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Division of Geriatric Medicine, Saint Louis University, St. Louis, Missouri.
Address correspondence to Margaret-Mary G. Wilson, MD, Division of Geriatric Medicine, Saint Louis University, 1402 S. Grand Blvd., Rm. M238, St. Louis, MO 63104. E-mail: wilsonmg{at}slu.edu
... if a man will begin with certainties, he shall end in doubts; but if he will be content to begin with doubts, he shall end in certainties.—Francis Bacon (1561–1626)
The Proficience and Advancement of Learning
London, 1605
Healthy skepticism, once the traditional foundation of scientific advancement, is now frequently misconstrued as a partisan political sport. Thus, Dr. Aronow's article proposing aggressive lipid-lowering strategies in older adults instinctively evokes rather strong and opinionated views (1). Clinicians and medical researchers will rush to take up arms and reaffirm loyalty to their chosen party line. Cardiologists will likely wholeheartedly agree with Dr. Aronow, while geriatricians will most probably issue the usual and rather monotonous battle cry of "insufficient evidence." Whatever position one takes, Dr. Aronow's article is a concise, well-written, and evidence-based statement on the subject. Skeptics who oppose lipid-lowering strategies will most certainly lose the battle if their chosen bone of contention is Dr. Aronow's advocacy for statin therapy in elderly persons based on the evidence presented. In the true spirit of courageous warfare, healthy skeptics will be reasonably armed only if the validity of the evidence itself is challenged.
National Cholesterol and Education Program guidelines, culled from recommendations of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults, have assumed liturgical dimensions in the literature. Indeed, based on results of recent studies, lipid-lowering proponents favor a lower threshold for the initiation of statin therapy in order to achieve recommended serum low-density lipoprotein levels <70 mg/dl in high-risk patients (2). Within the popular media, The New York Times described the revised guidelines as the answer to "the number one killer in the United States" (3). With the scene set as such, the physician is faced with either proclaiming the gospel of statin therapy or swimming against the tide of public, professional, medicolegal, and scientific opinion. Understandably, few physicians have the time or the resources to undertake the latter endeavor. Nevertheless, scientific objectivity and healthy intellectual discourse must not be silenced on the altar of conformity or political restraint.
Dr. Aronow puts forward an excellent argument for the use of statin therapy in older adults. Completely free of commercial bias and clearly directed by thoughtful and critical analysis, one senses that Dr. Aronow seeks to finally resolve the issue of lipid management in elderly persons. Thus, in the true spirit of constructive political debate, geriatricians who advocate for withholding statin therapy in older adults face an uphill battle. Such physicians must not only successfully negate the case made by Dr. Aronow in this article, but are also mandated to outline an equally convincing alternative evidence-based approach to hypercholesterolemia in older adults. However, prior to the initiation of such a debate, the foremost question that must be answered is whether hypercholesterolemia does indeed pose a real threat, not only to longevity, but also to the quality of life of older adults.
In the Heart Protection Study (HPS), as Dr. Aronow quite rightly points out, comparable risk reduction of adverse cardiac and vascular events was achieved in adults older than 65 years, compared to their younger counterparts (4). Nevertheless, the findings in the HPS relate mainly to the young elderly group, as few patients older than age 80 years were included in the study. Extrapolating the results of this trial to octogenarians and nonagenarians should be questioned. Shepherd and others examined the use of pravastatin in elderly individuals aged between 70 and 82 years with preexisting vascular disease or an elevated risk of vascular disease (PROSPER study) (5). On the surface, data from the PROSPER study indicate positive benefits of statin therapy in older adults. However, these benefits were restricted to cardiac events only. Pravastatin had no effect on stroke-related events in this cohort of patients. Furthermore, although cardiac mortality was reduced, all-cause mortality was not significantly changed in the statin-treated group. Cardiac mortality may be an impressive research endpoint, but all-cause mortality is probably of more relevance to the patient and family.
