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Release Date: September 21, 2006
The efficacy of statin therapy in primary and secondary prevention of coronary heart disease (CHD) has been well documented. Since the first major clinical trials of secondary CHD prevention -- the Scandinavian Simvastatin Survival Study (4S)[1] and the Cholesterol and Recurrent Events (CARE)[2] trial -- the effect of these drugs on preventing a first stroke has also been noted.
In 2004, Pierre Amarenco, MD, and colleagues published a meta-analysis of the effects of statin treatment on stroke prevention in 26 randomized clinical trials of primary or secondary prevention of CHD and found that statin therapy was associated with an incidental relative risk reduction of 21% in all strokes (P < .0001) (Figure).[3] The risk of fatal strokes was reduced by 9%, although the reduction was not significant. In addition, use of statin treatment was not associated with an increase in the incidence of hemorrhagic strokes.
However, it is important to note that all of the data available on statin treatment in the prevention of recurrent stroke were from clinical trials carried out in patients with CHD or with only CHD risk factors. Yet, although there are no hard data, it is thought that at least one quarter of ischemic stroke patients present with no underlying CHD, and thus, no prima facie reason to be on a statin. This left the question, then, of whether statins offered protection against recurrent stroke as opposed to being simply an incidental benefit of the therapy in patients traditionally thought to need statins.
A further important refinement for clinicians to define which patients should be assigned to statin therapy emerged from the Heart Protection Study (HPS).[4,5] This trial evaluated the effect of simvastatin 40 mg/day vs placebo in men and women with coronary disease, other occlusive arterial disease (eg, cerebrovascular disease), or diabetes and total cholesterol ≥ 135 mg/dL (3.5 mmol/L). Overall, the HPS showed a highly significant 25% reduction in the risk of stroke for simvastatin vs placebo (P < .0001), reflecting a 28% reduction in the risk of presumed ischemic stroke (P < .0001), but no apparent difference in the risk of hemorrhagic stroke.[5]
In a prespecified subanalysis,the patients with preexisting cerebrovascular disease randomized to statin treatment showed a significant reduction in the incidence of coronary events and revascularizations, but no reduction in the rate of stroke.[5] Of these patients, 1820 had no history of CHD, but were not analyzed separately from the total group with prior cerebrovascular disease. Therefore, HPS failed to distinguish the benefit of statin treatment as protection against recurrent stroke.
Against this background, it was seen as important to assess the potential benefit of statin therapy as protection against cerebrovascular events, irrespective of the presence of underlying cardiovascular disease or disease risk, with a controlled, randomized, multicenter clinical trial. To this end, the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)[6,7] trial was set up as the first study designed primarily to prospectively evaluate the effects of statin treatment in secondary stroke prevention.
Epidemiologic studies have generally not found relationships between cholesterol levels and stroke risk. In the meta-analysis by Amarenco and colleagues,[3] however, the size of the statin effect was closely associated with the degree of reduction in low-density lipoprotein (LDL) cholesterol, which explained 34% to 80% of the observed benefit, they suggested. From this finding, they concluded that each 10% reduction in LDL-cholesterol was estimated to reduce the risk of all strokes by 13.2%. However, there is some doubt in the medical community that the reduction in LDL-cholesterol directly mediates the effect on stroke, and some contend that this reduction is instead only an indicator of adherence and a marker for other actions. These discrepancies are sometimes called the "cholesterol paradox."
Medscape: To what extent are lipids or cholesterol levels considered risk factors for first or second stroke?
Dr Goldstein: I think there are 2 points about this. One is that epidemiologic data can be misleading, because studies generally combine all kinds of strokes into one group. Data from the Multiple Risk Factor Intervention Trial (MRFIT)[8] study, however, showed a positive relationship between increasing cholesterol and ischemic stroke and a negative relationship between cholesterol levels and hemorrhagic stroke. The primary prevention guidelines from the American Heart Association/American Stroke Association Stroke Council[9,10] state that dyslipidemia (high total cholesterol or low high-density lipoprotein cholesterol) carries a relative risk of 1.5- to 2.5-fold for ischemic stroke. So it depends on the type of stroke and how the data are interpreted.
