High-Dose Statins Following a Stroke Can Prevent a Second

Review

CHICAGO, Aug. 9 -- Loading up on a statin within six months of a stroke or transient ischemic attack reduced the risk of recurrent stroke or TIA, according to results of a major trial published today.

Lipitor (atorvastatin) at 80 mg/day begun during that period was associated with 2.2% five-year absolute reduction in risk of stroke (P=0.03) and a 16% relative reduction in risk of fatal or nonfatal stroke, found the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial.

Secondary endpoints, with the exception of death, also significantly favored the Lipitor group, reported K. Michael Welch, M.B., Ch.B., of Rosalind Franklin University of Medicine and Science, and colleagues, in the Aug. 10 issue of the New England Journal of Medicine.

These were stroke or TIA (P<0.001); TIA (P=0.004), major coronary event (P=0.003), nonfatal MI (P<0.001), major cardiovascular event (P=0.002), acute coronary event (P=0.001), any coronary event (P<0.001), revascularization (P<0.001) and any cardiovascular event (P<0.001).

There were 216 deaths in the Lipitor arm and 211 in the placebo arm (P=0.98).

It's not news that patients with established cardiovascular disease are less likely to have a stroke if they are taking statins, but Dr. Welch and colleagues wrote that it was unknown whether statins could reduce stroke risk in the absence of established heart disease. SPARCL, they contend, answered that lingering question.

The Lipitor benefit was driven by a reduction in "risk of cerebral infarction, the mechanism of which largely has been attributed in to a reduction in LDL cholesterol levels," they wrote. The mean LDL in the Lipitor group was 73 mg/dL versus 129 mg/dL in the placebo group.

But Lipitor increased the risk of hemorrhagic stroke (hazard ratio 1.66 95% CI 1.08 to 2.55). Of the 88 patients who had at least one hemorrhagic stroke, 55 were in the Lipitor group, they wrote.

Nonetheless, the SPARCL investigators concluded that their data "support the initiation of [Lipitor] treatment soon after a stroke or TIA."

In an accompanying editorial, David M. Kent, M.D., of the Institute for Clinical Research and Health Policy Studies at Tufts-New England Medical Center in Boston wrote that the case for a change in recommendations is not so clear cut.

He pointed out that "the relative risk of hemorrhagic stroke was increased by 66% among patients in the [Lipitor arm], an effect that is likely to be of some import among patients presenting with a hemorrhagic stroke."

He also pointed out the stroke paradox, that there is little epidemiologic evidence linking cholesterol levels to stroke, yet there is convincing evidence that statins prevent stroke. "This so-called stroke paradox can be easily explained, either by the heterogeneous effects of cholesterol on different subtypes of stroke in the epidemiologic studies5 or by the pleiotropic (e.g.,antithrombotic, antiinflammatory, and plaque stabilizing) effects of statins in the clinical trials," he wrote.

Between September 1998 and March 2001, the double-blind SPARCL trial randomized 4,731 patients who had baseline LDL levels of 100 to 190 mg/dL and no known history of coronary heart disease to 80 mg Lipitor or placebo. All patients were enrolled within six months of a stroke or TIA.

The average age of patients was 63 and 60% were men. In both arms the baseline mean LDL levels were about 133 mg/dL. The median duration of follow-up was 4.9 years.

Finally, although Dr. Kent was not persuaded that high dose Lipitor should be recommended for all stroke or TIA survivors, he predicted that the SPARCL trial results are likely to add to the "gathering momentum favoring the promotion of ischemic stroke to a 'coronary heart disease risk equivalent,' the adoption of statin therapy on discharge as a 'quality indicator,' and the inclusion of statins in preprinted stroke orders to improve adherence by physicians."

And all of those changes would be good, Dr. Kent wrote, because statins are currently under prescribed even for patients who are eligible for statin therapy based on current Adult Treatment Panel (ATP) III guidelines of the National Cholesterol Education Program. He concluded, "it does not take a recursive subgroup analysis to show that the greatest current risk to patients with ischemic stroke vis-à-vis statins remains gross under treatment."

The SPARCL trial was supported by Pfizer, maker of Lipitor. Dr. Welch reported having received consulting fees from Eisai, GlaxoSmithKline, Medpointe, AstraZeneca, NMT Medical, and Ortho-McNeil; lecture fees from GlaxoSmithKline; and grant support from Pfizer. Dr. Kent reported having received grant support from Pfizer.