ABSTRACT: Results of the Heart Protection Study (HPS)-the largest prospective statin trial to date-have confirmed that the cardioprotective effects of statin therapy extend to high-risk patients regardless of age, sex, or baseline serum cholesterol levels. Yet despite compelling efficacy data, statins are not prescribed as often or as aggressively as they should be, even among patients at high risk for coronary heart disease (CHD). Recent studies have shown a significant reduction in the risk of CHD among patients 65 years and older with statin treatment. These agents are also recommended as first-line therapy for prevention of CHD in postmenopausal women. Statins appear to be cardioprotective even in patients with average baseline serum total cholesterol levels.
Until recently, limited data were available on the effectiveness of statin therapy in elderly persons, women, and those with low to normal baseline serum cholesterol levels. New evidence makes it clear that patients in these groups can derive substantial benefit from treatment, which would considerably reduce morbidity and mortality.
The implication for clinical practice is that the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III guidelines may not be aggressive or inclusive enough. Ongoing trials will help define treatment goals and identify patients who can most benefit from lipid-lowering regimens (Box).
In this article, I review the data from key clinical trials that support the use of statins in patients for whom these agents have not been routinely considered.
The reductions in cardiovascular morbidity and mortality demonstrated in the landmark statin trials provide compelling evidence for the use of statins for both primary and secondary prevention of coronary heart disease (CHD).1-5 Nevertheless, despite the proven efficacy of statins in improving cardiovascular outcomes in a broad range of patients across a wide spectrum of risk, these agents are not prescribed as often or as aggressively as they should be.
The Lipid Treatment Assessment Project (L-TAP) reported that among 4888 patients treated for dyslipidemia, only 38% achieved the low-density lipoprotein (LDL) cholesterol goals established by the NCEP, which suggests that these patients were undertreated.6 (L-TAP may have actually underestimated the magnitude of undertreatment by current standards, because it was based on the less stringent and less inclusive guidelines of the NCEP ATP II.) Moreover, only 18% of patients with established CHD reached their target LDL cholesterol levels. The reasons for this may include failure to adhere to dietary and exercise regimens and to continue medical therapy over the long term.
Lipid-lowering therapy is also underused in specific subpopulations of high-risk patients. Studies indicate that women with CHD are less likely to be treated with lipid-lowering agents than men and are less likely to reach NCEP target LDL cholesterol levels. In an evaluation of the use of lipid-lowering therapy among 825 patients with CHD at 16 academic medical centers in the United States and Canada, only 35% of women were receiving lipid-lowering therapy, compared with 55% of men.7 In the multicenter Heart and Estrogen/Progestin Replacement Study of postmenopausal women with documented CHD, fewer than half (47%) were taking lipid-lowering drugs, and only 9% met their NCEP ATP II LDL cholesterol goal of 100 mg/dL or less.8
A major impediment to treatment is the lack of awareness about the benefits of lipid-lowering therapy in a broad range of patients. Other obstacles include the cost of medication, the fact that dyslipidemia does not produce symptoms, and concern about side effects. Published subgroup analyses from the landmark statin trials show significant reductions in coronary events in both men and women, those older and younger than 65 years, patients with and without established CHD, and patients with normal and elevated baseline cholesterol levels. Results of the recent Heart Protection Study (HPS)-the largest prospective, randomized, placebo-controlled statin trial to date-have confirmed what earlier subgroup analyses suggested: the protective effects of statin therapy extend to high-risk patients regardless of age, sex, or baseline cholesterol levels.9 Nonlipid benefits of statin therapy may include a reduction in levels of C-reactive protein and a decreased incidence of Alzheimer disease and stroke.
STATINS AND THE ELDERLY
Because evidence of cardiovascular risk reduction in the elderly was derived from subgroup and post hoc analyses of data from the landmark statin trials, the value of lipid-lowering therapy in this group had remained in question until recently. Results of the latest studies are summarized in Table 1.
