Management of hyperlipidemia in the elderly population: an evidence-based approach.

ABSTRACT: Coronary heart disease (CRD) is the leading cause of morbidity and mortality in patients more than 65 years old. Within this population, elevated cholesterol levels are prevalent and associated with increased risk of CHD. Despite increasing emphasis on lipid-lowering treatment in the elderly population, questions remain regarding secondary and primary prevention of CHD. According to current clinical trial evidence, lipid-lowering therapy, specifically with HMG-CoA-reductase inhibitors, can reduce CHD morbidity and mortality without increased adverse effects in the elderly population. Lipid-lowering treatment should be considered for patients aged 65 to 75 years with a history of CHD or who are at moderate to high risk for CHD. Estrogen replacement therapy (ERT), which has also been shown to lower cholesterol levels, raises special considerations for postmenopausal women. However, recent findings suggest that postmenopausal women with a history of CHD should not be given estrogen solely for secondary prevention of CHD events.

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CORONARY HEART DISEASE (CHD) is the leading cause of morbidity and mortality in the elderly population. The incidence and prevalence of CHD are highest in patients older than 65 years. (1) Approximately 80% of all deaths due to CHD occur in this age group. Elevated cholesterol level, a risk factor for CHD, is prevalent in this age group. Approximately 25% of men and 42% of women more than 65 years old have a serum total cholesterol (TC) level greater than 240 mg/dL. (2) The potential for treatment benefit within this population is high. The National Cholesterol Education Program's Second Adult Treatment Panel (NCEP-ATP II) has recommended increased emphasis on treatment of high-risk elderly patients--ie, those with TC levels >240 mg/dL and low-density lipoprotein (LDL) cholesterol >160 mg/dL--who are in otherwise good health. (1,3,4)

Elevated serum cholesterol levels, specifically TC and LDL cholesterol, have clearly been shown to increase the risk of CHD in middle-aged adults. In addition, the benefit of cholesterol lowering in this population has been proven. The association of elevated cholesterol and CHD within the elderly population is less clear. Initially, it was thought that elevated serum cholesterol was less predictive of new-onset CHD and those with high serum cholesterol might actually have increased longevity. (5) More recent studies have shown that elevated cholesterol level does correlate with CHD in the elderly but not as strongly as in the middle-aged population. (6,8) These differing findings have produced a question of whether to treat older patients for elevated cholesterol, especially in the setting of primary prevention. Newer lipid-lowering trials are focusing more on patients older than 65 to see whether lipid-lowering therapy can reduce CHD mortality and which treatments are beneficial in this age group. (1,9)

We reviewed the major lipid lowering trials that have included subpopulations more than 65 years old to determine the efficacy of lipid-lowering treatment in the elderly population. Focus was placed on secondary CHD prevention, primary CHD prevention, and special considerations in the treatment of postmenopausal women.

HYPERLIPIDEMIA AND CHD IN THE ELDERLY

Several prospective studies examining CHD risk in older patients have shown that elevated cholesterol levels (specifically TC or LDL cholesterol) increase the risk of CHD development. (6-8,10,11) The Framingham Heart Study showed that the relative risk of CHD due to elevated cholesterol actually decreased in the older population. (5) The CHD relative risk between patients with highest and lowest cholesterol decreased with age. (5) This finding can be explained by the cumulative nature of CHD with age and the contribution of other factors such as hypertension or diabetes mellitus in the development of CHD. (1) As a population gets older, people with lower cholesterol may also have CHD due to these other risk factors, decreasing the relative risk based on cholesterol levels. Attributable CHD risk, the difference in absolute CHD risk between patients with high cholesterol and those with low cholesterol, is more accurate in measuring the direct effect of cholesterol on CHD development. (1) The attributable risk a ctually increases with age, showing that elevated cholesterol has a larger effect on development of CHD as one gets older (Figure) (12,13) Rubin et al (8) reported similar findings in the Kaiser Permanente Coronary Heart Disease in the Elderly Study. The attributable CHD risk due to elevated cholesterol increased with age.

