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Results The mean LDL cholesterol level during the trial was 73 mg per deciliter (1.9 mmol per liter) among patients receiving atorvastatin and 129 mg per deciliter (3.3 mmol per liter) among patients receiving placebo. During a median follow-up of 4.9 years, 265 patients (11.2 percent) receiving atorvastatin and 311 patients (13.1 percent) receiving placebo had a fatal or nonfatal stroke (5-year absolute reduction in risk, 2.2 percent; adjusted hazard ratio, 0.84; 95 percent confidence interval, 0.71 to 0.99; P=0.03; unadjusted P=0.05). The atorvastatin group had 218 ischemic strokes and 55 hemorrhagic strokes, whereas the placebo group had 274 ischemic strokes and 33 hemorrhagic strokes. The five-year absolute reduction in the risk of major cardiovascular events was 3.5 percent (hazard ratio, 0.80; 95 percent confidence interval, 0.69 to 0.92; P=0.002).

The overall mortality rate was similar, with 216 deaths in the atorvastatin group and 211 deaths in the placebo group (P=0.98), as were the rates of serious adverse events. Elevated liver enzyme values were more common in patients taking atorvastatin. Despite the efficacy of a variety of secondary preventive therapies, patients who have had a stroke or transient ischemic attack (TIA) remain at risk for stroke as well as coronary and other cardiovascular events. Therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) reduces the risk of stroke among patients with coronary heart disease and those at increased risk for cardiovascular disease. A meta-analysis of 90,000 patients included in these previous statin trials showed that the reduction in the risk of stroke was primarily related to the extent to which low-density lipoprotein (LDL) cholesterol levels were lowered. No data exist to show that statin treatment decreases the risk of stroke among patients with a history of stroke or TIA. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial was designed to determine whether a daily dose of 80 mg of atorvastatin would reduce the risk of stroke in patients with no known coronary heart disease who had had a stroke or TIA within the previous six months.

Study Hypothesis and Patient Population The primary hypothesis of the study was that treatment with 80 mg of atorvastatin per day would reduce the risk of fatal or nonfatal stroke among patients with a history of stroke or TIA. Eligible patients were men and women over 18 years of age who had had an ischemic or hemorrhagic stroke or a TIA (diagnosed by a neurologist within 30 days after the event) 1 to 6 months before randomization. Patients with hemorrhagic stroke were included if they were deemed by the investigator to be at risk for ischemic stroke or coronary heart disease. Stroke was defined by focal clinical signs of central nervous system dysfunction of vascular origin that lasted for at least 24 hours; TIA was defined by the loss of cerebral or ocular function for less than 24 hours, presumably owing to atherosclerotic causes.

Patients had to be ambulatory, with a modified Rankin score of no more than 3 (scores can range from 0 to 6, with higher scores indicating more severe disability or death), and to have an LDL cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter) and no more than 190 mg per deciliter (4.9 mmol per liter). The exclusion criteria, which have been described in detail previously, included atrial fibrillation, other cardiac sources of embolism, and subarachnoid hemorrhage. Patients were enrolled between September 1998 and March 2001. Study Protocol Patients who were taking lipid-altering drugs had to stop these medications 30 days before the screening phase of the study. Within 30 days after the initial screening visit, eligible patients were randomly assigned to double-blind therapy with either 80 mg of atorvastatin per day or placebo. To ensure that investigators remained unaware of a patient's treatment assignment on the basis of changes in LDL cholesterol levels during the study, if LDL cholesterol levels dropped below 40 mg per deciliter (1.0 mmol per liter) in a patient treated with atorvastatin, the investigator for a randomly chosen placebo patient was notified and LDL cholesterol levels were remeasured in both patients.

All patients were counseled to follow the National Cholesterol Education Program Step 1 (or similar) diet throughout the study. Follow-up visits were scheduled one, three, and six months after enrollment and every six months thereafter. Surviving patients made their last study visit between March and June 2005. Efficacy Outcomes The primary outcome was the time from randomization to a first nonfatal or fatal stroke. Statistical Analysis The study was designed to have a statistical power of 90 percent to detect an absolute reduction of 25 percent in the primary end point in the atorvastatin group as compared with the placebo group during a median follow-up of five years with a two-sided significance level of P.

