Michael W. Rich, MD, is associate professor of Medicine, Washington University School of Medicine, St. Louis, Missouri.

In the United States, 42% of acute myocardial infarctions (MIs) and more than 60% of deaths attributable to acute MIs occur in the 6.1% of the population 75 years of age or older.^1,2 Nevertheless, elderly people, even those with established coronary artery disease, are substantially less likely than younger individuals to receive lipid-lowering treatment, including statins.^3,4

What accounts for this marked disparity between disease burden and preventive therapy in elderly patients? Several factors contribute to this paradox (Table).

First, despite the large body of evidence linking serum lipid levels with cardiovascular risk in middle-aged men and women, data in the elderly have been less consistent, with some studies showing a modestly strong correlation, while others have shown no correlation or even an inverse association.^5-7 However, in considering the totality of the available evidence, it is clear that while the strength of the associations of total cholesterol and low-density lipoprotein (LDL) cholesterol with coronary risk decline with age, the population attributable risk (ie, the number of cases attributable to a specific risk factor) is at least as great in older patients as in younger ones.⁸ In addition, as reported by Clarke, the ratio of total cholesterol to high-density lipoprotein (HDL) cholesterol remains a robust independent predictor of cardiovascular risk in people of all ages.

Second, while many of the statin trials have enrolled sizable numbers of older subjects, few have included patients older than 75 years and none have included patients older than 85 years. Moreover, patients with significant comorbid conditions, such as hepatic or renal disease, have generally been excluded from these trials. Thus, although the available data do indeed support the use of statins in selected patients up to perhaps 80 or 85 years of age,^9,10 the applicability of study findings to moderately old patients (75-85 years) with major comorbidities and to very old patients (85 or older) remains uncertain. Furthermore, limited life expectancy in elderly patients with moderate or advanced comorbidities raises concern that statin therapy may expose these patients to the risk of side effects without materially increasing survival.

Third, there is a perception among clinicians that older patients may be at increased risk for statin toxicity, and there are theoretical reasons why this may indeed be the case. Hepatic function and skeletal muscle mass both decline inexorably with age, which may predispose to hepatocellular toxicity and myopathy in elderly patients treated with statins. In addition, altered metabolism results in higher statin blood levels in older patients, potentially increasing the risk of toxicity. Moreover, older patients are often taking multiple medications that may interact with statins, thereby increasing the likelihood of adverse effects. Despite these concerns, however, studies to date have not shown significantly greater toxicity in older compared with younger patients treated with statins. Finally, for all of the reasons cited above, current guidelines for cholesterol management in older patients appropriately state that "clinical judgment assumes increased importance in choice of LDL-lowering therapies in older persons."¹¹ However, despite the obvious wisdom of this caveat, it affords the clinician a rationale for withholding statin therapy, even in elderly patients who are most likely to benefit.

So what is the take-home message of the study by Clarke? Well, it does provide additional evidence that we should be looking beyond total cholesterol in elderly patients—at the very least, we should examine the total cholesterol to HDL-cholesterol ratio as a superior marker for coronary risk. In addition, given the marked benefits associated with statins in secondary prevention trials that have included patients into their 80s, it is my belief that patients with established vascular disease and a life expectancy of at least 2 years (which includes most patients up to age 90 in average or above-average health) should not be excluded from statin treatment merely on the basis of age. Clearly, additional study is needed to more precisely define the value of alternative lipid parameters (such as the apo B to apo A₁ apolipoprotein ratio suggested by Clarke), as well as the risk and benefits of statins and other lipid-lowering therapies in the very elderly.

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