Selective prescribing led to overestimation of the benefits of lipid-lowering drugs

Abstract

Objective

Observational studies have found beneficial effects of lipid-lowering drugs on diverse outcomes, including venous thromboembolism, hip fracture, dementia, and all-cause mortality. Selective use of these drugs in frail people may confound these relationships.

Study Design and Setting

We measured 1-year mortality in two cohorts of New Jersey residents, aged 65–99 years, enrolled in state-sponsored drug benefits programs: 112,463 persons hospitalized during the years 1991–1994 and 106,838 nonhospitalized enrollees. Use of lipid-lowering drugs and other medications, as well as diagnoses, were evaluated before follow-up.

Results

In age- and sex-adjusted analyses, users of lipid-lowering drugs had a 43% reduced death rate relative to nonusers among hospitalized enrollees and a 56% reduction in the nonhospitalized sample. Available markers of frailty and comorbidity predicted decreased use of these drugs. Control for the propensity to use lipid-lowering drugs attenuated but did not eliminate these effects. After such adjustment, users had a 30% reduction in death rate (95% confidence interval [CI]: 25%–35%) among hospitalized enrollees and a 41% reduction (95% CI: 35%–47%) in the nonhospitalized sample. Unmeasured frailty associated with a 26%–33% reduced odds of receiving lipid-lowering therapy could explain this effect.

Conclusion

Frailty and comorbidity that influence use of preventive therapies can substantially confound apparent benefits of lipid-lowering drugs on outcomes.

Introduction

Large-scale randomized trials have documented the clear benefits of drug treatment for lipid disorders in both primary and secondary prevention of coronary heart disease, stroke, and cardiovascular mortality [1], [2], [3], [4], [5]. In addition to lowering lipid levels, statins reduce multiple cardiovascular risk factors, including markers of inflammation, thrombosis, and platelet function [6], [7], [8]. Observational studies have also found beneficial effects of lipid-lowering drugs on diverse outcomes including venous thromboembolism [9], [10], age-related maculopathy [11], hip fracture [12], [13], [14], dementia [15], [16], lower extremity functioning [17], and all-cause mortality [10], [18], [19], [20], [21], [22]. These studies have used sophisticated design and analysis strategies to control for potential confounding factors that might influence the decision to initiate or persist in a regimen of lipid-lowering drugs, as well as affecting the outcome; however, the mechanisms for the apparent protective effects of lipid-lowering drugs on several of these outcomes are unclear, and all of these outcomes share a common increased risk associated with frailty and increased age.

In the case of all-cause mortality, the magnitude of the protective effect seen in observational studies has generally greatly exceeded the benefits of lipid-lowering drugs noted in randomized trials [1], [2], [3], [4], [5]. Overviews of randomized evidence found a mortality reduction with these drugs in the range of 6%–21%, with generally smaller benefits among patients with no prior cardiovascular disease [1], [2]. Evidence from randomized trials [5], [23] and a few observational studies [24], [25], [26], [27], [28] suggests that selective prescribing of lipid-lowering drugs may introduce a bias that leads to exaggerated associations in observational studies.

Factors associated with a physician's decision to prescribe lipid-lowering drugs and a patient's decision to persist in their use remain poorly understood. Many patients who would benefit from these drugs either have not started or do not continue such therapy over time [29]. Medications that do not treat symptomatic or acute conditions are commonly underutilized in patients with unrelated comorbidities [30], [31]. In such situations, the absence of preventive therapy (e.g., lipid-lowering drugs) becomes a marker for frailty that is related to increased mortality and a range of other morbidities. Diseases with little or no association with lipid levels are sometimes ignored in studies of lipid-lowering drugs and their outcomes because these comorbidities are unrelated to the underlying condition of interest. Often, however, the exposure of interest in these studies is not the presence of elevated lipid levels, but the more complex decision to use a treatment in people who often have many other illnesses. Hence, comorbidities unrelated to lipid disorders may confound observed relationships with disease outcomes if they influence use of lipid-lowering drugs, either because physicians are less likely to prescribe preventive therapies in persons with short life expectancies or significant concurrent illness, or because such patients are less likely to initiate or persist in their use.

We sought to evaluate the relationship between the presence of comorbid conditions and the propensity to use lipid-lowering drugs. We further attempted to determine whether controlling for these factors would reduce the apparent protective effect of lipid-lowering drugs on mortality to levels seen in randomized trials.