Results Of 6670 screened, eligible patients, 4731 (70.9 percent) fulfilled the inclusion criteria and underwent randomization ( Figure 1 Screening, Enrollment, and Outcomes. The median duration of follow-up was 4.9 years (range among survivors, 4.0 to 6.6). Among survivors, there was no significant difference in the number of patients in each treatment group lost to follow-up (P=0.42). More patients in the placebo group than in the atorvastatin group withdrew consent after randomization (P=0.07), permanently discontinued study treatment (20.2 percent vs. 15.4 percent of follow-up time for the primary end point, respectively; P=0.07), and began open-label, nonstudy statin therapy (7.5 percent vs. 1.0 percent of follow-up time for the primary end point, respectively; the net difference in statin use between groups was 78.1 percent). During the trial, the treatment assignment of nine patients (three assigned to atorvastatin and six assigned to placebo) was revealed to the study physician.

Discussion This prospective, randomized, placebo-controlled trial demonstrated that treatment with 80 mg of atorvastatin per day reduced the risk of subsequent stroke in patients without known coronary heart disease and with LDL cholesterol levels of 100 to 190 mg per deciliter who had had a recent stroke or TIA. The study was not powered to assess the effect of treatment on the risk of death from any cause or on fatal and nonfatal stroke separately, but the risk of fatal stroke was significantly reduced. The reduction in the risk of nonfatal stroke was consistent with the treatment effect, but not significant. Download Story Of A Girl Zarr Pdf Free here. Although at enrollment, patients had no known coronary heart disease, the risk of cardiovascular events, including major coronary events and revascularization procedures, was also substantially reduced. On the basis of our data, 46 patients (95 percent confidence interval, 24 to 243) would need to be treated for five years to prevent one stroke, 29 patients (95 percent confidence interval, 18 to 75) to prevent one major cardiovascular event, and 32 patients (95 percent confidence interval, 22 to 59) to avoid one revascularization procedure.

These benefits were observed despite the increased use of open-label nonstudy statins during the study, a result suggesting that the effect is robust. As expected, the beneficial effect of statin therapy on the risk of recurrent stroke was due to a reduction in the risk of cerebral infarction, the mechanism of which largely has been attributed to a reduction in LDL cholesterol levels. The lower average LDL cholesterol level achieved in the atorvastatin as compared with the placebo group is consistent with this hypothesis. Other putative mechanisms include a variety of possible pleiotropic effects. Our results contrast with those of the Heart Protection Study (HPS), which found no reduction in the risk of stroke among patients with prior cerebrovascular disease (10.4 percent of patients in the statin group had a recurrent stroke, as compared with 10.5 percent of patients in the placebo group).

A possible explanation for this difference in results is that patients in the HPS were enrolled an average of 4.3 years after the index event, whereas the risk of recurrence is highest within the first years after stroke. Another explanation may be the larger reduction in LDL cholesterol in our study than in the HPS (56 mg per deciliter [1.4 mmol per liter] vs.

39 mg per deciliter [1.0 mmol per liter]). Other differences between the trials have been reviewed previously. Although patients with known coronary heart disease were excluded at baseline, 9.2 percent (434 patients) had a coronary event or a noncoronary revascularization procedure during the trial.

Treatment with atorvastatin reduced the risk of these events. This observation adds to evidence from previous studies involving patients at increased risk for cardiovascular disease showing that statin treatment reduces atherosclerotic complications. Our results support the concept that from the standpoint of statin treatment, stroke or TIA should be considered a coronary heart disease risk equivalent. In our study, the overall benefit in terms of the reduction in the risk of stroke was significant despite an increase in hemorrhagic stroke in the atorvastatin group. Statistical heterogeneity was observed in the effects of atorvastatin on ischemic and hemorrhagic stroke.

An increase in the incidence of hemorrhagic stroke among patients with cerebrovascular disease treated with simvastatin (40 mg) was noted in the HPS. Epidemiologic studies have suggested an association between low cholesterol levels and brain hemorrhage. Statin trials conducted largely in patients without cerebrovascular disease have reduced LDL cholesterol levels to 70 mg per deciliter (1.8 mmol per liter) or below, with no increase in the incidence of hemorrhagic stroke. The small number of patients with brain hemorrhage at entry in our study precludes any meaningful conclusions regarding the relative risks and benefits of statin treatment in this population. The potential risk of recurrent hemorrhage should be considered when one is deciding whether to administer a statin to patients who have had a hemorrhagic stroke.

