What the Statin Trials Have Taught Us

Transcription

1 What the Statin Trials Have Taught Us David D. Waters, MD a,b, * It has taken a century since Anitschkow began feeding cholesterol to rabbits to study the role of cholesterol in atherosclerosis to be fully appreciated and for the potential of cholesterol reduction to prevent cardiovascular events to be fully realized. The body of clinical trial data testing the effects of statins on coronary heart disease is extensive and convincing. A 1% reduction in low-density lipoprotein cholesterol reduces coronary events by approximately 1%. With large doses of potent statins, low-density lipoprotein cholesterol levels and coronary events can thus be reduced by approximately 50%. The antiinflammatory effects of large doses of atorvastatin likely contribute to the early event reduction seen early after acute coronary syndromes. Translating this information into clinical practice presents a challenge: many patients who would benefit from statins remain untreated or undertreated or discontinue treatment soon after it is initiated Elsevier Inc. All rights reserved. (Am J Cardiol 2006;98: ) Controversy persisted throughout most of the 20th century as to whether cholesterol reduction would prevent coronary disease. Anitschkow established near the beginning of the century that feeding cholesterol to rabbits would produce aortic lesions similar to human atherosclerosis. 1 This evidence was largely dismissed as being irrelevant to human disease because the findings could not be reproduced in dogs or rats. In 1939, Müller 2 linked familial hypercholesterolemia and tendon xanthoma to symptoms of coronary disease in 76 patients from 17 Norwegian families, but these findings were believed to apply only to patients with extremely high blood cholesterol levels. In 1966, Keys et al 3 published a landmark study linking dietary fat and blood cholesterol levels to coronary mortality in 7 countries, as depicted in Figure 1. A decade later, it was shown that Japanese subjects who moved to Hawaii had higher blood cholesterol levels and coronary event rates than those who did not migrate, and that Japanese subjects who immigrated to San Francisco had even higher blood cholesterol and coronary event rates. 4 These epidemiologic data were persuasive, but the results of early intervention trials to reduce coronary events by lowering blood cholesterol levels yielded mixed results. 5 Most of these trials were underpowered or had other methodologic limitations. The main problem was the lack of an intervention that could reliably reduce low-density lipoprotein (LDL) cholesterol levels by a large amount without adverse events. Nevertheless, in the Lipid Research Clinics Primary Prevention Trial, in which 3,806 asymptomatic, middle-aged men with hypercholesterolemia were randomized to placebo or cholestyramine and followed for a mean a Division of Cardiology, San Francisco General Hospital; and b Department of Medicine, University of California, San Francisco, San Francisco, California. Manuscript received November 18, 2005; revised manuscript received and accepted January 11, * Corresponding author: Tel: ; fax: address: dwaters@medsfgh.ucsf.edu (D.D. Waters). of 7.4 years, a 13% greater LDL cholesterol reduction in the cholestyramine group was associated with a 19% reduction in the primary end point cardiac death or myocardial infarction (MI). 6 Using a 1-sided test, the p value for the reduction in events was In the Program on the Surgical Control of the Hyperlipidemias, 838 postinfarction patients with hypercholesterolemia were randomized to partial ileal bypass surgery or to a control group. 7 Over a mean follow-up of 9.7 years, LDL cholesterol levels were 38% lower and the rate of coronary death or MI was 35% lower in the surgery group (p 0.001). Despite these findings, the value of cholesterol reduction was still being actively debated in the late 1980s and early 1990s The role of cholesterol in atherogenesis was still being questioned, and the potential dangers of a low-fat diet were highlighted. 8 The possibility that cholesterol reduction might increase noncardiovascular mortality was a lingering concern. 9 In fact, it was possible to conclude in 1992, at the end of an overview of cholesterol reduction trials, that lowering serum cholesterol concentrations does not reduce mortality and is unlikely to prevent coronary heart disease. 