- Email: [email protected]
Ongoing clinical trials of statins
Ongoing Clinical Trials of Statins Antonio M. Gotto, Jr,
MD, DPhil
Lipid-lowering treatment with statins is effective for primary and secondary prevention of coronary artery disease in patients with either hypercholesterolemia or average cholesterol levels. Several clinical trials in progress will investigate the use of statins in entirely elderly or diabetic cohorts, and larger trials will continue to include significant numbers of these patients, as well as greater numbers of women. Additional clinical endpoint trials are assessing the potential benefits of low-
ering lipid levels to below currently recommended goals and of aggressive early statin treatment to prevent ischemic events in patients with stable coronary disease or acute coronary syndromes. These trials are expected to yield important data on the relation of lipid reduction to the prevention of coronary artery disease and on the potential for extending the use of statins. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88(suppl):36F– 40F
linical trials have established that lowering cholesterol, particularly low-density lipoprotein choC lesterol (LDL-C), decreases the incidence of coronary
not been represented adequately in most large-scale clinical statin trials. Clinical endpoint trials: Recently, 2 large-scale, randomized, parallel-group, placebo-controlled trials were initiated to evaluate statin treatment in patients aged 65 to 85 years. The Risk Evaluation and Stroke Prevention in the Elderly Cerivastatin Trial (RESPECT) will assess the effect of cerivastatin 0.4 and 0.8 mg/day versus placebo administered for 4 years in 10,000 elderly (65 to 80 years) patients with mild-tomoderate elevations in LDL-C (130 to 199 mg/dL [3.36 to 5.15 mmol/L]) and hypertension (blood pressure ⬎160/95 mm Hg or taking antihypertensive medications). Participants will have no pre-existing coronary artery disease or cerebrovascular disease but will be at increased risk for stroke. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)8 includes 5,804 patients (⬇3,000 women) aged 70 to 82 years with a total-cholesterol level of 155 to 348 mg/dL (4 to 9 mmol/L) and existing vascular disease or a high risk for vascular disease because of the presence of smoking, hypertension, or diabetes. Participants will be observed for a minimum of 3.5 years. The primary outcome measure in RESPECT is survival time until stroke, coronary artery disease event, or death, whereas PROSPER has a combined endpoint of coronary artery disease death, nonfatal myocardial infarction (MI), and fatal or nonfatal stroke. In addition, the Medical Research Council, British Heart Foundation (MRC/BHF) Heart Protection Study,9 which is discussed in the section on mega trials, includes ⬎9,500 elderly (⬎65 years of age) patients. Surrogate endpoint trial: Although statin therapy has been clearly demonstrated to lead to reductions in mortality and morbidity, evidence of its anti-ischemic effects is more limited, particularly among the elderly. A new trial to assess the effect of lipid lowering with a statin on ischemia in the elderly (70 to 85 years), the Study Assessing Goals in the Elderly (SAGE), is a large (1,500 patients) multinational study of a predominantly female (4:1 ratio of women to men) population with hypercholesterolemia (LDL-C levels 150 mg/dL to 250 mg/dL [3.87 mmol/L to 6.46 mmol/L]). Subjects will receive either atorvastatin 80 mg/day or pravastatin 40 mg/day for 12 months. The primary
artery disease and major coronary events. Although cholesterol reduction is equally effective in lowering the relative risk for coronary artery disease in patients with and without established disease, it is of particular importance in secondary prevention, because the risk for clinical events in coronary artery disease patients is 5-fold higher than that in the general population.1 Numerous clinical trials have demonstrated that treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decreases the risk for coronary events and mortality in patients with and without evident coronary artery disease.2– 6 In addition, secondary-prevention trials of statin treatment have shown a reduction in coronary artery disease and all-cause mortality.2,3 The relation between serum cholesterol levels and risk for coronary artery disease has been established in studies of middle-aged men. Less well known is the characterization of the benefits of lipid-lowering therapy in other at-risk groups. Several statin trials are currently being conducted to clarify the potential benefits of treatment in different populations, including the elderly, patients with diabetes, and women. Also being evaluated are the effects of lowering lipid levels beyond currently established goal levels and the potential role of aggressive statin treatment in preventing early recurrent ischemic events.
ELDERLY PATIENTS According to World Health Organization estimates, the elderly population (ie, persons ⱖ65 years of age) will increase by ⬎80% in the next 25 years. This statistic is alarming, because ⬎80% of deaths from cardiovascular disease occur in the elderly.7 Despite the apparent importance of lowering cardiovascular disease risk in the elderly, this population has From the Weill Medical College of Cornell University, New York, New York, USA. Address for reprints: Antonio M. Gotto, Jr., MD, DPhil, c/o Mr. Jesse Jou, Weill Medical College of Cornell University, 445 East 69th Street, Olin Hall 205, New York, New York 10021. E-mail: [email protected].
36F
©2001 by Excerpta Medica, Inc. All rights reserved.
0002-9149/01/$ – see front matter PII S0002-9149(01)01876-8
efficacy endpoint is ischemic burden, determined from ST-segment analysis of 48-hour electrocardiograms.
PATIENTS WITH DIABETES MELLITUS Type 2 diabetes mellitus, a well-established coronary artery disease risk factor, causes a 2- to 4-fold increase in the likelihood of coronary artery disease.10 Moreover, the risk for death from coronary artery disease and serious nonfatal coronary artery disease events is markedly increased,11 and the prognosis of clinically evident coronary artery disease is worse12 in patients with diabetes. Despite their heightened risk, patients with diabetes generally have not been included in studies assessing the clinical effects of statins. Clinical endpoint trials: Numerous randomized, double-blind, placebo-controlled trials of the effects of statin treatment in diabetic patients aged 40 to 75 years are under way, including the Atorvastatin as Prevention of Coronary Heart Disease Endpoints in Patients With Non–Insulin-dependent Diabetes Mellitus (ASPEN) study and the Collaborative Atorvastatin Diabetes Study (CARDS). Although ASPEN is multinational and includes 2,421 patients, both with and without a history of heart disease, CARDS is a primary-prevention trial of 2,120 diabetic patients being conducted in the United Kingdom (UK) and Republic of Ireland. Both trials are assessing atorvastatin 10 mg and have a planned duration of treatment of 4 years. The primary efficacy parameter of ASPEN is time to the combined primary endpoint (cardiovascular death, nonfatal MI, revascularization, coronary artery bypass graft [CABG], or stroke), and that of CARDS is time to MI or to CABG or other revascularization procedure. Patients with type 2 diabetes tend to have hypertriglyceridemia and low levels of high-density lipoprotein cholesterol (HDL-C) compared with control subjects.13 Comparative studies indicate that fibrates (fibric acid derivatives) lower triglyceride levels to a greater degree than do statins, suggesting that combination therapy may be necessary in patients with type 2 diabetes and combined hyperlipidemia.14,15 The 6-year, randomized, placebo-controlled, 2⫻2 factorial design Lipids in Diabetes Study (LDS) is assessing whether lowering lipid levels with a statin (cerivastatin) or a fibrate (fenofibrate), either alone or in combination, can substantially reduce cardiovascular morbidity and mortality in patients aged 40 to 75 years with type 2 diabetes, but without evidence of cardiovascular disease. The 4,000 patients to be enrolled in this UK study were not considered candidates for lipid-lowering therapy at the time the study was designed, although their levels are borderline high (LDL-C level ⬍155 mg/dL [⬍4 mmol/L], triglycerides ⬍400 mg/dL [⬍4.52 mmol/L]). The MRC/BHF Heart Protection Study9 includes patients with, or at high risk for developing, coronary artery disease over the next 5 years and has enrolled nearly 6,000 patients with diabetes, of whom almost 4,000 do not have a history of coronary artery disease. This trial may provide important information on the
benefit and role of early treatment with statins in patients with diabetes who do not have coronary artery disease.
