SPARCL published: Statins should be a part of preventive management in stroke patients

Shelley Wood

August 09, 2006

Boston, MA - Statin therapy should be initiated soon after stroke or transient ischemic attack (TIA) to reduce the risk not only of stroke, but also coronary events, even in patients with no prior cardiovascular disease (CVD), results from the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial show. The findings, first reported by heart wire in May 2006 when they were presented at the 15th European Stroke Conference, are now published in the August 10, 2006 issue of the New England Journal of Medicine [1].

I think that, in practice, physicians will start to call for adding statins in folks who are admitted to the hospital with a stroke or TIA as part of the established preventive management of these patients.

With only a few months for the trial results to be absorbed by clinicians since the data were first unveiled, primary investigator for the study, Dr Michael Welch (Rosalind Franklin University of Medicine and Science, Chicago, IL), said it is too soon to know what their impact will be. Already, however, "most of the vascular neurologists that I've talked to now believe that this will become an established part of the way patients are managed after they've had a stroke or a TIA, in addition, of course, to the rigorous control of blood pressure and the use of antiplatelet medications," Welch told heart wire .

SPARCL: Main findings

SPARCL was the first trial to specifically look at the effect of a statin—atorvastatin—in patients with a prior stroke or TIA but with no history of elevated cholesterol or coronary artery disease. The study randomly assigned 4731 patients with a stroke or TIA within the past one to six months to either atorvastatin 80 mg/day or placebo. The mean baseline LDL cholesterol in SPARCL participants was 133 mg/dL (2.6 to 4.9 mmol/L) but dropped to a mean level of 73 mg/dL (1.9 mmol/L) in the atorvastatin-treated patients during the trial, a 37% reduction. LDL levels fell by 7% during the study over the mean 4.9-year follow-up.

This appeared to translate into a significant reduction in the primary end point of nonfatal or fatal stroke, which occurred in 11.2% of atorvastatin-treated patients and 13.1% of placebo-treated patients, a five-year absolute reduction in risk of 2.2% and an adjusted hazard ratio of 0.84 (adjusted p=0.03). No significant differences were seen between the two groups in terms of adverse events. The treated group also showed significant reductions in fatal stroke, ischemic stroke, and a trend toward fewer nonfatal strokes, but a slight increase in hemorrhagic stroke, with a hazard ratio of 1.66. Strikingly, given the lack of baseline CVD in the SPARCL cohort, risk of major coronary events was also significantly reduced in the atorvastatin-treated patients, at a rate of 3.4% vs 5.1% (p=0.003).

-SW

"Certainly the cardiologists love this study," Welch told heart wire , "because for them it's actually a primary-prevention study. Here we have patients who have no known cardiovascular disease who have had a stroke or TIA, and there was a 35% reduction in heart disease, which is quite extraordinary. I think that, in practice, physicians will start to call for adding statins in folks who are admitted to the hospital with a stroke or TIA as part of the established preventive management of these patients."

Hemorrhage risk should be considered

As noted in previous heart wire coverage of the SPARCL trial, the apparent increased risk of hemorrhagic stroke was included in the overall stroke analysis, suggesting a net benefit for statin use. Commenting on the issue, Welch emphasized that the increased hemorrhagic stroke in atorvastatin-treated patients, while small (2.3% in the atorvastatin arm vs 1.4% in the placebo arm), has also been seen in other statin trials.

"It's a concern, enough for us to do further analyses to see whether we can identify those patients who might be at risk so they can be managed in a different way," Welch told heart wire . "We will certainly look at those conditions like age, male gender, and blood pressure before the event, which are well-known to be associated with a risk of hemorrhage into the brain, and we'll see if there's some kind of imbalance between the two groups that might have accounted for this."

At the same time, he cautioned, "The people who do have hemorrhage also are at risk for heart disease and stroke: they all have hypertension, they all have problems with their lipids and cholesterol, with obesity, etc, so they will need protection. And in the [SPARCL] study, the benefits in preventing stroke and heart disease—which was remarkable since these folks had no known heart disease to start with—those benefits far outweigh the small increased risk of hemorrhage."

In the paper, the authors advise that the potential risk of recurrent hemorrhage "be considered when one is deciding whether to administer a statin to patients who have had a hemorrhagic stroke."

A question of timing

Welch also emphasized the "critical" importance of timing of statin treatment, noting that, in the Heart Protection Study (HPS), which also included patients with previous stroke or TIA but no established CVD, no benefit of statin treatment was seen in this group.

"If you have a stroke or a TIA your risk of having another one in the next five years is about 40%, but the HPS began to recruit patients about four years after their stroke or TIA. So our feeling was that it would have been much tougher to show a difference when treating after four years than within the first six months. And that's when you really want to treat these folks, because the risk is so high within the next four years, not only for stroke but for death."

Statins, still debatable, but perhaps a place to start

In an editorial accompanying the SPARCL results, Dr David M Kent (Tufts-New England Medical Center, Boston, MA) observes that while the SPARCL results are "roughly consistent" with the stroke benefits seen in heart-disease trials, questions about the link between cholesterol lowering and stroke prevention remain.

Stroke etiology is much more heterogeneous than heart attacks, he notes, and only a minority of strokes are caused by large-vessel atherothrombosis. Yet, SPARCL enrolled patients with not only ischemic strokes but also hemorrhagic, embolic, lacunar, and cryptogenic strokes/TIAs, while patients with atrial fibrillation and other cardiac sources of emboli were excluded. Cardioembolic strokes are less likely than other types of ischemic stroke to be responsive to cholesterol-lowering agents, Kent points out.

"This raises the issue of whether the SPARCL results apply to the roughly one in five ischemic strokes that are cardioembolic in origin," Kent writs. "The heterogeneity of the patients enrolled in the trial, in terms of not only the cause of stroke but also vascular risk, is important to keep in mind in the interpretation of the results, since the rate of fatal or nonfatal stroke was relatively low and the absolute benefit of treatment with atorvastatin was relatively modest. A modest overall benefit across a heterogeneous population often obscures a more dramatic treatment effect in an influential subgroup among others that are highly unlikely to benefit."

It does not take recursive subgroup analyses to show that the greatest current risk to patients with ischemic stroke vis- à -vis statins remains gross undertreatment.

Kent also points out that 20% of SPARCL participants had diabetes, and while Framingham risk scores were not provided in the paper, extrapolating from event rates in the placebo-treated patients would suggest that the cohort as a whole likely had a 10-year CHD risk of roughly 10%. Thus, according to the ATP III criteria for statin therapy, "even without any change in guidelines, it is apparent that many of the patients enrolled would already qualify for statin therapy," Kent writes.

All the same, he concludes, the SPARCL results will likely add to the mounting momentum behind adding ischemic stroke as a CHD risk equivalent and the inclusion of statins in stroke prevention guidelines and quality performance indicators.

"Those who might object to this collective-treatment approach to such a heterogeneous disease should be reminded of our abysmal performance as individual doctors taking care of individual patients. . . . Although we can all agree with the calls for careful science and although we await the various SPARCL substudies to help clarify some controversies, it does not take recursive subgroup analyses to show that the greatest current risk to patients with ischemic stroke vis-à-vis statins remains gross undertreatment."

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