The 3 secondary prevention trials of statins-Scandinavian Simvastatin Survival Study (4S), Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID)-enrolled large numbers of patients 65 years or older and demonstrated comparable risk reductions in older and younger patients.10-12 In subgroup analyses, the incidence of coronary events was reduced by 26% to 34% and CHD death by 24% to 45% in patients 65 years or older (see Table 1).9-13 Because the risk of cardiovascular events and mortality increases with age, the absolute risk reduction associated with treatment was substantially greater in older patients10-12; in 4S and LIPID, statin treatment prevented twice as many deaths in patients 65 years or older as in patients younger than 65 years.10,12
The maximum age of patients in these studies was 75 years; however, results of an observational study of 1410 patients between the ages of 60 and 100 years (mean, 81 years) suggest that treatment with statins was associated with a significant reduction in recurrent coronary events.14 In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study, lipid-lowering therapy with atorvastatin, 80 mg/d, was initiated 24 to 96 hours after hospitalization. The results showed a significant decrease in recurrent ischemic events (specifically, recurrent symptomatic myocardial ischemia with objective evidence and emergency rehospitalization) after as little as 6 months of statin therapy in patients with acute coronary syndromes whose mean age was 65 years.15
Convincing new data. Results of HPS provide even more convincing evidence of the benefit of statin therapy in the elderly. This trial enrolled more than 20,000 patients between the ages of 40 and 80 years, including approximately 5800 patients aged 70 years or older and 1200 older than 75 years.9,16 Eligible patients had baseline total cholesterol levels of 135 mg/dL or higher and were considered at high risk for CHD death because of previous myocardial infarction (MI) or other CHD event, occlusive disease of noncoronary arteries, diabetes, or treated hypertension (in men 65 years or older).9 The HPS enrolled only patients not deemed eligible for statin treatment by their physician, including large numbers of the elderly, women, and patients with below-average cholesterol levels who would have been excluded from previous statin trials despite their high-risk status. Patients were randomized to simvastatin, 40 mg/d, or placebo and followed for 5.5 years.
Overall, treatment with simvastatin was associated with significant reductions in vascular mortality (17%), all-cause mortality (13%), strokes (25%), and major vascular events (including revascularization) (24%), with no increase in the incidence of hemorrhagic stroke.9 Similar reductions in vascular events were seen in both patients younger than 65 years and patients 65 years or older. Even among patients aged 75 to 80 years, the reduction in vascular event rate was substantially higher in the simvastatin group (32%) than in the placebo group (23%) (P = .0002).9
Recommendations from recent guidelines. Current NCEP (ATP III) and American Heart Association (AHA) guidelines recommend pharmacologic lipid-lowering therapy for eligible elderly patients with established CHD, and as primary prevention for persons with multiple risk factors or advanced subclinical atherosclerosis.17,18 These guidelines, published before the HPS results became available, place no restriction on lipid-lowering treatment based on age. They conclude that there is no evidence to suggest that risk factors for CHD are any less predictive, or that lipid-lowering therapy is any less effective, in elderly persons than in younger ones.17,18
STATINS AND WOMEN
Although statin therapy appeared to benefit women in the initial landmark trials (Table 2),19 not enough women were included for definitive conclusions to be reached. In 4S, treatment with simvastatin, 20 mg/d, yielded the same significant 34% reduction in major coronary events (primarily CHD death and nonfatal MI) in both men (n = 3617) and women (n = 827) with CHD and moderately elevated LDL cholesterol levels.10
In the CARE trial, which enrolled 576 women and 3583 men with CHD and average total and LDL cholesterol levels, the reduction in major coro-nary events associated with statin therapy (pravastatin, 40 mg/d) was significantly greater in women (46%) than in men (20%), and the benefit was observed earlier in the course of treatment in women.2,20 Women had a 43% risk reduction in the primary end point, which was coronary death or nonfatal MI.
The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) of primary prevention enrolled 997 women and 5608 men with average total and LDL cholesterol levels and below-average high-density lipoprotein (HDL) cholesterol levels. Patients were randomized to lovastatin, 20 to 40 mg/d, or placebo in addition to dietary intervention.4 After approximately 5 years, reduction in the rate of first acute major coronary events was greater in women than in men (46% vs 37%), although the difference was not statistically significant.
The assumption that hormone replacement therapy (HRT) protects postmenopausal women against CHD has not withstood the scrutiny of recent clinical trials.17,21 Results of both primary and secondary prevention trials of HRT have failed to demonstrate a reduction in CHD risk.22-24 In fact, principal results from the randomized, controlled Women's Health Initiative trial showed an increased risk of CHD with HRT.24
The latest recommendations. The AHA/American College of Cardiology statement on the primary and secondary prevention of CHD in women recommends statins as first-line therapy in postmenopausal women, based on clinical trial evidence.21 In addition, the most recent NCEP guidelines recommend that women be treated with lipid-lowering medication instead of HRT for CHD risk reduction.17 Although women generally experience a first CHD event at least a decade later than men, CHD is a disease that progresses over long periods.17,21 Because women often have undiagnosed cardiovascular events, primary prevention may actually be considered secondary prevention, particularly in high-risk patients.