The second part of this paradox is that lipid-lowering therapies in general do not seem to necessarily decrease the risk of stroke. There have been a number of studies on diet, fibrates, resins, and omega-3 fatty acids, which may decrease other cardiovascular events, but none of them has been associated with a reduction in the risk of stroke. Again, this may be in part because compared with cardiovascular events, stroke occurs in a relatively smaller number of patients. However, statins are associated with about a 20% relative risk reduction in stroke, again predominantly in patients with CHD, and it is not necessary to invoke anything other than LDL-cholesterol lowering to explain the benefits or the effects of statins, just as statins are much more potent at lowering LDL-cholesterol than other classes of lipid-lowering agents. As noted in the 2004 meta-analysis, for every 10% lowering of LDL-cholesterol there is a 13% relative risk reduction in stroke. That is not to say that there are not other, so-called pleiotropic effects that are occurring that may be contributing to the benefit.
Medscape: At the time that SPARCL was designed, what were the recommendations about prescribing statins to patients with cerebrovascular disease but no CHD?
Dr. Goldstein: The third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) (ATP III) guidelines, published in 2001,[11] said that carotid disease and carotid stroke or transient ischemic attack (TIA) could be considered as a CHD equivalent. That was based mainly on epidemiologic data showing that over the long term, the major secondary morbidity or mortality in patients who have carotid disease is from coronary disease. So the idea was that carotid stenosis or carotid distribution stroke or TIA was a marker for atherosclerotic disease and as such is a risk factor equivalent to having CHD. But there were no prospective randomized data showing that that was the case. It also did not specifically refer to patients who had no known CHD at the onset.
Even though the recommendation was there, it was not based on the types of patients that were in SPARCL (ie, patients who have had stroke or TIA without CHD). Until SPARCL, the benefit of statin therapy for patients with recent cerebrovascular disease and no history of CHD was uncertain. SPARCL was designed as a critical test to provide evidence to support -- or refute -- the benefits of statin therapy in these patients.
SPARCL was a prospective, multicenter, international, double-blind, randomized, placebo-controlled trial designed to evaluate the effects of atorvastatin 80 mg/day on specified cerebrovascular (primary) and cardiovascular (secondary) endpoints in patients with a recent stroke or TIA but with no known CHD.[6] Entry criteria for the trial included:
Patients were excluded if they had any of the following:
A total of 4731 patients were enrolled at 205 study sites worldwide.[3] Within 30 days of initial screening, patients were randomized to receive either atorvastatin 80 mg/day (n = 2365) or placebo (n = 2366). Patients were also counseled to follow the NCEP-ATP III Step 1 diet throughout the study.[11] Follow-up was scheduled at 1, 3, and 6 months after enrollment, and every 6 months thereafter.
Medscape: Why were patients with hemorrhagic stroke included in SPARCL?
Dr. Goldstein: The reasoning at the time was that, very often, patients who have hemorrhagic stroke have much the same risk factors as patients with ischemic stroke. Obviously, SPARCL was a study aimed at ischemic stroke; only about 2% of the patients in the entire study had a brain hemorrhage at onset.
Medscape: Although approximately 1 in 5 ischemic strokes are embolic, patients with a history of atrial fibrillation and other cardiac sources of embolism were excluded from the trial. Why was this?
Dr. Goldstein: Patients with cardioembolic strokes were excluded because many such patients have CHD, and we did not think that CHD patients should be included in the study because we already knew that these types of patients benefit from statins. Whether patients who have cardioembolic strokes but who do not have CHD might also benefit from statins is not known. Some patients that had post-randomization stroke might have developed cardioembolic causes later on. This can be looked at in future analyses, but drawing any treatment conclusions from posthoc analyses is hazardous because patients were not prospectively randomized according to those features, and erroneous conclusions might be drawn.
Medscape: Was the SPARCL population representative of the stroke population in real life?
