Is Cholesterol-Lowering Therapy Worthwhile in the Elderly?

Research still in progress will clarify the issues, but a major panel of experts cites enough existing evidence to suggest that older adults can benefit as much from aggressive antihyperlipidemia therapy as can the general population.

By W. Richey Neuman, MD, and Caroline Milne, MD

Coronary heart disease (CHD) is the leading cause of death in older adults in the United States, accounting for more than half of all deaths in patients older than 65. The incidence and prevalence of CHD is highest among men and women in this age group, in whom 80% of all CHD deaths occur. Several well-recognized risk factors contribute to the development of CHD, including hypertension, smoking, and diabetes. In the last decade, however, cholesterol has emerged as an independent risk factor for the development of CHD in the elderly population.

Data from recent clinical trials have shown that elderly patients who undergo treatment for hyperlipidemia are at decreased risk for CHD-related disability and death. In addition, lipid-lowering agents, particularly HMG-CoA reductase inhibitors, known as statins, have been shown to be effective and well tolerated by patients older than 65. For these reasons, the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (NCEP/ATP-III) recommends screening for and treating hyperlipidemia in elderly patients.

In this review we will discuss the medical evidence and clinical rationale supporting the evaluation and treatment of hyperlipidemia in elderly patients. We will then review screening recommendations and treatment guidelines regarding diet, exercise, and medical therapy.

EPIDEMIOLOGY OF CHD IN THE ELDERLY

The burden of atherosclerotic disease among the elderly is high: two thirds to three quarters of people older than 65 have either subclinical or clinical CHD. In 1993, the NCEP/ATP-II declared age to be an independent risk factor for CHD. In fact, they concluded, age alone raises the risk for CHD in men aged 45 or older and in women aged 55 and older. The other risk factors they found to be related to CHD include hyperlipidemia, hypertension, diabetes mellitus, current cigarette smoking, and a family history of premature CHD-that is, a CHD event occurring before the age of 55 in a father or first-degree male relative or before the age of 65 in a mother or first-degree female relative. The NCEP/ATP-II also pointed out that patients who have an elevated high-density lipoprotein (HDL) level are at a reduced risk for the development of CHD.

The debate about the role of serum cholesterol in the development of coronary artery disease (CAD) in the elderly is still ongoing. Lipoprotein metabolism undergoes several hormone-mediated and liver-related changes that occur with aging. As a result, low-density lipoprotein (LDL) levels progressively increase after puberty in men and women (although more slowly in women), and total and LDL cholesterol levels gradually decline after 50 years in men and 60 years in women.

Although those age-related metabolic changes have been documented and understood, some studies that have addressed increased total serum cholesterol or LDL as a possible risk factor for CHD have failed to show a link between that phenomenon and an increased relative risk among the elderly population. Other prospective studies, however, have demonstrated that link. The differing conclusions are thought to be due to the methods used by the investigators in those studies to express risk.

In studies reporting negative findings, researchers usually use a relative risk ratio to describe differences in risk between groups. Given the high frequency of CHD in the elderly, however, attributable risk (the difference in absolute risk between groups with high and low cholesterol levels) is thought to be a more appropriate method of expressing CHD risk related to high serum cholesterol in this population. When analyzed this way, as Grundy and colleagues discovered, attributable risk does reveal the high impact of elevated serum cholesterol among the adult population older than 65 (Archives of Internal Medicine, vol. 159, p. 1670, 1999). Thus, this population has a high absolute risk for CHD, and a significant portion of that risk can be attributed to elevated serum cholesterol. This conclusion usually applies to the elderly population aged 65 to 85; limited data are available for patients older than 85.

PATHOPHYSIOLOGY OF CHD

The formation of cholesterol plaques is a process that begins in puberty and continues throughout life. A high serum cholesterol concentration causes cholesterol deposits to form in blood vessel walls, leading to plaque formation. A significant component of plaque formation is thought to involve an inflammatory reaction in which immune system cells and modulators process cholesterol in the arterial wall. An excessive serum cholesterol concentration promotes increased activity of this inflammatory component, which in turn produces a plaque that is vulnerable to rupture.

