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1 November 1998 | Volume 129 Issue 9 | Pages 681-689
Background: A majority of all myocardial infarctions occur in patients who are 65 years of age or older and have average cholesterol levels, but little information is available on whether cholesterol lowering in such patients reduces the rate of recurrent cardiovascular disease.
Objective: To determine whether pravastatin reduces the rate of recurrent cardiovascular events in older patients.
Design: Subset analysis of a randomized, controlled trial.
Setting: 80 hospitals and affiliates in the United States and Canada.
Patients: 1283 patients aged 65 to 75 years who had had myocardial infarction and had a plasma total cholesterol level less than 6.2 mmol/L (240 mg/dL) and a low-density lipoprotein cholesterol level of 3.0 to 4.5 mmol/L (115 to 174 mg/dL).
Intervention: Pravastatin, 40 mg/d, or placebo.
Measurements: Five-year event rates of major coronary events (coronary death, nonfatal myocardial infarction, angioplasty, or bypass surgery) and stroke.
Results: Major coronary events occurred in 28.1% of placebo recipients and 19.7% of pravastatin recipients (difference, 9.0 percentage points [95% CI, 4 to 13 percentage points]; relative risk reduction, 32%; P < 0.001). Coronary death occurred in 10.3% of the placebo group and in 5.8% of the pravastatin group (difference, 4.6 percentage points [CI, 1.9 to 6.5 percentage points]; relative risk reduction, 45%; P = 0.004). Stroke incidence was 7.3% in the placebo group and 4.5% in the pravastatin group (absolute reduction, 2.9 percentage points [CI, 0.3 to 4.5 percentage points]; relative reduction, 40%; P = 0.03). The numbers of older patients needed to treat for 5 years were 11 (CI, 8 to 24) to prevent a major coronary event and 22 (CI, 15 to 53) to prevent a coronary death. For every 1000 older patients treated, 225 cardiovascular hospitalizations would be prevented compared with 121 hospitalizations in 1000 younger patients.
Conclusions: In older patients with myocardial infarction and cholesterol levels in the average range, pravastatin is associated with a clinically important reduction in risk for major coronary events and stroke. Given the high cardiovascular event rate in older patients, the potential for absolute benefit in this age group is substantial.
Almost all trials of cholesterol treatment have excluded patients who were 65 years of age or older. The National Cholesterol Education Panel guidelines [33] therefore extrapolated findings from the treatment of younger patients in their recommendations for treating older patients, noting the considerable potential for absolute risk reduction given the high incidence of cardiovascular events in older patients. More recently, researchers observed that simvastatin treatment of hypercholesterolemic patients with coronary artery disease reduced recurrent major coronary events in the subset of patients who were 65 to 70 years of age at study entry [34]. However, information is needed on the effect of lipid treatment in older patients who have had myocardial infarction and have average cholesterol levels; most patients who have had myocardial infarction have cholesterol values in the average, not elevated, range [35-37].
The Cholesterol and Recurrent Events (CARE) trial [38] investigated whether reducing average cholesterol levels by using pravastatin in patients who have had myocardial infarction would prevent recurrent cardiac events. It showed that in patients with average cholesterol levels, pravastatin therapy reduced the risk for coronary death or recurrent myocardial infarction by 24% (P = 0.003), reduced the risk for fatal and nonfatal myocardial infarction by 25% (P = 0.006), reduced the risk for coronary artery bypass grafting and angioplasty by 27% (P < 0.001), and reduced the risk for stroke by 31% (P = 0.03) [38]. It also reported that patients who were older than the median age of 59 years had a reduced rate of coronary death, nonfatal myocardial infarction, coronary artery bypass grafting, or percutaneous transluminal coronary angioplasty. Of the 4159 patients in the CARE trial, 1283 (31%) were 65 to 75 years of age at baseline; these patients are eligible for retirement health care (Medicare) benefits in the United States. We report on the effect of pravastatin on individual cardiovascular events in these older patients, including myocardial infarction, coronary artery bypass grafting, angioplasty, and stroke, as well as on overall hospitalization for cardiovascular disease.