HPS, the largest trial of statins to include women (more than 5000), provides more evidence of the benefit of statin therapy regardless of sex.9 The relative risk reduction for major vascular events was similar in men and women (22% and 20%, respectively).9
PATIENTS WITH LOW BASELINE LDL CHOLESTEROL LEVELS
One of the persistent quandaries in the treatment of dyslipidemia relates to optimal targets for lipid-lowering therapy. The NCEP ATP III guidelines identify LDL cholesterol as the primary target of lipid-lowering therapy and define the optimal LDL level as below 100 mg/dL.17 This goal applies particularly to patients with established CHD or other forms of atherosclerotic disease, diabetes mellitus, or 2 or more risk factors that confer a 10-year CHD risk higher than 20%.17 For patients with multiple risk factors, no established CHD, and a 10-year CHD risk of 20% or higher, the LDL goal is below 130 mg/dL; for those with no risk factors or 1 risk factor, the LDL goal is below 160 mg/dL.
Evidence suggests, however, that achieving levels of LDL cholesterol lower than current recommended goals provides greater protection against the risk of CHD. In an 8- to 13-year follow-up study of more than 9000 men and women, those with total cholesterol levels considered normal or even low by Western standards (mean total cholesterol, 162 mg/dL) still had CHD.25 There was no evidence of a threshold level below which total cholesterol was no longer associated with CHD risk.
The effects of treatment in patients with "average" cholesterol levels were evaluated in 2 major statin trials.2,4 AFCAPS/TexCAPS enrolled generally healthy persons with average levels of total cholesterol (180 to 264 mg/dL) and LDL cholesterol (130 to 190 mg/dL), but below-average levels of HDL cholesterol (45 mg/dL or lower for men and 47 mg/dL or lower for women).4 CARE included patients with a history of MI, total cholesterol levels below 240 mg/dL and LDL cholesterol levels from 115 to 174 mg/dL.2 Both studies demonstrated significant reductions in coronary events associated with statin treatment.2,4
Interestingly, less than a quarter of the AFCAPS/TexCAPS study population would have qualified for drug treatment under the NCEP guidelines at the time, which suggests that millions of Americans considered ineligible for lipid-lowering therapy would have benefited from treatment.4 The CARE investigators noted that because the average cholesterol levels in the study population are representative of levels in most MI survivors, the benefit of lipid lowering may extend to most patients with established CHD even in the absence of hypercholesterolemia.2
More recent statin trials also support the argument that the opti-mal LDL cholesterol goal of below 100 mg/dL may be too high. In the Atorvastatin Versus Revascularization Treatment (AVERT) study, patients with stable CHD who were referred for percutaneous revascularization were treated with either aggressive lipid lowering (atorvastatin, 80 mg/d) or angioplasty followed by usual care (which could include lipid-lowering treatment).26 The atorvastatin-treated patients had a 46% reduction in LDL cholesterol levels (to 77 mg/dL), compared with the 18% reduction (to 119 mg/dL) in the group that underwent angioplasty plus usual care. Atorvastatin treatment was associated with a 36% lower incidence of ischemic events and a significantly longer time to the first ischemic event (P = .03).
In the MIRACL trial, a reduction in mean LDL cholesterol-from a "normal" level of 124 mg/dL to 72 mg/dL with atorvastatin, 80 mg/d-resulted in a significant reduction in symptomatic myocardial ischemia.15
The HPS has provided compelling evidence that statins protect against CHD regardless of baseline cholesterol levels.9 This trial enrolled large numbers of patients with low to normal cholesterol levels: approximately 6800 patients had baseline LDL cholesterol levels below 116 mg/dL, and 3400 had baseline LDL cholesterol levels below 100 mg/dL.9 Simvastatin, 40 mg/d, lowered LDL cholesterol levels from less than 116 mg/dL to less than 77 mg/dL. This was associated with a reduction of about 25% in vascular disease risk.9
Even in patients with a pretreatment LDL level of less than 100 mg/dL, lowering LDL cholesterol from 97 mg/dL (with placebo) to 65 mg/dL (with statin therapy) produced a reduction in risk about as great as a 32 mg/dL reduction would produce at higher LDL levels.9 Based on these data from the HPS, there appears to be no level of LDL cholesterol below which statin therapy does not produce benefit.