Notably, approximately 60% of all acute myocardial infarctions (MIs) occur in patients whose coronary artery stenosis measures 50% or less, a finding that shows the impact and danger of unstable plaques on CHD-related morbidity and mortality. In animal studies, researchers have observed that a reduced cholesterol concentration attenuates the mechanism of plaque instability, which in turn reduces the number of proinflammatory cells in plaques. This effect in animals is thought to mirror the mechanism in humans and is buttressed by data from human studies in which patients with CHD who reduced their C-reactive protein levels through statin therapy suffered fewer adverse events. There is no reason to believe that the pathophysiology of CHD in elderly patients differs from that in younger ones.

EFFECT OF LIFESTYLE CHANGES ON HYPERLIPIDEMIA

Physicians are often frustrated by the results of diet modification for lowering serum cholesterol concentration. Current trial data reported in the literature reflect the limited gains from this approach. The most recent study of lipid-lowering diet therapy is the Diet and Exercise for Elevated Risk trial, which enrolled men and postmenopausal women who had average HDL cholesterol and moderately elevated LDL cholesterol levels and no known heart disease. Patients randomly assigned to an American Heart Association (AHA) Step 2 diet alone (which limits daily cholesterol intake to 200 mg, total fat to less than 30% fat, and saturated fat to 7% or less) were successful in losing weight, but they did not significantly reduce their total or LDL cholesterol levels, nor did their HDL cholesterol levels change (New England Journal of Medicine, vol. 339, p. 12, 1998). Results from the Lifestyle Heart Trial, however, did show a significant decrease (37.4%) in serum LDL among patients who followed a very low-fat, whole-food vegetarian diet high in complex sugars and low in simple sugars (Lancet, vol. 336, p. 129, 1990).

The results of many epidemiologic studies have shown that the incidence of CHD is higher among sedentary people than among those who are physically active. Most studies have revealed that exercise of low to moderate intensity can produce a modest increase in HDL cholesterol concentration and a slight decrease in total and LDL cholesterol levels. The Diet and Exercise for Elevated Risk trial showed that the greatest benefits are seen from modifications in diet and exercise together. Subjects in this study showed a significant reduction in their total and LDL cholesterol levels at one year when compared with control subjects; however, no increase in HDL cholesterol levels was observed.

Nevertheless, it is clear that although exercise alone has only a minimal effect on a patient's lipid profile, regular exercise and optimal physical fitness significantly reduce the risk of death from cardiovascular or other causes. Research has shown that men who maintain adequate physical fitness are less likely than others to die from cardiovascular or other causes. Moreover, as the results of one study show, risk can be reduced by as much as 44% among men who improve their physical health status from "unfit" to "fit" after following a fitness program for five years.

PHARMACOLOGIC THERAPY

The drugs most often administered in clinical trials involving pharmacologic lipid-lowering therapy for elderly patients are statin agents, because they are effective and well tolerated by such patients. They are also known to be safe: In the major trials conducted so far, including those discussed below, no significant adverse events were observed among patient groups of any age after five years of therapy, and other studies have reported similar findings.

Efficacy and cost-effectiveness. Statins have been shown to be effective in lowering LDL and total cholesterol levels in elderly patients. In one study of 142 subjects 64 to 90 years old, Santinga and colleagues found that 16 weeks of pravastatin therapy lowered LDL and total cholesterol levels 31% and 22%, respectively (American Journal of Medicine, vol. 96, p. 509, 1994). In the Scandinavian Simvastatin Survival Study (4S), simvastatin therapy lowered LDL and total cholesterol levels by 36% and 26%, respectively, in 1021 subjects older than 65 (Lancet, vol. 344, p. 1383, 1994). The lipid-lowering role of niacin, fibric acid derivatives, and bile acid sequestrants is less clear in the elderly population, since these agents have not been studied as extensively in older populations.

