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Interview with Pierre Amarenco, MD on the SPARCL Trial

Pierre Amarenco, MD*

In cardiovascular clinical trials, treatment with statins has consistently been shown to reduce the risk for stroke. However, since statin trials have rarely included substantial numbers of patients with a history of stroke, this evidence supports the effectiveness of statins for primary but not for secondary stroke prevention. The recently concluded Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) ) trial¹ was the first clinical study designed to evaluate the efficacy and safety of statin therapy in the secondary prevention of stroke during the early poststroke period, when the risk for recurrence is highest.**  The trial included 4731 patients with low-density lipoprotein cholesterol levels of 100 to 190 mg/dL and no known coronary heart disease who had had a stroke or transient ischemic attack within the 6 months preceding their enrollment. The patients were randomly assigned to intensive therapy with atorvastatin 80 mg/d or placebo. In an interview with APOLLO, Dr. Pierre Amarenco of Denis Diderot University, Paris, one of the SPARCL investigators, described the results of the SPARCL trial and explained their clinical significance.

Dr. Amarenco, perhaps you could explain the current understanding and opinion with regard to primary and secondary prevention of stroke. 

Dr. Amarenco: Until the SPARCL results were available, the way to prevent stroke in patients who had already had a stroke or transient ischemic attack (TIA) was very simple. It was to give the patient an antiplatelet agent, if indicated, or an oral anticoagulant, following the guidelines, and to lower blood pressure. We know that lowering blood pressure in patients with stroke is the key point, because it may reduce the risk of having another stroke by 40%. 

These 2 strategies have been well known, particularly among neurologists, for decades now. But we lack other strategies, and that is important because patients receiving the preventive treatment just described have significant residual risk. The SPARCL trial was designed to test a new strategy to further decrease this risk; the strategy was to apply knowledge gained in the field of cardiology, and to examine whether lowering LDL-C levels can reduce the risk for stroke.

Statins have been shown to lower the risk for stroke in cardiovascular clinical trials. Why was this study needed?

Dr. Amarenco: Those trials have demonstrated the effectiveness of statins only in primary prevention. We performed a meta-analysis including 90,000 participants in 27 statin trials, most of which had prevention of stroke as a secondary end point, and only 1 of which included a substantial number of patients with a history of stroke.² The meta-analyses showed that, consistently, there was a 21% reduction of relative risk for stroke, with no heterogeneity between trials. So, after all of these trials and this meta-analysis, we could say to physicians: yes, for patients with a history of coronary heart disease, with hypertension, diabetes—patients with high vascular risk—statin treatment can reduce their risk for stroke by 21%.

The next question was, what about secondary prevention?  For this, we had no answer, until now. We only had the data, very slight data, from the Heart Protection Study (HPS).³ The HPS included 20,000 patients. Among them, 3280 had had a stroke before randomization. And it turned out that the incidence of recurrent stroke was 10.4% in the simvastatin arm and 10.5% in the placebo group.

So there was no benefit.

Dr. Amarenco: No benefit—a neutral effect of simvastatin on recurrent stroke. But there are some explanations for this. One main explanation is that the patients with previous stroke were randomized, on average, 4.6 years after the event. We know that the risk for recurrent stroke is very high just after stroke events and decreases over time. After 2 to 3 years it is very low, similar to the risk associated with asymptomatic carotid stenosis, for example. On the other hand, the risk for coronary events increases continuously over time. So in the HPS, the investigators were in a position to detect an effect on the late coronary events, which were reduced in these patients with stroke, but they were not in a position to detect an effect on the early burden of risk after stroke.

Within the first year, for example?

Dr. Amarenco:  Yes. The study did not have the power to find a difference for stroke recurrence—and in any case, recurrent stroke was not a prespecified end point. That is why SPARCL is so important. This was the only trial dedicated to patients with stroke or TIA. All of these patients were randomized within 6 months after their stroke event. So we were in a position to capture this early risk burden of stroke, and since we followed the patients up for 5 years, we were also in a position to capture the late coronary events. One other crucial point is that SPARCL only included patients with no history of coronary events. Roughly 20% of patients with stroke have a history of coronary events; SPARCL addressed the remaining 80% of patients with no known coronary heart disease.

Please describe SPARCL’s study design.

Dr. Amarenco: We randomized patients who had an LDL-C level between 100 and 190 mg/dL, and we were looking for a strong difference between the 2 arms, since we were comparing a high dosage of atorvastatin, 80 mg/d, and placebo. We were looking for an LDL-C reduction of at least 50%. The primary end point was the time to first occurrence of stroke, fatal or nonfatal. The secondary end points were combined end points of stroke and TIA and of all coronary or cardiovascular events. We also examined adverse events, such as myalgia and liver enzyme elevations.

What was found?

Dr. Amarenco: We found a positive effect on the primary end point: a 16% reduction of relative risk for stroke, with an adjusted P value of .03. The P value was adjusted because we had a slight imbalance in age and sex between groups. The patients in the atorvastatin group were 6 months older on average than the placebo group, and more of them were male, so the atorvastatin group was at higher risk with respect to these 2 factors.