Other studies have shown that elevated cholesterol levels are not associated with CHD events in the elderly and may actually increase longevity. (14,15) Many elderly patients with comorbid conditions and overall poor health status tend to have depressed cholesterol levels, leading to the conclusion that lower cholesterol decreases lifespan. Corti et al (6) showed that after adjusting for indicators of frailty and poor health, elevated TC levels were associated with a statistically significant increase in risk of CHD mortality in subjects more than 65 years old. In addition, high-density lipoprotein (HDL) cholesterol levels less than 35 mg/dL were also associated with increased risk of CHD mortality. (6)

Overall, elevated TC, elevated LDL cholesterol, and low HDL cholesterol levels are associated with increased risk of CHD in the elderly but not as strongly as in middle-aged adults. However, the incidence and prevalence of CHD are highest in the population over 65, so that the attributable risk is greater in the elderly than in younger populations. (1, 12) Treatment for elevated cholesterol level in patients over age 65 has the potential to provide substantial benefit.

SECONDARY PREVENTION IN THE ELDERLY

The NCEP-ATP II has placed increased emphasis on aggressive cholesterol management in patients with established CHD. Low-density lipoprotein cholesterol is the primary target of cholesterol lowering treatment. The goal LDL cholesterol level in patients with CHD is 100 mg/dL or less. (3) Dietary modification with the American Heart Association (AHA) Step 2 diet is prescribed for 6 months, followed by cholesterol lowering medications if necessary. Recently, three large secondary prevention trials involving hydroxymethylglutaryl coenzyme A (HMG Co-A) reductase inhibitors (statins) have included a substantial sample of patients more than 65 years of age. These include the Scandinavian Simvastatin Survival Study (4S), the Cholesterol and Recurrent Events Trial (CARE), and the Long-term Intervention With Pravastatin in Ischemic Disease Study (LIPID) (Table 1). (16-18)

The 4S trial involved treatment with simvastatin or placebo in patients with hypercholesterolemia (TC, 213 to 309 mg/dl) and established CHD. Of 4,444 total patients, it included 1,021 patients aged 65 years or older who had follow-up for 6 years. (16-19) In this subgroup, all-cause mortality was reduced in the treatment group by 33%, with an absolute risk reduction (ARR) of 6.2%. (16) Mortality due to CHD was reduced by 42% (ARR of 6%) and the rate of major coronary events (CHD death or nonfatal MI) was reduced by 33% (ARR of 9.8%). (16) According to these figures, with 1000 patient-years of treatment, 10 deaths due to CHD would be prevented and approximately 17 major coronary events would be prevented. Simvastatin was well tolerated by these patients, and the frequency of adverse effects was similar to that in the placebo group. (16,20)

The CARE trial compared treatment with pravastatin or placebo in patients with established CHD. Patients had average TC levels of less than 240 mg/dL and LDL levels ranging from 115 to 174 mg/dL. This trial included 1,283 patients aged 65 or older who had follow-up for 5 years. (17,21) In the population more than 65 years old, CHD death was reduced in the treatment group by 44% (ARR of 4.6%). (17) Major coronary events (CHD death, nonfatal myocardial infarction [MI], coronary artery bypass grafting, percutaneous transluminal coronary angioplasty) were reduced by 30% (ARR of 8.4%) (17) The results of this study indicate that with 1000 patient-years of treatment, 9.1 deaths from CHD would be prevented and 17 major coronary events would be prevented. (17) Again, the rate of adverse effects was similar in placebo and treatment groups.

The LIPID trial examined treatment with pravastatin or placebo in patients with a history of CHD and TC levels between 155 and 271 mg/dL. This trial included 3,514 patients older than 65, with follow-up for approximately 6 years. (18) Death from CHD and nonfatal MI was reduced in the treatment group by 21% (ARR of 4.2%). With 1000 patient years of treatment, 7 deaths from CHD or nonfatal MI would be prevented. (18) All-cause mortality was also reduced in the pravastatin treatment group. (18) These trials support the use of statin therapy in elderly patients with a history of CHD and elevated cholesterol.

The Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) examined the effect of gemfibrozil on CHD events in men who had CHD, low HDL levels, and mild hypertriglyceridemia. (22) This study included 1,266 men aged 66 to 74 years. Within the treatment group, there was a 26% risk reduction (ARR of 7%) in the combined endpoints of CHD death, nonfatal MI, and stroke.

Secondary prevention of CHD with drug treatment in patients older than 65 is effective and does not increase adverse effects or total mortality. The population aged 65 to 75 with CHD should receive cholesterol-lowering therapy to reduce LDL cholesterol levels to a goal of 100 mg/dL. (9) In patients older than 75, special consideration must be given to overall health status, comorbid conditions, and physiologic age before initiating drug treatment. (9) In this age group, emphasis should be placed on dietary modification, weight control, smoking cessation, and exercise. Yet, if a patient older than 75 with CHD is in relatively good health, cholesterol-lowering therapy should be seriously considered. Because they are well tolerated, statins should be considered the drug of choice for the elderly population. (9,23) Bile acid sequestrants would be the second choice for treatment of patients with isolated elevated cholesterol. Bile acid sequestrants can increase serum triglyceride levels and should not be used in p atients with elevated triglyceride levels. If triglycerides are also elevated (>250 to 300 mg/dL), niacin or fibrin acid derivatives may be added, but patients should be closely monitored for myopathy and hepatotoxicity when combining these drugs with statins. (9,24) The incidence of myopathy and hepatotoxicity may be greater when fibrin acid derivatives are added to statins.

PRIMARY PREVENTION IN THE ELDERLY

Primary prevention of CHD in the elderly population is also of great importance. The majority of first CHD events occur after the age of 65. (1) The NCEP recommends that lifestyle interventions take precedence over drug treatment in the primary prevention of CHD. (3) These lifestyle changes include dietary modification, regular exercise, weight control, and smoking cessation. Dietary modifications include the AHA Step 1 and Step 2 diet, which can be expected to lower LDL cholesterol by 10% to 20%. (24) Six months of dietary and lifestyle modification is recommended before drug therapy is initiated. (3) Some patients, especially those with LDL cholesterol levels more than 160 mg/dL, may not be able to achieve target cholesterol levels by dietary treatment alone. In this situation, drug therapy can be considered. Clinicians may be reluctant to start lipid-lowering drug treatment because of concerns about side effects and effectiveness in the elderly population.

Previously, most trials involving drug therapy for primary prevention of CHD focused on the middle-aged adult population. These included the Helsinki Heart Study examining gemfibrozil, (25) the Lipid Research Clinics Coronary Primary Prevention Trial examining cholestyramine, (26) and the World Health Organization clofibrate trial. (27) Recently, clinical trials involving statin therapy have included elderly subgroups and have shown a reduction in coronary events as well as total mortality within this group. The West of Scotland Coronary Prevention Study (WOSCOPS), (28) a randomized, double-blind, placebo-controlled trial, compared pravastatin therapy to placebo in 6,595 men with hypercholesterolemia. Their mean TC was 272 mg/dL and the mean LDL was 192 mg/dL, placing these patients in the high-risk category. Within this group, 3,370 men were older than 55 at randomization. After 5 years of treatment, pravastatin therapy was associated with a 20% decrease in TC and 26% decrease in LDL cholesterol. Pravastatin reduced the coronary event rate by 31% and total mortality by 22%. (27) Patients over age 60 showed similar risk reduction as younger patients. This study suggests that primary prevention with pravastatin in the "younger" elderly population is beneficial.

