A few months after the release of AstraZeneca's widely heralded JUPITER Crestor study, physicians seem prepared to prescribe statins more broadly based on that evidence, according to discussion at the American College of Cardiology annual meeting.

Though the trial was first released at the American Heart Association annual meeting in November, the opening sessions, and several later sessions, of the ACC meeting March 29-31 were devoted to the implications of the JUPITER findings.

In addition to its primary endpoint, reported just a year ago, JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) was prospectively designed to address two questions raised but not resolved by earlier studies: whether statins have antithrombotic effects and whether their observed effect on high sensitivity C-reactive protein works separately from their LDL lowering qualities. The answer is yes on both counts.

In remarks at the opening plenary, JUPITER principal investigator Paul Ridker called for guidelines that advocate combined lifestyle and statin therapies for patients at risk for cardiovascular disease. Current treatment guidelines call for statin therapy based on presence of cardiovascular risk factors and elevated LDL levels - Ridker suggested that guidelines should also include CRP >2 mg/L as a trigger for statin use, now that there is evidence from completed randomized double-blind, placebo-controlled trials.

The guidelines are under revision - ATP IV is due out in 2009. The extent to which the JUPITER paradigm will be incorporated remains contentious, however.

JUPITER is a primary prevention trial that enrolled 17,832 healthy individuals, including men 50 and over and women 60 and over, whose LDL cholesterol was under 130 (not a level that would ordinarily trigger statin use) and whose CRP was slightly elevated, at >2. The study was stopped March 30, 2008, for efficacy.

Ridker, who directs the center for cardiovascular disease prevention at Brigham & Women's Hospital in Boston, subsequently reported at AHA in New Orleans that major cardiovascular events were reduced by 44 percent and mortality by 20 percent among participants in the treatment group - individuals currently not qualified under guidelines to receive statins (¹ Also see "Will JUPITER Change Statin Use?" - Pink Sheet, 10 November, 2008.). Subjects experienced an average 50 percent reduction in LDL and an average 37 percent reduction in CRP.

The results added to scientific curiosity over whether lower CRP levels achieved by statin therapy are associated with clinical outcomes in the same way or independent of better outcomes associated with lowering LDL.

Lowering CRP Does Make A Difference

Now the picture is clearer. At ACC March 30, Ridker released an analysis showing that lowering an individual's CRP level with a statin lowers cardiovascular event risk independent of a cholesterol effect - but that together the result is even better.

Looking at baseline and one-year data from approximately 15,500 participants, or 87 percent of the JUPITER cohort, Ridker and his team found that 2,685 participants who achieved LDL of <70 and="" crp=""><2 had="" a="" 65="" percent="" risk="" reduction,="" and="" another="" 944="" whose="" crp="" dropped="" even="" lower,="" to=""><1, had="" a="" 79="" percent="" decrease="" in="" event="" rate="" compared="" to="">

Those who achieved either LDL <70 or="" crp=""><2 but="" not="" both="" goals="" had="" a="" 36="" percent="" risk="" reduction="" compared="" to="">

The results held up when JUPITER investigators used an alternative analysis based on serum levels of Apo lipoprotein B, a protein necessary to LDL formation and a marker Ridker noted "many physicians have considered ... may be a better way to monitor statin therapy than necessarily LDL."

Using a cut point of ApoB <80, which="" corresponds="" very="" closely="" to="" the="" percent="" of="" the="" population="" with="" an="" ldl=""><70 and="" a="" crp=""><2, "that="" outcome="" is="" superior="" to="" the="" intermediate="" groups="" [hazard="" ratio="" 0.36]="" and="" clearly="" superior="" to="" those="" where="" the="" ldl="" was="">70 and >2 [HR 0.62]," he pointed out. They also measured the ratio of ApoB to ApoA, the major protein component of HDL cholesterol, to be >0.5, very similar to the CRP data.

Inflammation testing should be added to the cardiac checklist for patients, Ridker said. "I think JUPITER tells us that if [other cardiac risk factors] aren't present, maybe we should measure inflammation, and if it's above some threshold, I think you should be on a statin," he reiterated.

Statins Also Ward Off Blood Clots In Veins

A second JUPITER analysis presented March 29 by Robert Glynn, a biostatistician on Brigham & Women's preventive medicine faculty, showed that rosuvastatin significantly lowered the risk of venous thromboembolism by 43 percent compared to placebo, tracking the study's successful cardiovascular event primary endpoint.