The design and results of the CARE trial have been described in detail elsewhere [38, 39]. The study was a randomized, double-blind, placebo-controlled trial with a planned average follow-up of 5 years. Patients were recruited from 80 participating centers in the United States and Canada. Institutional review board approval was obtained for investigation of human participants. Patients were eligible if they had had an acute myocardial infarction 3 to 20 months before randomization; were 21 to 75 years of age; and had plasma total cholesterol levels less than 6.2 mmol/L (240 mg/dL), low-density lipoprotein (LDL) cholesterol levels of 3.0 to 4.5 mmol/L (115 to 174 mg/dL), and fasting triglyceride levels less than 4.0 mmol/L (350 mg/dL). The diagnosis of myocardial infarction was confirmed by the MI Confirmation Core Laboratory, which evaluated reports of changes in serum creatine kinase levels, electrocardiographic evidence, and clinical symptoms [38, 39]. Plasma lipids were measured at least 2 months after discharge from hospitalization for the index myocardial infarction. Women were required to be postmenopausal or surgically sterile. All participants received dietary counseling according to the National Cholesterol Education Program Step 1 guidelines.
After the screening visits were completed, eligible patients returned for a randomization visit, during which they were assigned to receive either pravastatin (40 mg/d) or identically appearing placebo by means of a telephone call from a clinical center to the Data Coordinating Center. The patient was the unit of randomization, randomization was stratified within each clinical center, and the allocation schedule was generated by computer. The code for treatment assignment was maintained only at the Data Coordinating Center. The primary trial outcome was fatal coronary artery disease or confirmed nonfatal myocardial infarction. For the primary analysis of the treatment effects in subgroups, we used an expanded end point (death from coronary artery disease, nonfatal myocardial infarction, angioplasty, or coronary artery bypass grafting), called major coronary events.
Statistical Analysis
All analyses were done on an intention-to-treat basis. P values (all of which were two-sided) less than 0.05 were deemed statistically significant. Baseline characteristics in the two treatment groups were determined by using the standard z-test for continuous variables and chi-square tests for categorical variables [40]. All hypothesis testing and risk reductions (with their CIs) were assessed by using the Cox proportional-hazards model. Kaplan-Meier survival curves for the control and pravastatin groups were calculated [41]. The relative risk reduction was calculated as 1 –the hazard ratio. The upper and lower bounds of the 95% CIs for the relative risk reductions were applied to the rates in the placebo group to compute the CI for absolute risk reduction, and these bounds were inverted to provide the CIs for the number of patients needed to treat to prevent an event. To determine whether imbalances in risk factors at baseline could have affected the estimates of risk reduction attributable to therapy, we performed subsidiary multivariate analyses that included the following covariates: age, sex, baseline lipid levels, smoking, diabetes, hypertension, and left ventricular ejection fraction. Potential clinical center effects were assessed by including 79 indicator variables to denote the 80 clinical centers in the Cox proportional-hazards analysis. We used SAS software, version 6.12 (SAS Institute, Cary, North Carolina), to execute all analyses.
Role of the Study Sponsor
The CARE trial was an investigator-initiated study proposed to and funded by Bristol-Myers Squibb. The data were collected and analyzed by and are now maintained at the Coordinating Center, University of Texas School of Public Health. The sponsor is entitled to comment on manuscripts before submission. The authors may consider these comments, but the rights to publication reside contractually with the investigators. The sponsor, a member of the Executive Committee of the trial, was contractually required to fund the study until its conclusion. The sponsor maintained information on adverse events and other trial data, as required by federal regulations.
From a total of 11 207 patients identified from records in hospitals and ambulatory practices for possible inclusion in the CARE trial, 3244 (29%) were at least 65 years of age (hereafter referred to as "older patients"). Of these 3244 older patients, 1139 (35%) qualified for the trial. An additional 144 patients reached the age of 65 years between their screening date and randomization; thus, 1283 older patients were randomly assigned in the CARE trial. A similar percentage of the patients younger than 65 years of age (hereafter referred to as "younger patients")-39% (3020 patients)-qualified for the trial. Older patients were less likely than younger patients to be ineligible because of elevated total cholesterol, LDL cholesterol, or triglyceride levels (8% and 12%, respectively). However, older patients were more likely than younger patients to be ineligible because criteria for myocardial infarction were not met (61% and 53%, respectively) (P < 0.05 for all comparisons).