10 The importance of intervening to treat other major risk factors, diabetes, smoking, and hypertension, had all been established decades earlier and was no longer the subject of controversy. Proof of the Lipid Hypothesis Era The Scandinavian Simvastatin Survival Study (4S), published in 1994, was a landmark trial because it resolved many of these issues. A total of 4,444 patients with coronary disease and hypercholesterolemia were randomized to placebo or to simvastatin 20 to 40 mg/day and followed for a mean of 5.4 years. 11 LDL cholesterol levels were 35% lower in the simvastatin group throughout the study, an achievement that had not been possible in earlier cholesterol reduction drug trials. Total mortality, the primary end point of 4S, was reduced by 30% (8% vs 12%, p ), and /06/$ see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.amjcard

2 130 The American Journal of Cardiology ( Figure 1. Coronary death as a function of median serum cholesterol in the Seven Countries Study. B Belgrade, Yugoslavia; C Crevalcore, Italy; D Dalmatia, Yugoslavia; E East Finland; G Corfu, Greece; J Uhibuka, Japan; K Crete, Greece; M Montegiorgio, Italy; N Zutphen, The Netherlands; R Rome, Italy; S Slavonia, Yugoslavia; T Tanushimaru, Japan; U United States; V Velika Krsna, Yugoslavia; W West Finland; Z Zrenjanin, Yugoslavia. all other coronary end points were also reduced by 30% to 40%. The percentage reduction in events was roughly proportional to the percentage reduction in LDL cholesterol, a pattern that would hold for future statin trials. The benefit of statins in patients with coronary disease was quickly confirmed and extended in 2 other trials. The Cholesterol and Recurrent Events trial randomized 4,159 postinfarction patients with LDL cholesterol levels from 115 to 174 mg/dl to placebo or to pravastatin 40 mg/day. 12 During the 5-year follow-up, LDL cholesterol levels were 28% lower in the pravastatin treated group, and the primary end point, coronary death or nonfatal MI, was reduced by 24% (10.2% vs 13.2%, p 0.003). The Long-Term Intervention With Pravastatin in Ischemic Disease trial randomized 9,014 coronary patients with a broad range of baseline cholesterol levels to placebo or to pravastatin 40 mg/day and followed them for a mean of 6.1 years. 13 LDL cholesterol levels were 25% lower in the pravastatin group than in the placebo group, and the primary end point, coronary death, was correspondingly reduced by 24% (6.4% vs 8.3%, p 0.001). The combined end point of coronary death plus nonfatal MI was also reduced by 24% (12.3% vs 15.9%, p 0.001). What about primary prevention? In the West of Scotland Coronary Prevention Study, 6,595 middle-aged men with hypercholesterolemia were randomized to placebo or to pravastatin 40 mg/day and followed for a mean of 4.9 years. 14 LDL cholesterol was reduced by 26%, and the primary end point, coronary death or nonfatal MI, was reduced by 31% (5.5% vs 7.4%, p 0.001). In the Air Force/Texas Coronary Atherosclerosis Prevention Study, 6,605 middle-aged Texans with average total and LDL cholesterol levels and low high-density lipoprotein cholesterol levels were randomized to placebo or to lovastatin 20 to 40 mg/day. 15 Over a follow-up of 5.2 years, LDL cholesterol was reduced by 25%, and first acute major coronary events were reduced by 37% (6.8% vs 10.9%, p 0.001). What did we learn from this first wave of statin trials? First, statins reduced coronary events in patients with coronary disease and average or high cholesterol levels. Statins also reduced events in high-risk primary prevention, in men with high LDL cholesterol levels and in subjects with low high-density lipoprotein cholesterol levels. A 1% reduction in LDL cholesterol corresponded roughly to a 1% reduction in coronary events. Total mortality was reduced in the 2 trials that were powered to detect a difference in this end point, 4S and the Long-Term Intervention With Pravastatin in Ischemic Disease trial. Statins exhibited an excellent safety profile and were exceedingly well tolerated by study subjects. Noncardiovascular mortality was not increased in any of the trials. In each of the 3 secondary prevention trials, the risk for stroke (or stroke plus transient ischemic attack) was significantly reduced. This benefit was not entirely expected because the relation in observational studies between stroke and blood cholesterol levels is not nearly as clear as the relation between coronary events and cholesterol levels. Threshold of Benefit Era The Heart Protection Study randomized 20,536 