FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Published at www.nejm.org September 2, 2008 (10.1056/NEJMsa0806603)

	Full Text PDF Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Five years of statin therapy lowers low-density lipoprotein (LDL) cholesterol substantially and, over a 5-year period, results in reductions in the incidence of cardiovascular events. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) trial (ClinicalTrials.gov number, NCT00092677 [ClinicalTrials.gov] ) has raised the hypothesis that adding ezetimibe to statin therapy for larger LDL cholesterol reductions might increase the incidence of cancer.

Methods We compared the results of a hypothesis-generating analysis of the incidence of cancer in the SEAS trial of ezetimibe plus simvastatin in 1873 patients (mean follow-up after ezetimibe or matching placebo was begun, 4.1 years) with a hypothesis-testing analysis of cancer data from the two large ongoing trials of this regimen: the Study of Heart and Renal Protection (SHARP) (NCT00125593 [ClinicalTrials.gov] ) with 9264 patients (mean follow-up, 2.7 years) and the Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) (NCT00202878 [ClinicalTrials.gov] ), currently with 11,353 patients (mean follow-up, 1.0 year).

Results In the SEAS trial, assignment to ezetimibe was associated with an increase in any new onset of cancer (101 patients in the active-treatment group vs. 65 in the control group) from several cancer sites. In SHARP and IMPROVE-IT combined, there was no overall excess of cancer (313 active-treatment vs. 326 control; risk ratio, 0.96; 95% confidence interval, 0.82 to 1.12; P=0.61) and no significant excess at any particular site. Among patients assigned to ezetimibe, there were more, albeit not significantly more, deaths from cancer (97, vs. 72 in the control group; P=0.07), but there were also fewer, although not significantly fewer, other cases of cancer (216, vs. 254 in the control group; P=0.08). There was no evidence of a trend in the risk ratio for incidence of or death from cancer with increasing duration of follow-up.

Conclusions The available results from these three trials do not provide credible evidence of any adverse effect of ezetimibe on rates of cancer. Follow-up of longer duration will permit the balance of risks and benefits to be determined more reliably.

Source Information

From the Clinical Trial Service Unit & Epidemiological Studies Unit (CTSU), Oxford University, Oxford, United Kingdom (R.P., J.E., M.L., C.B., R. Collins); and the Duke Clinical Research Institute, Duke University, Durham, NC (R. Clare, R. Califf).

This article (10.1056/NEJMsa0806603) was published at www.nejm.org on September 2, 2008. It will appear in the September 25 issue of the Journal.

Address reprint requests to the CTSU, Richard Doll Bldg., University of Oxford, Old Road Campus, Oxford OX3 7LF, United Kingdom, or at secretary{at}ctsu.ox.ac.uk.

Full Text of this Article

This article has been cited by other articles:

