ACC 2009: JUPITER: Low LDL and Low CRP Best for Reducing Events in Primary Prevention

March 29, 2009

March 29, 2009 (Orlando, Florida) Reducing LDL cholesterol and high-sensitivity C-reactive protein (hs-CRP) in primary-prevention patients treated with rosuvastatin (Crestor, AstraZeneca) results in better event-free survival than when neither of these targets are achieved or when LDL cholesterol alone is reduced, a new analysis shows [1].

Presenting the results of the Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) study during an afternoon press conference at the American College of Cardiology 2009 Scientific Sessions, investigators say that initial interventions for low-risk primary-prevention patients remains lifestyle and dietary modifications, but for those choosing drug therapy, "reductions in both LDL cholesterol and hs-CRP are indicators of the success of treatment with statin therapy."

"Our data show that patients do better when they not only lower LDL cholesterol but also lower their CRP level," Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA)told the media. "This is good news. We have a way to improve care and can consider monitoring inflammation the same way that we monitor LDL cholesterol to benefit our patients."

Dr James Stein (University of Wisconsin, Madison), who was not part of the JUPITER study, told heartwire that the message from the JUPITER analysis is straightforward but important, especially since the data challenge current treatment paradigms and make a strong case for including hs-CRP in future guidelines.

"They challenge the concept of using LDL-cholesterol values as a threshold for starting treatment and now challenge using LDL cholesterol and non-HDL cholesterol as the sole primary and secondary targets for lipid therapy," said Stein. "There are almost as many data for using hs-CRP as a target as there are for using LDL cholesterol and certainly more data for using hs-CRP than there were for LDL cholesterol when [Adult Treatment Panel] III came out."

The findings, which will be presented here during a late-breaking clinical-trials session on Monday, March 30, 2009 at 2:00 pm local time, are now published in the Lancet.

Lowering LDL Cholesterol and Reducing Inflammation

When JUPITER was presented last November at the American Heart Association 2008 Scientific Sessions, investigators, along with other clinicians, suggested that reducing LDL cholesterol while simultaneously treating inflammation was one of the reasons treatment was successful. Other studies, including analyses of the PROVE-IT and REVERSAL trials, both of which were reported by heartwire, showed that lower CRP levels were associated with fewer cardiovascular events, independent of LDL-cholesterol levels. Data from the A to Z trial also showed that patients with acute coronary ischemia who achieved low LDL-cholesterol and CRP levels achieved the best clinical outcomes.

"The current guidelines emphasize LDL-cholesterol targets, and that is a very effective strategy," said Ridker. "But evidence has accumulated from our group and others over the past decade that suggests the benefit of statins is also related to underlying levels of inflammation, and the inflammation reduction you get with these drugs seems to be predictive of outcomes."

Still, inflammation, specifically whether or not it is necessary to lower hs-CRP levels after the initiation of statin therapy, is controversial. With this in mind, Ridker and colleagues prospectively assessed the benefits of lowering LDL cholesterol and hs-CRP in healthy men and women treated with rosuvastatin.

JUPITER Stopped Early

As reported previously by heartwire, the JUPITER trial included 17 802 healthy men and women assigned to rosuvastatin 20 mg or placebo and was designed to assess whether statin therapy should be given to apparently healthy individuals with normal LDL cholesterol but elevated CRP levels (CRP>2.0 mg/L).

JUPITER was designed as a four-year study but was stopped by AstraZeneca after just 1.9 years on the basis of recommendations from an independent data-monitoring board and the JUPITER steering committee. When the study was stopped on March 31, 2008, as reported by heartwire at that time, the company reported unequivocal evidence of a reduction in cardiovascular morbidity and mortality among patients treated with rosuvastatin, compared with those treated with placebo.

After 1.9 years of follow-up, treatment with rosuvastatin significantly reduced the primary end point--a composite of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes--44% compared with placebo. This reduction was observed among nearly all of the individual end points. In terms of absolute benefits, the proportion of patients who had an MI, stroke, revascularization, hospitalization for unstable angina, or who died from cardiovascular causes was 1.6% in the rosuvastatin arm and 2.8% in the placebo arm, an absolute risk reduction of 1.2%.

In this dual-target analysis, patients who reduced their LDL cholesterol to less than 70 mg/dL had a 55% reduction in vascular events, whereas those who reduced CRP levels to less than 2 mg/L had a 62% reduction in vascular events, compared with placebo-treated patients. Among those who achieved the dual LDL and CRP targets, there was a 65% reduction in vascular events, compared with the 36% reduction among those who reduced only LDL-cholesterol or CRP levels, or who reduced neither. The reductions were even more pronounced when investigators assessed event rates in patients who achieved hs-CRP levels of less than 1 mg/L.