Dr. Goldstein: The SPARCL patients were generally representative of the stroke population seen in general practice, with a mean age of 62.5 years (about 5 years older than the mean in major CHD trials) and a male/female ratio of 60% to 40%. In addition, about 20% of the SPARCL patients were current smokers, 62% were hypertensive, 16% had diabetes, and 20% had carotid stenosis. They were a fairly broad range of patients, and again, the reason they were selected was that it had not been shown in a randomized clinical trial that they would benefit from statin therapy. None of the patients who should have been on a statin based on what we knew before SPARCL were included, since we obviously wouldn't want to randomize such patients to a placebo.
Medscape: Was the dose of atorvastatin used in SPARCL the highest available?
Dr. Goldstein: Yes, and there was no run-in period in the trial. Patients were started on atorvastatin 80 mg/day straightaway after randomization.
Medscape: What other medications were the patients taking during the SPARCL trial?
Dr. Goldstein: Concomitant medication reflected a high standard of care in the trial, with 94% of patients on antiplatelet therapy and 69% on antihypertensive medication, including almost all the patients who were hypertensive (Table 1). Patients in clinical trials tend to get optimal care. The use of antithrombotic drugs such as aspirin or warfarin in SPARCL was extraordinarily high. The use of antihypertensive drugs in patients with hypertension was almost universal, in addition to instruction about diet, exercise, and smoking cessation.[7]
| Atorvastatin (%) | Placebo (%) | |
|---|---|---|
| Aspirin/antiplatelet drug excluding heparin | 93.6 | 94.1 |
| ACE inhibitor | 46.9 | 46.8 |
| Dihydropyridine derivative | 29.6 | 27.8 |
| Beta-blocker | 31.5 | 33.4 |
| Angiotensin receptor blocker | 14.8 | 14.1 |
| Vitamin K antagonist including warfarin | 12.2 | 12.4 |
| Open-label statin | 11.4 | 25.4 |
ACE = angiotensin converting enzyme
Medscape: Why were some of the patients placed on open-label statins?
Dr. Goldstein: If, for any reason, a doctor or a patient thought that they should be on a statin, they then dropped out of the randomized treatment group and went on to open-label statins. That could happen either in the group that was randomized to active treatment or in patients randomized to placebo. Then there were people who just discontinued statins, for whatever reason. Many of the people who had been randomized to atorvastatin and dropped out, opting to take an open-label statin, actually then chose [to go back on] atorvastatin, as did those who dropped out of the placebo group (5.1% in the atorvastatin group and 13.0% in the placebo group). Nevertheless, the overall net difference in statin use between the 2 groups was 78.1%.
The mean LDL-cholesterol level during the trial in the atorvastatin group was 73 mg/dL (1.9 mmol/L), and in some patients LDL-cholesterol was reduced as low as 40 mg/dL (1.0 mmol/L) (Table 2).
| Mean Level | Atorvastatin mg/dL (mmol/L) |
Placebo mg/dL (mmol/L) |
P |
|---|---|---|---|
| At baseline | 132.7 (3.43) | 133.7 (3.46) | -- |
| During trial | 72.9 (1.89) | 128.5 (3.32) | < .001 |
Medscape: Isn't LDL cholesterol ≤ 70 mg/dL (1.81 mmol/L) associated with an increased risk of hemorrhagic stroke?
Dr. Goldstein: That again is based predominantly on epidemiologic studies, which find this inverse relationship, with an increase in ischemic stroke with higher cholesterol levels and an increase in hemorrhagic stroke with lower cholesterol levels. That has not been seen in clinical trials. If you look at the 2004 meta-analysis of statin trials in patients with CHD,[3] none of the individual trials found an increased risk of hemorrhage with decreasing LDL levels < 70 mg/dL.
In SPARCL, physicians were alerted if the LDL-cholesterol level fell ≤ 40 mg/dL, and levels were measured in that patient and a randomly selected patient on placebo to maintain the blinding.