• Trompet, S., Jukema, J. W., Katan, M. B., Blauw, G. J., Sattar, N., Buckley, B., Caslake, M., Ford, I., Shepherd, J., Westendorp, R. G. J., de Craen, A. J. M. (2009). Apolipoprotein E Genotype, Plasma Cholesterol, and Cancer: A Mendelian Randomization Study. Am J Epidemiol 170: 1415-1421 [Abstract] [Full Text]  
• Ebbing, M., Bonaa, K. H., Nygard, O., Arnesen, E., Ueland, P. M., Nordrehaug, J. E., Rasmussen, K., Njolstad, I., Refsum, H., Nilsen, D. W., Tverdal, A., Meyer, K., Vollset, S. E. (2009). Cancer Incidence and Mortality After Treatment With Folic Acid and Vitamin B12. JAMA 302: 2119-2126 [Abstract] [Full Text]  
• Greenberg, M. E., Smith, J. D., Sehayek, E. (2009). Moderately Decreased Cholesterol Absorption Rates Are Associated With a Large Atheroprotective Effect. Arterioscler. Thromb. Vasc. Bio. 29: 1745-1750 [Abstract] [Full Text]  
• Califf, R. M., Harrington, R. A., Blazing, M. A. (2009). Premature Release of Data from Clinical Trials of Ezetimibe. NEJM 361: 712-717 [Full Text]  
• (2009). {blacktriangledown}Ezetimibe - an update. DTB 47: 91-95 [Abstract] [Full Text]  
• Psaty, B. M. (2009). Conflict of Interest, Disclosure, and Trial Reports. JAMA 301: 1477-1479 [Full Text]  
• Al Badarin, F. J., Kullo, I. J., Kopecky, S. L., Thomas, R. J. (2009). Impact of Ezetimibe on Atherosclerosis: Is the Jury Still Out?. Mayo Clin Proc. 84: 353-361 [Abstract] [Full Text]  
• Steinberg, D., Glass, C. K., Witztum, J. L. (2009). Response to Letter Regarding Article, "Evidence Mandating Earlier and More Aggressive Treatment of Hypercholesterolemia". Circulation 119: e377-e377 [Full Text]  
• Tonkin, A M, Forbes, A, Haas, S J (2009). The evidence on trial: cholesterol lowering and cancer. Heart Asia 2009: 6-10 [Full Text]  
• Parolari, A., Loardi, C., Mussoni, L., Cavallotti, L., Camera, M., Biglioli, P., Tremoli, E., Alamanni, F. (2009). Nonrheumatic calcific aortic stenosis: an overview from basic science to pharmacological prevention. Eur. J. Cardiothorac. Surg. 35: 493-504 [Abstract] [Full Text]  
• Whayne, T. F. Jr (2009). Response to Letter of Mascitelli L, Ravnskov U, Pezzetta F, and Goldstein M. ANGIOLOGY 60: 129-130  
• Nissen, S. E., Collins, R., Peto, R. (2009). Analyses of Cancer Data from Three Ezetimibe Trials. NEJM 360: 86-87 [Full Text]  
• Stebbing, J., Asghar, A. K., Holmes, P., Bower, M., Isenman, H. L., Nelson, M. (2009). Use of ezetimibe during HIV infection. J Antimicrob Chemother 63: 218-220 [Full Text]  
• Kristensen, S. D., Baumgartner, H., Casadei, B., Drexler, H., Eeckhout, E., Filippatos, G., Fox, K. A.A., Perk, J., Pierard, L. A., Poldermans, D., Schunkert, H., Vardas, P. E., van der Wall, E. E., Fox, K., Bax, J. J. (2008). Highlights of the 2008 Scientific Sessions of the European Society of Cardiology: Munich, Germany, August 30 to September 3, 2008. J Am Coll Cardiol 52: 2032-2042 [Full Text]  
• Fruchart, J.-C., Sacks, F. M, Hermans, M. P, Assmann, G., Brown, W V., Ceska, R., Chapman, M J., Dodson, P. M, Fioretto, P., Ginsberg, H. N, Kadowaki, T., Lablanche, J.-M., Marx, N., Plutzky, J., Reiner, Z., Rosenson, R. S, Staels, B., Stock, J. K, Sy, R., Wanner, C., Zambon, A., Zimmet, P. (2008). The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidaemic patients. Diabetes and Vascular Disease Research 5: 319-335 [Abstract]  
• O'Keefe, J. H., Bybee, K. A., Lavie, C. J. (2008). Is Carotid Intima-Media Thickness a Reliable Clinical Predictor?-Reply-I. Mayo Clin Proc. 83: 1300-1301 [Full Text]  
• (2008). More Trouble for Ezetimibe. JWatch General 2008: 3-3 [Full Text]  
• Drazen, J. M., D'Agostino, R. B., Ware, J. H., Morrissey, S., Curfman, G. D. (2008). Ezetimibe and Cancer -- An Uncertain Association. NEJM 359: 1398-1399 [Full Text]  
• Rossebo, A. B., Pedersen, T. R., Boman, K., Brudi, P., Chambers, J. B., Egstrup, K., Gerdts, E., Gohlke-Barwolf, C., Holme, I., Kesaniemi, Y. A., Malbecq, W., Nienaber, C. A., Ray, S., Skjaerpe, T., Wachtell, K., Willenheimer, R., the SEAS Investigators, (2008). Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis. NEJM 359: 1343-1356 [Abstract] [Full Text]  
• Fleming, T. R. (2008). Identifying and Addressing Safety Signals in Clinical Trials. NEJM 359: 1400-1402 [Full Text]