The results for the secondary end points in this population with no known coronary heart disease demonstrated a very strong 35% reduction of relative risk for major coronary events in the atorvastatin group, a 42% reduction for all coronary events, and a 45% reduction for revascularization procedures. So, with regard to coronary end points, it was a strongly positive trial.

What sort of LDL-C levels did the patients achieve?

Dr. Amarenco: That is a very good question. The mean LDL-C level was 133 mg/dL at baseline and was reduced, during the trial, to 73 mg/dL in the atorvastatin group, compared with 129 mg/dL in the placebo group. So we had a big difference, which we were looking for, because we knew from meta-analyses that the more you reduce LDL C, the more benefit you may have in stroke risk reduction. So these are the 2 important messages: One, we can reduce the risk for stroke recurrence with these agents. Second, we can reduce the risk for coronary events.

Please tell us about the safety/tolerability results of this trial, particularly as this is high-dose statin therapy.

Dr. Amarenco: In SPARCL, the safety of the drug was very good. It was very well tolerated. There was a slight but significant difference in the percentage of patients who had elevations of liver enzymes, 2.2% in the atorvastatin group versus 0.5% in the placebo group. This was in the range expected in such a statin trial, which is roughly between 2% and 5%; so it was in the lowest part of the expected range.

How about myopathy or myalgia?

Dr. Amarenco: This is a very important point. The trial used 80 mg/d of atorvastatin, with no run-in period, in a fairly elderly population almost all of whom were statin-naïve. We anticipated more frequent muscle adverse events in the atorvastatin arm, but in fact, there were very few cases of myalgia: 123 in the atorvastatin group versus 149 in the placebo group. The difference was not significant, but clearly there was no elevation, whatsoever, in myalgia. The result was the same for myopathy; with 7 cases in each group, and for rhabdomyolysis, with 2 cases in the atorvastatin group versus 3 in the placebo group. The HPS trial, by way of comparison, used a 6-week run-in period with simvastatin 20 mg/d, and patients were then randomized if they were statin tolerant. Simvastatin treatment had a very good safety profile in the HPS. Likewise, atorvastatin treatment had an excellent safety profile in SPARCL, but it is worth emphasizing that in this trial we used a high dose of atorvastatin with no run-in period.

I think it is very important that, altogether, with the TNT [Treating to New Targets] trial,⁴ with IDEAL [Incremental Decrease in End Points Through Aggressive Lipid Lowering],⁵ and  SPARCL, we can say that intensive statin therapy (atorvastatin 80 mg/d) has a very good safety profile, because there is no elevation of the frequency of muscle adverse events. As David Waters said, this treatment is much better tolerated than aspirin. We now have to convince practitioners that they don't have to worry about using the 80-mg dose of atorvastatin. It is very well tolerated, it has been tested, and we now have an evidence base. We ought to prescribe this treatment for those of our patients who can benefit from aggressive lipid lowering.

Some subset analyses were done in SPARCL. One was a prespecified analysis of fatal stroke and nonfatal stroke. Fatal stroke was shown to be reduced by 43%. This is the first time that we have been in a position to show that fatal stroke can be reduced significantly (P = .03) with a statin. Admittedly, the numbers were very small and did not have an impact on global cardiovascular mortality or total mortality. The trial was not powered to find a difference on vascular mortality or total mortality. For that, perhaps 50,000 patients would have been needed. But there was a trend toward a reduction in vascular mortality (22% relative risk reduction; P = .11). Total mortality was equal in both groups, and there was no increase in cancer, lymphoma, or suicide attempts; the groups were well balanced for the other causes of mortality.

Nonfatal stroke was also reduced, but the reduction did not reach statistical significance. However, in this kind of subanalysis it is important to look for heterogeneity. There was no heterogeneity between groups or between fatal stroke and nonfatal stroke. Since there was no heterogeneity, we have to speculate there was also a reduction in nonfatal stroke.

Tell about the difference between hemorrhagic stroke and ischemic stroke.

Dr. Amarenco: The first occurrence of ischemic stroke was reduced by 22%, which was well in line with the meta-analysis (21%). There were 55 hemorrhagic strokes in the atorvastatin group and 33 in the placebo group; the difference was significant, with a hazard ratio of 1.66. This was a significant but slight increase. Furthermore, in such an analysis, the possibility must be considered that the results are due to chance, because a post-hoc analysis does not allow control for all other risk factors. There are well-known risk factors for brain hemorrhage: uncontrolled hypertension, oral anticoagulants, dual antiplatelet therapy, and previous brain hemorrhage. It is possible that, by chance, there was also an imbalance in these other risk factors for brain hemorrhage. We did this analysis in SPARCL, and we will present it at the next American Stroke Association meeting. 

We'll look forward to that.