Most statin-related adverse effects are mild and transient. However, the use of a statin in combination with a fibric acid derivative increases the risk of rhabdomyositis and should be restricted to patients at very high risk. Refer these patients to a specialist.
REFERENCES:1. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994; 344:1383-1389.
2. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.
3. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. The Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. N Engl J Med. 1998;339:1349-1357.
4. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA. 1998;279: 1615-1622.
5. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med. 1995;333: 1301-1307.
6. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a mul-ticenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med. 2000;160:459-467.
7. Miller M, Byington R, Hunninghake D, et al, for the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) Investigators. Sex bias and underutilization of lipid-lowering therapy in patients with coronary artery disease at academic medical centers in the United States and Canada. Arch Intern Med. 2000;160:343-347.
8. Schrott HG, Bittner V, Vittinghoff E, et al. Adherence to National Cholesterol Education Program treatment goals in postmenopausal women with heart disease: the Heart and Estrogen/Progestin Replacement Study (HERS). JAMA. 1997;277:1281-1286.
9. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7-22.
10. Miettinen TA, Pyorala K, Olsson AG, et al. Cholesterol-lowering therapy in women and elderly patients with myocardial infarction or angina pectoris: findings from the Scandinavian Simvastatin Survival Study (4S). Circulation. 1997;96:4211-4218.
11. Lewis SJ, Moye LA, Sacks FM, et al. Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range: results of the Cholesterol and Recurrent Events (CARE) trial. Ann Intern Med. 1998;129:681-689.
12. Hunt D, Young P, Simes J, et al. Benefits of pravastatin on cardiovascular events and mortality in older patients with coronary heart disease are equal to or exceed those seen in younger patients: results from the LIPID trial. Ann Intern Med. 2001; 134:931-940.
13. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of coronary disease: a meta-analysis of randomized controlled trials. JAMA. 1999;282:2340-2346.
14. Aronow WS, Ahn C. Incidence of new coronary events in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol > or = 125 mg/dL treated with statins versus no lipid-lowering drug. Am J Cardiol. 2002;89:67-69.
15. Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001; 285:1711-1718.
16. Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract. 2002;56:53-56.
17. Executive summary of 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). JAMA. 2001;285:2486-2497.
18. Williams MA, Fleg JL, Ades PA, et al. Secondary prevention of coronary heart disease in the elderly (with emphasis on patients > or = 75 years of age): an American Heart Association scientific statement from the Council on Clinical Cardiology Subcommittee on Exercise, Cardiac Rehabilitation, and Prevention. Circulation. 2002;105:1735-1743.
19. Mosca LJ. Contemporary management of hyperlipidemia in women. J Womens Health Gend Based Med. 2002;11:423-432.
20. Lewis SJ, Sacks FM, Mitchell JS, et al. Effect of pravastatin on cardiovascular events in women after myocardial infarction: the Cholesterol and Recurrent Events (CARE) trial. J Am Coll Cardiol. 1998;32: 140-146.
21. Mosca L, Grundy SM, Judelson D, et al. Guide to Preventive Cardiology for Women. AHA/ACC Scientific Statement Consensus panel statement. Circulation. 1999;99:2480-2484.
22. Hulley S, Grady D, Bush T, et al, for the Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA. 1998;280:605-613.
23. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA. 2002; 288:49-57.
24. Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-333.
25. Chen Z, Peto R, Collins R, et al. Serum cholesterol concentration and coronary heart disease in population with low cholesterol concentrations. BMJ. 1991;303:276-282.
26. Pitt B, Waters D, Brown VB, et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med. 1999; 341:70-76.
27. Raggi P, Callister TQ, Davidson M, et al. Aggressive versus moderate lipid-lowering therapy in postmenopausal women with hypercholesterolemia: rationale and design of the Beyond Endorsed Lipid Lowering with EBT Scanning (BELLES) trial. Am Heart J. 2001;141:722-726.
28. Shepherd J, Blauw GJ, Murphy MB, et al, for 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.
29. LaRosa JC. Effect of lowering LDL-C beyond currently recommended minimum targets-the Treating to New Targets (TNT) Study. In: XIII International Symposium on Drugs Affecting Lipid Metabolism. Houston: Giovanni Lorenzini Medical Foundation; 1998:65.