Among the 5,695 randomized participants in the JUPITER trial who were age 70 years or older, rosuvastatin substantially reduced the incidence of major cardiovascular events. In these older people, clear benefits over time emerged shortly after treatment initiation and appeared in analyses of broader end points including total mortality, in separate analyses of myocardial infarction and stroke, among older men and women separately, and in high risk subgroups. The observed relative treatment effects in older people were consistent with those seen in younger trial participants, but absolute event rates and treatment benefits were greater in older people.
The JUPITER trial differed from prior primary prevention trials of statins in its enrollment of an older population, its inclusion of stroke in the primary end point, and its enrollment of individuals with normal LDL cholesterol but elevated high-sensitivity C-reactive protein. Because age is the dominant risk factor for a first cardiovascular event in non-diabetic individuals, the lower age limit and absence of an upper age limit contributed to enrollment of a population that incurred many cardiovascular events. Prevention of stroke is an important treatment target for statin therapy (20
), and stroke contributes an increasing proportion of total cardiovascular events with increasing age. Enrollment of individuals with elevated high-sensitivity C-reactive protein contributed further to the identification of a population at increased risk of both coronary heart disease and stroke (21
), who were found to benefit from statin therapy in spite of their normal LDL levels.
Meta-analysis of observational studies found that a 1 mmol/L lower total cholesterol level was associated with a 56% reduction (95% CI: 52%–58%) in the hazard of death from ischemic heart disease at ages 40–49, but a 17% reduction (95% CI: 15%–19%) at ages 70–89 years (5
). For stroke, a slightly reduced risk associated with lower total cholesterol at ages 40–69 did not persist upon control for blood pressure, and there was no reduction in the hazard of stroke associated with lower cholesterol at ages 70–89. The apparently attenuated associations of total cholesterol levels with cardiovascular events in older people may be partly due to confounding by age-related comorbid conditions (23
). Nonetheless, the weakened association of total cholesterol with cardiovascular risk in older people and the limited randomized evidence on statin therapy for primary prevention directed by lipid levels in older people, raise questions about how lipid levels should be used to inform treatment decisions in older people. Relative treatment benefits appear to be independent of baseline lipid levels (24
), many older people are at substantial risk in spite of apparently normal lipid levels, and the JUPITER findings indicate that these individuals receive a benefit regardless of their lipid levels if high sensitivity C-reactive protein is elevated.
The JUPITER trial provides new information on the effects of statins in older people that can inform evaluations of the impact of alternative prescribing strategies. Several authors have noted the limitations arising from the need to project prior treatment recommendations for healthy older people from the available randomized evidence in younger people, or in older people with diabetes or prevalent cardiovascular disease, or from the observational data on cholesterol levels and risk of cardiovascular disease (4
). For example, in their comparison of alternative treatment strategies, Pletcher et al (26
) assumed, in their base-case scenario, that the relative treatment benefit associated with a given LDL cholesterol reduction is much less in an older compared to a younger person. Their sensitivity analyses, under the assumption supported by the JUPITER data that relative treatment benefits are unchanged across age groups, found a preference for strategies more focused on treating older people. The JUPITER trial also points to the need to include stroke prevention in evaluations of cost-effectiveness, both because of its high personal and financial impact as well as its increased percentage of total cardiovascular events with age. Thus, evaluations restricted to coronary events can under-value treatment in older people.
Comorbidity and proximity to death are barriers to preventive care in older people. Physicians reasonably hesitate to initiate a therapy if they expect a patient will not live long enough to benefit. Data from JUPITER indicate that a treatment benefit emerges shortly after initiation, that absolute risk is high, and that the absolute risk reduction is greater in older versus younger individuals. Consideration of composite end points including total mortality provides a treatment evaluation that accounts for the competing risks of death. Adding total mortality to the end point indicates that fewer patients need to be treated to prevent one event.
These exploratory analyses need to be interpreted in light of the overall trial results, but they confirm that the overall treatment effect was reliably seen in older participants. Early stopping of the trial limited the information on the long-term effects of treatment, although cumulative risks between treatment groups continued to diverge up to 4 years of follow-up, and reliable estimates of effects were seen even in subgroups of older participants. Stopping early on the basis of a principled and conservative monitoring plan yields a valid estimate of treatment effects (27
) and meets ethical requirements to inform participants when equipoise no longer holds and society when better treatments are available (28
Overall, among individuals age 70 years and older in this randomized trial, rosuvastatin was associated with a significant reduction in the rate of a first major cardiovascular event. Because older participants had much higher event rates, absolute treatment benefits were greater in this age group.