Using data from 1999–2004 NHANES and applying NCEP ATP III 2004 Update (ATP III) criteria, Spatz et al308
calculated that 57.9% of older adults (men ≥ 60 years, women ≥ 50 years) are either taking a statin (24.4%) or eligible for a statin (33.5%). If one includes individuals satisfying strict JUPITER criteria – no history of cardiovascular disease, LDL <130 mg/dL, and CRP ≥ 2 mg/L – an additional 13.9% of the age group mentioned above, or nearly 8 million people, would become eligible for rosuvastatin therapy. If expanded JUPITER criteria were used – LDL between 130 and 160 mg/dL and CRP ≥ 2 mg/L – another 5.3%, or 3 million individuals, would become statin-eligible. Hence a grand total of just under 80% of the older population would have an indication for statin therapy. Compared to the remaining 20%, the “JUPITER group” was composed of more females, was older with a higher body mass index, and tended to have hypertension and metabolic syndrome. They also shared many characteristics with ATP III subjects, particularly the use of tobacco, visceral obesity, and hypertension. Interestingly, the investigators308
noted that in the Women’s Health Study, about 20% of the women with low and intermediate FRS were reclassified by using the Reynolds risk score, which incorporates CRP values.35
These findings support the growing realization that risk is greater than generally believed, and the validity of CRP-guided risk reduction.
Michos and Blumenthal309
also estimated the prevalence of JUPITER-eligible individuals in the US population using NHANES 1999–2004 data. They found about 6.5 million individuals would be added if strict JUPITER criteria were followed. Based upon the number needed to treat (NNT) of 25 at 5 years, they estimated about 260,000 cardiovascular events could be prevented with rosuvastatin therapy. A subsequent recalculation, after adding the number of venous thromboses that would be avoided, raised the number to about 500,000 per annum.
clarified aspects of the JUPITER study in mid- 2009, observing that all prespecified subgroups benefited by rosuvastatin therapy, including those participants considered at low risk. The decision to terminate the study early was based on rigorous pre-agreed principles. It was noted that the NNT to prevent 1 event for 5 years was comparable to that reported in AFCAPS/TexCAPS, and less than those accepted for the use of diuretics or beta-blockers in treating hypertension for primary prevention. Another point emphasized was that 80% of individuals who developed diabetes occurred among those participants who had impaired glucose tolerance at baseline, but those patients also benefited from treatment in terms of end points. Last, reduction of both LDL and CRP levels was especially successful, and dual targeting may simplify decisions to treat. Another detailed analysis of absolute risk reductions and consequent NNT within the JUPITER trial, including alternative statin regimens, concluded that NNT values are acceptable.311
Yang et al,312
using a JUPITER-eligible cohort from the Atherosclerosis Risk in Communities (ARIC) Study (men ≥ 50, women ≥ 60, CRP ≥ 2 mg/L, LDL <130 mg/dL), sought to determine if the absolute event rates and risk reduction seen in JUPITER would persist for a period longer than the 1.9 year follow-up. Of their JUPITER-eligible participants, there was an absolute CVD risk of ≈10.9% over a mean follow-up of 6.9 years, or 1.57% per year. Applying JUPITER HRs to this group generated an NNT of 38 over 5 years and 26 over 6.9 years. They concluded that the use of age and CRP level was a convenient method of identifying higher risk individuals.
Vaccarino and coworkers313
noted the absolute risk reduction of 0.59% per year for the primary end point required 169 persons to be treated for 1 year to prevent a single combination of events. To prevent a major coronary event, such as an MI, 500 patients needed to be treated for 1 year for a single event. An estimate of a drug cost for rosuvastatin of US$638,750 per year was made to prevent 1 event, and for a generic statin, US$24,000 per year. In their view, adding CRP screening costs of US$62,500, and then for additional liver function, glucose, and HbA1c
monitoring, a total of over US$137,000 was reached per year for each event prevented. These authors suggested that the funds instead be invested in effective, proven population-based strategies to lower risk, as discussed elsewhere.314
In general, the costs per life year for lifetime treatment using simvastatin vary from US$2500 to US$10,990, depending on age and risk.317
Accad and Fred318
also opined that, according to their calculations, treatment of 95 individuals for 2 years to avoid 1 event is not a sufficient reward for the person with a high CRP level, but may be acceptable on a population level. On the other hand, Slejko et al269
maintained that statin therapy in JUPITER patients is cost-effective, at a cost of US$40,457 per quality adjusted life-year, below the customary threshold of US$50,000. MacDonald271
estimated that treating JUPITER-eligible individuals with rosuvastatin is highly cost-effective, but is a function of the initial FRS.