Dr. Amarenco: Also, as you know, I presented this on-treatment analysis at the Barcelona meeting. What I can say today [before the publication of the subset analysis] is that the subgroup with a mean LDL-C reduction of more than 50% had the greater benefit, with a 31% percent reduction in relative risk for stroke; and in this subgroup there was no brain hemorrhage. What this analysis tells us is that the group of patients with profound LDL-C reduction had no increased risk for brain hemorrhage, and this group probably includes the patients most adherent to therapy. These results tell us that the increase of brain hemorrhage has nothing to do with profound LDL-C reduction or atorvastatin 80 mg/d and is most likely due to an imbalance between the 2 groups in other risk factors for brain hemorrhage. This analysis will be presented at the American Stroke Association meeting.

Dr. Amarenco, in conclusion, what do you think are the immediate clinical implications of the SPARCL results?

Dr. Amarenco: The clinical implications are fairly simple for me. We now have evidence that treatment with atorvastatin 80 mg/d soon after a stroke or TIA reduces the risk for recurrent stroke and for coronary events, with a very good safety profile. In my opinion, the appropriate recommendation would be to treat all patients with stroke who meet the SPARCL inclusion criteria with atorvastatin 80 mg/d. In SPARCL we excluded patients with coronary heart disease, but those patients already have a good indication for intensive statin therapy. Another group excluded from SPARCL was patients with cardiac embolism. High-dose statin therapy is not indicated for patients in the groups excluded from SPARCL, with the exception of those with previous coronary heart disease, who should receive statins also.

I think that the next step is to have these data included in the treatment guidelines that are generated by the European and American associations, to affirm that these results are important and should be the basis of our practice. Then we have to teach general practitioners, neurologists, and cardiologists that we now have a third line on our prescription list. Antiplatelet agents, blood pressure–lowering therapy, and now atorvastatin 80 mg/d. For me, this is the most important advance in stroke prevention since the adoption of those other 2 treatments.

Disclaimer

This editorial is intended for use by health care professionals for educational purposes only. The information conveyed and opinions expressed by the author in this editorial represent his own views, which do not necessarily reflect those of the APOLLO Steering Committee, The FCG Institute for Continuing Education, or AstraZeneca Pharmaceuticals LP. The posting of this editorial on cvspectrum.org does not imply endorsement either of the content or of the viewpoint expressed by the author.

 
References
1. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006; 355:549-559.
2. Amarenco P, Labreuche J, Lavallée P, Touboul PJ. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke. 2004;35:2902-2909.
3. Collins R, Armitage J, Parish S, Sleight P, Peto R. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in 20536 people with cerebrovascular disease or other high-risk conditions. Lancet. 2004;363:757-767.
4. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435.
5. Pedersen T, Faergeman O, Kastelein J, et al. High-dose atorvastatin versus usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. JAMA. 2005;294:2437-2445.

**The use of atorvastatin or other statins for the secondary prevention of stroke is not an FDA-approved indication.

*Pierre Amarenco, MD
Professor and Chairman, Department of Neurology and Stroke Center
Bichat University Hospital
Denis Diderot University and Medical School
Paris, France

Biographical Sketch

Pierre Amarenco is Professor and Chairman of the department of neurology and stroke center at Bichat University Hospital, Denis Diderot University and Medical School, Paris, France. Professor Amarenco’s main research interest is in understanding and preventing stroke. He is currently Principal Investigator of the GÉNIC study, which is assessing the genetic profile of stroke; of the Multiple Atherosclerotic Sites in Stroke Study (MASS), which is evaluating arterial and cardiac risk factors for ischemic stroke in a large autopsy data bank; of the Aortic arch Related Cerebral Hazard (ARCH) trial, which is assessing the benefit/risk of warfarin vs. clopidogrel plus aspirin in patients with stroke or TIA and plaque in the thoracic aorta greater than 4 mm in thickness; of the Lacunar Bain Infarction, Cerebral Hypereactivity, and Atorvastatin Trial (Lacunar-B.I.C.H.A.T.); The Bichat-TIA study; The TRUST-TPA trial which is evaluating remote decision for tPA treatment via visioconference vs. tPA after transfer; and of the AMISTAD study which is evaluating the prevalence of coronary and carotid atherosclerosis in TIA/stroke patients. He is also involved in several on-going epidemiological studies on carotid intima-media thickness. Professor Amarenco currently serves on the Steering Committee of the Stroke Prevention by Aggressive Reduction of Cholesterol Levels (SPARCL) study, on the Executive Committee of the PERFORM trial, on the Steering Committee of the CASTIA trial and on the Data Safety Monitoring Board of the CHARISMA trial. He is the Funding Editor-in-Chief for La Lettre du Neurologue and served on Editorial Board of many other internationally renown journals such as Stroke. Professor Amarenco has presented nearly 130 lectures in meetings worldwide and has published over 150 articles in peer-reviewed journals including 3 as first author in the New England Journal of Medicine, and 38 book chapters.

Faculty Disclosure Statement
Dr. Amarenco has indicated that he has no financial interests or relationships to report.