Therapy With Hydroxymethylglutaryl Coenzyme A Reductase Inhibitors (Statins) and Associated Risk of Incident Cardiovascular Events in Older Adults:  Evidence From the Cardiovascular Health Study FREE

THE NATIONAL Cholesterol Education Program (NCEP) generally recommends screening of cholesterol levels and treatment in the elderly for the prevention of coronary heart disease (CHD).^1- 2 Although secondary prevention trials support the benefits of treating the elderly with hydroxymethylglutaryl coenzyme A reductase inhibitors (statins),^3- 6 the evidence from primary prevention trials is limited. Only 1 primary prevention trial included adults 65 years or older,⁷ and that trial was restricted to persons who had low levels of high-density lipoprotein (HDL) cholesterol, who were otherwise at low risk of CHD, and who were younger than 74 years.

The Cardiovascular Health Study (CHS) is a cohort study of risk factors for cardiovascular disease in men and women 65 years and older at entry.⁸ We previously reported that cohort members appeared undertreated with drugs to lower cholesterol levels.⁹ In the present report, we investigated whether statin treatment of participants for whom therapy to lower cholesterol levels was recommended was associated with a reduction in risk of a first cardiovascular event and all-cause mortality.

The methods have been described elsewhere⁸ and are summarized briefly herein.

The CHS cohort consists of 5201 noninstitutionalized men and women 65 years and older, recruited beginning June 1989, from the following 4 US communities: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh (Allegheny County), Pa. An additional 687 African American adults were recruited beginning June 1992. Participants were sampled randomly from the Medicare eligibility lists of the Health Care Financing Administration. The cohort was followed up until June 1997. During follow-up, the study participants received usual medical care from their own physicians.

The baseline examination consisted of a home interview and a clinic examination. The methods of the baseline examination have been published elsewhere.⁸ Participants were then followed up by means of annual examinations. Data on medical history and personal habits were collected every year. Venipuncture and cholesterol level measurements were performed at baseline and, for the original cohort, in the third year of follow-up. Information on medications, including drugs to lower cholesterol levels, used in the 2 weeks preceding each annual examination, was collected directly from prescription bottles.¹⁰

Hypertension was defined as treatment with antihypertensive medicines and a self-reported history of high blood pressure. Diabetes was defined as a fasting plasma glucose level of greater than or equal to 126 mg/dL (≥7.0 mmol/L), self-report of diabetes, or treatment with insulin or oral hypoglycemic agents. Prevalent cardiovascular disease was defined as a history of angina confirmed by a review of medical records, verified coronary bypass surgery or angioplasty of the coronary arteries, or reported carotid endarterectomy or bypass procedure on a leg artery.

The primary outcome of interest consisted of the combined cardiovascular events of fatal and nonfatal myocardial infarction, fatal and nonfatal stroke, and deaths due to CHD, excluding revascularization procedures. A secondary outcome was all-cause mortality.

Participants were followed up by means of semiannual contacts and asked about cardiovascular events and all hospitalizations. For all potential cardiovascular events, additional information was collected from medical records. Interviews were conducted with surviving participants or with proxies. Deaths were confirmed by review of medical records, death certificates, and the Health Care Financing Administration database for utilization of health care services. Myocardial infarction was defined on the basis of cardiac enzyme levels, chest pain, and serial electrocardiographic changes.¹¹ Deaths were classified as CHD deaths if the fatal event did not meet the criteria for definite myocardial infarction, if the participant had chest pain within 72 hours of death or had a history of chronic ischemic heart disease, and if no other obvious cause of death was found. Strokes were defined as a persistent neurological deficit that lasted at least 24 hours. All strokes were reviewed and classified by neurologists. All cardiovascular events were classified by a Morbidity and Mortality Committee of physicians.¹¹

Participants who had not received drugs to lower cholesterol levels at baseline were classified into 3 mutually exclusive categories of recommended treatment based on the 1993 NCEP guidelines.¹ Recommended categories of treatment were: (1) no therapy for the lowering of cholesterol levels; (2) dietary therapy; and (3) drug therapy for the lowering of cholesterol levels after a trial of dietary therapy. Classification into the categories was based on lipoprotein cholesterol levels and the prevalence of CHD ascertained by means of an algorithm described previously.⁹ The main purpose of the classification was to identify and exclude from the analyses untreated participants at baseline for whom therapy for the lowering of cholesterol levels was not recommended by the 1993 guidelines. The classification was performed at baseline only and was not updated during follow-up.