Statin therapy has also proved to be a cost-effective method of preventing the occurrence of a second CHD-related cardiac event in elderly patients. For the monthly cost of statin therapy with various agents, see table below. As expressed in cost per year of life gained, values range from $3800 to $13,300 for patients aged 70, which are within the range of acceptable therapeutic costs in the United States, according to Johannesson and colleagues (New England Journal of Medicine, vol. 336, p. 332, 1997). In preventing a first CHD-related coronary event, the cost-effectiveness of statin therapy depends on the patient's overall risk for CHD; costs range from $35,166 per year gained for 70-year-old men at high risk to $75,725 for women of the same age at low risk. The optimal CHD risk profile for cost-effective prevention of a first cardiac event in the elderly has yet to be determined.

Preventing a first cardiac event. The practice of administering antihyperlipidemia therapy to elderly patients to prevent a first CHD-related cardiac event is not supported as well as that for preventing a second event. To date no large trials focusing on this population have shown elderly patients to derive clear benefit from the treatment. However, the results of two large studies that have included older patients do show clearly that cholesterol-lowering agents can reduce the risk for coronary events and death.

In the first of those two trials, the West of Scotland Coronary Prevention Study (WOSCOPS), researchers enrolled 6595 men aged 45 to 64 years who had hyperlipidemia and no history of MI and randomly assigned them to receive 40 mg of pravastatin or placebo. After an average follow-up period of 4.9 years, patients who received pravastatin had a lower serum cholesterol level and their risk for nonfatal MI and definite coronary events was reduced by 31% (New England Journal of Medicine, vol. 333, p. 1301, 1995). In addition, fewer patients in that group required coronary procedures, including coronary angiography and coronary revascularization procedures, and a nonsignificant decrease in all-cause mortality was also noted. In comparing patients older than 55 years old with younger patients, the investigators observed that the relative risk reduction attributable to pravastatin therapy was similar in the two groups. In addition, none of the patients who received pravastatin reported significant adverse events.

The second major trial, the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), compared lovastatin therapy with placebo among 6605 men and women who did not have CHD and were aged 45 to 73 years, 21% of whom were older than 65 years. After an average follow-up period of 5.2 years, the combined number of fatal and nonfatal MIs, episodes of unstable angina, and sudden cardiac deaths among patients receiving lovastatin was reduced by 37%, a finding that led the investigators to stop the trial early (JAMA, vol. 279, 1615, 1998). In addition, a subgroup analysis showed that men and women older than the median ages of 57 and 62, respectively, all benefited from lovastatin therapy. All subjects, regardless of age, tolerated the drug well.

Preventing a second event. The benefits of pharmacologic antihyperlipidemia therapy for preventing a second cardiac event in elderly patients are well supported in the literature. Three large trials have been conducted, all employing statin therapy, and the results indicate the effectiveness of cholesterol-lowering therapy and a reduced incidence of related cardiac events and death. The 4S trial enrolled subjects who had documented CHD (a history of MI or angina pectoris) and hypercholesterolemia and randomly assigned them to receive 20 mg of simvastatin or placebo. For patients whose cholesterol concentration was not reduced sufficiently by this dose, 40 mg was given.

After an average follow-up period of 5.4 years, the risk of death from all causes in patients older than 65 who received simvastatin was reduced by 34%. The risk of death from CHD was reduced by 43%, as was the incidence of major coronary events and nonfatal MI. These findings were similar to or better than those observed among patients younger than 65. After the study was extended two years (making it the longest clinical trial of its kind to date), the benefit of a much lower mortality rate was still observed among patients who continued their simvastatin therapy. Among patients older than 65, the risk of death from CHD or all causes was still 28% lower.

