Related information on this website: In the Current Literature section: Cholesterol Lowering in Atherosclerosis Brown WV. Am J Cardiol. 2000;86(suppl):29H-32H. Lowering LDL Cholesterol: Questions From Recent Meta-Analyses and Subset Analyses of Clinical Trial Data Issues From the Interdisciplinary Council on Reducing the Risk for Coronary Heart Disease, Ninth Council Meeting Gotto AM Jr, Grundy SM. Circulation. 1999;99:E1-E7. Depressive Symptoms and Risks of Coronary Heart Disease and Mortality in Elderly Americans Abraham A. Ariyo, MD, MPH, Mary Haan, MPH, PhD, Catherine M. Tangen, Phd, John C. Rutledge, MD, Mary Cushman, MD, MS, Adrian Dobs, MD, MHS, Curt D. Furberg, MD, PhD, for the Cardiovascular Health Study Collaborative Research Group. Circulation. 2000;102:1773-1779. In the Slide Library section: ATP III: Special Populations—Older Adults, Younger Adults Summary of Effects of Lipid Lowering on Lipids and Clinical Events in Recent Statin Trials 4S: Lipid Lowering Reduces CHD Event Rates in >65-Year-Old Subjects

The next 30 years are expected to bring significant changes to the number of older adults (aged 65 and over) in the United States: Their population is projected to double, growing to 70 million by 2030.¹ Within the current population of older adults, coronary heart disease (CHD) accounts for 70% to 80% of deaths. Although recent clinical trials have demonstrated that these patients benefit from CHD risk management, many older patients with confirmed CHD do not receive secondary-prevention therapy, while others do not receive therapy aimed at primary prevention.

Age is an independent risk factor for CHD and the most powerful of all predictors of atherosclerotic events.² Although the risk of dying from a CHD-related event increases with age—more than 85% of those who die of a heart attack are in the older age bracket—there is some question about whether an aggressive approach to preventing this disease or slowing its progression is warranted in the elderly.

Evidence of Undertreatment
Two studies conducted in the mid 1990s revealed that many older patients who were candidates for lipid-lowering agents did not receive them.^3,4 The Cardiovascular Health Study showed that, among 1,025 older adults who were untreated at baseline and eligible for cholesterol-lowering therapy, fewer than 20% began such treatment over 6 years of follow-up.³ Although previously untreated subjects with a history of CHD were twice as likely as those without prior CHD to start such therapy, rates of drug treatment in the subset with CHD—16.4% of men and 15.6% of women—were still low. Another study reported on patients admitted to a long-term healthcare facility with a documented Q-wave myocardial infarction (MI) and an LDL-C level >125 mg/dL. It showed very low percentages of those receiving lipid-lowering medications (see Figure 1).⁴



