Untitled
ORIGINAL INVESTIGATION Cholesterol Lowering, Cardiovascular Diseases,and the Rosuvastatin-JUPITER Controversy
A Critical Reappraisal
Michel de Lorgeril, MD; Patricia Salen, BSc; John Abramson, MD; Sylvie Dodin, MD; Tomohito Hamazaki, PhD;Willy Kostucki, MD; Harumi Okuyama, PhD; Bruno Pavy, MD; Mikael Rabaeus, MD Background: Among the recently reported cholesterol-
tality from stroke and myocardial infarction. Cardiovas- lowering drug trials, the JUPITER ( Justification for the cular mortality was surprisingly low compared with total Use of Statins in Primary Prevention) trial is unique: it mortality—between 5% and 18%—whereas the expected reports a substantial decrease in the risk of cardiovascu- rate would have been close to 40%. Finally, there was a lar diseases among patients without coronary heart dis- very low case-fatality rate of myocardial infarction, far from ease and with normal or low cholesterol levels.
the expected number of close to 50%. The possibility thatbias entered the trial is particularly concerning because of Methods: Careful review of both results and methods
the strong commercial interest in the study.
used in the trial and comparison with expected data.
Conclusion: The results of the trial do not support the
Results: The trial was flawed. It was discontinued (ac-
use of statin treatment for primary prevention of cardio- cording to prespecified rules) after fewer than 2 years of vascular diseases and raise troubling questions concern- follow-up, with no differences between the 2 groups on ing the role of commercial sponsors.
the most objective criteria. Clinical data showed a majordiscrepancy between significant reduction of nonfatalstroke and myocardial infarction but no effect on mor- Arch Intern Med. 2010;170(12):1032-1036 Author Affiliations: Laboratoire
Cœur and Nutrition, Faculty of
Medicine, Universite´ Joseph
Fourier and Centre National de
la Recherche Scientifique,
lesterol-lowering drug trials rosuvastatin therapy (20 mg/d) in pa- on decreasing morbidity and tients without cardiovascular history or mortality among persons established CHD and with normal or low with or without coronary cholesterol levels but relatively high lev- heart disease (CHD) have been consis- els of C-reactive protein, a fluctuating Grenoble, France (Dr de Lorgeril tently negative.1-9 However, there is one biologic marker of inflammation.18 The au- and Ms Salen); Harvard Medical exception, the JUPITER (Justification for thors reported a 50% reduction in low- School, Boston, Massachusetts the Use of Statins in Primary Prevention) density lipoprotein cholesterol levels, a (Dr Abramson); Department of 37% reduction in C-reactive protein lev- Obstetrics and Gynaecology, els, and a roughly 50% decrease in car- See also pages 1007,
Laval University, Quebec City, diovascular complications.10 The publica- Quebec, Canada (Dr Dodin); 1024, and 1073
tion of the JUPITER trial (in November Department of Clinical Sciences, 2008) was much anticipated since the Institute of Natural Medicine, trial,10 which showed—in primary preven- announcement of the trial's premature dis- University of Toyama, Japan tion—a striking decrease in CHD compli- (Dr Hamazaki); Cardiology continuation in March 2008,19,20 at a meet- cations. The JUPITER trial rapidly pro- Department, Clinique Antoine ing of the American College of Cardiol- voked controversy11-13 regarding both the Depage, Brussels, Belgium ogy, following the presentation of the results and the methods used in the trial.
(Dr Kostucki); Open Research disappointing results of the ENHANCE Center for Lipid Nutrition, Kinjo Although enthusiastic comments have (Ezetimibe and Simvastatin in Hypercho- Gakuin University, Nagoya, been published,14-17 and the results have lesterolemia Enhances Atherosclerosis Japan (Dr Okuyama); undoubtedly propelled many healthy per- Regression) trial.9 Similarly to ezetimibe sons without elevated cholesterol levels onto (tested in the ENHANCE trial), rosuva- Centre Hospitalier long-term statin treatment, the clinical rel- statin was already the subject of aggres- de Machecoul, Machecoul, evance of the JUPITER trial remains in ques- sive marketing despite the absence of evi- France (Dr Pavy); and tion. To understand the rosuvastatin- Cardiology Department, dence that its use actually decreased CHD Clinique de Genolier, Genolier, JUPITER controversy, we critically review complications. Indeed, disregarding open- Switzerland (Dr Rabaeus).