Two studies have investigated the effects of pravastatin on cardiac outcomes among patients who had hyperlipidemia and a history of CHD. In the Cholesterol and Recurrent Events Trial (CARE), 4159 patients who had a history of MI and moderate hypercholesterolemia (mean LDL, 139 mg/dl) were assigned to receive 40 mg of pravastatin a day or placebo. After a five-year period, the incidence of fatal coronary events or nonfatal MI was 24% lower among the patients taking pravastatin, who were also significantly less likely to require cardiac procedures (New England Journal of Medicine, vol. 335, p. 1001, 1996). These benefits were similar among patients younger and older than 60 years. In addition, the incidence of stroke among the treatment group was reduced 31%.

In the second study, the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial, researchers randomly assigned 9014 patients, of whom 39% were older than 65, to receive 40 mg of pravastatin a day or placebo. After a mean duration of 6.1 years, the study was stopped early when the mortality rate for each group differed. Among patients of all ages in the treatment group, the relative risk of death from CHD was reduced by 24%, and overall mortality was reduced by 22% as well. Also observed were significant reductions in the incidence of stroke, MI, coronary artery bypass surgery and angioplasty, and hospitalization for unstable angina.

Ample evidence shows that lipid-lowering therapy decreases the rate of disability and death from CHD in older adults. This benefit is less clear for elderly patients who do not have established CHD, but because the disease is strongly linked to hyperlipidemia, these patients should still undergo therapy and lifestyle changes to prevent a first cardiac event. In fact, in view of the evidence, the NCEP/ATP-III panel believes that statin therapy should no longer be withheld from patients simply because they are too old. The panel recommends lipid-lowering therapy not only for patients who must control their risk profile but also for men older than 65 and women older than 75 who are likely to enjoy a prolonged and healthy life. No age limit applies to this recommendation.

Elderly patients who have multiple medical problems or a poor prognosis would probably benefit more from attention to their functional status than from prevention therapy. They would not be good candidates for lipid-lowering treatment.

INSTRUCTING AND MONITORING PATIENTS WITH TYPE 1 DIABETES

The NECP/ATP-III guidelines for determining risk profiles and administering antihyperlipidemia therapy apply to all patients, including elderly ones (see tables below). Older adults whose functional status would benefit from preventive antihyperlipidemia therapy should undergo a screening evaluation based on a fasting lipid panel or at least serum total cholesterol and HDL determinations. The first step for all patients with hyperlipidemia is what the NECP/ATP-III refers to as therapeutic lifestyle changes (TLC), which include a diet low in saturated fat, weight reduction, and exercise.

Exercise. The NCEP/ATP-III guidelines recommend an aerobic exercise regimen for all patients who have elevated cholesterol levels and are physically able to follow an individually tailored program. Not only will aerobic exercise lower a patient's cholesterol levels but it will also benefit his or her overall health. Follow-up visits should be scheduled every six weeks to monitor the therapy's effectiveness.

Diet. A weight reduction program is recommended for obese patients, as is a diet low in saturated fats for patients who have hyperlipidemia. The TLC dietary guidelines recommend that less than 7% of total fat in the diet should be saturated fat, which equates to less than 200 mg a day. As with the exercise program, patients' progress should be monitored every six weeks.

Pharmacologic therapy. According to the NCEP/ATP-III guidelines, the LDL cholesterol level should be used to define a patient's risk for CHD and determine the appropriate therapy. Pharmacologic therapy should be initiated when exercise and dietary therapy fail. A statin drug should be tried first, since these agents have an excellent safety and tolerability profile, but if a patient's triglyceride level is above 200 mg/dl or HDL level is less than 40 mg/dl, niacin or a fibrate might be a more appropriate first choice.

A fasting lipid panel test and liver-associated enzyme level assessment should be performed before patients begin treatment and at six weeks afterward, at which time medication doses can be adjusted. Lipid and liver-associated enzyme levels should then be monitored every four to six weeks until a stable dose is achieved, then biannually thereafter. Less frequent monitoring may be necessary, depending on the specific statin agent used; physicians should follow the manufacturer recommendations.