Importantly, the result was achieved with no increase in incidence of bleeding - in contrast to anticlotting drugs such as warfarin and heparin used for VTE prevention.

Also noteworthy is the "overwhelming evidence" that VTE prevention was not secondary to cardiovascular events in the JUPITER study, Glynn stressed. Over 90 percent, 88 of 94 events that occurred, happened in people before they had a cardiovascular event, "so this VTE reduction is independent of the previously described cardiovascular benefits of rosuvastatin."

The results suggest statin prescribing should be broadened to include prevention of VTE and death as well as arterial thrombosis, Glynn said. Widening the treatment target for statins to include VTE results in a five-year number needed to treat (NNT) of 11, and expanding further to include total mortality, puts the NNT at only 18, he said.

Is Broader Statin Use An Economical Option?

Ridker argues that the NNT values seen in JUPITER bode well for expanded statin use as a public health strategy.

NNT - the number of patients needed to be treated before one bad outcome is prevented - is used to compare the clinical effectiveness of interventions. The five-year NNT for rosuvastatin in JUPITER ranges between 25 and 31 for the hard vascular endpoint limited to MI, stroke or death, Ridker said. Statins already given for hyperlipidemia are in the range of 40 to 60, while diuretics and beta blockers prescribed for hypertension, for example, have a range of 80 to 160, he said. NNTs for aspirin range up to the 300s.

Even limiting statin use to men and restricting their use to those with both a Framingham score above 10 percent and elevated CRP, "we once again have five-year NNT values completely within the range of already accepted therapies, if not more efficient," Ridker reasoned during the opening session discussion.

The plan might work using generic statins, but for more expensive branded ones, "it's not at all certain that using them provides enough additional benefit to justify their higher cost," Stanford University health economist Mark Hlatky countered.

Rather than adopt routine testing of CRP levels, the test should be used to tip the decision balance in patients for whom treatment decisions are a close call, Hlatky said. "There is a zone - intermediate risk - where testing will improve decisions about who to treat and is therefore cost effective."

Hlatky argued caution in sizing the "orbit of statin therapy" in a New England Journal of Medicine editorial published at the time the first JUPITER results were made public. NEJM also ran a letter with a cost-benefit analysis that calculated the cost-per-year to save a life (assuming 17,000 deaths out of 7 million additional patients would be prevented) was higher than is normally accepted (² Also see "Insurers View JUPITER With Caution; Can Benefit Be Achieved With Generics?" - Pink Sheet, 17 November, 2008., p. 8).

A new analysis, published in the Journal of the American College of Cardiology just before the meeting, came up with a different estimate of the preventive benefits suggested by JUPITER (³ Also see "Clinical And Economic Implications Of Crestor JUPITER Study Headline ACC Meeting" - Pink Sheet, 25 March, 2009.). Ridker said that applying the screening and treatment strategies tested prospectively in JUPITER could "conservatively" prevent more than a quarter of a million heart attacks and strokes, revascularization procedures and cardiovascular deaths in the U.S. over five years.

AstraZeneca has indicated it expects to make a regulatory submission based on the JUPITER data in the second quarter, and that the company will launch a major marketing push for Crestor upon approval of the application's undisclosed claims (⁴ Also see "Crestor Star Continues To Rise, And Trajectory Looks Good" - Pink Sheet, 29 January, 2009.).

Health insurer WellPoint has already removed step therapy and prior authorization requirements for Crestor, based on an initial review of JUPITER, though other insurers have not yet amended their coverage policies (⁵ Also see "WellPoint Expands Access To Crestor Based On JUPITER Review" - Pink Sheet, 12 January, 2009., p. 31). The release of the new treatment guidelines, whichever way they come down, will presumably trigger additional payer decisions.

The initial reaction from diagnostic experts was that more long-term data are needed before CRP testing should be expanded - which would be a vital step toward applying the broader use principle advocated by JUPITER (⁶ Also see "JUPITER Not Enough To Expand CRP Testing Indication, Experts Say" - Medtech Insight, 17 November, 2008. p. 11).

So while physicians may be ready to expand use, they likely still face obstacles for coverage.

- Shirley Haley (s.haley@elsevier.com)

JUPITER Shines Celestial Glow On Statin Use; Docs Ready, But Are Payers?

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