CRP & JUPITER Study Criticism Published in Archives of Internal Medicine
JUPITER gets a battering, but Ridker fights back|
June 28, 2010 | Sue Hughes
Chicago, IL (updated) - The JUPITER trial is on the receiving end of an avalanche of criticism in four papers published in the June 28, 2010 issue of the Archives of Internal Medicine.
The most outspoken comments appear in an article entitled "A critical reappraisal" of JUPITER  by a group of authors from several countries, led by Dr Michel de Lorgeril (Université Joseph Fourier, Grenoble, France). It claims that the trial is "flawed" on many levels and biased by commercial interests. This paper stands out from the others in that, as well as challenging the results, it makes personal comments about individuals involved in the study. This has angered some onlookers, one of whom branded the comments as "troubling" and "offensive."
In addition to the de Lorgeril paper, three other articles question some of the JUPITER findings. These include a "special article" on JUPITER  by Drs Sanjay Kaul, Ryan Morrissey, and George Diamond (Cedars-Sinai Medical Center, Los Angeles; CA), a meta-analysis of statin trials that suggests there might not be a mortality benefit of these drugs in primary prevention  by a group led by Dr Kausik Ray (University of Cambridge, UK); and an editorial by Dr Lee Green (University of Michigan Medical School, Ann Arbor) .
The JUPITER trial
JUPITER, first released in 2008, involved 17 802 healthy men and women with normal LDL-cholesterol levels but elevated CRP levels (>2.0 mg/L) assigned to rosuvastatin (Crestor, AstraZeneca) 20 mg or placebo. Stopped after 1.9 years of follow-up, 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) by 44%, compared with placebo. There was a 55% reduction in nonfatal MI, a 48% reduction in the risk of nonfatal stroke, and a 47% reduction in the risk of MI/stroke/CV death.
The conflict-of-interest issue is a particular feature of the de Lorgeril paper. The authors maintain that bias has been allowed to pervade the JUPITER trial, noting that nine of 14 authors have financial ties to the sponsor and the principal investigator-Dr Paul Ridker (Brigham and Women's Hospital, Boston, MA)-has a personal conflict of interest as a coholder of the patent for the CRP test. The chair of the data safety monitoring board (DSMB), which made the recommendation to stop the trial-Dr Rory Collins-also comes in for criticism on this front, with the authors saying that he "has been, and still is, involved in many other industry-sponsored lipid-lowering trials, raising issues of conflict of interest."
Needless to say, Ridker is extremely unhappy about these comments. To heartwire, he said: "In this world, no matter how clear and blue the sky is, there will always be people who look up and see nothing but rain."
On the conflict-of-interest issue, he said: "People are well aware of my conflict regarding the patent for the CRP test. It has been written about publicly. But the data are the data. If we were trying to maximize the value of the patent, we would never have done this study, as we wouldn't have risked it not showing benefit. The patent is owned by my hospital, not by me, and they fully comply with extremely rigorous rules. Yes, I do get some financial benefit from it, but when talking about conflict you have to look at the data. And our data are good. This is one of the most independent trials ever done. We had a truly independent DSMB, totally independent statisticians, and we structured this trial to be completely independent of the company. They're going after Rory Collins here, and he is one of the most highly respected independent clinical trialists there is."
Commenting on the papers for heartwire, Dr Steven Nissen (Cleveland Clinic, OH), who was not involved in JUPITER but has conducted other statin trials, said he found the de Lorgeril article "troubling and, frankly, offensive." He said: "The authors offer no new scientific data but essentially spend much of the manuscript suggesting that the JUPITER trial was manipulated to show benefit and impugning the integrity of Paul Ridker, the JUPITER principal investigator, and Rory Collins, who chaired the data monitoring committee. These two individuals are among the most respected physician scientists in all of medicine." Nissen added: "These people are of great scientific integrity. As clinical trialists, we do our best to further knowledge. I think Ridker did that. The de Lorgeril paper is not science. It is more of an assault."
The main scientific arguments made by the authors of all four papers seem to focus on the "lack of consistency" of some of the JUPITER data with what would have been expected in this population, particularly the apparently low cardiovascular mortality but large differences in other end points, such as stroke, MI, and total mortality, between rosuvastatin and placebo. The authors of all four papers suggest that the benefits in JUPITER may have been exaggerated by the early termination of the study.
