EVP
29.06.2006, 19:37
SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels
Disclosures
Linda Brookes, MSc
Presenter: K. Michael Welch, MBChB (Rosalind Franklin University of Medicine and Science, Chicago, Illinois)
The results of clinical trials are often referred to as "eagerly awaited," but this is seldom as true as for the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. SPARCL was the first, and to date only, trial designed to evaluate prospectively the effects of statin therapy in patients who previously had a stroke or transient ischemic attack (TIA) and who had no known cardiovascular disease (CVD). The first presentation of the SPARCL results, made by Dr. Welch on behalf of all the SPARCL investigators worldwide, confirmed what many people had predicted, that atorvastatin 80 mg/day significantly reduced the risk of stroke in these patients.[1] "These results support the initiation of atorvastatin 80 mg/day in patients with stroke or TIA soon after the event," Dr. Welch declared, referring to SPARCL as a "unique, landmark trial."
As well as bringing about a 16% reduction in the risk of stroke, the atorvastatin regimen also reduced the risk of major coronary events by 35%, coronary heart disease (CHD) events by 42%, and revascularization procedures by 45% in the SPARCL patients. A small increase in the incidence of hemorrhagic stroke was seen with atorvastatin, but the regimen of 80 mg/day of atorvastatin was well tolerated and the incidence of musculoskeletal adverse events was low, Dr. Welch reported.
Background
A large number of clinical trials have previously demonstrated that lowering cholesterol with statins reduces the risk of stroke in patients with CVD or major CVD risk. A meta-analysis of 26 randomized clinical trials testing statin drugs in such patients showed a relative risk reduction of 21% in stroke.[2] Fatal strokes were reduced, but not significantly, by 9%. There was no increase in hemorrhagic strokes. The statin effect was closely associated with the reduction in low-density lipoprotein (LDL)-cholesterol, which the investigators concluded explained 34%-80% of the observed benefit. Each 10% reduction in LDL-cholesterol was estimated to reduce the risk of all strokes by 13.2%.
Clinicians are currently advised to consider adding a statin in all stroke patients with a history of coronary events such as a myocardial infarction (MI), even when their LDL-cholesterol level is in the normal range. In patients with ischemic stroke and no history of a coronary event, however, no clear recommendations have been available, even though such patients make up 80% of the stroke population. SPARCL is regarded as critical in providing evidence to support -- or refute -- the benefits of statin therapy in the prevention of stroke in patients with cerebrovascular disease but no known CHD.
Patients
Patients were enrolled into SPARCL at 205 study sites in Africa, Australia, Europe, the Middle East, and North and South America.[3] The main entry criteria for men and women were:
Previously documented stroke (ischemic or hemorrhagic) or TIA, 1 to 6 months before randomization
LDL-cholesterol ≥ 100 mg/dL (2.6 mmol/L) and ≤ 190 mg/dL (4.9 mmol/L)
Modified Rankin score ≤3 (ie, functionally independent)
Patients were excluded if they had a history of CHD, significant peripheral vascular disease, atrial fibrillation, prosthetic heart valve, clinically significant mitral stenosis, sinus node dysfunction, uncontrolled hypertension, stroke caused by a revascularization procedure or trauma, subarachnoid hemorrhage, or liver or renal disease or dysfunction.
A total of 4731 patients were enrolled into the trial. The mean age (approximately 62.5 years) and male/female ratio (60%/40%) meant that the SPARCL patients were more representative of the true stroke population, with a substantially higher percentage of women and a mean age approximately 5 years older than the populations of major CHD statin trials. Approximately 20% of the SPARCL patients were current smokers, 62% were hypertensive, 16% had diabetes, and 20% had carotid stenosis.
Thirty percent of the patients had had a TIA and 70% a stroke, of which about 3% were hemorrhagic. Because the patients were selected by the investigators at each site, this did not reflect stroke incidence in the general population, Dr. Welch noted.
Treatment
Within 30 days of initial screening, patients were randomized to receive either atorvastatin 80 mg/day (2365 patients) or placebo (2366 patients). Patients were also counseled to follow the National Cholesterol Education Program (NCEP) Step I diet throughout the study. Concomitant medication reflected a high standard of care in the trial, Dr. Welch noted, with 94% of patients on antiplatelet therapy and 69% on antihypertensive medication, including all of the patients who were hypertensive.
Follow-up was planned for 5 years and patients were followed for a mean of 4.9 years (maximum 6.6 years). There was a 0.5% total loss to follow-up. There was a net difference in statin use between the 2 groups of 78%, reflecting good adherence in the trial, Dr. Welch pointed out.
Primary Endpoint
After prespecified adjustment of data for geographical region, entry event, time since entry event, gender, and baseline age, a statistically significant reduction of 16% was seen in the primary endpoint of the trial, time from randomization to first occurrence of fatal or nonfatal stroke, in the atorvastatin group compared with placebo (Table 1). There was also a significant reduction in fatal stroke and a nonsignificant reduction in nonfatal stroke.