adults at high risk because of coronary disease, other occlusive arterial disease, or diabetes to placebo or to simvastatin 40 mg/day. 16 During the 5-year treatment period, total mortality, the primary end point, was reduced in the simvastatin group (12.9% vs 14.7%, p ). LDL cholesterol levels were reduced by 29%, coronary events by 27% (8.7% vs 11.8%, p ), stroke by 25% (4.3% vs 5.7%, p ), and revascularization by 24% (9.1% vs 11.7%, p ). On the basis of the previous statin trials, these results were not unexpected. It had been suggested that there might be a threshold of LDL cholesterol at about 125 mg/dl below which reducing cholesterol would not reduce risk. 12,17 The Heart Protection Study demonstrated that this notion was wrong. Reducing LDL cholesterol from 116 mg/dl (3 mmol/l) to 77 mg/dl (2 mmol/l) reduced events by approximately 1/4, similar to the reduction in risk at higher cholesterol levels. Even the 3,500 patients with baseline LDL cholesterol 100 mg/dl experienced a statistically significant risk reduction of about 25%. This finding has important ramifications. Cholesterol reduction with a statin should no longer be considered as therapy for high cholesterol but rather for high risk. The absolute benefit of treating a population of patients at high risk with an average or low cholesterol level will exceed the benefit of treating a low-risk patient population with hypercholesterolemia. In high-risk hypertensives 18 and high-risk diabetics 19 who do not yet have symptomatic coronary disease, reducing LDL cholesterol reduces coronary events even when cholesterol levels are not elevated.

3 Editorials/Statin Trials 131 Figure 2. Event rates plotted against LDL cholesterol levels while receiving treatment in primary prevention statin studies. Event rates for the West of Scotland Coronary Prevention Study (WOSCOPS), the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), and the Anglo-Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm (ASCOT-LLA) are coronary heart disease and MI. Event rates for the Collaborative Atorvastatin Diabetes Study (CARDS) also include unstable angina and resuscitated cardiac arrest. P placebo treated; S statin treated; TNT includes resuscitated cardiac arrest and stroke. Figure 3. Event rates plotted against LDL cholesterol levels while receiving treatment in secondary prevention statin studies. Event rates for the Cholesterol and Recurrent Events (CARE) study, the Long-Term Intervention With Pravastatin in Ischemic Disease (LIPID) study, and the Heart Protection Study (HPS) are coronary heart disease death and nonfatal MI. Event rates for 4S also include resuscitated cardiac arrest; TNT includes resuscitated cardiac arrest and stroke. Lower Is Better Era Plotting coronary event rates against LDL cholesterol levels in the placebo and active treatment groups of the major primary prevention statin trials 14,15,18,19 yields a relatively consistent relation, with lower LDL cholesterol levels correlating with lower event rates, as shown in Figure 2. A similar relation, but with higher event rates, is seen for the major secondary prevention statin trials, 11 13,16 as shown in Figure 3. The Heart Protection Study has been included because most of the patients had either coronary disease or atherosclerosis in another vascular territory. On the basis of epidemiologic data, such as the Seven Countries Study 3 (Figure 1) and long-term follow-up of low-cholesterol populations, 20 it seemed reasonable that reducing LDL cholesterol to lower levels than those attained in previous studies would yield more event reduction. Treating to New Targets (TNT) was the first of 3 large trials designed to directly test the hypothesis that reducing LDL cholesterol beyond the treatment target of 100 mg/dl would yield a safe incremental clinical benefit. 