High-dose statins could become part of standard aftercare for first-time ischemic stroke and transient ischemic attack (TIA) patients, based on the results of a new study published last month (N Engl J Med 2006;355:549–559).
Data from the Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial, initially presented last May at the 15th European Stroke Conference in Brussels, Belgium, show that a daily regimen of 80 mg/dl atorvastatin (Lipitor), started within four months after an initial stroke, significantly reduced subsequent cerebrovascular and cardiovascular events in patients without a history of heart disease or cholesterol problems.
The five-year multicenter, double-blind, randomized, placebo-controlled trial found a 16 percent relative reduction (2.2 percent absolute reduction) in fatal and nonfatal strokes in treated patients compared to controls. However, an analysis of data, conducted after the study ended, showed that 85 percent of the strokes were ischemic and when only these patients were considered, there was a 22-percent reduction, according to principal investigator K. Michael Welch, MD, Professor of Neurology and President of Rosalind Franklin University of Medicine and Science in Chicago.
Treatment also reduced patients' risk of heart attack and other major coronary events by 35 percent and the need for coronary revascularization procedures by 45 percent. The trial was sponsored by Pfizer, Inc., which markets atorvastatin.
Atorvastatin was well tolerated, with only a slight rise in liver enzyme levels, and there was a slight increase in hemorrhagic strokes in treated patients, but because the number of such strokes was small, the researchers could not reach any meaningful conclusions, Dr. Welch told Neurology Today in a telephone interview.
At enrollment, about 66 percent of the patients had experienced an ischemic stroke, 2 percent had suffered a hemorrhagic stroke, and 30 percent had experienced TIA for the first time. There were 265 fatal or nonfatal ischemic strokes in treated patients over the five-year follow-up period, compared to 274 in untreated patients, and 55 hemorrhagic strokes, versus 33 in the placebo group, although the mortality rate was similar in both cohorts.
“These data are important for neurologists because our current treatment options to reduce second strokes are very limited,” Dr. Welch told Neurology Today. “The cardiovascular findings were quite surprising because this is a population not known to have had heart disease,” he added.
A total of 4,731 patients were recruited at 205 study sites in Africa, Australia, Europe, the Middle East, and North and South America. Other medications being taken in the placebo and atorvastatin groups included antiplatelets (94.1 percent, 93.6 percent) and antihypertensives (69 percent, 68.7 percent) agents, as well as simvastatin (11.0 percent, 4.7 percent) for a 78 percent net difference in statin use.
The findings should provide sufficient evidence to make statins an established part of secondary stroke prevention for ischemic strokes and TIAs, together with blood pressure control, anti-platelet medications, and lifestyle changes, according to Dr. Welch.
A 2004 Advisory Statement from the Stroke Council, the American Heart Association, and the American Stroke Association, based on 226 large-scale randomized trials, stated that “the vast majority” of patients with a history of ischemic stroke or transient ischemic attack could benefit from statins (Stroke 2004;35:1023). In that meta-analysis, statins as a class reduced strokes by 21 percent, and for every 10 percent reduction in LDL cholesterol there was a 15.6 percent reduction in stroke risk.
Larry B. Goldstein, MD, Director of the Duke University Center for Cerebrovascular Disease and Stroke Center in Durham, NC, and a member of the independent SPARCL steering committee, called the results “extremely encouraging,” and agreed that statins should become part of standard aftercare. “The results of this trial have been long awaited and much anticipated,” he told Neurology Today in a telephone interview. “It provides a missing piece to the puzzle of what we can do to prevent second strokes.”
HEMORRHAGIC STROKE CONCERNS
More treated patients in the study experienced hemorrhagic strokes (2.3 percent) than did patients taking placebo (1.4 percent), and Dr. Welch said the researchers are currently examining different factors that might explain the finding, such as age, gender, hypertension at time of hemorrhage, medications, and other factors.
In an accompanying editorial, David M. Kent, MD, Associate Professor of Medicine at the Institute for Clinical Research and Health Policy Studies at Tufts-New England Medical Center in Boston, expressed concern about the hemorrhagic stroke risk data, but he told Neurology Today that first-time ischemic stroke and TIA patients are at little risk, based on an analysis of the data.
“I think for people who have had a first ischemic stroke there isn't much reason for concern. But for those with hemorrhagic stroke there is some concern. Unfortunately, in the SPARCL trial both types of strokes were included. The risk of a second hemorrhagic stroke was pretty high, but the incremental risk for the vast majority of these patients is very low.”
Dr. Kent said the “real problem” is getting neurologists to prescribe statins when patients might benefit. Because statins are currently under-prescribed, even among patients who are candidates based on current Adult Treatment Panel (ATP) III guidelines of the National Cholesterol Education Program, it is unclear what impact the SPARCL results will have on treatment of first-time stroke and TIA patients, he said.
USING OTHER STATINS
Mitchell S. Elkind, MD, Associate Professor of Neurology at Columbia University Medical Center's Neurological Institute and Neurological Intensive Care Unit, in New York, said many first-time stroke patients are already being placed on statins by neurologists.
“I think SPARCL confirms what most of us have suspected. This study should help spread the word,” he said. But he added that he doubts the benefits are exclusive to treatment with atorvastatin, and that other statins probably have the same protective effect.
“Most of the evidence suggests that because all statins lower cholesterol, they should yield similar benefits in these patients. My suspicion is that this is a class effect. But that's one of the limitations of the study, in my opinion – they didn't test other statins. Overall, though, it's a step in the right direction.”
Dr. Kent agreed: “I think there is a lot of evidence that this is a class effect, and the benefits demonstrated here are probably uniform for all statins. That is certainly true for patients with myocardial infarction, and there is no reason to think it would be different in stroke prevention.”
ARTICLE IN BRIEF
- ✓ New data from a large placebo-controlled trial show that a daily regimen of 80 mg/dl atorvastatin, started within four months after an initial stroke, significantly reduced subsequent cerebrovascular and cardiovascular events in patients without a history of heart disease or cholesterol problems.