Effects of Torcetrapib in Patients at High Risk for Coronary Events
Philip J. Barter, M.D., Ph.D., Mark Caulfield, M.D., M.B., B.S., Mats Eriksson, M.D., Ph.D., Scott M. Grundy, M.D., Ph.D., John J.P. Kastelein, M.D., Ph.D., Michel Komajda, M.D., Jose Lopez-Sendon, M.D., Ph.D., Lori Mosca, M.D., M.P.H., Ph.D., Jean-Claude Tardif, M.D., David D. Waters, M.D., Charles L. Shear, Dr.P.H., James H. Revkin, M.D., Kevin A. Buhr, Ph.D., Marian R. Fisher, Ph.D., Alan R. Tall, M.B., B.S., Bryan Brewer, M.D., Ph.D., for the ILLUMINATE Investigators
Background Inhibition of cholesteryl ester transfer protein(CETP) has been shown to have a substantial effect on plasmalipoprotein levels. We investigated whether torcetrapib, a potentCETP inhibitor, might reduce major cardiovascular events. Thetrial was terminated prematurely because of an increased riskof death and cardiac events in patients receiving torcetrapib.
Methods We conducted a randomized, double-blind study involving15,067 patients at high cardiovascular risk. The patients receivedeither torcetrapib plus atorvastatin or atorvastatin alone.The primary outcome was the time to the first major cardiovascularevent, which was defined as death from coronary heart disease,nonfatal myocardial infarction, stroke, or hospitalization forunstable angina.
Results At 12 months in patients who received torcetrapib, therewas an increase of 72.1% in high-density lipoprotein cholesteroland a decrease of 24.9% in low-density lipoprotein cholesterol,as compared with baseline (P<0.001 for both comparisons),in addition to an increase of 5.4 mm Hg in systolic blood pressure,a decrease in serum potassium, and increases in serum sodium,bicarbonate, and aldosterone (P<0.001 for all comparisons).There was also an increased risk of cardiovascular events (hazardratio, 1.25; 95% confidence interval [CI], 1.09 to 1.44; P=0.001)and death from any cause (hazard ratio, 1.58; 95% CI, 1.14 to2.19; P=0.006). Post hoc analyses showed an increased risk ofdeath in patients treated with torcetrapib whose reduction inpotassium or increase in bicarbonate was greater than the medianchange.
Conclusions Torcetrapib therapy resulted in an increased riskof mortality and morbidity of unknown mechanism. Although therewas evidence of an off-target effect of torcetrapib, we cannotrule out adverse effects related to CETP inhibition. (ClinicalTrials.govnumber, NCT00134264
[ClinicalTrials.gov]
.)
Source Information
From the Heart Research Institute, Sydney (P.J.B.); St. Bartholomew's Hospital, London (M.C.); Karolinska University Hospital, Huddinge, Stockholm (M.E.); University of Texas Southwestern Medical Center, Dallas (S.M.G.); Academic Medical Center, University of Amsterdam, Amsterdam (J.J.P.K.); University Pierre et Marie Curie and Hôpital Pitié–Salpêtrière, Paris (M.K.); Hospital Universitario La Paz, Madrid (J.L.-S.); Columbia University, New York (L.M.); Montreal Heart Institute, Montreal (J.-C.T.); San Francisco General Hospital, San Francisco (D.D.W.); Pfizer, New London, CT (C.L.S., J.H.R.); University of Wisconsin, Madison (K.A.B., M.R.F.); Columbia University Medical Center, New York (A.R.T.); and Medstar Institute, Washington, DC (B.B.). This article (10.1056/NEJMoa0706628) was published at www.nejm.org on November 5, 2007.
Address reprint requests to Dr. Barter at the Heart Research Institute, 145 Missenden Rd., Camperdown, Sydney, NSW 2050, Australia, or at barterp{at}hri.org.au.
Torcetrapib and Coronary Events
Lackner K. J., Cohn L. J., Dullaart R. P., Kobold A. C. M., van Tol A., Barter P., Shear C. L., Revkin J. H., Rader D. J.
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N Engl J Med 2008;
358:1862-1864, Apr 24, 2008.
Correspondence
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