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Heartwire 2008. © 2008 Medscape

November 5, 2008 (New York, NY) — Cardiologists already know the key result from JUPITER, the opening late-breaking clinical trial at the upcoming American Heart Association (AHA) 2008 Scientific Sessions: rosuvastatin was superior to placebo in reducing hard end points in apparently healthy people with low or normal LDL levels but elevated C-reactive protein (CRP). Still, experts who spoke with heartwire said that as-yet-unreported details from the trial, which has the potential to radically expand the number of people eligible for statin therapy, will be key for understanding how patient screening or statin usage may change.

Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) will present the full results from JUPITER at 3:45 pm November 9 at the AHA 2008 meeting, in New Orleans.

As previously reported by heartwire, AstraZeneca, the study sponsor, announced it had stopped the trial last spring, with 17 802 patients enrolled, after an interim analysis showed death, MI, and other adverse events to be reduced among patients randomized to 20-mg rosuvastatin. Critically, JUPITER participants had normal to low LDL levels (less than 130 mg/dL) but increased CRP levels (>2.0 mg/L); depending on nuances in the results, JUPITER could ultimately lead to the expansion of statins to millions of adults currently not eligible for statin therapy.

Commenting on the potential impact of the study--without knowing the results--Dr Michael Miller (University of Maryland, Baltimore) pointed out that the anti-inflammatory effects of statins were known already, even in the absence of high LDL, as demonstrated in the ASCOT trial.

But in ASCOT, he points out, patients also had risk factors for coronary heart disease other than high CRP--it will be important to see what other risk factors JUPITER patients may have had, Miller notes. "Was the high CRP in JUPITER present by itself, or was it always accompanied by other risk factors? Our analysis of the NHANES database found that a high CRP was present only in one in 2000 [people] in the absence of traditional risk factors, thereby suggesting that high CRP is a biomarker rather than a direct promoter of coronary heart disease," Miller said. "Hence, if the JUPITER paper shows a high prevalence of subjects who had no other risk factors beside high CRP as the basis for the increased event rates, then that would argue for routine CRP screening in this group of middle-aged subjects."

Additional Benefit of CRP

Also commenting on the potential impact of JUPITER, Dr James Stein (University of Wisconsin, Madison) drew parallels between JUPITER and the METEOR study, which also addressed the question of treating low-risk patients on the basis of a biomarker, not a cholesterol cut point, but he adds that JUPITER was "much more important."

"METEOR showed that if you have the biomarker of high carotid [intima media thickness] IMT but LDL cholesterol at a level that would not qualify for treatment, you have less disease progression on rosuvastatin. JUPITER extends that finding to a more widely available biomarker--[high-sensitivity] hs-CRP--and shows the outcome we care most about: cardiovascular events. It is a landmark study. It shows something we all have suspected--that there are people out there who are at higher-than-apparent risk, and if they get identified and treated, they do better."

But the question will persist as to how much CRP adds to current screening, Stein suggested. "The rub is that hs-CRP is highly correlated with adiposity and abnormal levels of risk factors, so how many extra people do you identify with screening above just looking at those parameters?" he asked. Participants in JUPITER were older, overweight, with higher-than-normal blood pressure. "They were poster children for a biomarker test to see whether they were at higher-than-apparent risk," Stein said. The question for the medical community will be how to incorporate the JUPITER results into practice guidelines, Stein points out. "That mainly will depend on the magnitude of the benefit in absolute terms, rather than relative terms, as well as the cost of any screening strategies we implement," he said. "Do we screen for hs-CRP in everyone, or just certain subgroups? Or do we just lower our targets for treatment across the population and omit extra screening? Also, how do we account for the high intra-individual variability in hs-CRP? We can't begin to answer these questions until we see the final data and some of the subgroup analyses."

Other Trials at AHA 2008

The JUPITER trial is expected to steal the show at this year's meeting, although a range of other trials should also help cardiologists to fine-tune treatments for both primary and secondary prevention of cardiovascular disease.

Day two of the meeting features trials of clopidogrel, rivaroxaban (ATLAS ACS-TIMI 46), and an "intervention timing" trial for non-STE ACS (TIMACS). Diabetes is the focus of three late-breakers spread across different days of the meeting: two studies address atherosclerosis prevention in diabetic patients (the JPAD trial using aspirin and the APPROACH trial with rosiglitazone), while a third is a registry analysis of drug-eluting stents vs bare-metal stents in diabetic patients from the Massachusetts registry.

Speaking with heartwire about the upcoming meeting, Dr Gordon Tomaselli (Johns Hopkins University, Baltimore, MD), chair of the program committee, pointed out that JPAD may provide some much-needed new information. "The utility of aspirin specifically in patients with diabetes really has been difficult to sort out, so the trial will help us understand whether there really is any effect," he said.

The third late-breaking clinical-trial session, on Tuesday, is devoted to heart-failure trials: of these, the I-PRESERVE study, looking at the use of irbesartan in patients with preserved ejection fraction, has the power to pack the most punch, if positive, given the dearth of drugs for this form of heart failure. According to Tomaselli, "I-PRESERVE is really the first properly designed trial to address this question, so it could be very interesting." Additional late-breakers include results of a home INR-monitoring study (THINRS), the FIT study exploring a family-based exercise intervention for heart-disease prevention, and two randomized comparisons of vitamin-related strategies vs placebo for primary and secondary prevention.

Of these last, Tomaselli highlighted the SEARCH study, looking at effects of secondary prevention using both statins and folic acid. "The homocysteine hypothesis hasn't been abandoned, we just haven't figured out the correct way to reduce homocysteine. . . . I think that it may further confirm the recent trials that suggest using folic acid to lower homocysteine levels is not the right way to go, but I don't think it's going to firmly put the nail in the biological plausibility of the homocysteine hypothesis."

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.