Statin Efficacy in Older Patients
The question for healthcare providers is, Would older patients benefit from lipid-lowering therapy in terms of reduced morbidity, reduced mortality, or both? No clinical trials assessing the effects of antihyperlipidemic medications solely in older adults have been reported to date, although one trial is under way: the Prospective Study of Pravastatin in the Elderly (see "PROSPER," page 2). However, four landmark clinical trials evaluating statin use provide subgroup data that can help guide the clinical management of elderly patients. The first three of these trials addressed secondary prevention; the fourth, primary prevention.
    4S. In the Scandinavian Simvastatin Survival Study, treatment with simvastatin (relative to placebo) significantly reduced total mortality, the primary end point, by 30% in patients with hypercholesterolemia and history of acute MI or stable angina (aged 35–70 years; N=4,444).⁵ For the secondary end point of major coronary events, there was 34% risk reduction. Compared with placebo, subjects on treatment aged 60 years or older (n=2,282) experienced statistically significant reductions of 27% and 29% in all-cause mortality and major coronary events, respectively. A post-hoc subgroup analysis of 1,021 patients aged 65 and older found significant reductions in total and CHD mortality in the simvastatin group—similar to reductions observed in on-treatment patients under age 65.⁶ Because of an age-related increase in death, the absolute risk reduction for total and CHD mortality was approximately twice as high in older vs younger patients.
    CARE. Results of the Cholesterol and Recurrent Events trial show that pravastatin reduced the risk for fatal CHD or confirmed MI, the primary combined end point, by 24% in patients with a history of MI and TC levels under 240 mg/dL (age range, 21–75 years; N=4,159). The overall reduction in the rate of major coronary events was 46% for women and 20% for men.⁷ According to a subset analysis, patients aged 65 years or older (n=1,283) also benefited from treatment with pravastatin.⁸ In this subgroup, pravastatin (relative to placebo) significantly reduced the overall risk for major coronary events by 32%. There were 225 hospitalizations prevented per 1,000 older patients treated, compared with 121 prevented in patients under 65 years of age. In addition to the clinically important decrease in relative risk for major coronary events, there is a substantial potential for greater absolute benefit because older persons have a higher cardiovascular event rate.
    LIPID. The findings of 4S and the CARE trial were supported by the Long-Term Intervention with Pravastatin in Ischemic Disease study, which enrolled patients aged 31–75 years who had a history of acute MI or unstable angina (N=9,014).⁹ TC levels at baseline were 155–271 mg/dL. In this study, the primary end point was CHD death; however, treatment effects within prespecified subgroups were assessed using the predetermined outcome of nonfatal MI or death from CHD.¹⁰ In 3,514 patients aged 65–75 years of age, there was a 22% reduction in the relative risk for CHD death/nonfatal MI. The overall reduction in risk for the entire cohort was 24%; in patients aged 31–64 years, it was 25%. Because the risk for major coronary events is higher in older patients, the absolute benefit was greater in this subgroup than in younger patients, even though the relative risk reductions were similar.
    AFCAPS/TexCAPS. Patients in the Air Force/Texas Coronary Atherosclerosis Prevention Study had no clinical evidence of atherosclerotic cardiovascular disease.¹¹ They had average TC and LDL-C levels and below-average HDL-C levels. Nevertheless, this study found that treatment with lovastatin, relative to placebo, reduced the risk for a first acute major coronary event (fatal/nonfatal MI, unstable angina, sudden cardiac death) by 37% in men aged 45–73 years and women aged 55–73 years (N=6,605). In a predefined subgroup of subjects older than the median age (men >57 years and women >62 years; n=3,180), there was a 30% reduction in risk. According to these results, the benefit of lovastatin treatment in primary-prevention patients above the median age was similar to that in the overall study sample.

Meta-Analyses
Uniformity of benefit in older and younger patients was also the conclusion of the Prospective Pravastatin Pooling Project (PPP), which analyzed data from the CARE and LIPID trials and from the primary-prevention West of Scotland Coronary Prevention Study (WOSCOPS).¹² However, WOSCOPS did not include subjects older than age 65. In the CARE/LIPID patients aged 65–75 years at the time of enrollment, pravastatin reduced the relative risk for CHD death or nonfatal MI by 27%—a highly significant finding.
    A meta-analysis by LaRosa et al of data from the four statin studies described above (see Figure 2), plus WOSCOPS, revealed that the overall reduction in relative risk for major coronary events was 34% in the two primary-prevention trials and 30% in the three secondary-prevention trials.¹³ In subjects older than age 65, the primary-prevention AFCAPS/TexCAPS showed a 32% reduction in risk, and the three secondary-prevention trials showed reductions of 25% to 42%. The absolute risk reduction was higher in older patients than in those younger than age 65 (44 vs 32 per 1,000 patients). The authors conclude that "the benefits of LDL-C lowering on morbidity, particularly in older age groups, have been underappreciated," and that these benefits should not be denied to such individuals "while we await more definitive information about mortality …" This conclusion is consistent with the position of the American Heart Association that secondary prevention in the elderly appears to produce relative risk reductions similar to those in younger patients.¹⁴