WOMEN Coronary artery disease is the most common cause of death in women in industrialized countries. Yet women, particularly postmenopausal women, who are at higher risk for developing coronary artery disease than younger women, have represented a minority of patients enrolled in trials of primary and secondary prevention of coronary events. This may be related to diagnostic and treatment issues that are being explored in nonstatin trials such as the Women’s Ischemia Syndrome Evaluation (WISE) study.16 Clinical endpoint trials: Several ongoing clinical trials evaluating the effect of statin treatment on coronary artery disease risk and clinical events in women should provide important information. New treatment trials, which have been designed to include a substantial number of women, include PROSPER (⬇3,000 women)8 and the 2 large trials discussed in the next section: the MRC/BHF Heart Protection Study (⬎5,000 women)9 and the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial ([ALLHAT] approximately 18,000 women).17 Surrogate endpoint trials: The Beyond Endorsed Lipid Levels Evaluation Study (BELLES) is a prospective, randomized, double-blind study examining the effects of aggressive lipid-lowering therapy with atorvastatin 80 mg/day or pravastatin 40 mg/day for 12 months on regression of coronary atherosclerosis in 600 postmenopausal (aged 55 to 75 years) women with dyslipidemia and other coronary artery disease risk factors. The primary outcome measure is the percent change from baseline in calcium volume score as measured by electron-beam computed tomography. Secondary outcome measures include the percent change from baseline in lipid parameters and the proportion of patients reaching the goals for cholesterol treatment as defined by the National Cholesterol Education Program (NCEP) guidelines. The Cerivastatin for Hyperlipidemia after Reaching Menopause (CHARM) trial will assess the effect of 3 treatment strategies in approximately 180 postmenopausal women with hyperlipidemia and moderate osteoporosis. For a total follow-up period of 52 weeks, participants will receive 1 of the following regimens: (1) cerivastatin 0.4 mg/day; (2) placebo for 6 weeks, then fenofibrate 200 mg/day for 46 weeks; or (3) atorvastatin 10 mg/day for 6 weeks, then cerivastatin 0.8 mg/day for 46 weeks. Serum lipids will be measured at 6 weeks, and lipids and osteoporosis will be evaluated at the end of the trial.
MEGA TRIALS Additional evidence to support the use of statins to lower coronary artery disease risk and coronary events in the elderly, patients with diabetes, and women is expected from at least 2 large trials currently in progress—the MRC/BHF Heart Protection Study9 and ALLHAT.17 The randomized, placebo-controlled,
A SYMPOSIUM: IDENTIFYING AND MANAGING HYPERLIPIDEMIA
37F
2⫻2 factorial design of the 5-year MRC/BHF Heart Protection Study is evaluating simvastatin, antioxidant vitamin (vitamins C and E and -carotene), and placebo treatment in 20,536 patients aged 40 to 80 years who (1) are at increased risk for coronary artery disease death (prior MI or other coronary artery disease, occlusive disease of noncoronary arteries, diabetes, or treated hypertension); (2) may not have a clear indication for study treatments; and (3) have a totalcholesterol level ⱖ135 mg/dL (3.5 mmol/L). Of the 15,454 men and 5,082 women randomized to treatment (1) 9,515 were ⬎65 years of age at entry; (2) 5,963 (29%) had diabetes, most (3,985) with no history of coronary artery disease; and (3) 6,888 had an LDL-C level ⬍115 mg/dL (⬍3 mmol/L). Primary outcome measures in the MRC/BHF Heart Protection Study are all-cause mortality, coronary artery disease mortality, and noncoronary artery disease mortality in the lipid-lowering therapy arm, and total coronary artery disease and fatal coronary artery disease in the antioxidant vitamin arm. Comparisons of the effects of treatment on fatal coronary artery disease and total coronary artery disease are planned for specific patient subgroups: (1) with and without coronary disease, (2) occlusive noncoronary disease, (3) diabetes, (4) men and women, (5) aged ⱕ65 and ⬎65 years, and (6) smokers and nonsmokers. In addition, patients will be stratified by measurements of blood pressure, LDL-C, HDL-C, and vitamin levels. Findings from this large trial are thus expected to provide important evidence of the effects of statin treatment and antioxidant vitamins on all-cause and cause-specific mortality and on major morbidity in a number of different patient populations. An interim analysis estimates annual rates for nonfatal MI or fatal coronary artery disease, stroke, and all-cause mortality as 2.4%, 1.3%, and 2.2%, respectively.9 The second mega trial, ALLHAT,17 comprises 2 randomized, controlled, open-label, practice-based trials of 6 years’ duration—1 of cholesterol lowering and 1 of antihypertensive therapy. Total enrollment for ALLHAT is 42,448 high-risk hypertensive patients identified without the use of extensive diagnostic testing; 10,337 of the participants are enrolled in the cholesterol-lowering trial.18 The primary eligibility criteria are as follows: age ⱖ55 years, systolic or diastolic hypertension, and ⱖ1 additional risk factors for MI (eg, atherosclerotic disease and type 2 diabetes). For patients enrolled in the cholesterol-lowering trial, those without coronary artery disease must have an LDL-C level between 120 and 189 mg/dL (3.10 and 4.88 mmol/L), whereas the LDL-C level of those with known coronary artery disease must be between 100 and 129 mg/dL (2.58 and 3.33 mmol/L); triglyceride levels must be ⬍350 mg/dL (⬍3.95 mmol/L). Patients were randomized to treatment with pravastatin or usual care, which could include a lipid-lowering medication. The primary endpoint of the cholesterollowering trial is all-cause mortality. 38F THE AMERICAN JOURNAL OF CARDIOLOGY姞
TARGET LIPID LEVELS An unresolved issue is whether the current NCEP ATP III goal of LDL-C ⬍100 mg/dL19 is too high in patients who have had a coronary event. An analysis of data from the Scandinavian Simvastatin Survival Study (4S) of secondary prevention in frankly hypercholesterolemic men (baseline LDL-C, 188 mg/dL [4.86 mmol/L]) suggests that greater benefit may be realized if lower LDL-C levels are attained.20 In this trial, changes in levels of total cholesterol and LDL-C at 1 year in patients receiving statin therapy were highly correlated with reduction in risk for an event: each additional 1% reduction in LDL-C level was estimated to decrease the risk for a coronary event by 1.7%.20 However, another secondary-prevention trial, Cholesterol and Recurrent Events (CARE), in patients with average levels of total cholesterol (mean, 209 mg/dL [5.4 mmol/L]) and LDL-C (mean, 139 mg/dL [3.59 mmol/L]) found that the coronary event rate decreased with reductions in the LDL-C level to approximately 125 mg/dL (3.23 mmol/L), but no additional reduction in risk was observed at LDL-C levels ⬍125 mg/dL to as low as 71 mg/dL (1.83 mmol/L).21 Because of the different protocols for drug administration (dose titration of simvastatin in 4S and fixeddose pravastatin in CARE), it is not clear whether differences in statin dosing strategies influenced or contributed to differences in whether a