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Previous Volume 357:2109-2122 November 22, 2007 Number 21 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set CME Exam Supplementary Material Editorial by Rader, D. J. Letters Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited E-mail When Letters Appear PubMed Citation

ABSTRACT

Background Inhibition of cholesteryl ester transfer protein (CETP) has been shown to have a substantial effect on plasma lipoprotein levels. We investigated whether torcetrapib, a potent CETP inhibitor, might reduce major cardiovascular events. The trial was terminated prematurely because of an increased risk of death and cardiac events in patients receiving torcetrapib.

Methods We conducted a randomized, double-blind study involving 15,067 patients at high cardiovascular risk. The patients received either torcetrapib plus atorvastatin or atorvastatin alone. The primary outcome was the time to the first major cardiovascular event, which was defined as death from coronary heart disease, nonfatal myocardial infarction, stroke, or hospitalization for unstable angina.

Results At 12 months in patients who received torcetrapib, there was an increase of 72.1% in high-density lipoprotein cholesterol and 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 (hazard ratio, 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 to 2.19; P=0.006). Post hoc analyses showed an increased risk of death in patients treated with torcetrapib whose reduction in potassium or increase in bicarbonate was greater than the median change.

Conclusions Torcetrapib therapy resulted in an increased risk of mortality and morbidity of unknown mechanism. Although there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition. (ClinicalTrials.gov number, 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.

Full Text of this Article

Related Letters:

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.
Extract | Full Text | PDF  
N Engl J Med 2008; 358:1862-1864, Apr 24, 2008. Correspondence

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