We performed all statistical analyses with the use of Stata 6.0 (Stata Corp, College Station, Tex). We used Cox regression to assess the risk of cardiovascular events and all-cause mortality associated with the use of drugs to lower cholesterol levels. With the exception of demographic characteristics that were collected only at baseline, the use of statins and other drugs to lower cholesterol levels and cardiovascular risk factor variables (updated annually) were allowed to change over time and were modeled as time-dependent covariates. When risk factor information at an annual examination was missing, we used risk factor information at the visit the year before or 2 years before.

We included the variables of age and sex in all of the multivariate analyses. Other covariates were selected from traditional risk factors, markers of health status, and markers of socioeconomic status. We selected for the analyses the covariates that changed the estimated risks of cardiovascular events associated with the use of statins and other drugs to lower cholesterol levels by 5% or more when added to the statistical models. The analyses were based on the follow-up data up to 1997 that were subsequently updated to incorporate minor corrections as of March 2000.

We excluded CHS participants who had had a myocardial infarction or a stroke before the baseline examination (n = 759). We also excluded participants who had received no drugs to lower cholesterol levels at baseline and for whom no treatment was recommended according to the 1993 NCEP guidelines (n = 3120). In addition, we excluded untreated participants with missing plasma cholesterol values, because their treatment eligibility could not be established (n = 95). The analyses thus included 1914 of the 5888 CHS participants: 226 (33%) from the African American cohort, and 1688 (32%) from the original cohort. Among the 1914 participants, 251 were receiving drugs for the lowering of cholesterol levels and 1663 were untreated at baseline. Of the untreated subjects, drug therapy for the lowering of cholesterol levels after a trial of dietary therapy was recommended for 717, and dietary therapy was recommended for 946, according to the NCEP guidelines.

Baseline characteristics of the participants stratified by treatment or recommended treatment are shown in Table 1. Levels of total and low-density lipoprotein (LDL) cholesterol and prevalence of angina were highest in the untreated group for whom drug therapy was recommended, whereas the proportion of women who used postmenopausal estrogen therapy was highest in the group treated with drugs to lower cholesterol levels. Other characteristics were similar among the 3 groups.

The CHS participants were followed up for a median of 7 years 3 months, when 382 incident cardiovascular events (159 myocardial infarctions, 159 strokes and 64 CHD deaths) and a total of 362 deaths occurred. Of these events, African American participants contributed 32 incident cardiovascular events and 23 total deaths. Table 2 shows the distribution of events among the 3 recommended treatment groups.

During follow-up of the participants included in the analyses, the use of statins increased from 4.2% during baseline years 1989-1990 to 17.6% during 1996-1997, whereas the use of other drugs to lower cholesterol levels combined decreased from 8.2% to 2.8%. Use of drugs to lower cholesterol levels was associated with a decreased risk of incident cardiovascular events (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.36-0.76) after adjustment for sex, age, prevalent cardiovascular disease, and diabetes mellitus. When separated from other drugs used to lower cholesterol levels, use of statins in particular was associated with a decreased risk of incident cardiovascular events relative to no use of drugs to lower cholesterol levels (HR, 0.44; 95% CI, 0.27-0.71) (Table 3). In secondary analyses where myocardial infarction and stroke were separate outcomes, statin use appeared associated with incident myocardial infarction (HR, 0.35; 95% CI,0.15-0.79) and incident stroke (HR, 0.69; 95% CI, 0.36-1.33). Further adjustment for current smoking and pack-years of smoking, treated hypertension and class of antihypertensive drug used, HDL and LDL cholesterol levels, revascularization procedures, regular use of aspirin, income level at baseline, education, and cohort of entry had little effect on the risk estimates. Among women, risk estimates were changed only slightly by adjustment for postmenopausal estrogen use.