Kappagoda and Amsterdam319
reviewed treatment in the JUPITER study according to traditional risk factors and guidelines, and their calculations showed the following. Baseline characteristics of the participants revealed 2225 in each group with systolic blood pressures over 145 mm Hg. Treating these elevations would have lowered the number of strokes by 12 over the duration of the study. Similarly, by treating those individuals with LDL >119 mg/dL and HDL <40 mg/dL (about 25% of the subjects), and over-weight individuals (>50%) with weight loss, and eliminating tobacco use in the 16% who smoked, along with administering evidence-based aspirin prophylaxis in men for CHD prevention, and in women for stroke prevention, meaningful benefits would have changed outcomes. Aspirin alone could potentially have prevented 72 of the 99 MIs that occurred during the course of the JUPITER trial. Finally, since the baseline median HbA1c
was 5.7% (reference range 4.8% to 5.9%), 2225 individuals in each group had levels >5.9%, suggesting that close to 25% of the entire JUPITER population met this criterion for diabetes. These authors suggested that because guidelines for care were not strictly followed, a spuriously high event rate may have caused an appearance of higher benefit from statin therapy. The event rate, however, was similar in the ARIC profile cohort that was JUPITER-eligible,312
although smaller, which would argue against this view.
A most significant dual target analysis of the JUPITER study evaluated the effects of rosuvastatin 20 mg versus placebo on the prespecified end points according to on-treatment values of LDL (<70 or ≥ 70 mg/dL) and CRP (<2 mg/L, or <1 mg/L).320
Compared to placebo, those in the treatment group who achieved an LDL < 70 mg/dL had a 55% reduction in vascular events per 100-person years (). Those who achieved CRP < 2 mg/L had a 62% reduction in events. Among those who reached dual reductions, there was a 65% reduction in events compared to a 33% reduction in those who achieved one or neither target. Those who reached an LDL < 70 mg/dL and a CRP < 1 mg/L enjoyed a 79% reduction in events (). Treatment CRP levels predicted the event rate no matter what lipid end point was used, including the ratio of aopB/aopA-1. Therefore, regardless of the lipid profile, the lower the CRP, the better was the prognosis. An editorial concluded that JUPITER provided “key experimental data” that inflammation mediated the benefits of rosuvastatin, but mused at the prospect of comparing the absolute risk reduction of statins with the effects of weight loss and regular exercise, remarking that such a study is unlikely,321
both for lack of funding and interest. Many of the pleiotropic effects of rosuvastatin are anti-inflammatory, and a catalog of those actions – significant improvement in endothelial function, immune responses, plaque stabilization, vascular remodeling, and oxidative stress – and antithrombotic actions322
further underpins the observation that targeting CRP is worthwhile and clinically rewarding.
Cardiovascular events fell based on LDL cholesterol and on hs-CRP levels <2 mg/L
Cardiovascular events fell based on LDL cholesterol and on hs-CRP levels <1 mg/L
The use of statins in women, particularly for primary prevention, has been heavily debated.323
Mora and coworkers326
performed a specific gender-specific analysis from JUPITER using rosuvastatin 20 mg or placebo employing the criteria mentioned above. Focusing only on 6801 female participants in JUPITER, treatment significantly lowered the relative risk of the primary end point, composite of MI, stroke, revascularization, hospitalization for unstable angina, and death from cardiovascular causes, by 46%. The greatest benefit was seen for revascularization, associated with a treatment-related reduction of 76% compared to placebo. A meta-analysis of 5 studies reporting sex-specific outcomes was also undertaken. Absolute CVD rates per 100 person-years in JUPITER women were lower than for men, with similar relative risk reductions between the sexes. A total of 13,154 women were included from primary prevention trials, and a significant reduction in primary CVD events with statins by one-third was found (relative risk 0.63; 95% CI 0.49 to 0.82; P
< 0.001). These results were similar to prior results in men, and also to findings for secondary prevention in women. It was postulated that the greater numbers enrolled allowed JUPITER to demonstrate the benefit.327
CRP was noted as a tighter predictor of events in women than in men, along with the correlation between the degrees of CRP lowering and associated clinical benefit. These authors concluded that while CRP level as an independent predictor of events remains controversial, CRP is accepted as a marker which may be involved in the atherogenic process.237
The FDA approved rosuvastatin for primary prevention on February 9, 2010, following a 12-4 vote in a panel 2 months before, which only seemed to flare the ongoing controversy about its use in “healthy” individuals.328
The new indication was for men ≥ 50 years and women ≥ 60 years with fasting LDL ≤ 130 mg/dL, CRP ≥ 2.0 mg/L, triglycerides ≤ 500 mg/dL, no diagnosed CVD, and at least 1 additional CVD risk factor.