threshold LDL-C level was observed. Clearly, however, both dosing strategies produce significant clinical benefits in clinical trials. Clinical endpoint trials: The Treating to New Targets (TNT) trial22 was initiated to assess whether lowering LDL-C levels beyond current recommendations with a statin in patients with clinically evident coronary artery disease will lower clinical coronary event rates. Patients aged 35 to 75 years with prior MI, prior or present angina with objective evidence of atherosclerotic coronary artery disease, or prior coronary revascularization procedures, and with LDL-C and triglyceride levels of 130 to 250 mg/dL (3.36 to 6.46 mmol/L) and ⱕ600 mg/dL (ⱕ6.77 mmol/L), respectively, will undergo an 8-week open-label treatment phase with atorvastatin. Those attaining an LDL-C level ⬍130 mg/dL (⬍3.36 mmol/L) will be randomized to double-blind treatment with atorvastatin 10 mg/day or 80 mg/day; the anticipated on-treatment LDL-C levels at these doses are approximately 100 mg/dL (2.58 mmol/L) and 75 mg/dL (1.93 mmol/ L), respectively. In total, 10,000 patients are to receive treatment for an average of 5 years or until the number of primary coronary events reaches 750. The main efficacy measure is the occurrence of a primary event, defined as death from coronary artery disease or nonfatal MI. The large number of patients included in the TNT study may clarify whether attaining lower LDL-C levels further reduces coronary artery disease– related events in patients treated with a statin. The Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) trial also will examine whether lowering the LDL-C level beyond the current recommendations provides any additional
VOL. 88 (4A)
AUGUST 16, 2001
benefit in patients with coronary artery disease. This randomized, open-label study will enroll 7,600 men and women (ⱕ80 years of age, previously hospitalized with definite acute MI or a history of MI, and eligible at the time of discharge for statin therapy according to guidelines). Patients will receive either atorvastatin 80 mg/day or simvastatin 20 to 40 mg/day for 5.5 years. The primary efficacy endpoint is the occurrence of a major coronary event (coronary artery disease death or nonfatal MI). There are 2 studies in progress that are investigating the potential effects of further reductions in LDL-C levels with simvastatin. The first study involves approximately one third of the patients enrolled in the MRC/BHF Heart Protection Study who have only mildly elevated LDL-C levels (116 mg/dL [3 mmol/L]).9 After 30 months of follow-up time, the average reduction in LDL-C in this group was 42 to 46 mg/dL (1.1 to 1.2 mmol/L). Another simvastatin trial, the Study to Evaluate Additional Reductions of Cholesterol and Homocysteine (SEARCH; also known as Heart Protection II), is examining whether incremental clinical benefit will result from a ⬎35% reduction in the LDL-C level, which was the reduction achieved in the 4S study. The primary efficacy endpoint of SEARCH is the effect of high-dose versus low-dose simvastatin (with and without folic acid) on the incidence of total coronary artery disease events.
AGGRESSIVE EARLY LIPID LOWERING TO PREVENT ISCHEMIC EVENTS Statin treatment has been shown to reduce the risk for coronary artery disease death and nonfatal MI by 29% in patients hospitalized for unstable angina6 and to reduce the risk for new or worsening angina by 26%.23 Myocardial ischemia during daily life also is reduced significantly with statin treatment.24 Trials are therefore under way to assess the potential role of statins in the early treatment of patients with myocardial ischemia. Stable coronary disease: The 4-year Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) trial25 is a population-based, randomized, open-label trial involving 2,443 patients aged 18 to 75 years. The study assesses the effects of aggressive lipid lowering on the prevention of ischemic events in hypercholesterolemic patients (LDL-C level 130 to 250 mg/dL [3.36 to 6.46 mmol/L] if not on lipid-lowering therapy or 110 to 200 mg/dL [2.84 to 5.17 mmol/L] if on therapy) with established coronary artery disease (prior MI, CABG or other coronary intervention, or unstable angina). Patients have been randomized to usual care or atorvastatin 10 to 80 mg/day to achieve LDL-C levels ⱕ80 mg/dL (ⱕ2.06 mmol/L). The primary outcome measure is occurrence of an ischemic event, defined as cardiovascular death, nonfatal MI, resuscitated cardiac arrest, unstable angina, or coronary revascularization, including CABG. The ongoing surrogate endpoint study Reversal of Atherosclerosis with Lipitor (REVERSAL) is a prospective, randomized, double-blind, multicenter study designed to compare the effects of atorvastatin 80
mg/day and pravastatin 40 mg/day for 18 months on the progression and quantification of coronary atherosclerotic lesions. The coronary arteries of 600 patients, aged 30 to 75 years, with a history of coronary artery disease, who are scheduled to undergo cardiac catheterization and coronary angiography will be imaged by intravascular ultrasound. The primary efficacy endpoint is the percent change in total plaque volume for all slices of anatomically comparable segments of the target coronary artery. Acute coronary syndromes: The major secondaryprevention trials assessing the effects of statins on reducing mortality and recurrent coronary events in patients with coronary artery disease excluded patients with recent coronary artery disease events (eg, within the prior 3 to 6 months). The effects of statin treatment initiated within 5 to 10 days of an acute coronary syndrome (unstable angina or non–Q-wave MI) will be investigated in 2 ongoing clinical trials. The Aggrastat to Zocor (A-2-Z) trial is a 2-phase study in patients with unstable angina/non–ST-segment MI. Phase A, which has a duration of 120 hours, is evaluating the effects of tirofiban in combination with aspirin and either low-molecular-weight heparin or unfractionated heparin. Once stabilized, patients enter phase Z and are rerandomized (1) to treatment with simvastatin 40 mg/day for 1 month followed by 80 mg/day for 3 months or (2) to accepted care with diet and placebo for 4 months. Patients having an event would be changed from placebo to simvastatin 20 mg/day for the remainder of the study period. Phase Z is to continue until 970 primary events have occurred. A double-blind, randomized, multicenter comparative trial of pravastatin 40 mg/day and atorvastatin 80 mg/day, Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT), is assessing the reduction in risk for MI and other cardiac events in 4,000 patients who have had an acute coronary syndrome within the previous 10 days. Patients will be observed for at least 1.5 years. PROVE IT is also designed to evaluate the role of infection in cardiovascular disease; half of the patients assigned to each statin treatment group will receive an antibiotic and the other half an antibiotic placebo. Some research findings suggest that infection with organisms such as Chlamydia may have a role in the development of atherosclerosis. Findings from these studies are expected to shed light on the potential role of early and aggressive lipid-lowering treatment in acute coronary syndromes.