Hazard Ratios for Cardiovascular Events Based on LDL Cholesterol and on Hs-CRP Levels <2 Mg/L

LDL cholesterol (mg/dL) and hs-CRP (mg/L) levels Events/patients, n Event rate Hazard ratio (95% CI)
>70 and >2 31/1384 1.11 1.06 (0.72-1.55)
>70 and <2 8/726 0.54 0.42 (0.18-0.94)
<70 and >2 41/2921 0.62 0.53 (0.38-0.74)
<70 and 2 23/2685 0.38 0.35 (0.23-0.54)
>70 or >2 80/5031 0.38 0.64 (0.49-0.84)

Hazard Ratios for Cardiovascular Events Based on LDL and on Hs-CRP Levels <1 Mg/L

LDL cholesterol (mg/dL) and hs-CRP (mg/L) levels Events/patients, n Event rate Hazard ratio (95% CI)
>70 and >1 36/1874 0.95 0.89 (0.62-1.28)
>70 and <1 3/236 0.64 0.46 (0.11-1.85)
<70 and >1 59/4662 0.56 0.49 (0.37-0.66)
<70 and <1 5/944 0.24 0.21 (0.09-0.51)
>70 or >1 98/6772 0.67 0.59 (0.46-0.75)

"I think what JUPITER points out is that there is a very large number of individuals at risk for myocardial infarction, stroke, and cardiovascular death who clearly have LDL-cholesterol levels that are quite low, and that we can identify a high-risk group by screening for CRP," said Ridker. "A strategy of screening for CRP followed by statin therapy is rather effective at preventing these events, which can often be fatal."

Dr James de Lemos (University of Texas Southwestern, Dallas), who commented on the study for heartwire , said the results are not too surprising but are important because they confirm observations from secondary-prevention trials, which is important since JUPITER assesses CRP levels earlier in the disease process.

However, further studies are needed, he said, particularly to determine how best to treat these patients. For example, if a patient has a low LDL-cholesterol level but elevated CRP, it is not known whether the dose of statin should be increased or additional agents prescribed. Also, de Lemos noted that a failure to lower LDL-cholesterol and CRP levels is not necessarily a failure of therapy, but possibly a patient-related failure. In most studies, patients with elevated CRP levels are a "different type of patient" and are more often obese and tend to be women.

"I think the study gives us great prognostic information, and we can agree that you and I both want to have our LDL and CRP levels down as low as possible, but if that doesn’t happen, what do we do next?" wondered de Lemos.

Real World vs Observed Benefit

In an editorial accompanying the published study, Drs Salim Yusuf, Eve Lonn, and Jackie Bosch (McMaster University, Hamilton, ON) turn their focus to the benefit observed in the original JUPITER trial, which was presented and published last November, in light of other trials [2].

In a recently published meta-analysis, the Cholesterol Treatment Trialists (CTT) showed that a 40-mg/dL reduction in LDL cholesterol resulted in a 21% reduction in the risk of vascular events and a 12% reduction in mortality. Based on those findings, the "real benefits" of lowering LDL cholesterol by approximately 50 mg/dL over two years in JUPITER would be expected to yield a 20% to 30% reduction in the risk of ischemic events and a 10% reduction in total mortality, according to Yusuf and colleagues.

The editorialists also point to the CORONA and GISSI-HF trials, both of which used rosuvastatin 10 mg and resulted in significant reductions in LDL-cholesterol levels. Despite the reduction in LDL cholesterol, these two trials testing rosuvastatin in heart-failure patients did not show reductions in ischemic vascular events or cardiovascular mortality.

"The duration of the first two trials was much longer than that of JUPITER, and because the benefits of lipid lowering are enhanced by longer follow-up, the larger and more rapid benefit in JUPITER compared with previous statin trials is a surprise," according to Yusuf and colleagues.

To heartwire , Ridker said he does not understand how comparisons between heart-failure and primary-prevention trials can be made. He said the results of the JUPITER trial have "substantially raised the bar for any kind of future polypill trial," in which Yusuf is involved, given that a single agent, at an adequate dose, resulted in a 50% reduction in MI and stroke.

"So why would one give aspirin, three antihypertensives, and a low-dose statin, risking so many side effects, to get a similar benefit?" said Ridker. "What if a full-dose statin is indeed the perfect 'polypill'?"

What Is Low Risk?

During the press conference, Ridker stressed that the primary focus of prevention in these patients remains smoking cessation and lifestyle and dietary changes. Dr Roger Blumenthal (Johns Hopkins University Medical Center, Baltimore, MD), who was not affiliated with the JUPITER trial, said that the study, especially the 80% reduction in risk in patients who achieve the very low CRP target of less than 1 mg/L, serves as a public-health message.

"The way I'll use the information clinically is to tell patients that the best method we have to lower CRP is weight loss if you're overweight and better dietary and exercise habits," Blumenthal told heartwire . "I won't necessarily use the information now to recheck their CRP, but I will to emphasize the importance of these lifestyle changes."

Speaking to the media, Ridker said that the effect observed in JUPITER is a class effect common to all statins, but that more potent statins are able to lower LDL-cholesterol and CRP levels to a greater extent. Most important is the issue of identifying high-risk patients, even among apparently healthy individuals. "The question is: 'What is low risk?' " asked Ridker. "Is a Framingham score of less than 10 low risk if you have a high CRP? We don't think so, and the data don't suggest it."

Ridker did not comment on future guidelines, but press-conference moderator Dr Claudio Shuger (Henry Ford Hospital, Detroit, MI) said that future reports would likely consider the value of CRP screening on the basis of the data presented. "Guidelines should be determined by the guidelines committee that evaluates the information presented today, but I think reasonable people will argue that risk stratification will probably include CRP in the future."

AstraZeneca sponsored the JUPITER study. Ridker reports receiving research support, consulting fees, and/or lecture fees from AstraZeneca, Novartis, Merck, Abbott, Roche, Sanofi-Aventis, Merck-Schering Plough, ISIS, and Vascular Biogenics. He is listed as a coinventor on patents that relate to the use of inflammatory biomarkers in cardiovascular disease.

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