Risk estimates were similar in those younger than 74 years at baseline (HR, 0.46; 95% CI, 0.26-0.81) and those 74 years and older (HR, 0.42; 95% CI, 0.15-1.14). Risk estimates were also similar in men and women, in diabetic and nondiabetic subjects, in those with and without a history of angina, and in those with baseline HDL cholesterol levels of less than 46 mg/dL (<1.2 mmol/L) and in those with HDL cholesterol levels of 46 mg/dL and greater (≥1.2 mmol/L) (data not shown).

Among statin users, 62% used a modal dose of statin, defined as 20 mg/d of lovastatin or pravastatin sodium or 10 mg/d of simvastatin or atorvastatin calcium; 10% of statin users used less and 28% used more than the modal dose. In analyses restricted to users of statins, use of a statin dose above the modal dose was not associated with the risk of incident cardiovascular events (HR, 1.54; 95% CI, 0.54-4.41). The risk of incident cardiovascular events associated with the use of a statin dose below the modal dose could not be estimated because only 37 study subjects used the low dose of statins and none experienced an incident event. With regard to duration of use, 46% of statin users reported use at 1 or 2 annual examinations, 23% at 3 or 4 examinations, and 31% at 5 to 8 examinations. In analyses restricted to users of statins, duration of statin use was not linearly associated with the risk of incident cardiovascular events (P = .66), and there was no evidence of a threshold number of years beyond which the association would change.

The use of statins was associated with a decreased risk of all-cause mortality (HR, 0.56; 95% CI, 0.36-0.88) and cardiovascular mortality (HR, 0.54; 95% CI, 0.27-1.08) (Table 4). Use of other drugs to lower cholesterol levels was also associated with a decreased risk of all-cause mortality (HR, 0.43; 95% CI, 0.21-0.88). Risk estimates changed only slightly after further adjustments for current smoking and pack-years of smoking, hypertension and class of antihypertensive drug, HDL and LDL cholesterol levels, revascularization procedures, regular use of aspirin, and markers of health status, including self-perceived health status and the number of instrumental activities of daily living performed with difficulty.

We observed a 56% lower risk of incident cardiovascular events and a 44% lower all-cause mortality associated with the use of statins among CHS participants for whom therapy for the lowering of cholesterol levels was recommended and who were on average aged 72 years at entry into the cohort. Statin use was associated with a similar lower risk of incident cardiovascular events among participants 74 years and older and among participants aged 65 to 73 years.

Among statin users, statin dose and duration of use were not associated with the risk of incident cardiovascular events. In addition, the association of statin use with incident cardiovascular events was unchanged by adjustment for LDL or HDL cholesterol levels. The measurement of cholesterol levels, performed only twice in the study, may not have been precise enough to fully adjust the association; however, in clinical trials, statin use decreased the risk of cardiovascular events early.^7,12- 14 Furthermore, treated LDL cholesterol levels were only weakly associated with cardiovascular events in several clinical trials.^{6- 7,12,14- 17} Statins have effects other than reduction of LDL cholesterol levels, such as effects on plaque stability and thrombus formation, and these non–cholesterol related effects might explain early reduction of cardiovascular events in clinical trials and might explain, in part, the observed associations in the CHS study.^18- 20

The strengths of our study include the prospective study design, the reliable ascertainment of cardiovascular events, the wealth of information on potential risk factors collected from the study participants, and the repeated medication use and risk factor measurements in each study year. Study limitations include the small number of incident cardiovascular disease events and total deaths, which limited the power to find different associations in subgroup analyses. Small numbers of subjects also limited the number of risk factors we could adjust for simultaneously,²¹ and residual confounding by measured risk factors is possible. Because of the observational design of the study, residual confounding by unmeasured participant characteristics such as compliance²² is also possible. The use of drugs to lower cholesterol levels was ascertained only once a year, and the initial date of statin use was unknown. Therefore, the estimated duration of statin use was imprecise and may have resulted in random misclassification that could have biased an association toward the null.

We focused this investigation on statin use rather than combined use of all drugs to lower cholesterol levels, because the associations of various classes of these drugs with cardiovascular events might differ, because statins were used with increasing frequency in this cohort,⁹ and because we wanted to compare the study results with those of recent clinical trials.