PATIENTS WITH STROKE Several of the ongoing trials discussed above will evaluate the effect of statin therapy on the risk for stroke in patients with multiple coronary risk factors or evidence of coronary artery disease, including the elderly and patients with diabetes. However, there are no data on the role of statin therapy in preventing stroke in persons without coronary artery disease but with other forms of cardiovascular disease. The Stroke Prevention by Aggressive Reduction of
A SYMPOSIUM: IDENTIFYING AND MANAGING HYPERLIPIDEMIA
39F
Cholesterol Levels (SPARCL) study is the first to investigate the effect of statins on the risk for cerebrovascular events in patients without a history of coronary artery disease. This double-blind, randomized, placebo-controlled, multicenter trial will examine the effect of aggressive atorvastatin therapy (80 mg/day) on specified cerebrovascular endpoints in 4,200 patients. The anticipated duration of treatment and follow-up is 5 years. Patients are eligible for the study if they have had a previous transient ischemic attack or stroke, have an LDL-C level between 100 mg/dL (2.58 mmol/L) and 190 mg/dL (4.91 mmol/L), and have no evidence of coronary artery disease. The primary clinical endpoint is the time to first occurrence of a fatal or nonfatal stroke.
CONCLUSIONS The introduction of statins for lowering lipid levels was an important advance in decreasing the risk for major coronary events in patients with hypercholesterolemia and those at risk for coronary artery disease. Although statins have apparent benefit in the elderly, patients with diabetes, and women based on subgroup analyses, several clinical trials in progress are expected to provide additional information about the use of statins in these target patient populations. Other ongoing trials with statins may resolve the question of whether achieving LDL-C levels lower than those currently recommended by NCEP Adult Treatment Panel III will further decrease a patient’s risk for a major coronary event. Additional studies in progress are focusing on patients with acute coronary syndromes or other manifestations of vascular disease, such as stroke. In the next 5 to 6 years, as the results of these clinical trials become available, the role of statins in the treatment of patients at risk for coronary artery disease or with clinically evident coronary artery disease will be further elucidated, and their use may be broadened. 1. National Cholesterol Education Program. Second Report of the Expert Panel
on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994;89:1329 –1345. 2. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 3. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1307. 4. Sacks FM, Pfeffer MA, Moye´ LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 5. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in
40F THE AMERICAN JOURNAL OF CARDIOLOGY姞
men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615–1622. 6. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357. 7. American Heart Association. 2001 Heart and Stroke Statistical Update. Dallas: American Heart Association, 2000. 8. Shepherd J, Blauw GJ, Murphy MB, Cobbe SM, Bollen EL, Buckley BM, Ford I, Jukema JW, Hyland M, Gaw A, et al, on behalf of the PROSPER Study Group. The design of a Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Am J Cardiol 1999;84:1192–1197. 9. MRC/BHF Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999;20:725– 741. 10. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23:557–565. 11. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham Study. JAMA 1979;241:2035–2038. 12. Abbot RD, Donahue RP, Kannel WB, Wilson PW. The impact of diabetes on survival following myocardial infarction in men vs. women: the Framingham Study. JAMA 1988;260:3456 –3460. 13. Pyo¨ra¨la¨ K, De Backer G, Graham I, Poole-Wilson P, Wood D. Prevention of coronary heart disease in clinical practice. Eur Heart J 1994;15:1300 –1331. 14. Tikkanen MJ, Laakso M, Ilmonen M, Helve E, Kaarsalo E, Kilkki E, Saltevo J, for the study group. Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM: a multicenter comparison study. Diabetes Care 1998;21:477– 481. 15. Jeck T, Riesen WF, Keller U. Comparison of bezafibrate and simvastatin in the treatment of dyslipidaemia in patients with NIDDM. Diabet Med 1998;14: 564 –570. 16. Byers RJ, Eddleston JM, Pearson RC, Bigley G, McMahon RF. The Women’s Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report. Crit Care Med 1999;27:1787–1793. 17. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC, Grimm RH, LaRosa J, Whelton PK, Perry HM, et al, for the ALLHAT Research Group. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Hypertens 1996;9:342–360. 18. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000;283:1967– 1975. 19. Executive Summary of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 – 2497. 20. Pedersen TR, Olsson AG, Færgeman O, Kjekshus J, Wedel H, Berg K, Wilhelmsen L, Haghfelt T, Thorgeirsson G, Pyo¨ra¨la¨ K, et al, for the Scandinavian Simvastatin Survival Study Group. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97:1453–1460. 21. Sacks FM, Moye´ LA, Davis BR, Cole TG, Rouleau JL, Nash DT, Pfeffer MA, Braunwald E. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events trial. Circulation 1998;97:1446 –1452. 22. LaRosa JC, for the TNT Steering Committee. Effect of lowering LDL-C beyond currently recommended minimum targets: the Treating to New Targets (TNT) study. Abstract presented at the XIII International Symposium on Drugs Affecting Lipid Metabolism. Florence, Italy, May 30 –June 3, 1998. 23. Andrews TC, Raby K, Barry J, Naimi CL, Allred E, Ganz P, Selwyn AP. Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease. Circulation 1997;95:324 –328. 24. Pedersen TR, Kjekshus J, Pyo¨ra¨la¨ K, Olsson AG, Cook TJ, Musliner TA, Tobert JA, Haghfelt T. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). J Am Coll Cardiol 1998;81: 333–335. 25. Isaacsohn JL, Davidson MH, Hunninghake D, Singer R, McLain R, Black DM. Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE): rationale and design of atorvastatin versus usual care in hypercholesterolemic patients with coronary artery disease. Am J Cardiol 2000;86:250 –252.