Did the early stopping of the trial exaggerate the benefits?
The most detailed scientific arguments are made in the paper by Kaul et al. They note: "Prematurely truncated trials are notorious for being vulnerable to implausibly large (too-good-to-be-true) estimates of treatment benefits that later exhibit 'regression to the mean' on longer follow-up." On this basis, they conclude that "the treatment benefit in JUPITER, although real, is likely to be overestimated."
They point out that estimates from a given trial that seem implausibly high can be moderated using Bayesian methods to incorporate information from earlier trials. They report a Bayesian analysis of JUPITER, showing that the treatment benefit is reduced from 20% to 8% with respect to mortality; from 47% to 13% with respect to the combined end point of cardiovascular death, MI, or stroke; and from 54% to 27% with respect to MI, estimates that they say are in alignment with the results of subsequent rosuvastatin trials. They further note that the number needed to treat increases from 119 to 434, which they say has important implications for clinical practice, cost-effectiveness assessment, and policy and public-health discussions.
Ray et al express a similar opinion in their paper. In their meta-analysis of all the primary-prevention statin data, they did not find a significant reduction in all-cause mortality. They write: "The present data suggest that the all-cause mortality reduction of 20% reported in JUPITER is likely to be an extreme and exaggerated finding, as often occurs when trials are stopped early."
Kaul told heartwire that he "strongly disagreed" with the decision to stop the trial early. "This will probably be the last placebo-controlled statin trial. About one-quarter of patients had very low LDLs (below 45 mg/dL). We will never know for sure now the long-term safety in this group." Kaul said trials should only be stopped for two reasons-safety or futility. "Stopping for benefit usually occurs when there is an implausibly large benefit, and it serves the purpose of the sponsors. Some may argue that ethically they had to stop, but what about the larger ethical issue of overestimating the benefit and exposing society to a therapy that might be dangerous? We still don't know on what basis they stopped this trial. Was it because of mortality or the primary end point? If it was mortality, it certainly wasn't cardiovascular mortality, because that was not significantly different. If it was for other mortality, then is there a plausible mechanism? If they had been more transparent, then we might not be having these arguments."
Ridker strongly defends the decision to stop the study. "We had a very conservative DSMB. The p value that was published as <0.0001 was actually 10-8. This is not some random error. The DSMB looked at all the subgroups and waited for the results to become positive in all these subgroups before making the decision to stop." He added: "Even if I did capitulate to these arguments, which I don't-say there was a 10%, 20%, or even 30% overestimation of benefit in JUPITER-the results would still show a large benefit. It's okay with me if these physicians want to ignore the data. I just don't want them taking care of my patients or my family."
Commenting on all of the papers, Nissen observed: "The Kaul article provides more reasoned arguments to suggest that the benefit observed in JUPITER may have been magnified by stopping the study early. While perhaps a correct analysis, I don't see how the DSMB chair, Dr Collins, had any other choice. When we stop studies early, we lose information, but there is a moral imperative to protect patient safety, and I trust that Dr Collins and the other DSMB members carefully considered this decision and all alternatives."
Was the benefit anything to do with lowering CRP?
A separate issue raised in Kaul's paper is whether lowering CRP played any role in the benefit seen in JUPITER. Kaul and colleagues note that although the lowest cardiovascular event rate was achieved in JUPITER subjects who attained the "dual targets" of LDL <70 mg/dL and CRP <2 mg/L, CRP is not recommended by the guidelines as a secondary target of therapy because of the lack of clinical-trial evidence that targeting a particular CRP level results in clinical benefit.
They also point out that without including both a low- and high-CRP arm in JUPITER, it is not possible to fully evaluate the impact of CRP level on treatment response. They cite a post hoc analysis by the FDA that showed that when patients were stratified according to CRP level, the treatment effect was consistently greater in the below-median than in the above-median CRP subgroup. "These data appear to challenge the guideline recommendation that higher concentrations of CRP might predict preferential benefit from statins," they write.
Kaul et al provide three take-home messages: do not stratify treatment decisions by CRP level; do not expect 50% risk reductions in outcomes; and do not forget diet, exercise, weight loss, and risk-factor control (lifestyle modification trumps pharmacologic intervention for primary prevention, but if patients do not modify their lifestyle, statins can be used judiciously). They say these recommendations should suffice, at least until the next generation of guideline recommendations reignites the controversy.