several significant issues of that study.
label studies such as ASTEROID (A Study (REPRINTED) ARCH INTERN MED/ VOL 170 (NO. 12), JUNE 28, 2010 2010 American Medical Association. All rights reserved.
to Evaluate the Effect of Rosuvastatin on IntravascularUltrasound-Derived Coronary Atheroma Burden),21 3 Table. A Summary of the JUPITER Trial Resultsa
trials with rosuvastatin (CORONA [Controlled Rosu-vastatin Multinational Trial in Heart Failure],1 GISSI-HF [Gruppo Italiano per lo Studio della Sopravvivenza End Point
(n = 8901)
(n = 8901)
nell'Infarto Miocardio–Heart Failure],3 and AURORA [AStudy to Evaluate the Use of Rosuvastatin in Subjects on Primary end pointb Nonfatal myocardial infarction Regular Haemodialysis: An Assessment of Survival and Any myocardial infarction Cardiovascular Events]5) had been conducted, and all had failed to provide evidence that rosuvastatin therapy re- duces CHD complications. The failure of rosuvastatin to show a significant protective effect was also true for pa- Hospitalization for unstable angina tients with established CHD, because most patients in the Myocardial infarction, stroke, or confirmed deaths from cardiovascular causes CORONA and GISSI-HF trials were survivors of a pre- Death from any cause on known date vious myocardial infarction.
a Adapted from Ridker et al.10 b A combination of myocardial infarction, stroke, arterial revascularization, IN THE JUPITER TRIAL
hospitalization for unstable angina, or death from cardiovascular causes.
The JUPITER trial was prematurely terminated. Although CLINICAL AND EPIDEMIOLOGICAL
having prespecified early stopping rules is a well-accepted INCONSISTENCIES IN THE JUPITER TRIAL
feature of clinical trials, it is critical that the rules truly beprespecified. In the case of the JUPITER trial, the prespeci- In any trial, the consistency of clinical data must be ex- fied rules were not detailed in the published description of amined to determine whether methodological flaws have the study protocol.22 Indeed, we still do not know which increased the risk of bias. For instance, in cardiology, com- end point was used to define them, or which level of ben- parison of the rate of hard end points—fatal and nonfa- efits—unexpected on the basis of the a priori calculated hy- tal myocardial infarction and stroke, which represent most pothesis22—was required to justify early termination. Also, cardiovascular complications in any population—to those it was recently shown that truncated trials are associated expected from a comparable population, at least in the with greater effect sizes than trials that are not stopped early, placebo group, provides such a check on methodology.
and this effect is independent of the presence of statistical At first glance (Table), the difference between the 2 stopping rules.23 In defending the decision to end the trial groups in terms of hard end points seems impressive (157 early, the JUPITER investigators stated that the decision vs 83 for placebo and rosuvastatin, respectively). But are was not made by them but by members of an independent these differences plausible? Although an "unequivocal re- safety-monitoring board.24 However, the chairman of this duction in cardiovascular mortality" was announced in board—an investigator of the Clinical Trial Service Unit of March 2008 as the main justification for the premature trial Oxford University, Oxford, England—has been, and still termination,19,20 the absence of cardiovascular mortality is, involved in many other industry-sponsored lipid- data in the published article is striking. One may infer from lowering trials, raising issues of conflict of interest.25,26 the Table—although not indicated in the text—that the Fueling concern about the termination of the study is total number of fatal myocardial infarctions was 9 in the that the data are not consistent with a large difference be- rosuvastatin group (the difference between 31 "any myo- tween treatment and placebo. The primary end point cardial infarctions" and 22 "nonfatal myocardial infarc- (Table, line 1) is a composite of cardiovascular compli-
tions") and 6 (68−62) in the placebo group. Similar cal- cations, some of which—such as revascularization and hos- culations for fatal stroke (the difference between "any pital admission—are of less relevance because they are not stroke" and "nonfatal stroke") show 3 (33−30) in the ro- complications but medical decisions. Taking only the hard suvastatin group and 6 (64−58) in the placebo group.
