Boston, MA - The use of statin therapy in older adults with normal LDL-cholesterol levels but systemic inflammation assessed by C-reactive protein (CRP) significantly reduces the risk of cardiovascular events, a new study has shown [1]. The relative treatment effects were similar to the effects observed in younger patients, although absolute event rates and treatment benefits were larger in older adults, according to the researchers.

The subgroup analysis, from Justification for the Use of Statins in Primary Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), were first presented at the European Society of Cardiology 2009 Congress, in Barcelona, Spain, and reported by heartwire at that time.

"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," write lead investigator Dr Robert Glynn (Brigham and Women's Hospital, Boston, MA) and colleagues in the April 20, 2010 issue of the Annals of Internal Medicine. "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 four years of follow-up, and reliable estimates of effects were seen even in subgroups of older participants."

In an editorial accompanying the study [2], Drs Susan Zieman and Pamela Ouyang (Johns Hopkins Medical Institute, Baltimore, MD) write that the analysis raises some important questions, particularly which older patients are truly at high risk for cardiovascular events. They point out that, despite having low levels of LDL cholesterol, based on their age and the high prevalence of hypertension, many of these patients would be treated aggressively. They note that the benefit of rosuvastatin (Crestor, AstraZeneca) was absent in patients without hypertension.

"Whether high-sensitivity C-reactive-protein levels add additional information to risk prediction in older persons is also controversial, because high-sensitivity C-reactive-protein levels increase with age," write Zieman and Ouyang. "This increase may reflect, in part, an upregulation of inflammatory pathways and oxidative stress, increases due to comorbid conditions, or both."

Briefly, the JUPITER study, as reported previously by heartwire, was designed to assess whether statin therapy should be given to apparently healthy individuals with normal LDL-cholesterol levels but with CRP levels >2.0 mg/dL. Treatment with rosuvastatin reduced the primary end point—a composite of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes—by 44% compared with individuals treated with placebo.

As a result of this trial, the Food and Drug Administration agreed to broader labeling for the statin. Rosuvastatin is currently approved for reducing the risk of stroke, MI, and revascularization procedures in individuals who have normal LDL levels and no clinically evident coronary heart disease but who do have an increased risk based on age, CRP levels, and the presence of at least one additional CVD risk factor.

The latest analysis in patients aged 70 to 97 years old also showed a significant benefit, resulting in a 39% relative risk reduction in the primary end point. Individuals 70 years and older had a greater reduction in cardiovascular events than those younger than 70 years old.

In JUPITER, 75 patients treated with rosuvastatin experienced a nonfatal MI, nonfatal stroke, or hospitalization for unstable angina; underwent revascularization; or died from cardiovascular causes, whereas 119 patients treated with placebo had one of these events. Among those aged 50 to 69 years old, 67 patients treated with rosuvastatin experienced a primary end point compared with 132 in the placebo arm.

The JUPITER investigators point out that comorbidities and proximity to death are often barriers to preventive care in older patients, with physicians concerned that the patient will not live long enough to derive any benefit from treatment. However, the "data from JUPITER indicate that a treatment benefit emerges shortly after initiation, absolute risk is high, and the absolute risk reduction is greater in older vs younger persons," they argue.

Speaking with heartwire, Dr Rita Redberg (University of California, San Francisco), who was not involved in the JUPITER study, said data in elderly patients are limited, and overall, she does not believe the benefits of statins outweigh the potential harms of the drugs in this healthy patient population. She emphasized that these patients are without existing heart disease and are asymptomatic. "You're not going to make these patients feel any better by giving them statins, and you're not going to make them live any longer," said Redberg.

In JUPITER, treatment with rosuvastatin did not result in a significant reduction in mortality or cardiovascular mortality in the overall population or in those aged 70 years and older, she noted.

The editorialists, on the other hand, state that in the context of a post hoc analysis, the "magnitude of cardiovascular-event reduction associated with rosuvastatin was impressive in older persons" when nonfatal events were considered. They question, however, whether the substudy provides enough information to change clinical practice. Specifically, they point out that individuals with CRP levels >5 mg/dL did not have a statistically significant reduction in cardiovascular events, while those with CRP <5>

Redberg agreed, saying that she does not measure CRP in these older patients. Rather than looking to prescribe a statin in elderly patients without heart disease, clinicians should be emphasizing lifestyle modification, particularly walking and diet, to lower their risks of future cardiovascular events.

Zieman and Ouyang state the study helps address the "time to benefit" in older adults, but further study is still needed. They point out that the median age in JUPITER is 74 years, and that 75% of patients were younger than 77 years old. In their view, these are the "young-old," and further study is needed on accurate risk-prediction tools in those 80 years of age and older, because physicians are increasingly seeing this patient demographic in their practice.