In response, Ridker cites new JUPITER data from an American Journal of Cardiology paper published online , which he says shows that increasing baseline CRP levels are associated with increasing vascular risk. In the paper, he and his coauthors add that "the relative risk reduction associated with rosuvastatin was similar in magnitude across the tertile and threshold levels of entry CRP," and "as the absolute risk increased with increasing CRP, the absolute risk reduction associated with rosuvastatin within JUPITER was also greatest among those with the greatest entry CRP levels."
Confusion over cardiovascular mortality data
Meanwhile, de Lorgeril et al spend much of their paper arguing that the lack of significant effect on cardiovascular deaths in JUPITER does not fit with the strong effect on nonfatal complications and total mortality, which in turn are inconsistent with other data from primary-prevention trials. They write that although an "unequivocal reduction in cardiovascular mortality was announced in March 2008 as the main justification for the premature trial termination, the absence of cardiovascular mortality data in the published article is striking.
"If readers calculate the rate of cardiovascular mortality from the data in the paper, it's clear that the CV mortality in JUPITER is actually 'unexpectedly low' compared with total mortality-between 5% and 18%, depending on the means of calculation-whereas the expected rate would have been close to 40% in a non-Japanese and non-Mediterranean population," they write. "These mortality data are not epidemiologically consistent, and the early termination of the JUPITER trial likely was, at least partly, responsible for that lack of consistency."
In response, Ridker said the de Lorgeril paper contains so many factual errors that it should never have been published. "How it has been published under the title 'original investigation,' I don't know. There are no new data in this paper. It is just their opinions," he said, adding that some of the coauthors are known to be antistatin. "I have counted 29 factual errors in this paper alone. I find it hard to believe that it could have been peer reviewed," Ridker continued, and he questions the journal's agenda in publishing the paper.
Ridker believes that the reduction in cardiovascular mortality in JUPITER was not significant because of the extremely rigid criteria used to define cardiac death. "If we couldn't guarantee that it was cardiac, it was classified as noncardiac. That is the way clinical trials should be conducted. The important thing is that total mortality had a hazard ratio of 0.80 with rosuvastatin and was significant. Cardiovascular mortality had a hazard ratio of 0.82, and although this was not significant, it is totally consistent with the overall results. Why are people so unhappy that we saved lives?"
On the idea that the results are inconsistent with other data, Ridker said: "de Lorgeril et al are saying other trials haven't worked, so JUPITER shouldn't have either. These are kindergarten arguments. Many of the trials they mention are of different drug classes. They are taking statements completely out of context."
On de Lorgeril et al's accusation that drugs are being used in preference to lifestyle, Ridker commented: "We all concur that diet, exercise, and smoking cessation are the most important aspects of primary prevention. I run a prevention clinic, and I am known as one of the most aggressive doctors on lifestyle changes. But our data show that individuals who eat healthily, exercise, and don't smoke but have raised CRP and are at high vascular risk can still reduce their risk of cardiac events and stroke with rosuvastatin. Why would you ignore data that would have a substantial impact on your patients?"
JUPITER patients were not low risk
He continued: "The fundamental error many people make is that they think JUPITER patients were low risk. They were not. The actual event rate in the placebo group was substantially higher than in AFCAPS/TEXCAPS and in some hypertension trials. The number needed to treat (to prevent one event) is actually smaller than in several previous primary-prevention trials of hyperlipidemia and hypertension. Are these authors actually suggesting we shouldn't be treating these conditions as well?"
He added: "I understand that the data may have come as a surprise to some. Atherosclerosis has always been thought of as a cholesterol disorder, but we have shown a larger benefit of a statin in patients with low cholesterol levels than in patients with high cholesterol levels. That can be disconcerting. It makes you have to reevaluate the understanding of the disease. But as physicians, we have to do that."
Editor of the Archives, Dr Rita Redberg, provided the journal's perspective to heartwire, defending the decision to publish these papers.
"Every article in Archives is peer reviewed and carefully edited. We are committed to publishing high-quality science; that is our only 'agenda.' " On the four papers concerning JUPITER published this week, Redberg said: "We published a meta-analysis of primary-prevention trials, a critique of the science (not a personal critique) of the JUPITER study, and two accompanying editorials, one focused on cholesterol lowering and one on JUPITER. . . . Finally, in terms of balance, the overwhelming number of articles advocate for statins (often beyond the evidence), so by publishing these submitted papers, we are offering clinicians a more balanced view."
