Is Aggressive Lipid-Lowering Therapy Appropriate in the Very Elderly?

But are these recommendations applicable to the very elderly, and, in particular, to residents of long-term care facilities? Despite the fact that many such individuals are indeed at very high risk, several factors militate against an overly aggressive approach to lowering LDL cholesterol in these patients. First, as with virtually all major studies in cardiovascular medicine, patients over 85 years of age, those with multiple comorbidities, and residents of long-term care facilities were peremptorily excluded from participation in the lipid-lowering trials. Thus, the value of HMG-CoA reductase inhibitors (statins) and other agents in these subgroups is at best uncertain. Further, age and disease-related declines in renal and hepatic function and skeletal muscle mass, coupled with the increased propensity for drug-drug interactions due to “polypharmacy,”^7,8 place the very elderly patient at heightened risk for serious statin-related complications, including rhabdomyolysis, hepatic toxicity, and renal failure, especially when high doses of these agents are administered. In light of these considerations, the risk-benefit ratio of statins may be less favorable in the very elderly than in younger patients. Second, in the PROSPER trial, the only study specifically designed to assess the effects of statins in older adults, pravastatin 40 mg daily significantly reduced the risk of the combined endpoint of coronary death, nonfatal MI, or stroke by 15%, but had no effect on all-cause mortality.³ In addition, the incidence of new cancers was 25% higher in the pravastatin arm than in the placebo group (p = 0.02). Although a meta-analysis of 8 trials involving 29,410 patients did not confirm an increased risk of cancer associated with statin therapy, the mean age of patients in PROSPER (age 75 years) was substantially higher than in all other studies.³ Thus, the PROSPER trial raises further concern about the potential for serious adverse events in very elderly patients receiving statins. Third, the PROVE-IT study suggests that “lower is better” when it comes to reducing LDL-cholesterol levels following an acute coronary event.⁶ However, although the PROVE-IT study shows that atorvastatin 80 mg is superior to pravastatin 40 mg in this population, it is not clear from PROVE-IT that an LDL-cholesterol level of less than 70 mg/dL is necessarily better than an LDL level of less than 100 mg/dL. Indeed, among patients with an initial LDL level of less than 125 mg/dL, outcomes were similar among patients receiving atorvastatin or pravastatin, suggesting that “ultra-low” LDL levels afforded no additional protection beyond those achieved with conventional lipid targets (ie, LDL < 100 mg/dL). In addition, approximately 40% of patients in the pravastatin arm failed to achieve an on-treatment LDL level of < 100 mg/dL, implying that the benefit of atorvastatin may be attributable in large part to the fact that it was substantially more effective than pravastatin in lowering LDL to less than 100 mg/dL. Most importantly, however, the benefit of high-dose atorvastatin in PROVE-IT was limited to patients less than 65 years of age, since among the 1230 patients 65 years of age or older there was no significant difference in 2-year event rates between patients receiving atorvastatin or pravastatin. Moreover, atorvastatin was associated with a 3-fold greater incidence of elevated alanine aminotransferase (ALT) levels compared to pravastatin. The mean age of patients in PROVE-IT was 58 years, and although age-specific side effect rates were not reported, it seems likely that older age would be associated with an increased risk for liver function test abnormalities during therapy with high-dose atorvastatin, and that the risk would be greatest in the very elderly, especially long-term care residents. In summary, there is overwhelming evidence that statins substantially reduce morbidity and mortality in appropriately selected patients at moderate to high risk for cardiovascular events, including those with established coronary heart disease, peripheral arterial disease, or diabetes mellitus, as well as certain high-risk patients with multiple cardiovascular risk factors. The benefits of statins extend to the elderly, at least up to age 80 or 85,^2,3 and in the absence of contraindications or competing considerations, high risk older adults should receive statin therapy using proven drugs at proven dosages.⁹ However, currently available evidence does not, in my opinion, support a more aggressive approach to LDL-cholesterol reduction in the very elderly. In this regard, I concur with Dr. Dennis DeSilvey,¹⁰ who in a recent editorial stated that “the only time a more aggressive goal in the elderly is necessary is if there is evidence of further progression of disease or new acute events when on optimal therapy according to current guidelines.” On the other hand, in light of the widespread underutilization of statins and other cardiovascular therapies in older adults,^11,12 it is likely that a more aggressive approach to identifying and treating appropriately selected elderly patients with proven therapies, utilizing existing guidelines, would be a more efficacious and cost-effective approach to improving cardiovascular outcomes on a population-wide basis than efforts directed at more aggressive reduction of LDL levels. In any case, additional research is clearly needed to further define the role of lipid-lowering therapy in the very elderly, and to clarify the optimal targets for LDL reduction in order to maximize benefit while ensuring acceptable risk and cost for patients of all ages.