SPARCL: Stroke Prevention by Aggressive Reduction in Cholesterol Levels

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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.

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Although SPARCL was not powered for post-hoc analysis, analysis by type of stroke showed that there were more ischemic strokes, with a 22% reduction in risk (Table 2). A small increase was seen in the number of hemorrhagic strokes in the atorvastatin group, although there was no significant difference between the 2 treatment groups in fatal hemorrhagic stroke. The SPARCL investigators are investigating factors known to be associated with hemorrhagic stroke and trying to identify a phenotype with increased risk, Dr. Welch added.

Secondary Endpoints

Time to stroke or TIA was significantly reduced by 23% and time to TIA by 26% with atorvastatin (Table 3).

Dr. Welch said that it was "with some surprise and rejoicing" that he was able to report that the atorvastatin group also showed a 35% reduction in major coronary events (cardiac death, nonfatal myocardial infarction, or resuscitated cardiac arrest) (Table 4). Since this was a population with no known CVD at baseline, "this could be viewed by some in the cardiology world as primary prevention," he declared. Compared with placebo, major cardiovascular events (major coronary event or stroke) were reduced by 20% in the atorvastatin group, any CHD (acute coronary event, coronary revascularization, or angina/ischemia) by 42%, and any revascularization (coronary, carotid, or peripheral) by 45%.

Mortality

There was no statistically significant difference in all-cause mortality between the 2 groups (Table 5). A trend toward a reduction in cardiovascular mortality was seen with atorvastatin, but there was no difference between the 2 groups with regard to cancer-related mortality.

Safety

"Atorvastatin at high levels was extremely well tolerated," Dr. Welch stated. As expected, atorvastatin was associated with a slight increase in liver enzymes compared with placebo (ALT/AST > 3 x the upper limit of normal [ULN], 2.2% vs 0.4%, respectively), although the incidence was low, especially in a population that was 40% women, Dr. Welch added. There was no difference between the atorvastatin and placebo groups with regard to CPK > 10 x ULN (0.1 vs 0.0%, respectively) or in the incidence of musculoskeletal adverse events (myalgia 5.5% vs 6.0%, respectively, and myopathy 0.3% and rhabdomyolysis 0.1% in both groups).

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Cholesterol-Lowering Effect

Mean LDL-cholesterol at baseline in the SPARCL patients was 133 mg/dL (3.44 mmol/L). After 1 month of treatment, LDL-cholesterol had decreased by 53% in the atorvastatin group compared with a 1% rise in the placebo group. The mean decrease in LDL-cholesterol throughout the study was 38% and 7%, respectively. LDL-cholesterol was 56 mg/dL (1.45 mmol/L) lower in the atorvastatin group throughout the study (mean on-treatment levels, 73 mg/dL [1.89 mmol/L] vs 129 mg/dL [3.34 mmol/L], respectively). The contribution of the reduction in LDL-cholesterol to the reduction in stroke in this study is still under investigation; to date, no pleiotropic effect other than reduction in LDL-cholesterol has been identified, Dr. Welch said.
Treatment Benefit

The SPARCL investigators calculated that the number of patients who need to be treated for 5 years with atorvastatin to prevent 1 stroke is 46; to prevent 1 major cardiovascular event, 29; and to prevent 1 revascularization procedure, 32. Despite the "slight" increase in hemorrhagic stroke, the benefit over risk ratio for atorvastatin was clearly demonstrated: for stroke (11.2% vs 13.1%, respectively, P = .03), "and became clearly apparent" for stroke plus major coronary events (14.1% vs 17.2%, P = .002), Dr. Welch concluded.

Although the main results of the SPARCL data were presented at the conference, Dr. Welch declined to discuss them in detail, since they are in the process of being submitted for publication.

SPARCL was supported by Pfizer.
References
The SPARCL Investigators. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study. Cerebrovasc Dis. 2006;21(suppl 4):1. Abstract 1.
Amarenco P, Labreuche J, Lavallee P, et al. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke. 2004;35:2902-2909. Abstract
Amarenco P, Bogousslavsky J, Callahan AS, et al; SPARCL Investigators. Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study. Cerebrovasc Dis. 2003;16:389-395. Abstract



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