Disclosures
Linda Brookes, MSc
Presenter: K. Michael Welch, MBChB (Rosalind Franklin University of Medicine and Science, Chicago, Illinois)
The results of clinical trials are often referred to as "eagerly awaited," but this is seldom as true as for the results of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial. SPARCL was the first, and to date only, trial designed to evaluate prospectively the effects of statin therapy in patients who previously had a stroke or transient ischemic attack (TIA) and who had no known cardiovascular disease (CVD). The first presentation of the SPARCL results, made by Dr. Welch on behalf of all the SPARCL investigators worldwide, confirmed what many people had predicted, that atorvastatin 80 mg/day significantly reduced the risk of stroke in these patients.[1] "These results support the initiation of atorvastatin 80 mg/day in patients with stroke or TIA soon after the event," Dr. Welch declared, referring to SPARCL as a "unique, landmark trial."
As well as bringing about a 16% reduction in the risk of stroke, the atorvastatin regimen also reduced the risk of major coronary events by 35%, coronary heart disease (CHD) events by 42%, and revascularization procedures by 45% in the SPARCL patients. A small increase in the incidence of hemorrhagic stroke was seen with atorvastatin, but the regimen of 80 mg/day of atorvastatin was well tolerated and the incidence of musculoskeletal adverse events was low, Dr. Welch reported.
Background
A large number of clinical trials have previously demonstrated that lowering cholesterol with statins reduces the risk of stroke in patients with CVD or major CVD risk. A meta-analysis of 26 randomized clinical trials testing statin drugs in such patients showed a relative risk reduction of 21% in stroke.[2] Fatal strokes were reduced, but not significantly, by 9%. There was no increase in hemorrhagic strokes. The statin effect was closely associated with the reduction in low-density lipoprotein (LDL)-cholesterol, which the investigators concluded explained 34%-80% of the observed benefit. Each 10% reduction in LDL-cholesterol was estimated to reduce the risk of all strokes by 13.2%.
Clinicians are currently advised to consider adding a statin in all stroke patients with a history of coronary events such as a myocardial infarction (MI), even when their LDL-cholesterol level is in the normal range. In patients with ischemic stroke and no history of a coronary event, however, no clear recommendations have been available, even though such patients make up 80% of the stroke population. SPARCL is regarded as critical in providing evidence to support -- or refute -- the benefits of statin therapy in the prevention of stroke in patients with cerebrovascular disease but no known CHD.
Patients
Patients were enrolled into SPARCL at 205 study sites in Africa, Australia, Europe, the Middle East, and North and South America.[3] The main entry criteria for men and women were:
Previously documented stroke (ischemic or hemorrhagic) or TIA, 1 to 6 months before randomization
LDL-cholesterol ≥ 100 mg/dL (2.6 mmol/L) and ≤ 190 mg/dL (4.9 mmol/L)
Modified Rankin score ≤3 (ie, functionally independent)
Patients were excluded if they had a history of CHD, significant peripheral vascular disease, atrial fibrillation, prosthetic heart valve, clinically significant mitral stenosis, sinus node dysfunction, uncontrolled hypertension, stroke caused by a revascularization procedure or trauma, subarachnoid hemorrhage, or liver or renal disease or dysfunction.
A total of 4731 patients were enrolled into the trial. The mean age (approximately 62.5 years) and male/female ratio (60%/40%) meant that the SPARCL patients were more representative of the true stroke population, with a substantially higher percentage of women and a mean age approximately 5 years older than the populations of major CHD statin trials. Approximately 20% of the SPARCL patients were current smokers, 62% were hypertensive, 16% had diabetes, and 20% had carotid stenosis.
Thirty percent of the patients had had a TIA and 70% a stroke, of which about 3% were hemorrhagic. Because the patients were selected by the investigators at each site, this did not reflect stroke incidence in the general population, Dr. Welch noted.
Treatment
Within 30 days of initial screening, patients were randomized to receive either atorvastatin 80 mg/day (2365 patients) or placebo (2366 patients). Patients were also counseled to follow the National Cholesterol Education Program (NCEP) Step I diet throughout the study. Concomitant medication reflected a high standard of care in the trial, Dr. Welch noted, with 94% of patients on antiplatelet therapy and 69% on antihypertensive medication, including all of the patients who were hypertensive.
Follow-up was planned for 5 years and patients were followed for a mean of 4.9 years (maximum 6.6 years). There was a 0.5% total loss to follow-up. There was a net difference in statin use between the 2 groups of 78%, reflecting good adherence in the trial, Dr. Welch pointed out.
Primary Endpoint
After prespecified adjustment of data for geographical region, entry event, time since entry event, gender, and baseline age, a statistically significant reduction of 16% was seen in the primary endpoint of the trial, time from randomization to first occurrence of fatal or nonfatal stroke, in the atorvastatin group compared with placebo (Table 1). There was also a significant reduction in fatal stroke and a nonsignificant reduction in nonfatal stroke.