The use of drugs other than statins to lower cholesterol levels was associated with a 57% decrease in risk of all-cause mortality. In this cohort, fibrates were the most commonly used class of drugs to lower cholesterol levels other than statins.⁹ Randomized clinical trials have generally found a smaller or nonexistent benefit of fibrate use on all-cause mortality,^23- 24 particularly in the primary prevention setting.²⁵ Because of the small number of events among users of drugs other than statins for the lowering of cholesterol levels, adjustments for multiple risk factors was not possible, and residual confounding is a possible explanation for the results of our study.

Our study results complement the results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS), the trial for primary prevention of CHD with statin therapy that included adults 65 years and older.⁷ In the AFCAPS trial, the risk of major coronary events was decreased by 40% with lovastatin compared with placebo. The similarity of results of the AFCAPS trial and the CHS study are encouraging. It may be reasonable to apply the trial findings to the general elderly population, including groups that were excluded from the trial, ie, patients 74 years and older and patients with angina, patients with diabetes, and patients with HDL cholesterol levels of 46 mg/dL or greater (≥1.2 mmol/L).⁷

We used the 1993 NCEP guidelines to select the study subjects. The purpose of identifying diet-eligible and treatment-eligible study subjects was to identify a group at comparable risk of cardiovascular events at baseline in this study. The 2001 NCEP guidelines present broader recommendations to treat with drugs to lower cholesterol levels, based on risk of development of CHD.²⁶ For primary prevention among older persons, drug therapy should be considered for those at high risk, including persons with diabetes, multiple risk factors, or subclinical disease. In our study, 80% of the subjects would be considered at high risk by the definition used in the 2001 guidelines. Our findings of a lower risk of cardiovascular events and mortality associated with statin use in this group support the NCEP recommendations.

In the absence of data from clinical trials directed at the elderly, results of our study suggest that statin use in elderly subjects for whom therapy for the lowering of cholesterol levels is recommended is associated with decreased risks of incident cardiovascular events and all-cause mortality.

Accepted for publication November 15, 2001.

This study was supported by contracts N01-HC-85079 through N01-HC-85086, Georgetown Echo NOC-HC-35129, and NOC-HC-15103 from the National Heart, Lung, and Blood Institute, Bethesda, Md, and grant AG09556 from the National Institute on Aging, Bethesda. Dr Psaty is a Merck/Society for Epidemiologic Research Clinical Epidemiology Fellow, sponsored by the Merck Co Foundation, Rahway, NJ, and the Society for Epidemiologic Research, Baltimore, Md.

Participating Institutions and Principal Investigators

Forsyth County, North Carolina—Wake Forest University School of Medicine, Winston-Salem: Gregory L. Burke, MD.

Sacramento County, California—University of California–Davis: John Robbins, MD, MHS.

Washington County, Maryland—The Johns Hopkins University, Baltimore: Linda P. Fried, MD, MPH.

Allegheny County, Pennsylvania—University of Pittsburgh, Pittsburgh: Lewis H. Kuller, MD, PhD.

Reading Centers—Wake Forest University School of Medicine Electrocardiographic Reading Center: Pentti M. Rautaharju, MD, PhD; The Johns Hopkins University Magnetic Resonance Imaging Reading Center: Norman J. Beauchamp, MD, Nick Bryan, MD, PhD; University of California–Irvine Echocardiography Reading Center (baseline): Julius M. Gardin, MD; Georgetown Medical Center Echocardiography Reading Center, Washington, DC (follow-up): John S. Gottdiener, MD; New England Medical Center Ultrasound Reading Center, Boston, Mass: Daniel H. O'Leary, MD; University of Vermont Central Blood Analysis Laboratory, Colchester: Russel P. Tracy, PhD; University of Arizona, Tucson Pulmonary Reading Center: Paul Enright, MD.

Coordinating Center—University of Washington, Seattle: Richard A. Kronmal, PhD.

National Heart, Lung, and Blood Institute Project Office, Bethesda, Md— Diane Bild, MD, MPH.

Corresponding author and reprints: Rozenn N. Lemaitre, PhD, MPH, Cardiovascular Health Research Unit, Metropolitan Park, East Tower, Suite 1360, 1730 Minor Ave, Seattle, WA 98101 (e-mail: rozenl@u.washington.edu).