VOL. 88 (4A)
AUGUST 16, 2001
MD, DPhil
Lipid-lowering treatment with statins is effective for primary and secondary prevention of coronary artery disease in patients with either hypercholesterolemia or average cholesterol levels. Several clinical trials in progress will investigate the use of statins in entirely elderly or diabetic cohorts, and larger trials will continue to include significant numbers of these patients, as well as greater numbers of women. Additional clinical endpoint trials are assessing the potential benefits of low-
ering lipid levels to below currently recommended goals and of aggressive early statin treatment to prevent ischemic events in patients with stable coronary disease or acute coronary syndromes. These trials are expected to yield important data on the relation of lipid reduction to the prevention of coronary artery disease and on the potential for extending the use of statins. 䊚2001 by Excerpta Medica, Inc. Am J Cardiol 2001;88(suppl):36F– 40F
linical trials have established that lowering cholesterol, particularly low-density lipoprotein choC lesterol (LDL-C), decreases the incidence of coronary
not been represented adequately in most large-scale clinical statin trials. Clinical endpoint trials: Recently, 2 large-scale, randomized, parallel-group, placebo-controlled trials were initiated to evaluate statin treatment in patients aged 65 to 85 years. The Risk Evaluation and Stroke Prevention in the Elderly Cerivastatin Trial (RESPECT) will assess the effect of cerivastatin 0.4 and 0.8 mg/day versus placebo administered for 4 years in 10,000 elderly (65 to 80 years) patients with mild-tomoderate elevations in LDL-C (130 to 199 mg/dL [3.36 to 5.15 mmol/L]) and hypertension (blood pressure ⬎160/95 mm Hg or taking antihypertensive medications). Participants will have no pre-existing coronary artery disease or cerebrovascular disease but will be at increased risk for stroke. The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER)8 includes 5,804 patients (⬇3,000 women) aged 70 to 82 years with a total-cholesterol level of 155 to 348 mg/dL (4 to 9 mmol/L) and existing vascular disease or a high risk for vascular disease because of the presence of smoking, hypertension, or diabetes. Participants will be observed for a minimum of 3.5 years. The primary outcome measure in RESPECT is survival time until stroke, coronary artery disease event, or death, whereas PROSPER has a combined endpoint of coronary artery disease death, nonfatal myocardial infarction (MI), and fatal or nonfatal stroke. In addition, the Medical Research Council, British Heart Foundation (MRC/BHF) Heart Protection Study,9 which is discussed in the section on mega trials, includes ⬎9,500 elderly (⬎65 years of age) patients. Surrogate endpoint trial: Although statin therapy has been clearly demonstrated to lead to reductions in mortality and morbidity, evidence of its anti-ischemic effects is more limited, particularly among the elderly. A new trial to assess the effect of lipid lowering with a statin on ischemia in the elderly (70 to 85 years), the Study Assessing Goals in the Elderly (SAGE), is a large (1,500 patients) multinational study of a predominantly female (4:1 ratio of women to men) population with hypercholesterolemia (LDL-C levels 150 mg/dL to 250 mg/dL [3.87 mmol/L to 6.46 mmol/L]). Subjects will receive either atorvastatin 80 mg/day or pravastatin 40 mg/day for 12 months. The primary
artery disease and major coronary events. Although cholesterol reduction is equally effective in lowering the relative risk for coronary artery disease in patients with and without established disease, it is of particular importance in secondary prevention, because the risk for clinical events in coronary artery disease patients is 5-fold higher than that in the general population.1 Numerous clinical trials have demonstrated that treatment with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) decreases the risk for coronary events and mortality in patients with and without evident coronary artery disease.2– 6 In addition, secondary-prevention trials of statin treatment have shown a reduction in coronary artery disease and all-cause mortality.2,3 The relation between serum cholesterol levels and risk for coronary artery disease has been established in studies of middle-aged men. Less well known is the characterization of the benefits of lipid-lowering therapy in other at-risk groups. Several statin trials are currently being conducted to clarify the potential benefits of treatment in different populations, including the elderly, patients with diabetes, and women. Also being evaluated are the effects of lowering lipid levels beyond currently established goal levels and the potential role of aggressive statin treatment in preventing early recurrent ischemic events.
ELDERLY PATIENTS According to World Health Organization estimates, the elderly population (ie, persons ⱖ65 years of age) will increase by ⬎80% in the next 25 years. This statistic is alarming, because ⬎80% of deaths from cardiovascular disease occur in the elderly.7 Despite the apparent importance of lowering cardiovascular disease risk in the elderly, this population has From the Weill Medical College of Cornell University, New York, New York, USA. Address for reprints: Antonio M. Gotto, Jr., MD, DPhil, c/o Mr. Jesse Jou, Weill Medical College of Cornell University, 445 East 69th Street, Olin Hall 205, New York, New York 10021. E-mail: [email protected].
36F
©2001 by Excerpta Medica, Inc. All rights reserved.
0002-9149/01/$ – see front matter PII S0002-9149(01)01876-8
efficacy endpoint is ischemic burden, determined from ST-segment analysis of 48-hour electrocardiograms.
PATIENTS WITH DIABETES MELLITUS Type 2 diabetes mellitus, a well-established coronary artery disease risk factor, causes a 2- to 4-fold increase in the likelihood of coronary artery disease.10 Moreover, the risk for death from coronary artery disease and serious nonfatal coronary artery disease events is markedly increased,11 and the prognosis of clinically evident coronary artery disease is worse12 in patients with diabetes. Despite their heightened risk, patients with diabetes generally have not been included in studies assessing the clinical effects of statins. Clinical endpoint trials: Numerous randomized, double-blind, placebo-controlled trials of the effects of statin treatment in diabetic patients aged 40 to 75 years are under way, including the Atorvastatin as Prevention of Coronary Heart Disease Endpoints in Patients With Non–Insulin-dependent Diabetes Mellitus (ASPEN) study and the Collaborative Atorvastatin Diabetes Study (CARDS). Although ASPEN is multinational and includes 2,421 patients, both with and without a history of heart disease, CARDS is a primary-prevention trial of 2,120 diabetic patients being conducted in the United Kingdom (UK) and Republic of Ireland. Both trials are assessing atorvastatin 10 mg and have a planned duration of treatment of 4 years. The primary efficacy parameter of ASPEN is time to the combined primary endpoint (cardiovascular death, nonfatal MI, revascularization, coronary artery bypass graft [CABG], or stroke), and that of CARDS is time to MI or to CABG or other revascularization procedure. Patients with type 2 diabetes tend to have hypertriglyceridemia and low levels of high-density lipoprotein cholesterol (HDL-C) compared with control subjects.13 Comparative studies indicate that fibrates (fibric acid derivatives) lower triglyceride levels to a greater degree than do statins, suggesting that combination therapy may be necessary in patients with type 2 diabetes and combined hyperlipidemia.14,15 The 6-year, randomized, placebo-controlled, 2⫻2 factorial design Lipids in Diabetes Study (LDS) is assessing whether lowering lipid levels with a statin (cerivastatin) or a fibrate (fenofibrate), either alone or in combination, can substantially reduce cardiovascular morbidity and mortality in patients aged 40 to 75 years with type 2 diabetes, but without evidence of cardiovascular disease. The 4,000 patients to be enrolled in this UK study were not considered candidates for lipid-lowering therapy at the time the study was designed, although their levels are borderline high (LDL-C level ⬍155 mg/dL [⬍4 mmol/L], triglycerides ⬍400 mg/dL [⬍4.52 mmol/L]). The MRC/BHF Heart Protection Study9 includes patients with, or at high risk for developing, coronary artery disease over the next 5 years and has enrolled nearly 6,000 patients with diabetes, of whom almost 4,000 do not have a history of coronary artery disease. This trial may provide important information on the
benefit and role of early treatment with statins in patients with diabetes who do not have coronary artery disease.