Baseline Characteristics
The median follow-up was 5 years (25th and 75th percentiles, 4.3 and 5.4 years). The mean age of the older patients was 69 years at randomization (25th and 75th percentiles, 66 and 73 years) and 74 years at the end of the trial. Baseline coronary risk factors significantly differed between the two age groups (Table 1). Older patients more frequently were female (18% compared with 12% of younger patients), had hypertension (48% compared with 40%), and had diabetes (19% compared with 12%). In addition, they were more likely to have had a second previous myocardial infarction (21% compared with 15%) and less frequently were current smokers (12% compared with 24%), had ever smoked (70% compared with 81%), or had a family history of coronary artery disease (33% compared with 44%) (P < 0.05 for all comparisons). ARTICLE
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
Three fourths of deaths from myocardial infarction occur in patients older than 65 years of age, making cardiovascular disease the leading cause of death in older persons [1, 2]. Older patients, despite their high risk for cardiovascular death, are less likely to receive cardioprotective medications or interventions [3-15] or to be enrolled in clinical trials that test potentially beneficial treatments [3]. Although much information is available on serum cholesterol as a predictor of coronary artery disease in younger patients, as well as on the benefits of reduction of serum cholesterol levels, the role of cholesterol in coronary artery disease in older patients is less clear. Elevated cholesterol levels do not strongly predict coronary events in older patients [16-23]; thus, the need for cholesterol screening and treatment in older persons has generated much divergent opinion [22-31]. Recent analysis of a cohort of older persons (mean age, 80 years) strongly suggested that concomitant disease or debilitation was associated with low blood cholesterol levels and was responsible for the reduced ability of serum cholesterol levels to predict the incidence of coronary events. After adjustment for low serum iron and albumin levels and exclusion of events in the first year of follow-up, serum cholesterol levels became a significant predictor of coronary death [32]. Without this adjustment, no such association was seen [32].
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Screening and Exclusion before Randomization
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Between the time of meeting the CARE criteria for myocardial infarction and the time of randomization, older patients less frequently received thrombolytic therapy (36% compared with 45% of younger patients), angiography (75% compared with 80%), and angioplasty (29% compared with 35%) but more frequently had coronary artery bypass grafting (31% compared with 25%). Older persons also had a higher incidence of angina (23% compared with 20%) and history of congestive heart failure (11% compared with 5%) (P < 0.05 for all comparisons).
Therapy at the time of randomization also differed significantly between the two age groups. Fewer older patients than younger patients were receiving ß-blockers (37% compared with 41%) and more were receiving calcium-channel blockers (42% compared with 38%), angiotensin-converting enzyme inhibitors (16% compared with 14%), digitalis preparations (13% compared with 6%), and diuretics (19% compared with 9%) (P < 0.05 for all comparisons).
Effects on Plasma Lipids
The baseline total, high-density lipoprotein, and LDL cholesterol levels were similar in both age groups, but triglyceride levels were lower in older patients (Table 1). In both age groups, pravastatin therapy compared with placebo had similar effects on plasma lipid levels. Total cholesterol levels decreased by 20% in the older group and 19% in the younger group; LDL cholesterol levels decreased by 29% and 27%; high-density lipoprotein cholesterol levels increased by 4% and 5%; and triglyceride levels decreased by 12% and 14% (P < 0.001 for all comparisons with placebo). In older patients, LDL cholesterol levels decreased promptly after the start of therapy, and the reduction was maintained for the 5-year duration of the study (Figure 1).