The primary outcome of SPARCL was a first nonfatal or fatal stroke. During a median follow-up of 4.9 years, the primary endpoint occurred in 265 patients (11.2%) in the atorvastatin arm and 311 patients (13.1%) in the placebo arm.[7] After prespecified adjustment of data for geographic region, entry event, time since entry event, gender, and baseline age, a statistically significant risk reduction of 16% (HR 0.84, P = .03) in the primary outcome was seen for atorvastatin vs placebo . In addition, atorvastatin was associated with a significant reduction in the risk of fatal stroke and a nonsignificant risk reduction in nonfatal stroke relative to placebo (Table 3).
| Atorvastatin (No. [%]) |
Placebo (No. [%]) |
HR | 95% CI | P | |
|---|---|---|---|---|---|
| Fatal/nonfatal stroke | 265 (11.2) | 311 (13.1) | 0.84 | 0.71-0.99 | .03 |
| Fatal stroke | 24 (1.0) | 41 (1.7) | 0.57 | 0.35-0.95 | .03 |
| Nonfatal stroke | 247 (10.4) | 280 (11.8) | 0.87 | 0.73-1.03 | .11 |
CI = confidence interval; HR = hazard ratio
Medscape: Looking at Table 3, we see that the 16% reduction in stroke risk was not as large as the stroke reduction of approximately 21% observed in statin trials of patients with established cardiovascular disease. What is the likely explanation for this?
Dr. Goldstein: Again, as Amarenco and colleagues showed, this higher rate was seen in patients with CHD, not in patients who had had a stroke or a TIA. It is difficult to know what to expect in a patient population that has not been studied before. The other thing to keep in mind is that this benefit was, as we just discussed, added on to best medical therapy as far as could be delivered. This was also an intention-to-treat analysis, not an on-treatment analysis. In the end, the difference in statin use between the 2 groups was 78%; had there been a 100% difference (ie, complete compliance, with no drop-outs or drop-ins), the reduction in risk of stroke may very well have been greater. But that is not the way trials are analyzed.
Analysis of the primary outcome in SPARCL showed that there were significantly fewer ischemic strokes in the atorvastatin group, a 22% reduction in risk (Table 4). However, a small increase was seen in the number of hemorrhagic strokes in the atorvastatin group, with no significant difference between the 2 treatment groups with regard to the risk of fatal hemorrhagic stroke.
Table 4. SPARCL: Analysis of Primary Outcome by Type of Stroke
| Type of Stroke | Atorvastatin (No. [%]) |
Placebo (No. [%]) |
HR | 95% CI | P |
|---|---|---|---|---|---|
| Ischemic | 218 (9.2) | 274 (11.6) | 0.78 | 0.66-0.94 | .01 |
| Hemorrhagic | 55 (2.3) | 33 (1.4) | 1.66 | 1.08-2.55 | .02 |
CI = confidence interval; HR = hazard ratio
Medscape: How can one account for the finding of a small increase in the number of hemorrhagic strokes in the atorvastatin group, but no difference in the rate of fatal hemorrhagic stroke between the 2 groups?
Dr. Goldstein: We thought it was important to analyze the different types of stroke events, but it is important to remember that this was a posthoc analysis and that it was based on a relatively small number of events. Because it was a small number of patients, our ability to probe this is going to be limited. The other thing to keep in mind is that the overall benefit -- the 16% reduction in the risk of fatal and nonfatal stroke -- also included hemorrhagic strokes. We did not separate those out from ischemic strokes. The overall effect included all types of stroke. Whether this is an aberration is difficult to say, but we will be carrying out other analyses to try to better understand the observation.
The only other relevant information we have -- the only population with any sizable numbers of patients with prior stroke -- comes from the HPS study, and interestingly, looking at the patients 4.3 years afterwards, the effect on hemorrhagic stroke and ischemic stroke appeared to be heterogeneous, meaning that the benefit was not the same.[5] There was a tiny number of patients with hemorrhages in HPS (of the patients with prior cerebrovascular disease, only 21 patients on statin therapy and 11 on placebo had hemorrhagic stroke).[5] Although it is impossible to draw conclusions with such small numbers, [in SPARCL] we saw potentially the same type of effect. However, it is like anything else in medicine: No matter what we do, there is always a potential risk -- but the benefits have to include that risk, and that is the way this analysis was done.