HPS
Complete results of the yet-to-be-published Heart Protection Study should provide researchers with a robust data set concerning statin use in the elderly. The largest cholesterol-lowering drug trial to date (N=20,536; age range, 40–80 years; baseline TC >135 mg/dL), HPS included 10,697 persons aged 65 and above; 4,892 aged 65 to 69; and 5,805 aged 70 and above.¹⁵ Patients were randomized to either simvastatin 40 mg/day or placebo. Treatment and follow-up averaged 51/2 years in 69 hospitals in the United Kingdom. Data available at this time suggest that about one third of all MIs and strokes can be prevented in persons at high risk for CHD by using statins to reduce blood cholesterol levels. These benefits were found in a wide range of at-risk individuals, including those older than age 70.

ATP III
The National Cholesterol Education Program (NCEP), which last year published the Third Adult Treatment Panel, or ATP III, made specific recommendations for older persons.² The guidelines suggest that cholesterol-lowering drugs be considered for primary prevention in older persons who are at high risk for CHD or with established CHD.

Statin Safety
Approximately 12 million patients in the US take statins,¹⁶ with a total of approximately 97 million prescriptions dispensed between January and December 2000.¹⁷ Clinically significant myopathy, one of the potential side effects of statins, is uncommon with the drugs. However, definite rhabdomyolysis—when defined as a 10-fold elevation of creatine kinase levels associated with a compatible symptom complex and myoglobinuria—occurs in approximately 0.1% of patients who receive statin monotherapy.¹⁸
    Between October 1997 and December 2000, 772 rhabdomyolysis cases, including 72 deaths, were reported to the US Food and Drug Administration.¹⁹ Approximately one third of the cases and one quarter of the deaths occurred in patients also taking lipid-modifying fibrate drugs. Also, half of the rhabdomyolysis cases (387 of 772) occurred in patients on cerivastatin. In August 2001, the manufacturer of cerivastatin voluntarily withdrew the drug from the market because of a disproportionate number of deaths (31) associated with rhabdomyolysis—especially when it was combined with gemfibrozil.
    To develop a reliable assessment of the tolerability and safety of pravastatin 40 mg qd, the PPP analyzed data based on more than 112,000 patient-years and more than 230,000 blood samples.²⁰ Results indicate that pravastatin was well tolerated, with no confirmed cases of rhabdomyolysis. Data did not support concerns about myopathy and hepatic liver enzyme abnormalities. Furthermore, tolerability was similar in patients under age 65 and over age 65.²¹
    Data from 4S show that the study's drug discontinuation rates were similar between the younger and older subsets.⁶ Furthermore, a review of clinical adverse events did not reveal any age-specific toxicities of simvastatin. Although a significantly greater number of older simvastatin recipients than younger simvastatin recipients experienced liver enzyme elevations, these changes were minor and transient, and did not prompt treatment cessation. The other three landmark trials did not report drug-related toxicities by age category.
    The danger of adverse drug reactions in older patients is often related to altered drug metabolism and to polypharmacy.²² For example, fluvastatin is metabolized primarily by the cytochrome CYP2C9 enzyme and may interact with other CYP2C9 substrates (eg, warfarin) or with CYP2C9 inhibitors (eg, amiodarone, azole antifungals, selective serotonin reuptake inhibitors).^23,24 Atorvastatin, lovastatin, and simvastatin are metabolized primarily by the CYP3A4 enzyme and may interact with other CYP3A4 substrates (eg, gemfibrozil) or with CYP3A4 inhibitors (eg, azole antifungals, macrolide antibiotics, diltiazem, verapamil, protease inhibitors, nefazodone).²⁵ These interactions can result in higher statin levels and an increased risk for myositis.

Conclusion
The benefits of statins on cardiovascular morbidity and mortality have been demonstrated in randomized controlled trials and in widespread clinical use. These benefits extend to persons of different age groups and in both primary and secondary prevention. Statins not only appear to be safe for use in older patients, but also may confer benefits that extend beyond cholesterol lowering (see "Other Possible Benefits of Statins").

References