The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) (29) was a randomized double-blind placebo-controlled primary prevention trial that examined the effects of lovastatin and placebo therapy on the incidence of first coronary events (unstable angina, MI, sudden CHD death) in patients with average serum cholesterol levels. In this study, 6,605 patients were randomized to receive lovastatin or placebo therapy. Initially, their mean TC level was 221 mg/dL and the mean LDL level was 150 mg/dL. This population would fall into the intermediate CHD risk category. Within this study population, 1,416 patients were between the ages of 65 and 73 years at the start of the study. After 5.2 years of treatment, lovastatin therapy decreased first major coronary events by 37% compared with placebo within the entire study sample. (29) Within the elderly subgroup, lovastatin decreased first major coronary events by approximately 30%, with an ARR of approximately 2%. (29,30) There was no significant di fference in total mortality or adverse effects between treatment groups. The AFCAPS/TexCAPS study suggests that primary prevention with a statin is beneficial in elderly patients. Both AFCAPS/TexCAPS and WOSCOPS also showed that primary prevention with statin therapy is safe in the elderly population. Satinga et al, (3) as well as the CRISP Pilot study, (32) also showed long-term safety and tolerability with statin use within the elderly population.

Currently, WOSCOPS and AFCAPS/TexCAPS are the only major primary prevention trials of lipid-lowering therapy in elderly populations. The Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALL-HAT), (33) which will be completed in 2002, examines whether lowering LDL cholesterol and blood pressure will reduce the incidence of CHD in older patients without a history of CHD. On the basis of results of WOSCOPS and AFCAPS/TexCAPS, it is reasonable to extend the NCEP primary prevention guidelines to patients aged 65 to 75. The NCEP-ATP II recommends cholesterol screening starting after the age of 20 and then at least every 5 years. (3) No maximum age is specified. These general screening guidelines have also been adopted by the AHA. (34,35) The American College of Physicians (ACP) recommends cholesterol screening up to age 65. (36) The ACP does not discourage or recommend screening in patients aged 65 to 75 years. (36) Kafonek and Kwiterovich (37) recommend cholesterol screening through age 75. Screening should involve measurement of TC, HDL cholesterol, and triglycerides if necessary.

In the setting of primary prevention, patients aged 65 to 75 with an LDL cholesterol level of 130 to 159 mg/dL (intermediate risk) should have dietary treatment and lifestyle modifications as the main intervention. (1,9) Drug treatment should be avoided unless a patient has a history of diabetes mellitus or peripheral vascular disease, in which case treatment with a statin would be appropriate (Table 2). If the LDL cholesterol level is 160 to 189 mg/dL (moderately high risk) and the patient has less than 2 CHD risk factors, the target goal for LDL cholesterol is below 160 mg/dL. (3) In this case, dietary treatment and lifestyle changes should be maximized. (1,9) If the LDL cholesterol is 160 to 189 mg/dL and there are more than 2 CHD risk factors, the target LDL cholesterol is below 130 mg/dL. (3) Drug treatment with a statin or bile acid sequestrant can be considered. (1,12) Because of the results of the statin trials and since statins are well tolerated, a statin should be considered as first-line treatment for primary prevention. If the LDL cholesterol level is 190 mg/dL or more, dietary treatment and lifestyle modifications are maximized and drug treatment is added, starting with a statin or bile acid sequestrant. (1,4,12) In patients who also have elevated triglycerides, niacin or a fibrin acid derivative can also be considered.

For patients more than 75 years of age, consideration must be given to overall prognosis, comorbidity, and physiologic age. Currently, no clinical trial data are available for this age group quantifying benefit from drug treatment for primary prevention. Interventions other than cholesterol lowering should be tried first, such as smoking cessation, weight reduction, decreasing blood pressure, and increasing physical activity. (9) Patients who have already begun taking cholesterol-lowering medications before reaching this age can continue their medications.