Final rebuttal from de Lorgeril
Offered the chance to make a final rebuttal, de Lorgeril said he would "be very happy" to hear about the factual errors in his paper and that he stands by the questions his paper raised, specifically those surrounding the anomalies they identified in the JUPITER papers and some of the changes as to how data were presented in different articles. "Instead of speculating on our feelings and sentiments, Paul Ridker should first explain the many anomalies we . . . can find in his report."
On the accusation that de Lorgeril and his coauthors were predisposed against drug therapy, he responded: "The four cardiologists who cosigned the present article use pharmacotherapy in their patients on a daily basis when necessary and for as long as it is in accordance with truly evidence-based medicine." But he added that they are in the process of critically reviewing the positive trials of agents used for the prevention and treatment of atherosclerotic disease and will show that most of these indicate biases similar to those seen in JUPITER.
Of note, De Lorgeril and one of his coauthors are members of a group called The International Network of Cholesterol Skeptics (THINCS), who oppose the belief that animal fat and high cholesterol play a role in the causation of atherosclerosis and cardiovascular disease-a footnote reported Tuesday on Cardiobrief.
Different JUPITER indications approved in Europe vs North America
The JUPITER results have had a different effect on the approved indications for rosuvastatin on the different sides of the Atlantic.
The US FDA has allowed the JUPITER indication, and Ridker notes that the new Canadian guidelines, which are the only major guidelines to have come out since JUPITER was published, have fully incorporated the JUPITER concepts. But the Europeans have not granted the JUPITER indication but have instead extended the labeling for rosuvastatin to include the highest-risk primary-prevention patients.
Ridker wrote a recent letter to the Lancet questioning the European position .
Ridker commented to heartwire: "The Europeans did not disagree with JUPITER. It is just that they had no internal way of acknowledging CRP. In the biomarker-assessment program, CRP never got assessed, so they cannot make recommendations based on CRP levels. They wedged JUPITER into the current structure and have given it a label for people at high vascular risk. They are silent on CRP but have endorsed use of rosuvastatin in patients with a Framingham risk score over 20% or a SCORE [risk model used in Europe] over 5%. This is a small extension of the label. But this is not an accurate portrayal of JUPITER."
He added: "I think they felt boxed in by the fact they had no structure to deal with CRP. Many senior cardiologists in Europe have told me they are embarrassed by this decision; that this is more evidence that Europe doesn't really want to prevent heart disease."
Kaul suggested that the European decision was probably made for economic reasons. He explained that allowing the whole JUPITER indication would open up a vast new population of patients for statins, which would be expensive to fund, so the Europeans did a post hoc analysis of JUPITER and identified a small group of the highest-risk patients who derived the greatest benefit on a secondary end point of CV death/MI/stroke.
He added: "The Europeans have given rosuvastatin a small additional indication based on a secondary end point in a post hoc analysis." But despite this, he believes it is a sensible decision. "I don't like the methodology, but I understand why they have done it. They didn't want to give a broader primary-prevention indication as this would break the bank. So they have found the subgroup that derived the most benefit."
The JUPITER trial was sponsored by AstraZeneca US. Ridker has received grant support and consulting fees from AstraZeneca and is listed as a coinventor on patents held by the Brigham and Women's Hospital that relate to the use of inflammatory biomarkers in cardiovascular disease and have been licensed to Siemens and AstraZeneca. Coauthor on the de Lorgeril paper, Dr John Abramson (Harvard Medical School, Boston, MA), has served as an expert for plaintiffs' attorneys in litigation involving the pharmaceutical industry (not involving rosuvastatin), as an unpaid consultant to the Federal Bureau of Investigation and the Department of Justice in investigations involving the pharmaceutical industry, and as a consultant to Wells Fargo Insurance Services. Nissen has previously disclosed receiving research support through his institution from Pfizer, AstraZeneca, Novartis, Roche, Daiichi-Sankyo, Takeda, Sanofi-Aventis, Resverlogix, and Eli Lilly, and reports that he consults for many pharmaceutical companies and requires them to donate all compensation directly to charity. Kaul has previously disclosed having served as an advisor or consultant for Novo Nordisk and Hoffmann-La Roche. Ray has received honoraria for lectures and advisory boards from the majority of companies that market lipid-lowering agents.