In SPARCL, the 5-year absolute reduction in the risk of major cardiovascular events (major coronary event or stroke), CHD (acute coronary event, coronary revascularization, or angina/ischemia), and revascularization (coronary, carotid, or peripheral) was significantly reduced in the atorvastatin group. The statin regimen reduced the risk of major coronary events by 35%, CHD events by 42%, and coronary revascularization procedures by 45% (Table 5).
| Atorvastatin (No. [%]) |
Placebo (No. [%]) |
HR | 95% CI | P | |
|---|---|---|---|---|---|
| Any cardiovascular event | 530 (22.4) | 687 (29.0) | 0.74 | 0.66-0.83 | < .001 |
| Major cardiovascular event | 334 (14.1) | 407 (17.2) | 0.80 | 0.69-0.92 | .002 |
| Any coronary event | 123 (5.2) | 204 (8.6) | 0.58 | 0.46-0.73 | < .001 |
| Major coronary event | 101 (4.3) | 151 (6.4) | 0.65 | 0.50-0.84 | .001 |
| Revascularization | 94 (4.0) | 163 (6.9) | 0.55 | 0.43-0.72 | < .001 |
CI = confidence interval; HR = hazard ratio
Medscape: Were the observed risk reductions surprising, given that these patients were supposedly free of CHD?
Dr. Goldstein: Another way to look at this is to say that SPARCL was a primary prevention trial from the standpoint of CHD. The reductions in coronary events with statins vary from study to study, so these types of numbers are not out of line with those types of benefits. What is important here is that the benefits were seen despite the patients having no known CHD at the time of randomization, suggesting that non-cardioembolic stroke in general might be considered as a CHD equivalent.
Medscape: What was the overall treatment benefit in SPARCL?
Dr. Goldstein: The SPARCL investigators calculated that 46 patients need to be treated with atorvastatin for 5 years to prevent 1 stroke, 29 to prevent 1 major cardiovascular event, and 32 to prevent 1 revascularization procedure.
Medscape: There was no statistically significant difference in all-cause mortality or cardiovascular mortality between the 2 study groups (Table 6). Wouldn't patients be expected to show a reduction in cardiovascular mortality in this trial?
Dr. Goldstein: There was a trend toward a decrease in cardiovascular mortality with atorvastatin vs placebo. SPARCL was not intended to detect differences in mortality rates, so these results are not surprising. The mortality data also were intended as a safety parameter. We would not have wanted to see an increased mortality in the group that was randomized to active treatment, and there wasn't any.
| Atorvastatin (No. [%]) |
Placebo (No. [%]) |
HR | 95% CI | P | |
|---|---|---|---|---|---|
| All-cause | 216 (9.1) | 211 (8.9) | 1.00 | 0.82-1.21 | .98 |
| Cardiovascular | 78 (3.3) | 98 (4.1) | 0.78 | 0.58-1.06 | .11 |
| Cancer | 57 (2.4) | 53 (2.2) | 1.05 | 0.72-1.53 | .80 |
CI = confidence interval; HR = hazard ratio
Medscape: Were there any unexpected adverse events associated with atorvastatin?
Dr. Goldstein: For any trial like this, the incidence of adverse events is obviously close to 100%, because everything that happens gets reported. The increase in liver enzymes, which you monitor in any patient on this class of drugs, was well within the expected range. The rates of serious adverse events were almost identical in both study groups and the serious adverse events associated with stopping treatment were identical (Table 7). The other major side effects that are of concern to people with statins are musculoskeletal effects. The rates of myalgia in this trial were virtually the same in the treatment and placebo groups (5.5% vs 6%, respectively). Myopathy was almost unheard of in either group, occurring in only 7 cases (0.3%) in each group. The incidence of rhabdomyolysis was also identical (0.1% in both groups), with actually 1 more event in the placebo group (3 vs 2 in the atorvastatin group).