end points of fatal and nonfatal myocardial infarction and Cardiovascular mortality (fatal stroke plus fatal myo- stroke (Table, line 8)—the end points that are less open cardial infarction) would therefore be identical in both to bias and manipulation—the trial was stopped after only groups (12 vs 12). Such a lack of effect on cardiovascu- 240 events. Furthermore, there was no difference in the lar mortality associated with a strong effect on nonfatal incidence of serious adverse events (total hospitaliza- complications strongly suggests a bias in the data set and tions, prolongations of hospitalizations, cancer, and per- should have led to the continuation of the trial rather than manent disability) between the 2 groups.
to its premature ending. Other inconsistencies add to the Moreover, a close examination of the all-cause mortal- ity curves (Figure 1D in the first JUPITER article10) shows First, the ratio of fatal myocardial infarction (9 for ro- that the curves were actually converging when the trial was suvastatin and 6 for placebo) to nonfatal myocardial in- ended, suggesting that the borderline significant differ- farction (22 and 62) is incredibly low, especially in the pla- ence between groups may have disappeared in case of a cebo group. Mortality from acute myocardial infarction is slightly longer follow-up. Strangely, in a subsequent ar- a very important issue in cardiology. The data would sug- ticle27 that was apparently written to defuse the contro- gest that the hearts of the JUPITER patients were unex- versy, the all-cause mortality curves were truncated so that pectedly—and inexplicably—highly resistant to acute is- the previous converging portion was no longer displayed.
chemia and infarction. The worst consequence of low (REPRINTED) ARCH INTERN MED/ VOL 170 (NO. 12), JUNE 28, 2010 2010 American Medical Association. All rights reserved.
myocardial resistance to ischemia is death, often sudden None of these clinically inconsistent numbers has been cardiac death (SCD). Myocardial infarction–related death, explained in the different JUPITER articles.10,27,33 Al- the "case-fatality rate" in epidemiological reports, is usu- though it is quite unusual that the burden of calculating ally very high and is known, thanks to the World Health cardiovascular mortality is placed on the readers, all meth- Organization's MONICA study, in many populations with ods used, however, lead to the same conclusion: there is very different risks.28 Out of 100 patients who have a myo- no significant difference in cardiovascular mortality be- cardial infarction, an average of 50 die immediately— tween the 2 groups in the JUPITER trial. Moreover, car- usually out of hospital—or within the 3 to 4 weeks that diovascular mortality in the JUPITER trial appears to be follow, and almost never fewer than 40 out of 100, even unexpectedly low compared with total mortality— in populations with low cardiovascular mortality, for ex- between 5 and 18%, depending on the means of calcu- ample in Japan and around the Mediterranean sea.28 In the lation—whereas the expected rate would have been close JUPITER trial, the case-fatality rate in the placebo group to 40% in a non-Japanese and non-Mediterranean popu- was incredibly low: 8.8%, a clinical inconsistency that sug- lation.28,34 These mortality data are not epidemiologi- gests a major flaw in the study. Moreover, the case- cally consistent, and the early termination of the JUPITER fatality rate in the rosuvastatin group was 29%. This rate trial likely was, at least partly, responsible for that lack was significantly different from that in the placebo group of consistency.