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Clinical Cardiovascular Events
In older patients, the rates of major coronary events were 28.1% in the placebo group and 19.7% in the pravastatin group, an absolute reduction of 9.0 percentage points (95% CI, 4 to 13 percentage points); the relative risk reduction was 32% (CI, 15% to 46%) (Table 2). Death from coronary artery disease occurred in 10.3% of placebo recipients and 5.8% of pravastatin recipients, an absolute reduction of 4.6 percentage points (CI, 1.9 to 6.5 percentage points) and a 45% relative risk reduction (CI, 18% to 63%). Stroke incidence was 7.3% in the placebo group and 4.5% in the pravastatin group, an absolute reduction of 2.9 percentage points (CI, 0.3 to 4.5 percentage points) and a relative risk reduction of 40% (CI, 4% to 62%). For both older and younger patients, the event rates in the pravastatin group began to separate from those in the placebo group at about the same time (2 years after the start of the study) (Figure 2). Older women and men showed similar reductions in the rate of major coronary events (Figure 3). Younger patients receiving pravastatin also experienced a lower rate of coronary events than did younger patients receiving placebo (Table 3). The numbers of older and younger patients needed to treat to prevent a major coronary event during the initial 5-year treatment period were 11 and 20, respectively; corresponding numbers were 15 and 67 for coronary death or nonfatal myocardial infarction and 34 and 250 for stroke. Considering all cardiovascular events resulting in hospitalization, including several events per patient, a total of 225 events would be prevented for every 1000 older patients treated compared with 121 in 1000 younger patients (Table 4). This corresponds to 4 older patients and 8 younger patients needed to treat to prevent a hospitalization for cardiovascular events during an initial treatment period of 5 years. Although younger patients had a lower relative risk reduction for the primary end point (major coronary events) and for coronary artery bypass grafting than did older patients, none of the differences between the age groups was statistically significant (the difference for the primary end point was of borderline significance [P = 0.06 for the test of interaction between age group and treatment assignment]). This finding suggests that the inherent efficacy of pravastatin treatment is similar for older and younger patients. Adjustment for imbalances in risk factors at baseline did not affect the risk reductions attributable to therapy. Adjustment for potential clinical center effects did not affect the risk reductions in either age group.
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Almost all trials of cholesterol treatment have excluded patients who were 65 years of age or older. The Stockholm Ischaemic Heart Disease Secondary Prevention Study [42] prospectively defined age groups of younger than 60 years (n = 425) and 60 to 70 years (n = 130) and randomly assigned the patients in each age group to receive either clofibrate and nicotinic acid therapy or placebo for 5 years. Clofibrate and nicotinic acid reduced total and coronary mortality by 28% and 36%, respectively, in the older patients, a result similar to the reductions in the younger patients [42]. The Los Angeles Wadsworth Veterans Administration Hospital trial [43], which studied a diet high in polyunsaturated fats, enrolled 846 patients aged 50 to 90 years (mean age, 65 years). The diet reduced cardiovascular events in the entire study group, but the benefit was statistically significant only in the younger patients, despite their lower event rate. These limited and inconclusive findings from randomized clinical trials, in combination with the inability of blood cholesterol levels to consistently predict coronary events in older populations [16-23], led to controversy about whether cholesterol screening or treatment is advisable [22-31].
However, it was suspected that the attenuated predictive value of blood cholesterol levels in older persons was due to the effects of concomitant disease or debilitation that could decrease blood cholesterol levels as well as cause a cardiovascular death. This type of confounding was demonstrated by using serum iron and albumin levels as markers of "frailty" or poor health. When added to the multivariate analysis, blood cholesterol levels became a significant predictor of cardiovascular death [32].
It is also difficult to justify, from a pathophysiologic perspective, why coronary lesion progression and acute coronary artery thrombosis in older persons should somehow become immune to the effects of atherogenic lipoproteins. Accordingly, the National Cholesterol Education Panel guidelines [33] extrapolated findings from the treatment of younger patients in their recommendations for treating older patients. This judgment (that older patients should be treated) has been validated by subgroup analysis of older patients in two clinical trials of statin therapy. Simvastatin treatment of hypercholesterolemic patients (mean total cholesterol level, 260 mg/dL) with coronary heart disease significantly reduced recurrent major coronary events in the 1021 patients who were 65 to 70 years of age at study entry [34]. The CARE trial established the efficacy of pravastatin treatment in older patients with myocardial infarction who have average cholesterol levels; this finding is relevant to secondary prevention because most patients who have had a myocardial infarction have cholesterol values in the average, not elevated, range [35-37].
Important remaining issues concerning cholesterol treatment in older persons pertain to primary prevention and to defining an upper age limit, if any, for effectiveness. First, there is no reason to suspect that a fundamental difference in biological processes causes a first or recurrent coronary event, and primary and secondary prevention trials of cholesterol treatment have reported relative risk reductions [34, 38, 44-46]. With age, cardiovascular disease becomes a more important cause of morbidity and death; thus, lipid therapy has the potential to benefit the general population of older patients. Second, because no evidence suggests that cholesterol treatment in older populations is related to decreased relative risk reduction and because clear evidence supports the increasing absolute benefit of cholesterol treatment, it is reasonable to hypothesize that cholesterol treatment is effective in patients older than 75 years of age. These hypotheses are being tested with pravastatin in two ongoing large-scale trials [47, 48].
