The reason for the enthusiasm and early termination of JUPITER was a hazard ratio of 0.56 (95% CI, 0.46 to 0.69), translating into a 44% relative risk reduction for the primary outcome favoring statin treatment, with similar reductions in other cardiovascular endpoints. But as Dr. Hlatky cautioned, in his editorial to the JUPITER trial,5
what really matters for dictating changes in clinical practice is the absolute risk reduction. This is because the absolute benefit of the treatment must be large enough to justify its potential risks and costs. Importantly, the threshold for tolerating risks and costs are particularly low when dealing with predominantly healthy populations who have low event rates, such as the sample enrolled in JUPITER. The question therefore is: are the treatment benefits achieved in the JUPITER trial large enough to advocate an expansion in the clinical indications for statins?
JUPITER used a composite outcome as the primary outcome of this trial, a technique used to minimize the enrolled sample size and a subject of potential controversy in the medical literature, especially when including outcomes of markedly different clinical severity (e.g., arterial revascularization vs. mortality).6
The rate of the primary end point, a composite of five conditions (nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, arterial revascularization, or confirmed death from cardiovascular causes) was only 0.77% per year in the rosuvastatin arm and 1.36% in the placebo arm. These rates translate into an absolute risk reduction of about a half percentage point per year (0.59%), or 1.2% over the approximately 2-year total duration of the trial. This figure is obviously much less impressive to the casual reader than the relative risk reduction of 44%. If one considers the more important and customary outcome of major coronary events, including nonfatal or fatal myocardial infarction, the yearly rate in the two arms was 0.17% and 0.37% respectively, yielding an absolute risk reduction of only 0.20% per year. However, the corresponding relative risk reduction remained an impressive 54%. When dealing with low event rates, even a small absolute difference in rates can appear dramatic when expressed in relative terms (e.g., as a hazards ratio, or relative risk reduction).
A useful measure to assess effectiveness of health care interventions is the number needed to treat.7
This is the number of patients who need to be treated in order to prevent one additional adverse outcome, and is calculated as the inverse of the absolute risk reduction. Based on an absolute risk reduction of 0.59% per year for the primary endpoint, 169 persons need to be treated for one year to prevent one combination of clinical events measured in JUPITER. For more unambiguous major coronary events, including fatal or non-fatal myocardial infarction, 500 persons need to be treated for one year to prevent one event. These are large numbers, considering that the persons being treated were deemed to be healthy at the start of the study. Therefore, the safety and costs associated with treating such patients need to be carefully considered.
While more formal cost-effectiveness studies are needed, a preliminary estimate of the economic impact of applying JUPITER in clinical practice can be approximated. Treatment with rosuvastatin costs approximately $3.50 per day, translating into a potential cost of $638,750 per year for each major coronary event averted. Using a generic statin, which costs approximately $4 per month, this figure is lower, at $24,000 per year, but still substantial. These estimates do not include the costs of screening patients and monitoring safety. In JUPITER, approximately 80% of the people who attended the screening visit eventually did not qualify for inclusion; it follows that many people would be screened for CRP and other tests who eventually would not be treated. Assuming a CRP screening test cost of $25, an additional $62,500 would have to be spent per year for each major coronary event averted. To these costs one would have to add the costs of initial testing and monitoring for liver function as recommended before and during statin therapy, and the costs of testing for plasma glucose and glycated hemoglobin, as glycated hemoglobin and diabetes incidence were elevated in JUPITER in the rosuvastatin group. Assuming that all these tests could be done for a total of $30, this could bring the costs of screening and monitoring to >$137,000 per year for each event averted.
As an alternative to screening and prescribing medications to eligible patients, potentially safer and less costly strategies could be considered for the primary prevention of cardiovascular diseases. For example, while less than 3% of health care expenditures are currently targeted towards the amelioration of behavioral risk factors such as smoking, poor diet and physical inactivity, these factors are attributed as the principal etiology of almost 40% of deaths in the United States.8
Preventive strategies aimed at these risk factors are supported by good evidence of effectiveness9
and yield a high return on investment.10
Incidentally, a modest absolute risk reduction is not unique to JUPITER, but is a characteristic of statin trials in general. In a meta-analysis including 90,056 patients with hypercholesterolemia of whom 47% had pre-existing CHD,11
there was a 23% relative risk reduction of nonfatal or fatal myocardial infarction, but only a 2.4% absolute risk reduction over a mean of 5 years, or approximately 0.48% per year (number needed to treat: 208). Thus, on average the absolute risk reduction was higher and the number needed to treat lower in previous statin trials than in JUPITER, which is expected since JUPITER enrolled lower-risk individuals. However, the relative risk reduction was higher in JUPITER (54% versus 23%, for major coronary events). This magnitude of the relative risk reduction in JUPITER raises the possibility that the effect of statin treatment was overestimated in JUPITER.