21 A total of 10,001 patients with coronary disease within the preceding 5 years, MI, a coronary revascularization procedure, or angina with objective documentation of coronary disease, were randomly assigned to 10 or 80 mg/day of atorvastatin. Patients had to have had LDL cholesterol levels from 130 to 250 mg/dl when not receiving treatment and LDL cholesterol levels 130 mg/dl during a run-in period taking atorvastatin 10 mg/day. These entry criteria were designed to ensure that the patients in the 10-mg dose group would have an average LDL cholesterol of approximately 100 mg/dl, whereas those in the 80-mg dose group would have an average LDL cholesterol level of approximately 75 to 80 mg/dl. During the mean follow-up of 4.9 years, LDL cholesterol levels were almost exactly as predicted in the 2 groups. On the basis of previous statin trials, in which an approximate 1% relative risk reduction was seen for every 1% difference in LDL cholesterol between the treatment groups, a 20% to 25% reduction at the 80-mg dose would be expected in TNT for the primary end point. The primary end point, a composite of cardiac death, nonfatal MI, resuscitated cardiac arrest, and stroke, was 22% lower in the high-dose group (8.7% vs 10.9%, p 0.001). Fewer patients in the 80-mg group experienced any cardiovascular event (28.1% vs 33.5%, p 0.001), and the number needed to treat with the higher as opposed to the lower dose to prevent such an event was The Incremental Decrease in End Points Through Aggressive Lipid Lowering study randomized 8,888 patients with a history of MI to the treatment used in 4S, simvastatin 20 to 40 mg/day, or atorvastatin 80 mg/day and followed them for a mean of 4.8 years. 22 The mean LDL cholesterol levels were 104 mg/dl in the simvastatin group and 81 mg/dl in the atorvastatin group. The primary end point, a composite of coronary death, nonfatal MI, and resuscitated cardiac arrest, occurred in 10.4% of simvastatin patients and 9.3% of atorvastatin patients, an 11% reduction (p 0.07). If stroke had been included in the primary end point, as it was for TNT, the difference would have been 13.7% versus 12%, a 13% reduction (p 0.02). Nonfatal MI (p 0.02), coronary revascularization (p 0.001), any coronary heart disease event (p 0.001), and any cardiovascular event (p 0.01) were all reduced significantly in the Incremental Decrease in End Points Through Aggressive Lipid Lowering study. In the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine, 12,000 post-mi patients have been randomized to either 20 or 80 mg/day simvastatin and are being followed for 5 years. 23 Using a 2 2 factorial design, the Study of the Effectiveness of

4 132 The American Journal of Cardiology ( Additional Reductions in Cholesterol and Homocysteine is also testing the effectiveness of folic acid or vitamin B12 compared with placebo. The robust results of TNT and the Incremental Decrease in End Points Through Aggressive Lipid Lowering study suggest that the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine will confirm the mantra that lower is better. Statins for Acute Coronary Syndromes The statin trials discussed up to this point have involved coronary patients with stable disease. However, the highest risk patients are those with recent acute coronary syndromes, and the potential for the greatest absolute risk reduction thus lies with this group. The pathophysiologic mechanisms leading to recurrent events after acute coronary syndromes likely differ from the mechanisms that cause events in patients with stable coronary disease. It would therefore be hazardous to extrapolate from stable to unstable coronary patients either the degree of benefit or the timing of benefit with statins. The Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering study randomized 3,086 patients with unstable angina or non Q-wave infarction from 24 to 96 hours after hospitalization to atorvastatin 80 mg/day or to placebo. 24 The follow-up period was limited to 16 weeks so that only the early effects of high-dose statin therapy were evaluated. The composite end point of death, MI, resuscitated cardiac arrest, and recurrent symptomatic myocardial ischemia with objective evidence requiring emergency rehospitalization was lower in the atorvastatin arm by 16% (14.8% vs 17.4%, p 0.048). In the Pravastatin or Atorvastatin Evaluation and Infection Therapy trial, 4,162 patients who had been hospitalized with acute coronary syndromes within 10 days were randomized to pravastatin 40 mg/day (the treatment proved to reduce events in the Cholesterol and Recurrent Events trial, 12 the Long-Term Intervention With Pravastatin in Ischemic Disease trial, 13 and the West of Scotland Coronary Prevention Study 14 ) or to atorvastatin 80 mg/day. 25 The composite end point of death, MI, unstable angina requiring hospitalization, coronary revascularization, and stroke was 26.3% in the pravastatin group over the 2-year follow-up, compared with 22.4% in the atorvastatin group (p 0.005). Unlike the statin trials in stable patients, in which event reduction correlated well with the reduction attained in LDL cholesterol, it appears that other mechanisms may contribute to the benefit of statins after an acute coronary syndrome. In the Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering study, neither baseline nor LDL cholesterol while receiving treatment were predictive of events, 26 but C-reactive protein (CRP) levels were lower at the end of the 16-week follow-up in the atorvastatin treatment group. 