WOMEN Coronary artery disease is the most common cause of death in women in industrialized countries. Yet women, particularly postmenopausal women, who are at higher risk for developing coronary artery disease than younger women, have represented a minority of patients enrolled in trials of primary and secondary prevention of coronary events. This may be related to diagnostic and treatment issues that are being explored in nonstatin trials such as the Women’s Ischemia Syndrome Evaluation (WISE) study.16 Clinical endpoint trials: Several ongoing clinical trials evaluating the effect of statin treatment on coronary artery disease risk and clinical events in women should provide important information. New treatment trials, which have been designed to include a substantial number of women, include PROSPER (⬇3,000 women)8 and the 2 large trials discussed in the next section: the MRC/BHF Heart Protection Study (⬎5,000 women)9 and the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial ([ALLHAT] approximately 18,000 women).17 Surrogate endpoint trials: The Beyond Endorsed Lipid Levels Evaluation Study (BELLES) is a prospective, randomized, double-blind study examining the effects of aggressive lipid-lowering therapy with atorvastatin 80 mg/day or pravastatin 40 mg/day for 12 months on regression of coronary atherosclerosis in 600 postmenopausal (aged 55 to 75 years) women with dyslipidemia and other coronary artery disease risk factors. The primary outcome measure is the percent change from baseline in calcium volume score as measured by electron-beam computed tomography. Secondary outcome measures include the percent change from baseline in lipid parameters and the proportion of patients reaching the goals for cholesterol treatment as defined by the National Cholesterol Education Program (NCEP) guidelines. The Cerivastatin for Hyperlipidemia after Reaching Menopause (CHARM) trial will assess the effect of 3 treatment strategies in approximately 180 postmenopausal women with hyperlipidemia and moderate osteoporosis. For a total follow-up period of 52 weeks, participants will receive 1 of the following regimens: (1) cerivastatin 0.4 mg/day; (2) placebo for 6 weeks, then fenofibrate 200 mg/day for 46 weeks; or (3) atorvastatin 10 mg/day for 6 weeks, then cerivastatin 0.8 mg/day for 46 weeks. Serum lipids will be measured at 6 weeks, and lipids and osteoporosis will be evaluated at the end of the trial.
MEGA TRIALS Additional evidence to support the use of statins to lower coronary artery disease risk and coronary events in the elderly, patients with diabetes, and women is expected from at least 2 large trials currently in progress—the MRC/BHF Heart Protection Study9 and ALLHAT.17 The randomized, placebo-controlled,
A SYMPOSIUM: IDENTIFYING AND MANAGING HYPERLIPIDEMIA
37F
2⫻2 factorial design of the 5-year MRC/BHF Heart Protection Study is evaluating simvastatin, antioxidant vitamin (vitamins C and E and -carotene), and placebo treatment in 20,536 patients aged 40 to 80 years who (1) are at increased risk for coronary artery disease death (prior MI or other coronary artery disease, occlusive disease of noncoronary arteries, diabetes, or treated hypertension); (2) may not have a clear indication for study treatments; and (3) have a totalcholesterol level ⱖ135 mg/dL (3.5 mmol/L). Of the 15,454 men and 5,082 women randomized to treatment (1) 9,515 were ⬎65 years of age at entry; (2) 5,963 (29%) had diabetes, most (3,985) with no history of coronary artery disease; and (3) 6,888 had an LDL-C level ⬍115 mg/dL (⬍3 mmol/L). Primary outcome measures in the MRC/BHF Heart Protection Study are all-cause mortality, coronary artery disease mortality, and noncoronary artery disease mortality in the lipid-lowering therapy arm, and total coronary artery disease and fatal coronary artery disease in the antioxidant vitamin arm. Comparisons of the effects of treatment on fatal coronary artery disease and total coronary artery disease are planned for specific patient subgroups: (1) with and without coronary disease, (2) occlusive noncoronary disease, (3) diabetes, (4) men and women, (5) aged ⱕ65 and ⬎65 years, and (6) smokers and nonsmokers. In addition, patients will be stratified by measurements of blood pressure, LDL-C, HDL-C, and vitamin levels. Findings from this large trial are thus expected to provide important evidence of the effects of statin treatment and antioxidant vitamins on all-cause and cause-specific mortality and on major morbidity in a number of different patient populations. An interim analysis estimates annual rates for nonfatal MI or fatal coronary artery disease, stroke, and all-cause mortality as 2.4%, 1.3%, and 2.2%, respectively.9 The second mega trial, ALLHAT,17 comprises 2 randomized, controlled, open-label, practice-based trials of 6 years’ duration—1 of cholesterol lowering and 1 of antihypertensive therapy. Total enrollment for ALLHAT is 42,448 high-risk hypertensive patients identified without the use of extensive diagnostic testing; 10,337 of the participants are enrolled in the cholesterol-lowering trial.18 The primary eligibility criteria are as follows: age ⱖ55 years, systolic or diastolic hypertension, and ⱖ1 additional risk factors for MI (eg, atherosclerotic disease and type 2 diabetes). For patients enrolled in the cholesterol-lowering trial, those without coronary artery disease must have an LDL-C level between 120 and 189 mg/dL (3.10 and 4.88 mmol/L), whereas the LDL-C level of those with known coronary artery disease must be between 100 and 129 mg/dL (2.58 and 3.33 mmol/L); triglyceride levels must be ⬍350 mg/dL (⬍3.95 mmol/L). Patients were randomized to treatment with pravastatin or usual care, which could include a lipid-lowering medication. The primary endpoint of the cholesterollowering trial is all-cause mortality. 38F THE AMERICAN JOURNAL OF CARDIOLOGY姞
TARGET LIPID LEVELS An unresolved issue is whether the current NCEP ATP III goal of LDL-C ⬍100 mg/dL19 is too high in patients who have had a coronary event. An analysis of data from the Scandinavian Simvastatin Survival Study (4S) of secondary prevention in frankly hypercholesterolemic men (baseline LDL-C, 188 mg/dL [4.86 mmol/L]) suggests that greater benefit may be realized if lower LDL-C levels are attained.20 In this trial, changes in levels of total cholesterol and LDL-C at 1 year in patients receiving statin therapy were highly correlated with reduction in risk for an event: each additional 1% reduction in LDL-C level was estimated to decrease the risk for a coronary event by 1.7%.20 However, another secondary-prevention trial, Cholesterol and Recurrent Events (CARE), in patients with average levels of total cholesterol (mean, 209 mg/dL [5.4 mmol/L]) and LDL-C (mean, 139 mg/dL [3.59 mmol/L]) found that the coronary event rate decreased with reductions in the LDL-C level to approximately 125 mg/dL (3.23 mmol/L), but no additional reduction in risk was observed at LDL-C levels ⬍125 mg/dL to as low as 71 mg/dL (1.83 mmol/L).21 Because of the different protocols for drug administration (dose titration of simvastatin in 4S and fixeddose pravastatin in CARE), it is not clear whether differences in statin dosing strategies influenced or contributed to differences in whether a