JUPITER: reduced events in patients with low LDL, raised CRP

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In JUPITER (Justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin), a clinical trial enrolling individuals who do not currently qualify for statin therapy, rosuvastatin significantly reduced all-cause mortality by 20%.

 

The investigator-initiated trial, funded by AstraZeneca, enrolled 17,802 apparently healthy men and women with elevated levels of C-reactive protein (hsCRP), stated Professor Paul Ridker, Harvard School of Public Health, Boston, MA. JUPITER, presented at the American Heart Association’s 2008 Scientific Sessions, was widely anticipated and received as the highpoint of last year’s meeting.

Dr Ridker noted that while current guidelines endorse statin therapy among patients with established vascular disease, diabetes, or hyperlipidemia, half of all heart attacks and strokes occur among individuals with average or even low levels of cholesterol. hsCRP is an inflammatory biomarker that reproducibly and independently predicts future vascular events, even when cholesterol levels are low. In Ridker’s 2001 post-hoc analysis (Ridker et al, New England J Med 2001;344:1959-65) of the AFCAPS/TexCAPS trial, individuals with low levels of both LDL cholesterol (LDL-C) and hsCRP had extremely low vascular event rates which were not improved by statin therapy. Among those with low LDL-C but high hsCRP, however, vascular event rates were just as high as rates among those with overt hyperlipidemia. Statin therapy significantly reduced events in this group, Ridker said.

In JUPITER, a prospective multi-national randomised double-blind placebo controlled trial in which individuals (men >50 years, women > 60 years) with no prior cardiovascular disease or diabetes, were randomised to rosuvastatin 20mg (n=8,901) or placebo (n=8,901), all had LDL <130mg/dL and hsCRP ≥2mg/L. The actual median hsCRP level was 4.2 and 4.3 in the rosuvastatin and placebo groups, respectively, and the median LDL level was 108mg/dL for both groups.

Endpoints

The primary endpoint was planned as combined MI/stroke/unstable angina/revascularisation and cardiovascular death at five years. However, the trial was stopped prematurely after review by an independent data safety monitoring board after 1.9 years of follow-up. At that time, the primary endpoint was reported at a rate of 251/8,901 (2.82%) in the placebo group and 142/8,901 (1.60%) in the rosuvastatin group (44% risk reduction, p<.00001), with a number needed to treat (NNT) of 25. Risk reductions of 47% were found for rosuvastatin in combined MI/stroke/or cardiovascular death and for arterial revascularisation or hospitalisation for unstable angina (both p<.00001). Subgroup analysis showed consistent benefit across gender, age, smoking status, racial, regional (USA/Canada/rest of world), or hsCRP >2mg/L only subgroups. Serious adverse event rates were similar (15.2% rosuvastatin, 15.5% placebo).

The secondary endpoint of all cause mortality was reduced 20% in the rosuvastatin group (247/8,901 placebo, 198/8,901 rosuvastatin, p=.02).

Ridker concluded, “Despite evaluating a population with lipid levels widely considered to be ‘optimal’ in almost all current prevention algorithms, the relative benefit observed in JUPITER was greater than in almost all prior statin trials.” He said further, “The screening and treatment strategy tested in JUPITER is likely to be cost effective, benefiting both patients and payers.” Also, he said, the NNT of 25 for the primary endpoint is a value smaller than that associated with treating hyperlipidemia in primary prevention.

Finally, Ridker said, “Application of the simple screening and treatment strategy tested in the JUPITER trial over a five-year period could conservatively prevent more than 250,000 heart attacks, strokes, revascularisation procedures, and cardiovascular deaths in the US alone.”

Issues to be clarified

AHA discussant Dr Andrew M Tonkin, Melbourne, Australia, said, “The benefits of rosuvastatin when hsCRP is >2mg/L and LDL-C is <130 mg/dL were clearly proven in JUPITER, even if patients were otherwise at low risk.” He noted further, however, that the relative importance of the effects of rosuvastatin on LDL-C and/or inflammation (hsCRP) remains unclear. Subsequent data analyses, he suggested, may help clarify these issues. The trial did not, Tonkin continued, shed light on whether hsCRP is a marker or a mediator of cardiovascular risk. Importantly, he said, there were no safety concerns. He recommended, as a consequence of JUPITER, that guidelines concerning hsCRP in risk assessment and statin treatment in primary cardiovascular disease prevention be reviewed. Consideration needs to be given, Tonkin said, to whether hsCRP needs to be incorporated in absolute risk equations.

Among those without cardiovascular disease or diabetes, Tonkin would recommend statin treatment in the presence of high absolute risk. For those with hsCRP >2mg/L, consideration of rosuvastatin’s treatment effects, effects of age-related elevation of hsCRP, analyses of absolute risk reductions for various subgroups and their cost effectiveness, and elevated hsCRP detection need to be included. The question of an ideal LDL-C target, perhaps 70mg/dL, needs to be addressed as well.

Risk factors

Closing with a comment on implementation of JUPITER findings in family practice, Tonkin said, “Universal screening at the present would be inappropriate.” Existing predictive algorithms may inform who should be tested for hsCRP. Such screening costs do need to be included in cost effectiveness analyses to enable translation of JUPITER results to usual clinical environments.

Dr Marvin Lipman, New York Medical College, Valhalla, NY, and chief medical adviser for Consumer Reports, commented in an interview, “You have to look at the minutiae. About half the population had significant risk factors. About 15% were smokers, and about 41% had metabolic syndrome. So this is not exactly a low risk population that he was studying – as was implied by the low LDL levels.” Also, Lipman pointed out that the calculation of an NNT of 25 was based on extrapolations to five years. At 1.9 years, when the study was stopped, the NNT was 125.

“I don’t think this study will change my way of using a CRP in the treatment of patients. I find it handy where the LDL-C is borderline – between 125–140mg/dL – where you hem and haw about putting someone on a statin for rest of his or her life. There, CRP helps you decide. I go to lifestyle first – at least four months of changes in diet and exercise before going to a statin for any reason.”

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