27 In the Pravastatin or Atorvastatin Evaluation and Infection Therapy trial, low LDL cholesterol levels and low CRP levels while receiving treatment were associated with better outcomes. 28 In the Aggrastat to Zocor Trial 29, simvastatin reduced LDL cholesterol levels substantially in patients with recent acute coronary syndromes, but with only a small difference in CRP levels between statin-treated and placebo groups and with no reduction in events. Taken together, this circumstantial evidence suggests that at least part of the early benefit of statins in patients with acute coronary syndromes may be related to the anti-inflammatory effects of these drugs. Negative Statin Trial Results Not all statin trials have shown a benefit from treatment. Two small trials in patients with acute coronary syndromes, 1 with pravastatin 30 and 1 with fluvastatin, 31 did not show a statistically significant reduction in events, probably because they were underpowered. The Aggrastat to Zocor Trial randomized 4,497 patients after acute coronary syndromes to simvastatin 40 mg/day for 1 month followed by 80 mg/day or to placebo for 4 months followed by 20 mg/day. 29 The primary end point was a composite of cardiovascular death, nonfatal MI, readmission for acute coronary syndrome, and stroke. Median follow-up was nearly 2 years. Despite an early difference in LDL cholesterol levels between the groups (68 vs 122 mg/dl at 1 month in the simvastatin 40 mg and placebo groups, respectively), the outcome curves did not begin to separate until 8 months of follow-up, and the overall reduction in events did not attain statistical significance (hazard ratio 0.89, 95% confidence interval 0.76 to 1.04, p 0.14). The investigators of the Aggrastat to Zocor Trial offered several explanations for the failure of the trial to show a significant reduction in events. 29 The event rate was about 1/3 lower than anticipated, and about 1/3 of the study patients discontinued their medication, greatly reducing the power of the study. In contrast to the Myocardial Ischemia Reduction With Aggressive Cholesterol Lowering study and the Pravastatin or Atorvastatin Evaluation and Infection Therapy trial, an early difference in CRP levels between the treatment groups was not present in the Aggrastat to Zocor Trial, perhaps accounting for the absence of early treatment benefit. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial randomized 10,355 hypertensive subjects aged 55 years with 1 additional risk factor and a mean LDL cholesterol level of 146 mg/dl to pravastatin 40 mg/day or to usual care. 32 Notably, slightly 1/3 of the patients were black, and nearly 1/4 of them were Hispanic. The primary outcome was all-cause mortality, and mean follow-up was 4.8 years. All-cause mortality was similar in the 2 treatment groups, and the composite end point of coronary death plus nonfatal MI was only slightly lower in the pravastatin group, 9.3% versus 10.4% (relative risk 0.91, 95% confidence interval 0.79 to 1.04, p 0.16). The failure of this study to show a significant event reduction in the statin group was attributed by the investi-

5 Editorials/Statin Trials 133 gators to the modest differential in LDL cholesterol levels, 16.7%, between the treatment groups; 32% of the usual-care patients began taking statins during the follow-up period. Interestingly, coronary death plus nonfatal MI was significantly reduced in blacks (relative risk 0.73, 95% confidence interval 0.58 to 0.92), but their stroke rate was higher, so that overall cardiovascular events were not significantly lower in blacks in the pravastatin group. It is unfortunate that more clinical trial data on the effects of statins on clinical end points is not available for ethnic groups such as blacks or Asians, because genetic differences in these ethnic groups produce different responses to statins than those seen in Caucasians. 1. Steinberg D. An interpretive history of the cholesterol controversy: part I. J Lipid Res 2004;45: Müller C. Angina pectoris in hereditary xanthomatosis. 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