threshold LDL-C level was observed. Clearly, however, both dosing strategies produce significant clinical benefits in clinical trials. Clinical endpoint trials: The Treating to New Targets (TNT) trial22 was initiated to assess whether lowering LDL-C levels beyond current recommendations with a statin in patients with clinically evident coronary artery disease will lower clinical coronary event rates. Patients aged 35 to 75 years with prior MI, prior or present angina with objective evidence of atherosclerotic coronary artery disease, or prior coronary revascularization procedures, and with LDL-C and triglyceride levels of 130 to 250 mg/dL (3.36 to 6.46 mmol/L) and ⱕ600 mg/dL (ⱕ6.77 mmol/L), respectively, will undergo an 8-week open-label treatment phase with atorvastatin. Those attaining an LDL-C level ⬍130 mg/dL (⬍3.36 mmol/L) will be randomized to double-blind treatment with atorvastatin 10 mg/day or 80 mg/day; the anticipated on-treatment LDL-C levels at these doses are approximately 100 mg/dL (2.58 mmol/L) and 75 mg/dL (1.93 mmol/ L), respectively. In total, 10,000 patients are to receive treatment for an average of 5 years or until the number of primary coronary events reaches 750. The main efficacy measure is the occurrence of a primary event, defined as death from coronary artery disease or nonfatal MI. The large number of patients included in the TNT study may clarify whether attaining lower LDL-C levels further reduces coronary artery disease– related events in patients treated with a statin. The Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) trial also will examine whether lowering the LDL-C level beyond the current recommendations provides any additional
VOL. 88 (4A)
AUGUST 16, 2001
benefit in patients with coronary artery disease. This randomized, open-label study will enroll 7,600 men and women (ⱕ80 years of age, previously hospitalized with definite acute MI or a history of MI, and eligible at the time of discharge for statin therapy according to guidelines). Patients will receive either atorvastatin 80 mg/day or simvastatin 20 to 40 mg/day for 5.5 years. The primary efficacy endpoint is the occurrence of a major coronary event (coronary artery disease death or nonfatal MI). There are 2 studies in progress that are investigating the potential effects of further reductions in LDL-C levels with simvastatin. The first study involves approximately one third of the patients enrolled in the MRC/BHF Heart Protection Study who have only mildly elevated LDL-C levels (116 mg/dL [3 mmol/L]).9 After 30 months of follow-up time, the average reduction in LDL-C in this group was 42 to 46 mg/dL (1.1 to 1.2 mmol/L). Another simvastatin trial, the Study to Evaluate Additional Reductions of Cholesterol and Homocysteine (SEARCH; also known as Heart Protection II), is examining whether incremental clinical benefit will result from a ⬎35% reduction in the LDL-C level, which was the reduction achieved in the 4S study. The primary efficacy endpoint of SEARCH is the effect of high-dose versus low-dose simvastatin (with and without folic acid) on the incidence of total coronary artery disease events.
AGGRESSIVE EARLY LIPID LOWERING TO PREVENT ISCHEMIC EVENTS Statin treatment has been shown to reduce the risk for coronary artery disease death and nonfatal MI by 29% in patients hospitalized for unstable angina6 and to reduce the risk for new or worsening angina by 26%.23 Myocardial ischemia during daily life also is reduced significantly with statin treatment.24 Trials are therefore under way to assess the potential role of statins in the early treatment of patients with myocardial ischemia. Stable coronary disease: The 4-year Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE) trial25 is a population-based, randomized, open-label trial involving 2,443 patients aged 18 to 75 years. The study assesses the effects of aggressive lipid lowering on the prevention of ischemic events in hypercholesterolemic patients (LDL-C level 130 to 250 mg/dL [3.36 to 6.46 mmol/L] if not on lipid-lowering therapy or 110 to 200 mg/dL [2.84 to 5.17 mmol/L] if on therapy) with established coronary artery disease (prior MI, CABG or other coronary intervention, or unstable angina). Patients have been randomized to usual care or atorvastatin 10 to 80 mg/day to achieve LDL-C levels ⱕ80 mg/dL (ⱕ2.06 mmol/L). The primary outcome measure is occurrence of an ischemic event, defined as cardiovascular death, nonfatal MI, resuscitated cardiac arrest, unstable angina, or coronary revascularization, including CABG. The ongoing surrogate endpoint study Reversal of Atherosclerosis with Lipitor (REVERSAL) is a prospective, randomized, double-blind, multicenter study designed to compare the effects of atorvastatin 80
mg/day and pravastatin 40 mg/day for 18 months on the progression and quantification of coronary atherosclerotic lesions. The coronary arteries of 600 patients, aged 30 to 75 years, with a history of coronary artery disease, who are scheduled to undergo cardiac catheterization and coronary angiography will be imaged by intravascular ultrasound. The primary efficacy endpoint is the percent change in total plaque volume for all slices of anatomically comparable segments of the target coronary artery. Acute coronary syndromes: The major secondaryprevention trials assessing the effects of statins on reducing mortality and recurrent coronary events in patients with coronary artery disease excluded patients with recent coronary artery disease events (eg, within the prior 3 to 6 months). The effects of statin treatment initiated within 5 to 10 days of an acute coronary syndrome (unstable angina or non–Q-wave MI) will be investigated in 2 ongoing clinical trials. The Aggrastat to Zocor (A-2-Z) trial is a 2-phase study in patients with unstable angina/non–ST-segment MI. Phase A, which has a duration of 120 hours, is evaluating the effects of tirofiban in combination with aspirin and either low-molecular-weight heparin or unfractionated heparin. Once stabilized, patients enter phase Z and are rerandomized (1) to treatment with simvastatin 40 mg/day for 1 month followed by 80 mg/day for 3 months or (2) to accepted care with diet and placebo for 4 months. Patients having an event would be changed from placebo to simvastatin 20 mg/day for the remainder of the study period. Phase Z is to continue until 970 primary events have occurred. A double-blind, randomized, multicenter comparative trial of pravastatin 40 mg/day and atorvastatin 80 mg/day, Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT), is assessing the reduction in risk for MI and other cardiac events in 4,000 patients who have had an acute coronary syndrome within the previous 10 days. Patients will be observed for at least 1.5 years. PROVE IT is also designed to evaluate the role of infection in cardiovascular disease; half of the patients assigned to each statin treatment group will receive an antibiotic and the other half an antibiotic placebo. Some research findings suggest that infection with organisms such as Chlamydia may have a role in the development of atherosclerosis. Findings from these studies are expected to shed light on the potential role of early and aggressive lipid-lowering treatment in acute coronary syndromes.