The CARE trial indicates that pravastatin may help prevent stroke in older patients. Epidemiologic studies did not find a relation between cholesterol levels and cerebrovascular events in older persons [49]. Prevention of stroke is particularly important in older patients because the incidence of stroke increases with age. In absolute terms, the findings in the CARE trial suggest that threefold to fourfold more cerebrovascular events could be prevented by treating older compared with younger populations. These results should give impetus to studies of stroke prevention by lipid treatment in older patients who do not yet manifest clinical evidence of atherosclerotic cardiovascular disease.
Our analysis of the benefits of lipid treatment in normolipidemic patients with cardiac disease has several limitations. The number of older patients in the CARE trial, although larger than those in other published studies of lipid treatment, is not great enough to allow detection of benefit for all end points. The number of older women is also too small to permit us to investigate benefit separately in women. The same is true for other subgroups, such as older diabetic patients, although all diabetic patients had significant reductions in the rate of events [38]. Because randomization was not conducted (stratified) separately for the older and younger patients, imbalances in baseline risk factors may have occurred between the pravastatin and placebo groups. This influence is likely to be small because the baseline characteristics of the older patients in the pravastatin and placebo groups are similar, and adjustment for baseline risk factors did not alter the risk reduction. All analyses were done according to the intention-to-treat principle (all randomly assigned patients were included, regardless of adherence); thus, the findings are influenced by drop-outs. This influence is mild because adherence at the end of the trial was 92% in the pravastatin group, the highest in any lipid trial, and 86% in the placebo group. It could be anticipated that a cohort with 100% adherence would experience slightly more risk reduction than found in our trial. Finally, the trial assessed therapy during an average 5-year duration of therapy. Longer duration of treatment, as recommended [33], would be expected to increase the proportion of patients receiving benefit.
In conclusion, the results of the CARE trial support pravastatin treatment in older patients with known coronary heart disease (that is, as secondary prevention), even if their lipid profiles are in the average range. The older patients in the trial had average LDL cholesterol levels at baseline of 3.57 mmol/L (138 mg/dL), a level consistent with the average levels expected in the aging population and similar to levels in most patients with myocardial infarction [35-37]. These findings are consistent with the National Cholesterol Education Panel's approach, in which older and younger patients with clinical coronary disease are treated similarly if the LDL cholesterol level is 3.36 mmol/L (130 mg/dL) or greater [33]. The ability of pravastatin treatment to prevent stroke, coronary death, myocardial infarction, and need for revascularization in the CARE older population has major implications for the preservation of the health of older patients with cardiac disease. Because of the high rate of recurrent cardiovascular events in older patients, more older patients experience benefit than do younger patients. It could therefore be anticipated that the cost-effectiveness of pravastatin is favorable in older patients.
From Legacy Portland Hospital, Portland Cardiovascular Institute, Portland, Oregon; University of Texas School of Public Health, Houston, Texas; Harvard School of Public Health, Harvard Medical School, and Brigham and Women's Hospital, Boston, Massachusetts; Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada; William Beaumont Hospital, Royal Oak, Michigan; University of Florida, Gainesville, Florida; University of Alabama, Birmingham, Alabama; and University of Calgary, Calgary, Alberta, Canada.
Drs. Moye and Davis: University of Texas School of Public Health, 1200 Herman Pressler, Houston, TX 77030.
Dr. Sacks: Nutrition Department, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115.
Dr. Johnstone: Division of Cardiology, Queen Elizabeth II Health Sciences Center, 1796 Summer Street, Halifax, Nova Scotia B3H 3A7, Canada.
Dr. Timmis: Cardiology Division, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, MI 49073.
Ms. Mitchell: 2428 Tarleton Twins Terrace, Charlotte, NC 28270.
Dr. Limacher: College of Medicine, University of Florida, Box 100-277, JHMHC, 1600 Archer Road, Gainesville, FL 32610.
Dr. Kell: Novartis Pharmaceuticals, 7373 North Scottsdale Road, C-244, Scottsdale, AZ 85253.
Dr. Glasser: University of South Florida, 3500 East Fletcher, Suite 218, Tampa, FL 33613.
Ms. Grant: University of Calgary, Suite 1140, Room 1103, 3350 Hospital Drive NW, Calgary, Alberta T2N 2T9, Canada.
Drs. Pfeffer and Braunwald: Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
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