The JUPITER trial was a randomized, double-blind, placebo-controlled multicentre trial conducted at 1315 sites in 26 countries.13
Men 50 years of age or older and women 60 years of age or older were eligible for inclusion if they had no history of cardiovascular disease or diabetes and, at the initial screening visit, had an LDL cholesterol level below 130 mg/dL (3.4 mmol/L) and a high-sensitivity C-reactive protein level of 2.0 mg/L or greater.13,14
Other requirements included a willingness to participate for the duration of the trial, provision of written informed consent and a triglyceride level below 500 mg/dL (5.6 mmol/L).
Exclusion criteria included the use of lipid-lowering therapy within six weeks before screening, current use of postmenopausal hormone-replacement therapy, cancer within five years before enrolment (except for basal cell or squamous-cell carcinoma of the skin), diabetes and uncontrolled hypertension. Patients were also excluded if they had inflammatory conditions (e.g., severe arthritis, lupus or inflammatory bowel disease) or if they were taking immunosuppressant agents (e.g., cyclosporine, tacrolimus, azathioprine and long-term oral glucocorticoid treatment).
Randomization and follow-up
Between Mar. 14, 2003, and Dec. 15, 2006, a total of 17 802 participants were randomly assigned in a 1:1 ratio to receive either 20 mg of rosuvastatin daily or placebo. Follow-up visits were scheduled to occur at 13 weeks and at 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months after group assignment.
On Mar. 30, 2008, the trial’s steering committee accepted the recommendation of the independent data and safety monitoring board to end the trial on the basis of convincing evidence of efficacy with respect to the primary cardiovascular outcome. Participants were asked to continue their blinded treatment and were followed for adverse events, including infections, until they attended a closeout visit, when they learned their treatment assignment. The last closeout visit occurred on Aug. 20, 2008.
We evaluated the incidence of infections occurring between treatment assignment and unblinding at the final closeout visit by reviewing reports of adverse events from the study investigators, who were unaware of the treatment assignments. The adverse events were coded by the investigators using MedDRA-11 criteria. (MedDRA — the Medical Dictionary for Regulatory Activities — lists medical terminology used to classify adverse events associated with the use of biopharmaceuticals and other medical products.)
All adverse events coded as infections were grouped into nine non-exclusive categories: non-tuberculosis pneumonia, all respiratory infections, soft-tissue infections, gastrointestinal infections, urinary tract infections, gynecologic infections, viral infections, fungal infections and systemic sepsis. For participants who had more than one infection, the first occurrence within each category was used in the primary analyses.
Incident pneumonia was the main focus of the current study. The following MedDRA codes as reported by the study investigators were used to define pneumonia: bronchopneumonia (22 cases), pneumonia (441), Chlamydia pneumonia (2), Haemophilus pneumonia (1), Moraxella pneumonia (1), pneumoccocal pneumonia (1), atypical pneumonia (1), staphylococcal pneumonia (1), viral pneumonia (1) and bacterial pneumonia (7). We also performed an analysis of total pneumonia, in which recurrent events that occurred at least 90 days apart were considered as independent events.
To assess the severity of the pneumonia, we used the definition of “serious adverse event” as reported by the study investigators. For this analysis, an adverse event was considered serious if it was fatal, life-threatening, resulted in admission to hospital or prolongation of a hospital stay, required intervention to prevent permanent impairment or damage, or resulted in persistent or significant disability.
Analyses were done on an intention-to-treat basis. We used univariable Cox regression models to assess the rate ratio associated with rosuvastatin therapy and each category of infection. We used the Kaplan–Meier method to assess time to incident pneumonia.
Because cardiovascular events such as venous thromboembolism can result in an increased risk of infection (and because cardiovascular events were reduced by more than 40% in the rosuvastatin arm of the JUPITER trial13,14
), we performed a sensitivity analysis in which patients were censored at the time of a cardiovascular event (nonfatal myocardial infarction, nonfatal stroke, unstable angina requiring admission to hospital, arterial revascularization, venous thromboembolism or confirmed death from a cardiovascular cause). This is a standard approach to account for competing risks.15
We investigated the association between rosuvastatin treatment and the occurrence of all pneumonias, including multiple events in some participants. For this analysis, we considered recurrent pneumonia as a separate event if it occurred at least 90 days after the first event. The overall incidence of pneumonia, including recurrent events, was calculated as the total number of events divided by the total person-time until participants had their closeout visit.16
We estimated the relative hazard of pneumonia, counting recurrent events in a proportional hazards model that used a robust variance estimate to account for possible overdispersion associated with multiple events per person.17
Following an approach recommended by Cox,18
we evaluated the proportional hazards assumption in our models by including an interaction term between age and log study time, with log time centred on the mean. In the presence of a nominal violation of this assumption (p
< 0.05), we fitted separate proportional hazards models, as was done in the initial report from the trial. In addition, we examined possible heterogeneity in the effect of rosuvastatin on pneumonia across geographic regions through the use of a likelihood ratio test of interaction. For this analysis, we classified participants into five regions previously considered in the JUPITER trial: Canada and the United States; Central and South America; Europe; South Africa; and Israel. To investigate potential associations between risk factors and pneumonia, and whether control for these risk factors would influence the estimated treatment effect, we fitted a proportional hazards model with a robust variance estimate that counted all pneumonia events after treatment assignment and included as independent variables baseline age, sex, cigarette smoking, body mass index, presence of metabolic syndrome, total cholesterol and triglyceride levels, level of high-sensitivity C-reactive protein and treatment assignment.
All p values and 95% confidence intervals (CIs) are two-sided.
Role of the sponsor
The JUPITER trial was initiated by the investigators and was supported financially by AstraZeneca. The sponsor collected the trial data and monitored the study sites but played no role in the conduct of the analyses or drafting of the manuscript.