In conclusion, in patients with a recent stroke or TIA, treatment with 80 mg of atorvastatin per day decreased the risk of stroke, major coronary events, and revascularization procedures. These results support the initiation of atorvastatin treatment soon after a stroke or TIA. Supported by Pfizer. Amarenco reports having received consulting fees from AstraZeneca, Novartis, Pfizer, and Sanofi-Aventis; lecture fees from Otsuka Pharmaceutical and Pfizer; and grant support from Pfizer. Bogousslavsky reports having received consulting fees from Pfizer and grant support from Pfizer. Callahan reports having received consulting fees from Sanofi, lecture fees from Bristol-Myers Squibb and Sanofi, and grant support from Pfizer.

Goldstein reports having received consulting fees from Pfizer, Bayer, AstraZeneca, Bristol-Myers Squibb/Sanofi, GlaxoSmithKline, Merck Research Laboratories, Johnson & Johnson Cordis, and Organon; lecture fees from Bayer; and grant support from AGA Medical, Boehringer Ingelheim, the National Institutes of Health, Pfizer, and the Department of Veterans Affairs. Hennerici reports having received grant support from Pfizer and Servier. Rudolph is an employee of Pfizer and reports owning stock in the company.

Sillesen reports having received consulting fees from Sanofi-Aventis; lecture fees from AstraZeneca, Bristol-Myers Squibb, Merck, and Sanofi-Aventis; and grant support from Pfizer. Simunovic and Mr. Szarek are employees of Pfizer and report owning stock in the company. Welch reports having received consulting fees from Eisai, GlaxoSmithKline, Medpointe, AstraZeneca, NMT Medical, and Ortho-McNeil; lecture fees from GlaxoSmithKline; and grant support from Pfizer. Zivin reports having received consulting fees from Angel Pharmaceuticals, MEDACorp, MEDIACorp, Pfizer, and Sirex; and grant support from PhotoThera and Pfizer. No other potential conflict of interest relevant to this article was reported. We are indebted to all the trial participants and the vast numbers of doctors, nurses, and hospital staff across the globe for their long-term commitment to the study; to Ellen Huang for her dedication and support; and to Sheila Auster, Sandra Brown, Marlen Castano, Lana De Weaver, Karen Ivanac, Sinde Krapf, Jaman Maroni, Scott McBride, James Nawrocki, Connie Newman, Lekan Odeleye, Bill Sasiela, Robert Sawyer, Heike Schwende, John Tsai, and Bernd Wagner (all at Pfizer) for their contributions.

Source Information Pierre Amarenco, M.D. (Denis Diderot University, Paris), Julien Bogousslavsky, M.D. (University of Lausanne, Lausanne, Switzerland), Alfred Callahan, III, M.D. (Neurologic Consultants, Nashville), Larry B. Goldstein, M.D. (Duke University Medical Center, Durham, N.C.), Michael Hennerici, M.D., Ph.D. (Universitat Heidelberg, Mannheim, Germany), Amy E.

Rudolph, Ph.D. (Pfizer, New York), Henrik Sillesen, M.D., D.M.Sc. (University of Copenhagen, Copenhagen), Lisa Simunovic, M.S. (Pfizer, New York), Michael Szarek, M.S. (Pfizer, New York), K.M.A.

Welch, M.B., Ch.B., (Rosalind Franklin University of Medicine and Science, North Chicago), and Justin A. Zivin, M.D., Ph.D.

(University of California, San Diego) assume full responsibility for the overall content and integrity of the article. Address reprint requests to Dr.

Welch at the Rosalind Franklin University of Medicine and Science, 3333 Green Bay Rd., North Chicago, IL 60064,. References • 1 Sacco RL, Adams R, Albers G, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a statement for healthcare professionals from the American Heart Association/American Stroke Association Council on Stroke: co-sponsored by the Council on Cardiovascular Radiology and Intervention: the American Academy of Neurology affirms the value of this guideline.

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