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Background: Patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease., Methods: In this multicenter, double-blind trial, we randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo. Eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. The primary outcome was fatal or nonfatal stroke or myocardial infarction., Results: By 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007). Diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001). There was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P=0.52). Pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P=0.003)., Conclusions: In this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Background: Previous studies have suggested that the obstructive sleep apnea syndrome may be an important risk factor for stroke. It has not been determined, however, whether the syndrome is independently related to the risk of stroke or death from any cause after adjustment for other risk factors, including hypertension., Methods: In this observational cohort study, consecutive patients underwent polysomnography, and subsequent events (strokes and deaths) were verified. The diagnosis of the obstructive sleep apnea syndrome was based on an apnea-hypopnea index of 5 or higher (five or more events per hour); patients with an apnea-hypopnea index of less than 5 served as the comparison group. Proportional-hazards analysis was used to determine the independent effect of the obstructive sleep apnea syndrome on the composite outcome of stroke or death from any cause., Results: Among 1022 enrolled patients, 697 (68 percent) had the obstructive sleep apnea syndrome. At baseline, the mean apnea-hypopnea index in the patients with the syndrome was 35, as compared with a mean apnea-hypopnea index of 2 in the comparison group. In an unadjusted analysis, the obstructive sleep apnea syndrome was associated with stroke or death from any cause (hazard ratio, 2.24; 95 percent confidence interval, 1.30 to 3.86; P=0.004). After adjustment for age, sex, race, smoking status, alcohol-consumption status, body-mass index, and the presence or absence of diabetes mellitus, hyperlipidemia, atrial fibrillation, and hypertension, the obstructive sleep apnea syndrome retained a statistically significant association with stroke or death (hazard ratio, 1.97; 95 percent confidence interval, 1.12 to 3.48; P=0.01). In a trend analysis, increased severity of sleep apnea at baseline was associated with an increased risk of the development of the composite end point (P=0.005)., Conclusions: The obstructive sleep apnea syndrome significantly increases the risk of stroke or death from any cause, and the increase is independent of other risk factors, including hypertension., (Copyright 2005 Massachusetts Medical Society.)

Background: Observational studies have suggested that estrogen-replacement therapy may reduce a woman's risk of stroke and death., Methods: We conducted a randomized, double-blind, placebo-controlled trial of estrogen therapy (1 mg of estradiol-17beta per day) in 664 postmenopausal women (mean age, 71 years) who had recently had an ischemic stroke or transient ischemic attack. Women were recruited from 21 hospitals in the United States and were followed for the occurrence of stroke or death., Results: During a mean follow-up period of 2.8 years, there were 99 strokes or deaths among the women in the estradiol group, and 93 among those in the placebo group (relative risk in the estradiol group, 1.1; 95 percent confidence interval, 0.8 to 1.4). Estrogen therapy did not reduce the risk of death alone (relative risk, 1.2; 95 percent confidence interval, 0.8 to 1.8) or the risk of nonfatal stroke (relative risk, 1.0; 95 percent confidence interval, 0.7 to 1.4). The women who were randomly assigned to receive estrogen therapy had a higher risk of fatal stroke (relative risk, 2.9; 95 percent confidence interval, 0.9 to 9.0), and their nonfatal strokes were associated with slightly worse neurologic and functional deficits., Conclusions: Estradiol does not reduce mortality orthe recurrence of stroke in postmenopausal women with cerebrovascular disease. This therapy should not be prescribed for the secondary prevention of cerebrovascular disease.

Background: Phenylpropanolamine is commonly found in appetite suppressants and cough or cold remedies. Case reports have linked the use of products containing phenylpropanolamine to hemorrhagic stroke, often after the first use of these products. To study the association, we designed a case-control study., Methods: Men and women 18 to 49 years of age were recruited from 43 U.S. hospitals. Eligibility criteria included the occurrence of a subarachnoid or intracerebral hemorrhage within 30 days before enrollment and the absence of a previously diagnosed brain lesion. Random-digit dialing identified two matched control subjects per patient., Results: There were 702 patients and 1376 control subjects. For women, the adjusted odds ratio was 16.58 (95 percent confidence interval, 1.51 to 182.21; P=0.02) for the association between the use of appetite suppressants containing phenylpropanolamine and the risk of a hemorrhagic stroke and 3.13 (95 percent confidence interval, 0.86 to 11.46; P=0.08) for the association with the first use of a product containing phenylpropanolamine. All first uses of phenylpropanolamine involved cough or cold remedies. For men and women combined, the adjusted odds ratio was 1.49 (95 percent confidence interval, 0.84 to 2.64; P=0.17) for the association between the use of a product containing phenylpropanolamine and the risk of a hemorrhagic stroke, 1.23 (95 percent confidence interval, 0.68 to 2.24; P=0.49) for the association with the use of cough or cold remedies that contained phenylpropanolamine, and 15.92 (95 percent confidence interval, 1.38 to 184.13; P=0.03) for the association with the use of appetite suppressants that contained phenylpropanolamine. An analysis in men showed no increased risk of a hemorrhagic stroke in association with the use of cough or cold remedies containing phenylpropanolamine. No men reported the use of appetite suppressants., Conclusions: The results suggest that phenylpropanolamine in appetite suppressants, and possibly in cough and cold remedies, is an independent risk factor for hemorrhagic stroke in women.

Background and Methods: The use of cocaine, especially one of its alkaloidal forms ("crack"), has been increasingly associated with cerebrovascular disease. To clarify the clinical, radiologic, and pathological features of the events associated with cocaine use, we identified 28 patients at four medical centers who had stroke temporally related to the use of alkaloidal cocaine (during or within 72 hours of use)., Results: The 28 patients had the following types of cerebrovascular event: cerebral infarction (n = 18 [2 hemorrhagic; 1 fatal]) in the areas supplied by the middle cerebral artery (n = 10), anterior cerebral artery (n = 3), posterior cerebral artery (n = 1), and vertebrobasilar arteries (n = 4); subarachnoid hemorrhage (n = 5); intraparenchymal hemorrhage (n = 4); and primary intraventricular hemorrhage (n = 1). Eighteen patients (64 percent) had acute neurologic symptoms immediately or within one hour of using cocaine. Fifteen patients (45 percent) with either occlusive or hemorrhagic strokes had sever headache as an early symptom. Vasculitis was not suggested by radiography in any patient, nor was it identified on pathological examination in one patient who died. All the patients were young (mean age, 34 years; range, 23 to 49) and had no other apparent, direct cause of stroke. Other risk factors for stroke among the patients included mild mitral-valve prolapse (n = 4), hypertension (n = 4), cigarette smoking (n = 8), and regular alcohol use (n = 6)., Conclusions: There is a strong temporal association of the use of alkaloidal cocaine with both ischemic and hemorrhagic cerebrovascular events. Cocaine-related stroke probably has many causes. A thorough history focusing on the use of cocaine and toxicologic screening of urine and serum should be part of the evaluation of any young patient with a stroke.