(Fisher exact test, P=.01) and more consistent with (though Therefore, the JUPITER data set appears biased. Three still lower than) the range reported in the MONICA study.28 other trials1,3,5 involving rosuvastatin therapy in high- Another dilemma is raised by this figure as it would im- risk patients did not show any protection. The authors ply that the use of rosuvastatin tripled the case-fatality rate.
of the JUPITER study fail to comment on these negative This figure is not credible.
trials but go on to report secondary end point and sub- Second, other ways of calculating cardiovascular mor- group analyses that appear to support the efficacy (and tality in the JUPITER trial could be used. For instance, safety) of rosuvastatin therapy.35-38 For example, an en- Chan et al29 used the combined end point "myocardial tire article was devoted to reporting a significant benefit infarction⫹stroke⫹confirmed death from cardiovascu- in 1 secondary end point, reduction of venous throm- lar causes" (line 8 of the Table), from which they re- boembolisms,35 whereas the significant increase in new moved nonfatal myocardial infarction (line 2) and non- diagnoses of diabetes among patients taking rosuva- fatal stroke (line 4). They calculated that the numbers of statin—a no less important secondary outcome—was rel- deaths from cardiovascular causes were 31 and 37 in the egated to a short comment.10 Similarly, secondary analy- rosuvastatin and placebo groups, respectively, not a sig- ses of subgroups—women,36 patients with moderate nificant difference. Because the total number of fatal myo- chronic kidney disease,37 or persons 70 years or older38— cardial infarction and stroke was 12 in both groups, it are subject to all the limitations of the main data set.
would mean that there were 19 and 25 cardiovasculardeaths that were not due to myocardial infarction or stroke.
THE SPONSOR'S ROLE AND CONFLICTS
The question raised is obvious: What are the causes of OF INTEREST IN THE JUPITER TRIAL
these so many "other" cardiovascular deaths? In the March5, 2009, issue of the New England Journal of Medicine, The JUPITER trial involved multiple conflicts of inter- Ridker and Glynn24 explain that the calculations by Chan est. It was conducted by a sponsor with obvious com- and colleagues are incorrect "because they do not ac- mercial interests. Nine of 14 authors of the JUPITER ar- count for deaths from vascular causes, such as aneu- ticle10 have financial ties to the sponsor. The principal rysm rupture." Would this mean that in the same pe- investigator has a personal conflict of interest as a co- riod of time there were 6 fatal infarctions and 25 fatal holder of the patent for the C-reactive protein test.
aneurysm ruptures in the placebo group? This is highly The sponsor's pervasive role is clearly described in the unlikely and still does not explain why the calculations second paragraph of the "Methods" section of the re- made by Chan and coauthors are incorrect. Even Ridker port: "the sponsor collected the trial data and moni- and Glynn write that the number of confirmed deaths tored the study sites."10 It means that the sponsor's own from cardiovascular causes was 35 in the rosuvastatin investigators controlled and managed the raw data. This group and 43 in the placebo group (no significant dif- does not mean that raw data have been modified before ference), based on "very strict end point classification cri- being transmitted to statisticians, but it does increase the teria" that are not clearly described, and surprisingly do chance of bias seeping into the data set, as the misrep- not mention SCD.
resentation of data about rofecoxib,39,40 gabapentin,41 and Sudden cardiac death actually is the simplest and most ENHANCE9,42-44 have shown.
reliable diagnosis in cardiology because, contrary to myo- In conclusion, the results of the JUPITER trial are clini- cardial infarction, there is no need for biologic and/or elec- cally inconsistent and therefore should not change medi- trocardiographic criteria. It is defined as a death occur- cal practice or clinical guidelines. The results of the ring within 1 hour after the first symptoms of heart JUPITER trial support concerns that commercially spon- attack—or as an unwitnessed death.30 It is therefore very sored clinical trials are at risk of poor quality and bias. Docu- surprising that no SCD is reported in the JUPITER trial mentation of the failure of the JUPITER trial to demon- because SCD usually represents about 65% to 70% of total strate a protective effect of rosuvastatin is all the more cardiac mortality.31 As previously underlined,32 the way important as it occurred in the context of the failure of more SCD is reported—or not reported—may be a good indi- than 12 other cholesterol-lowering trials published in re- cator of the quality of the methods used in a trial.
cent years and in various clinical settings.1-9,45-48 None of (REPRINTED) ARCH INTERN MED/ VOL 170 (NO. 12), JUNE 28, 2010 2010 American Medical Association. All rights reserved.