| Atorvastatin (No. [%]) |
Placebo (No. [%]) | |
|---|---|---|
| Adverse event | ||
| Any adverse event | 2199 (93.0) | 2156 (91.1) |
| Any serious adverse event | 988 (41.8) | 975 (41.2) |
| Adverse event leading to discontinuation of treatment |
415 (17.5) | 342 (14.5) |
| Musculoskeletal adverse event | 138 (5.9) | 151 (6.4) |
| Rhabdomyolysis | 2 (0.1) | 3 (0.1) |
| Myalgia | 129 (5.5) | 141 (6.0) |
| Laboratory values: | ||
| ALT/AST > 3?ULN | 51 (2.2) | 11 (0.5) |
| Creatine kinase > 10?ULN | 2 (0.1) | 0 (0.0) |
ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal
So, the adverse events that people are concerned about with statins seem to be very well balanced between the active treatment and the placebo group without any real or unexpected differences at all. It should again be noted that this was with high-dose atorvastatin and without a "run-in" period to determine tolerability.
Medscape: Can the results of SPARCL be extrapolated to all statins at appropriate doses?
Dr. Goldstein: We see differences all the time between individual drugs, even within a given class. If we had another study that treated the same patient population and found a similar benefit, you could say that there might be a class effect. However, when there is only a single drug tested at 1 dose in a given patient population, there would be no evidence that another drug would have the same effect.
In this particular patient population, this is the first study ever to show a reduction in recurrent stroke in patients with stroke or TIA and there is nothing to compare it with, so it is difficult to say there is a class effect. There is, however, also no evidence that a class effect does not exist. That would require another trial showing no benefit of another drug of this class. Lack of data is not evidence of a lack of an effect.
Medscape: Presumably, patients should receive the statin immediately post stroke rather than 1-6 months post stroke as in SPARCL?
Dr. Goldstein: Yes. Although patients were randomized between 1 and 6 months after stroke, I think it would be reasonable to start the statin during the hospitalization. We know from many other sources that patient compliance increases significantly if they are started on a medication during hospitalization for an acute event.
Medscape: Should these patients continue taking the statin indefinitely?
Dr. Goldstein: Given the reduction in other events, not only stroke, it would seem very likely that they should be taking it indefinitely. However, we only have data covering the length of the study's follow-up period.
Medscape: What else does SPARCL tell us about treatment of these patients with stroke/TIA, but no CHD?
Dr. Goldstein: The other point that we made in this trial is that statin treatment is added on to all the other things that you need to do to try to prevent recurrent stroke. Many of these things are individualized, depending on the mechanism of stroke type and other characteristics, and statin treatment must be considered against a background of trying to provide the best of other medical therapies. So, attention to all of those other opportunities to reduce the risk of stroke is also critically important.
A 70-year-old male with hypertension (158/90 mm Hg), but otherwise healthy, presented to the local emergency room with complaints of left arm weakness for 2 hours. After a rapid initial assessment, the patient was treated with thrombolytic therapy and experienced resolution of his initial presenting symptoms over the next few hours.
During the course of his early assessment, the patient was noted to have the following lipid profile:
Total cholesterol 220 mg/dL
The patient is a 60-year-old female who had a transient ischemic attack 6 months prior and continues to have persistent left-sided arm and leg weakness. Previously, she was noted to have an LDL-cholesterol of 130 mg/dL, and based on recent trial evidence, was started on atorvastatin 80 mg/day for secondary stroke prevention. She is maintained on aspirin and amlodipine and is otherwise well. After 6 months, repeat testing showed LDL-cholesterol was reduced to 68 mg/dL.
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Larry B. Goldstein, MD
Professor of Medicine, Duke University; Director, Duke Stroke Center, Duke University Medical Center, Durham, North Carolina
Disclosure: Larry B. Goldstein, MD, has disclosed that he has received consulting fees from Pfizer, Bayer, AstraZeneca, Bristol-Myers Squibb/Sanofi, GlaxoSmithKline, Merck Research Laboratories, Johnson & Johnson Cordis, and Organon; lecture fees from Bayer; and grant support from AGA Medical, Boehringer-Ingelheim, the National Institutes of Health, Pfizer, and the Department of Veterans Affairs.
Ariana Del Negro
Associate Editorial Director, Medscape Cardiology
Disclosure: Ariana Del Negro has disclosed no relevant financial relationships.
David Good
Editorial Director, Medscape Cardiology
Disclosure: David Good has disclosed no relevant financial relationships.