ELDERLY WOMEN

Coronary heart disease is the leading cause of death in women over 65 years of age. (1) About 42% of women older than 65 have serum TC levels more than 240 mg/dL as compared with 25% of men. (2) At the menopause, there is substantial increase in LDL cholesterol due to declining estrogen levels as well as weight gain. (38) After age 65, the mortality from CHD is equal in men and women. High cholesterol levels, specifically LDL, are predictive of CHD in postmenopausal women. (37) Several observational studies have shown that ERT reduces the risk for CHD. Meta-analyses of these studies show a reduction in risk of about 35%. (38) Many studies have also shown an improvement in lipid profiles with ERT, specifically increases in HDL and decreases in LDL. (40-42) The NCEP ATP II recommends that their guidelines for cholesterol screening and treatment be applied equally in postmenopausal women as in men of the same age group. (3) However, on the basis of observational studies of ERT and CHD risk, the NCEP ATP II sugge sts considering ERT as a first line of treatment for postmenopausal women with elevated LDL levels, since this may obviate the need for drug treatment in primary and secondary prevention. (3) This recommendation should be reconsidered, especially based on results of the Heart and Estrogen/Progestin Replacement Study (HERS). (41)

The HERS study was a multicenter randomized, double-blind, placebo-controlled trial comparing estrogen/progesterone therapy and placebo in preventing CHD events in postmenopausal women with a history of CHD (a secondary prevention trial). (43) The study sample included 2,763 women, with a mean age of 67.7 years and mean LDL cholesterol of 145 mg/dL. To date, it is the only large randomized trial that has examined the effect of hormone therapy on CHD events in women. The results showed no significant difference in the number of CHD events between women treated with estrogen/progesterone and those given placebo through an average of 4.1 years of follow-up. (43) This lack of effect occurred despite an 11% decrease in LDL and 10% increase in HDL cholesterol with estrogen/progesterone therapy. Estrogen/progesterone therapy was associated with a 52% increase in CHD event rate during the first year of treatment compared with placebo. The estrogen/progesterone therapy group also had an increased rate of venous thromb oembolic events throughout the entire study. (43) Lower CHD event rates did not occur until after 3 years of ERT, producing a net neutral effect through the entire study period. (43)

According to the HERS study, postmenopausal women with a history of CHD should not have ERT started solely for the secondary prevention of CHD events. It may be appropriate for patients already receiving hormone treatment for several years to continue it in conjunction with conventional lipid-lowering medications. Since the release of NCEP ATP II findings, several studies (4S, LIPID, CARE) have shown that statins are effective in secondary prevention of CHD in postmenopausal women. (16-18) In terms of secondary prevention of CHD in postmenopausal women, we recommend intense lifestyle modifications and first-line treatment with statins. The goal of treatment should be an LDL cholesterol <100 mg/dL. (3) In a patient with several years of ERT (more than 3 or 4 years), a statin can be added to ERT. Estrogen replacement therapy should not be started for the sole purpose of secondary prevention of CHD events.

Currently, no large randomized trials show a mortality/morbidity benefit in women taking ERT for primary prevention of CHD. Studies that are under way include the Women's Health Initiative and WISDOM trial. (42) In terms of primary prevention for postmenopausal women, the first line of therapy should be lifestyle modifications and dietary treatment. (3) Because of the lack of randomized trial evidence regarding ERT in the primary prevention of CHD, no definitive recommendations can be made in this area. Conventional lipid-lowering medications such as statins, bile acid sequestrants, niacin, and fibrates should be considered for primary prevention until further evidence emerges. Treatment goals are similar to those in men and are based on TC, HDL, LDL, and other CHD risk factors (Table 2).

CONCLUSIONS

Treatment of hyperlipidemia in the elderly population should begin with lifestyle and dietary modifications. Pharmacologic therapy, specifically with statins, can be used safely in the elderly population to reduce the morbidity and mortality of CHD. In the context of secondary CHD prevention, therapy should be focused on LDL cholesterol levels. On the basis of current data, statins should be the first-line agent used in this population. In terms of primary CHD prevention, elderly patients with moderate to high risk of CHD (based on LDL cholesterol level and risk factors) should be considered for lipid-lowering therapy. Presently, there is evidence only for the use of statins within this population. With patients older than 75 years, an assessment of overall health and comorbidity should be made before starting lipid-lowering therapy. Current evidence does not support a role for ERT solely to prevent the progression of CHD in postmenopausal women. Further data are needed on the role of ERT in secondary as well as in primary CHD prevention.