Certainly, in younger adults, there is convincing evidence to support the efficacy of lipid-lowering strategies in the primary prevention of adverse cardiovascular events. However, in octogenarians and older adults, similar evidence is lacking. Analysis of data from the PROSPER study failed to show any benefit from the use of pravastatin as primary prevention. Findings of the Framingham study suggest that the positive correlation between total serum cholesterol and all-cause mortality levels off in the seventh decade of life. Indeed, past the age of 80 years, a negative correlation emerges. Five-year survival for an 80-year-old man with a serum cholesterol level >240 mg/dl was approximately 75%. However, over the age of 80 years, 5-year survival dropped to approximately 50% (6). Similarly, data from older subjects in the Established Population for the Epidemiologic Study of the Elderly (EPESE trial) and The Cardiovascular Health Study, failed to show any association between serum cholesterol and the incidence of adverse cardiac events, cardiac mortality, or all-cause mortality. Paradoxically, patients with lower cholesterol levels had lower survival rates (7–9). Convincing clinical evidence also indicates that hypocholesterolemia in older adults is associated with increased all- cause mortality in older nursing home and hospitalized older adults (10–12). Thus, even if one concedes to Dr. Aronow that lipid-lowering therapy reduces cardiovascular events in older adults, it can be argued that any survival benefit derived from such treatment is offset by the deleterious effects of hypocholesterolemia on other (noncardiac) aspects of health of elderly persons. Reasons for the association of statin therapy in elders and increased mortality are unknown. One plausible hypothesis is that statins lower, not only serum cholesterol levels, but also metabolic antioxidant derivatives such as squalene and ubiquinone (CoQ10) (13). Regardless, current epidemiologic evidence does not support the contention that detecting and/or treating hypercholesterolemia in octogenarians and nonagenarians will reduce morbidity or mortality.
Adverse drug reactions are a notable cause of morbidity and mortality in elderly people. Thus, the repeated public health alerts regarding the dangers of statin therapy are concerning. Cerivastatin was withdrawn by the Food and Drug Administration (FDA) due to episodes of myositis and fatal rhabdomyolysis occurring particularly in elderly individuals. More recently, the FDA issued another public health alert advising caution in the prescription of rosuvastatin due to several reports of rhabdomyolysis and nephrotoxicity associated with use of this agent in older patients (14,15). Aggressive proponents of statin therapy may argue that most health professionals were probably already aware of this risk and would therefore monitor patients on statin therapy very closely. However, other less-publicized adverse drug effects are not so readily dismissed. Animal studies have shown carcinogenic effects associated with statin therapy at serum concentrations achieved in routine clinical practice (16). Studies in human subjects also show a trend toward an increased risk of cancer in older adults treated with statins. In the PROSPER study, there was a significant increase in the risk of new cancer diagnoses, as well as a trend toward an increased risk of cancer deaths in the pravachol-treated group (4). Analysis of data from the Cholesterol and Recurrent Events (CARE) trial also revealed a significant increase in breast cancer in women with a previous history of treatment for breast cancer (17). Similarly, in the HPS study, there was a trend toward an increase in nonmelanoma skin cancer in women treated with simvastatin (p =.06). Analysis of previous data from the Scandinavian Simvastatin Survival Study (4S) also indicated a trend toward an increase in the incidence of nonmelanoma skin cancer (3,18). Interestingly, skeptical researchers have pointed out that, though independently insignificant, when data from both simvastatin trials—HPS and 4S—are combined, the incidence of nonmelanoma skin cancer in simvastatin-treated patients rises to the level of statistical significance (simvastatin groups 256/12490, control groups 218/12490; p =.028) (19).
Overall, geriatricians are unlikely to reach a consensus anytime soon regarding the optimal approach to hypercholesterolemia in the older adult. Dissociating the clinical benefits of treating persistently high cholesterol levels from the increased morbidity and mortality associated with hypocholesterolemia is a complex task in the absence of proven causal relationships. Thus, for now, a truce may have to be drawn between intuition, clinical consensus, and objective scientific evidence... and the beat goes on.
References
This article has been cited by other articles:
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  C. G. P. Roberts, E. Guallar, and A. Rodriguez Efficacy and Safety of Statin Monotherapy in Older Adults: A Meta-Analysis J. Gerontol. A Biol. Sci. Med. Sci., August 1, 2007; 62(8): 879 - 887. [Abstract] [Full Text] [PDF]
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