AHA 2008: JUPITER Hits New Orleans: Landmark Study Shows Statins Benefit Healthy Individuals With High CRP Levels

November 09, 2008

November 9, 2008 (New Orleans, Louisiana) — The Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) started the American Heart Association (AHA) 2008 Scientific Sessions here today with a bang, shaking up the field of primary prevention with new data showing that the treatment of apparently healthy patients with a statin cuts their risk of cardiovascular disease morbidity and mortality by almost half [1].

In a study of individuals with low LDL cholesterol but elevated C-reactive-protein (CRP) levels, investigators showed that rosuvastatin (Crestor, AstraZeneca) 20 mg significantly reduced the primary end point--a composite of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes--by 44% compared with individuals treated with placebo.

Presented by Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA) during the late-breaking clinical-trials session and published online in the New England Journal of Medicine to coincide with the AHA presentation, investigators showed that the benefits extended to all subgroups, including "robust reductions in cardiovascular events with statin therapy in women and black and Hispanic populations, for which data on primary prevention are limited," write the JUPITER investigators.

Calling JUPITER "one of the most important clinical trials in the long history of statin studies," Dr Steven Nissen (Cleveland Clinic, OH) told heartwire that such large reductions in clinical events in less than two years among patients considered healthy by conventional definitions is likely to change the guidelines.

"Ideally, if a patient comes to me with normal LDL-cholesterol levels--in JUPITER, the median LDL-cholesterol level was 108 mg/dL--I tell him to keep doing what he's doing and to go about his business," said Nissen. "Now, what happens when that same patient arrives in my office and I know his CRP is elevated? I know that treating him with intensive statin therapy, despite what the guidelines state, is going to cut his risk of cardiovascular morbidity and mortality in half."

Dr James Stein (University of Wisconsin Medical School, Madison) echoed the sentiments of others when he said that the findings are going to pose challenges, particularly as clinicians grapple with changing how they think about and treat seemingly low-risk patients.

"It is a true landmark in preventive cardiology, not only for its findings, but even more so for the challenges it raises to our current strategies for use of cholesterol-lowering medications and to our risk-assessment paradigms," said Stein.

Stopped After 1.9 Years of Study

JUPITER was designed as a four-year study but was stopped by AstraZeneca after just 1.9 years based on recommendations from an independent data monitoring board and the JUPITER steering committee. When the study was stopped on March 29, 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. Despite the benefits, Dr Sanjay Kaul (Cedars Sinai Medical Center, Los Angeles, CA) questioned why it was stopped so early, "especially when we have no idea about the long-term safety of very low LDL levels as achieved in this trial."

Reductions in Cardiovascular Events Line Up in JUPITER

JUPITER is a large, multinational, long-term, double-blind, placebo-controlled, randomized clinical trial that included 17 802 healthy men and women assigned to rosuvastatin 20 mg or placebo. The study was designed to assess whether statin therapy should be given to apparently healthy individuals with normal LDL cholesterols but elevated C-reactive protein levels (CRP >2.0 mg/L).

Among patients treated with rosuvastatin, LDL-cholesterol levels were cut in half, decreasing from a median 108 mg/dL at baseline to 55 mg/dL at 12 months. CRP levels were also significantly reduced, declining from 4.2 mg/L at baseline to 2.2 mg/L at 12 months. Triglyceride levels were reduced 17% from baseline among those treated with statin therapy. These effects persisted over the course of the study.

Baseline and Change in LDL Cholesterol and CRP Levels During Study Period

Measure Baseline 12 mo 24 mo 36 mo 48 mo
LDL cholesterol (mg/dL)          
Rosuvastatin 20 mg 108 55 54 53 55
Placebo 108 110 108 106 109
High-sensitivity CRP (mg/L)          
Rosuvastatin 20 mg 4.2 2.2 2.2 2.0 1.8
Placebo 4.3 3.5 3.5 3.5 3.3

p<0.001 for all between-group comparisons

After 1.9 years of follow-up, treatment with rosuvastatin significantly reduced the primary composite end point 44% compared with placebo. This reduction was observed among nearly all of the individual end points, including a 55% reduction in nonfatal MI, a 48% reduction in the risk of nonfatal stroke, and a 47% reduction in the risk of hard cardiac events (a composite of MI, stroke, and death from cardiovascular causes).