[GRAPH OMITTED]

Table 1

Secondary CHD Prevention Trials Including Elderly Subgroups


   Trial,                    Sample Aged  Follow-up
 References    Intervention   >65 Years    (years)

4S (16, 19)    Simvastatin      1,021         6
CARE (17, 21)  Pravastatin      1,283         5
LIPID (18)     Pravastatin      3,514         6
VA-HIT (22)    Gemfibrozil      1,266         5

                    ARR in CHD
   Trial,      Mortality in Patients
 References       Aged > 65 Years

4S (16, 19)            6.0%
CARE (17, 21)          4.6%
LIPID (18)             4.2%
VA-HIT (22)            7.0%

CHD = Coronary heart disease; ARR = absolute risk reduction, difference
in risk reduction and placebo.

TABLE 2

Approach to Primary CHD Prevention in the Elderly Population

LDL Cholesterol                       Risk
    Level                           Factors          Goal

130-159 mg/dL                          <2         <130 mg/dL

  (intermediate risk)            [greater than    <130 mg/dL
                                 or equal to] 2

160-189 mg/dL                          <2         <160 mg/dL


  (moderately high risk)         [greater than    <130 mg/dL
                                 or equal to] 2

[greater than or equal to] 190         <2         <160 mg/dL
  mg/dL (high risk)




                                [greater than or  <130 mg/dL
                                   equal to]2





LDL Cholesterol
    Level                       Therapeutic Considerations

130-159 mg/dL                     Lifestyle changes, *
                                  avoid drug therapy.
  (intermediate risk)           Lifestyle changes, consider
                                  low-dose statin if DM or
                                  PVD present.
160-189 mg/dL                   Intensity lifestyle changes, +
                                  consider low-dose statin
                                  if needed.
  (moderately high risk)        Intensity lifestyle changes,
                                  consider (1) statin,
                                  (2) bile acid sequestrant.
[greater than or equal to] 190  Intensity lifestyle changes,
  mg/dL (high risk)               consider (1) statin,
                                  (2) bile acid sequestrant,
                                  (3) fibrate or niacin if
                                  triglyceride level is
                                  also elevated.
                                Intensity lifestyle changes,
                                  consider (1) statin,
                                  (2) bile acid sequestrant,
                                  (3) Fibrate or niacin if
                                  triglyceride level is also
                                  elevated.

Modified from Grundy et al. (1)

* Lifestyle changes include American Heart Association (AHA) Step 1
diet, weight control, regular exercise, smoking cessation.

LDL = Low-density lipoprotein, DM = diabetes mellitus, PVD = peripheral
vascular disease.

+ Intensified lifestyle changes include AHA Step 2 diet, medically
supervised weight reduction, exercise program, smoking cessation.

Acknowledgments. We thank Christine Matson, MD, and Richard Morrison, PhD, for coordinating the evidence-based medicine elective and assisting in manuscript preparation.

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RELATED ARTICLE: KEY POINTS

* Elevated total cholesterol, elevated low-density lipoprotein cholesterol, low high-density lipoprotein cholesterol are associated with increased coronary heart disease (CHD) risk in patients more than 65 years old.

* Secondary prevention trials, including patients more than 65 years old, show statins are effective in decreasing CHD risk within this population.

* In regard to primary CHD prevention, elderly patients with moderate to high CHD risk should be considered for lipid-lowering treatment.

* Estrogen replacement therapy should not be started in postmenopausal women for the sole purpose of secondary prevention of CHO events.

From the Departments of Education and Internal Medicine, Eastern Virginia Medical School, Norfolk.

Correspondence to Deep Dalal, MD, 4201 South 31st St, No. 432, Arlington, VA 22206. (Reprints not available.)