PATIENTS WITH STROKE Several of the ongoing trials discussed above will evaluate the effect of statin therapy on the risk for stroke in patients with multiple coronary risk factors or evidence of coronary artery disease, including the elderly and patients with diabetes. However, there are no data on the role of statin therapy in preventing stroke in persons without coronary artery disease but with other forms of cardiovascular disease. The Stroke Prevention by Aggressive Reduction of
A SYMPOSIUM: IDENTIFYING AND MANAGING HYPERLIPIDEMIA
39F
Cholesterol Levels (SPARCL) study is the first to investigate the effect of statins on the risk for cerebrovascular events in patients without a history of coronary artery disease. This double-blind, randomized, placebo-controlled, multicenter trial will examine the effect of aggressive atorvastatin therapy (80 mg/day) on specified cerebrovascular endpoints in 4,200 patients. The anticipated duration of treatment and follow-up is 5 years. Patients are eligible for the study if they have had a previous transient ischemic attack or stroke, have an LDL-C level between 100 mg/dL (2.58 mmol/L) and 190 mg/dL (4.91 mmol/L), and have no evidence of coronary artery disease. The primary clinical endpoint is the time to first occurrence of a fatal or nonfatal stroke.
CONCLUSIONS The introduction of statins for lowering lipid levels was an important advance in decreasing the risk for major coronary events in patients with hypercholesterolemia and those at risk for coronary artery disease. Although statins have apparent benefit in the elderly, patients with diabetes, and women based on subgroup analyses, several clinical trials in progress are expected to provide additional information about the use of statins in these target patient populations. Other ongoing trials with statins may resolve the question of whether achieving LDL-C levels lower than those currently recommended by NCEP Adult Treatment Panel III will further decrease a patient’s risk for a major coronary event. Additional studies in progress are focusing on patients with acute coronary syndromes or other manifestations of vascular disease, such as stroke. In the next 5 to 6 years, as the results of these clinical trials become available, the role of statins in the treatment of patients at risk for coronary artery disease or with clinically evident coronary artery disease will be further elucidated, and their use may be broadened. 1. National Cholesterol Education Program. Second Report of the Expert Panel
on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994;89:1329 –1345. 2. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 3. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ, for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301–1307. 4. Sacks FM, Pfeffer MA, Moye´ LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JMO, Wun C-C, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001–1009. 5. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr, for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in
40F THE AMERICAN JOURNAL OF CARDIOLOGY姞
men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998;279:1615–1622. 6. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357. 7. American Heart Association. 2001 Heart and Stroke Statistical Update. Dallas: American Heart Association, 2000. 8. Shepherd J, Blauw GJ, Murphy MB, Cobbe SM, Bollen EL, Buckley BM, Ford I, Jukema JW, Hyland M, Gaw A, et al, on behalf of the PROSPER Study Group. The design of a Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). Am J Cardiol 1999;84:1192–1197. 9. MRC/BHF Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering therapy and of antioxidant vitamin supplementation in a wide range of patients at increased risk of coronary heart disease death: early safety and efficacy experience. Eur Heart J 1999;20:725– 741. 10. American Diabetes Association. Management of dyslipidemia in adults with diabetes. Diabetes Care 2000;23:557–565. 11. Kannel WB, McGee DL. Diabetes and cardiovascular disease: the Framingham Study. JAMA 1979;241:2035–2038. 12. Abbot RD, Donahue RP, Kannel WB, Wilson PW. The impact of diabetes on survival following myocardial infarction in men vs. women: the Framingham Study. JAMA 1988;260:3456 –3460. 13. Pyo¨ra¨la¨ K, De Backer G, Graham I, Poole-Wilson P, Wood D. Prevention of coronary heart disease in clinical practice. Eur Heart J 1994;15:1300 –1331. 14. Tikkanen MJ, Laakso M, Ilmonen M, Helve E, Kaarsalo E, Kilkki E, Saltevo J, for the study group. Treatment of hypercholesterolemia and combined hyperlipidemia with simvastatin and gemfibrozil in patients with NIDDM: a multicenter comparison study. Diabetes Care 1998;21:477– 481. 15. Jeck T, Riesen WF, Keller U. Comparison of bezafibrate and simvastatin in the treatment of dyslipidaemia in patients with NIDDM. Diabet Med 1998;14: 564 –570. 16. Byers RJ, Eddleston JM, Pearson RC, Bigley G, McMahon RF. The Women’s Ischemia Syndrome Evaluation (WISE) study: protocol design, methodology and feasibility report. Crit Care Med 1999;27:1787–1793. 17. Davis BR, Cutler JA, Gordon DJ, Furberg CD, Wright JT Jr, Cushman WC, Grimm RH, LaRosa J, Whelton PK, Perry HM, et al, for the ALLHAT Research Group. Rationale and design for the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). J Hypertens 1996;9:342–360. 18. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000;283:1967– 1975. 19. Executive Summary of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486 – 2497. 20. Pedersen TR, Olsson AG, Færgeman O, Kjekshus J, Wedel H, Berg K, Wilhelmsen L, Haghfelt T, Thorgeirsson G, Pyo¨ra¨la¨ K, et al, for the Scandinavian Simvastatin Survival Study Group. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97:1453–1460. 21. Sacks FM, Moye´ LA, Davis BR, Cole TG, Rouleau JL, Nash DT, Pfeffer MA, Braunwald E. Relationship between plasma LDL concentrations during treatment with pravastatin and recurrent coronary events in the Cholesterol and Recurrent Events trial. Circulation 1998;97:1446 –1452. 22. LaRosa JC, for the TNT Steering Committee. Effect of lowering LDL-C beyond currently recommended minimum targets: the Treating to New Targets (TNT) study. Abstract presented at the XIII International Symposium on Drugs Affecting Lipid Metabolism. Florence, Italy, May 30 –June 3, 1998. 23. Andrews TC, Raby K, Barry J, Naimi CL, Allred E, Ganz P, Selwyn AP. Effect of cholesterol reduction on myocardial ischemia in patients with coronary disease. Circulation 1997;95:324 –328. 24. Pedersen TR, Kjekshus J, Pyo¨ra¨la¨ K, Olsson AG, Cook TJ, Musliner TA, Tobert JA, Haghfelt T. Effect of simvastatin on ischemic signs and symptoms in the Scandinavian Simvastatin Survival Study (4S). J Am Coll Cardiol 1998;81: 333–335. 25. Isaacsohn JL, Davidson MH, Hunninghake D, Singer R, McLain R, Black DM. Aggressive Lipid-Lowering Initiation Abates New Cardiac Events (ALLIANCE): rationale and design of atorvastatin versus usual care in hypercholesterolemic patients with coronary artery disease. Am J Cardiol 2000;86:250 –252.
VOL. 88 (4A)
AUGUST 16, 2001