these trials provided significant evidence of protection points in Non–Insulin-Dependent Diabetes Mellitus (ASPEN). Diabetes Care. 2006; against CHD complications—especially fatal complica- 8. Cowell SJ, Newby DE, Prescott RJ, et al; Scottish Aortic Stenosis and Lipid Low- tions—by cholesterol lowering. Two other cholesterol- ering Trial, Impact on Regression (SALTIRE) Investigators. A randomized trial lowering studies were either not published49 or abruptly of intensive lipid-lowering therapy in calcific aortic stenosis. N Engl J Med. 2005; halted50 because of lack of effect. These failures strongly 9. Kastelein JJ, Akdim F, Stroes ES, et al; ENHANCE Investigators. Simvastatin with suggest that the presumed preventive effects of cholesterol- or without ezetimibe in familial hypercholesterolemia. N Engl J Med. 2008;358 lowering drugs have been considerably exaggerated.32,51 Clearly, the time has come for a critical reappraisal of 10. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER Study Group. Rosuvastatin cholesterol-lowering and statin treatments for the preven- to prevent vascular events in men and women with elevated C-reactive protein.
N Engl J Med. 2008;359(21):2195-2207.
tion of CHD complications. The emphasis on pharmaceu- 11. Donner-Banzhoff N, Sönnichsen A. Statins and primary prevention of cardiovas- ticals for the prevention of CHD diverts individual and pub- cular events. BMJ. 2008;337:a2576.
lic health attention away from the proven efficacy of 12. Nissen SE. The Jupiter trial: key findings, controversies and implications. Curr adopting a healthy lifestyle, including regular physical ac- Cardiol Rep. 2009;11(2):81-82.
13. Vaccarino V, Bremner JD, Kelley ME. JUPITER: a few words of caution. Circ Car- tivity, not smoking, and a Mediterranean-style diet.52,53 diovasc Qual Outcomes. 2009;2(3):286-288.
14. Hlatky MA. Expanding the orbit of primary prevention: moving beyond JUPITER.
N Engl J Med. 2008;359(21):2280-2282.
Accepted for Publication: April 20, 2010.
15. Spatz ES, Canavan ME, Desai MM. From here to JUPITER: identifying new pa- Correspondence: Michel de Lorgeril, MD, Laboratoire
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diovascular disease among patients with low levels of low-density lipoprotein Financial Disclosure: Dr Abramson has served as an ex-
cholesterol and elevated high-sensitivity C-reactive protein: rationale and de- pert for plaintiffs' attorneys in litigation involving the phar- sign of the JUPITER trial. Circulation. 2003;108(19):2292-2297.
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and risks of cardiovascular complications after recent acute myocardial infarction.
45. Asselbergs FW, Diercks GFH, Hillege HL, et al; Prevention of Renal and Vascular Call for Photographs The Archives is seeking photographs to be included asfillers in our journal. We believe that our readers maybe an excellent source of interesting and thoughtful pho-tographs. If you would like us to consider your photog-raphy for publication, we invite you to submit your pho-tograph to our Web-based submission site under thecategory Images From Our Readers at http://manuscripts.archinternmed.com. Please upload photograph submis-sions in .jpg or .tif format. Hard copy photographs arenot acceptable. For more information please [email protected].
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SOGC CLINICAL PRACTICE GUIDELINE No. 311, September 2014 (Replaces No. 222, January 2009) This clinical practice guideline has been prepared by the The literature searches and bibliographic support for this Menopause and Osteoporosis Working Group, reviewed guideline were undertaken by Becky Skidmore, Medical by the Clinical Practice Gynaecology and Family Physician
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Boletín Electrónico sobre Integración Regional del CIPEI ISSN: 2223-2117, Vol. 3, mayo de 2013 «Actos Unilaterales Internacionales: ¿Nicaragua tiene Derecho al pago de la indemnización contra Estados Unidos derivada de la sentencia de la CIJ del 27 de Junio de 1986? » Marisol Victoria Ruiz Mendoza y Andrés Noé Urbina Munguía