In terms of absolute benefits, the proportion of patients who had an MI, stroke, revascularization, or hospitalization for unstable angina or 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%. Similarly, the proportion of patients with hard cardiac events--cardiovascular death, MI, and stroke--was reduced from 1.8% in the placebo arm to 0.9% in the rosuvastatin arm, an absolute reduction of 0.9%.

JUPITER: Outcomes According to Study Group

End point Patients with event, rosuvastatin (n=8901), n Patients with event, placebo (n=8901), n Hazard ratio (95% CI)
Primary end point* 142 251 0.56 (0.46–0.69)
Nonfatal MI 22 62 0.35 (0.22–0.58)
Any MI 31 68 0.46 (0.30–0.70)
Nonfatal stroke 30 58 0.52 (0.33–0.80)
Any stroke 33 64 0.52 (0.34–0.79)
Revascularization 71 131 0.54 (0.41–0.72)
Hospitalization for unstable angina 16 27 0.59 (0.32–1.10)
Revascularization or hospitalization for unstable angina 76 143 0.53 (0.40–0.70)
MI, stroke, or death from cardiovascular causes 83 157 0.53 (0.40–0.69)
Death on any known date 190 235 0.81 (0.67–0.98)
Any death 198 247 0.80 (0.67–0.97)

*Primary end point: composite of nonfatal MI, nonfatal stroke, hospitalization for unstable angina, revascularization, and confirmed death from cardiovascular causes

A subgroup analysis revealed no heterogeneity in any of the results, including an analysis of subgroups based on age, race, or ethnic group, as well as baseline LDL-cholesterol and CRP levels. The investigators report that even patients considered to be at very low risk--those who did not smoke, were not overweight, did not have metabolic syndrome, or had a Framingham risk score of 10% or less--benefited from statin therapy.

Of note, among the 6801 women included in JUPITER, rosuvastatin significantly reduced the primary composite end point by 46%. "These are our most impressive data in women in the primary-prevention setting," Dr Roger Blumenthal (Johns Hopkins Medical Institute, Baltimore, MD) told heartwire .

In terms of side effects, significantly more patients in the rosuvastatin arm developed new diabetes, and they also had significantly higher glycated hemoglobin levels, report investigators. Any reported serious adverse events were similar between the placebo and statin-therapy arms.

Lulled Into a False Sense of Security With "Normal" LDL Cholesterol Levels

To heartwire , Stein said the results, despite the significant risk reduction in apparently healthy individuals, are not surprising. He praised the JUPITER investigators and the study sponsor for exposing the current LDL-cholesterol thresholds for lipid-lowering therapy as arbitrary, but more important, as a poor indicator of cardiovascular risk.

"Many patients with heart attacks have normal LDL-cholesterol values," said Stein. "Thus, doctors and patients are lulled into a false sense of security when their LDL cholesterol is 'normal' and then are surprised when they have a heart attack. JUPITER illustrates this point perfectly. If you look at the median values--age 66 years, body-mass index 28.3 kg/m2, systolic blood pressure 134 mm Hg, and 41% with metabolic syndrome--you know these people are going to have heart attacks and strokes and die.  Indeed, in the placebo arm, the event rate was 1.36% per year.  But current guidelines say not to treat them."

Nissen pointed out that there has been a lot of recent pushback against the cholesterol hypothesis, with many speculating that lowering LDL-cholesterol levels had no impact on the reduction of cardiovascular risk. Patients in the JUPITER study, he pointed out to heartwire , had a significant 50% reduction in LDL-cholesterol levels, coupled with the significant 37% reduction in CRP levels, and this suggests that LDL cholesterol remains an important end point clinicians should treat.

