = 1.03; 95% CI 0.96 to 1.11; P = 0.44 NS) with significant reductions in intracranial hemorrhage (0.5% vs 0.7%, P = 0.02) and fatal bleeding.

ARISTOTLE was a similar randomized, double-blind trial, comparing apixaban 5 mg twice a day with warfarin (target INR = 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke, testing for noninferiority. The primary outcome (stroke or systemic embolism) was 1.27% per year in the apixaban group compared to 1.60% per year in the warfarin group (HR = 0.79; 95% CI 0.66 to 0.95; P < 0.001 for noninferiority; P = 0.01 for superiority). The rate of major bleeding was 2.1% per year for apixaban and 3.09% per year for warfarin with the rates of death from any cause 3.52% and 3.94% respectively. The rate of hemorrhagic stroke was less with apixaban.

Both of these studies strongly suggest that the new direct thrombin inhibitors are as good or better than warfarin in preventing ischemic stroke in patients with atrial fibrillation, and appear to have a lower risk of hemorrhagic complications. An unresolved issue with this entire class of agents is that there are no known antidotes, but because they have relatively short half-lives, the anticoagulant effects will wear off in less than 24 hours. Dabigatran (Pradaxa) has been approved by the FDA; rivaroxaban and apixaban are being evaluated by the FDA.

Stroke Hospitalizations in Young Adults and Children

Source: George MG, et. al. Trends in stroke hospitalizations and associated risk factors among children and young adults, 1995-2008. Ann Neurol 2011 DOI:10.1002/ana.22539.

Investigators from the centers for disease control and Prevention in Atlanta queried the National Inpatient Sample database during the interval from 1995-2008 to determine hospitalization rates for stroke and prevalence of stroke risk factors among children and young adults, from age 5 to age 44 years. Subarachnoid hemorrhage (SAH), intracerebral hemorrhage, and ischemic stroke (AIS) were identified and sorted into seven consecutive 2-year time intervals, and into three age groups — 5-14 years, 15-34 years, and 35-44 years. Cases, risk factors, and comorbidities were identified by ICD-9-CM codes.

During the time interval investigated, the prevalence of hospitalizations for AIS increased among all groups except for females aged 5-14 years. A decrease in hospitalizations from SAH was noted in females aged 15-34 years, and males and females aged 35-44 years. Females aged 5-14 years showed increases for SAH. Traditional stroke risk factors (hypertension, diabetes, obesity, lipid disorders, and tobacco use) were common coexisting conditions and their prevalence increased from 1995-2008, in all groups hospitalized for AIS. Hospitalization for AIS has increased in all age groups of children and young adults and is associated with an increased prevalence of atherosclerotic stroke risk factors.

SAMMPRIS Results Published After Enrollment for Intracranial Stenting Trial Was Terminated

Source: Chimowitz MI, et al for the SAMMPRIS Trial Investigators. Stenting versus aggressive medical therapy for intracranial arterial stenosis. N Engl J Med 2011;365:993-1003.

In a previous issue of neurology alert, we noted that enrollment into SAMMPRIS was stopped after an interval evaluation of the data noted a significantly higher rate of early complications in the "stenting" group compared to medical controls. In this trial, patients with recent TIA or stroke attributed to stenosis of a major intracranial artery (70% to 99%) were randomized to aggressive medical management alone, or aggressive medical management plus percutaneous transluminal angioplasty and stenting (PTAS). The primary endpoint was stroke or death within 30 days after enrollment.

Enrollment was stopped after 451 patients were randomized, because the 30-day rate of stroke or death was 14.7% in the PTAS group (nonfatal stroke = 12.5%; fatal stroke = 2.2%) and 5.8% in the medical management group (non-fatal stroke = 5.3%; non-stroke-related death = 0.4%). Beyond 30 days, stroke in the same territory occurred in 13 patients in each group. Follow-up is continuing with a mean of 11.9 months. The probability of occurrence of the primary endpoint over time differed significantly between the two treatment groups at 1 year, with 20.0% in the PTAS group and 12.2% in the medical management group. The differences between the groups can be explained by a higher than expected risk in the placement of intracranial stents, and a lower than expected risk with aggressive medical management.

Severe Carotid Artery Stenosis Does Not Appear to be a Significant Risk Factor for Stroke in Patients Undergoing Coronary Artery Bypass Surgery

Source: Mahmoudi M, et al. Patients with severe asymptomatic carotid artery stenosis do not have a higher risk of stroke and mortality after coronary artery bypass surgery. Stroke 2011;42:2801-2805.

The authors performed a retrospective analysis of 878 patients with documented carotid duplex ultrasound who underwent isolated coronary artery bypass surgery at Washington Hospital Center in D.C. from 2003 to 2009 and compared those with severe (> 50% stenosis) asymptomatic carotid artery stenosis (CAS) (n = 117) to those without severe CAS (n = 761) for rates of stroke and death while hospitalized.

Patients with severe CAS were older and had more comorbidities, but had similar rates of in-hospital stroke (3.4% vs 3.6%) and mortality (3.4% vs 4.2%) compared with patients without severe CAS. In addition, the 30-day rate of mortality was also similar between the two groups.