"Reducing LDL cholesterol while at the same time treating inflammation is one of the reasons why this treatment was so successful," said Nissen. Two other studies, analyses of the PROVE-IT and REVERSAL trials, by Ridker and Nissen, respectively, previously showed that lower CRP levels are associated with fewer cardiovascular events independent of LDL-cholesterol levels [2,3]. Stein said he thinks LDL-cholesterol levels of 100 mg/dL are still too high if the patient has other markers of risk, such as increased age, obesity, and hypertension.

Should Every Patient Undergo CRP Testing?

In an editorial accompanying the published study, Dr Mark Hlatky (Stanford University School of Medicine, CA) agreed that guidelines are likely to be revisited, although he is cautious on just how big an impact the findings will have on clinical practice [4].

 
JUPITER provides yet more evidence about the effectiveness of statin therapy in reducing cardiovascular risk, even among persons who would not currently be considered for pharmacotherapy.
 

"JUPITER provides yet more evidence about the effectiveness of statin therapy in reducing cardiovascular risk, even among persons who would not currently be considered for pharmacotherapy," writes Hlatky. "Guidelines for primary prevention will surely be reassessed on the basis of the JUPITER results, but the appropriate size of the orbit of statin therapy depends on the balance between the benefits of treatment and its long-term safety and cost."

To heartwire , Kaul said he is not quite as bullish on the findings as others, noting that nearly one out of every five patients screened was enrolled, which has implications about the generalizability for clinical practice, as very few patients have elevated CRP without traditional risk factors. Moreover, clinicians and health-policy experts should focus on the absolute risk reductions, he said.

"The absolute risk differences are less impressive than the relative differences and, together with cost and long-term safety considerations, will serve to temper the conclusions of the study," said Kaul.

In his editorial, Hlatky calculated that 120 patients need to be treated for 1.9 years to prevent one death from cardiovascular causes, MI, or stroke, and this benefit needs to be balanced against concerns about significantly higher glycated hemoglobin levels and increased diabetes incidence observed in the rosuvastatin arm. The JUPITER investigators, on the other hand, calculated the number needed to treat (NNT) based on the primary-end-point event and report that the NNT with rosuvastatin for two years to prevent one primary end point is 95 and just 31 need to be treated for four years to prevent one primary-end-point event.

In his editorial, Hlatky said the design of JUPITER provides only limited information about the role of CRP testing in clinical practice, since investigators did not compare subjects with and without CRP measurements and did not compare the use of CRP with the use of other markers of cardiovascular risk.

"At this point, the current guidelines for measurement of high-sensitivity CRP remain reasonable," writes Hlatky. Measurements of CRP may be obtained in asymptomatic individuals who have an intermediate level of risk, based on standard clinical risk markers, and in whom treatment might change depending on the high-sensitivity CRP level. Blumenthal said most doctors use CRP as a "tie-breaker" to make a decision about which men >50 years and women >60 years would benefit from statins.

Stein told heartwire that the use of more widespread screening of CRP values needs more investigation. The test has high variability and is elevated with infections and injuries, so abnormally high CRP levels do not always reflect arterial injury or cardiovascular-disease risk.

"However, I suspect we should start using it more often," he said. "For starters, it makes communication easier. It summarizes a myriad of metabolic problems that individually are not bad enough to treat but collectively indicate increased risk. Increased CRP tells you that.  It is one number, and explaining and implementing it may be easier for physicians and patients than trying to explain why 'borderline' high blood pressure and being 'a little overweight' are bad. They damage and inflame blood vessels, and high CRP shows it."

AstraZeneca sponsored the JUPITER study.

  1. Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. New Engl J Med 2008; DOI: 10.1056/NEJMoa0807646. Available at: http://www.nejm.org.

  2. Ridker PM, Cannon CP, Morrow D et al. C-reactive protein levels and outcomes after statin therapy. New Engl J Med 2005; 352:20-8. Abstract

  3. Nissen SE, Tuzcu EM, Schoenhagen P et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005l 352: 29-38. Abstract

  4. Hlatky M. Expanding the orbit of primary prevention--moving beyond JUPITER. New Engl J Med 2008; 359: published online before print November 9, 2008. DOI: 10.1056/NEJMe0806320. Available at: http://www.nejm.org.

 

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