Effects of torcetrapib in patients at high risk for coronary events

Philip J. Barter, Mark Caulfield, Mats Eriksson, Scott M Grundy, John J P Kastelein, Michel Komajda, Jose Lopez-Sendon, Lori Mosca, Jean Claude Tardif, David D. Waters, Charles L. Shear, James H. Revkin, Kevin A. Buhr, Marian R. Fisher, Alan R. Tall, Bryan Brewer

Research output: Contribution to journalArticle

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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.)

Original languageEnglish (US)
Pages (from-to)2109-2122
Number of pages14
JournalNew England Journal of Medicine
Volume357
Issue number21
DOIs
StatePublished - Nov 22 2007

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Cholesterol Ester Transfer Proteins
Potassium
Confidence Intervals
Blood Pressure
Lipoprotein(a)
Sodium Bicarbonate
Unstable Angina
Bicarbonates
torcetrapib
Aldosterone
Serum
Double-Blind Method
LDL Cholesterol
HDL Cholesterol
Lipoproteins
Coronary Disease
Cause of Death
Hospitalization
Stroke
Myocardial Infarction

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Barter, P. J., Caulfield, M., Eriksson, M., Grundy, S. M., Kastelein, J. J. P., Komajda, M., ... Brewer, B. (2007). Effects of torcetrapib in patients at high risk for coronary events. New England Journal of Medicine, 357(21), 2109-2122. https://doi.org/10.1056/NEJMoa0706628

Effects of torcetrapib in patients at high risk for coronary events. / Barter, Philip J.; Caulfield, Mark; Eriksson, Mats; Grundy, Scott M; Kastelein, John J P; Komajda, Michel; Lopez-Sendon, Jose; Mosca, Lori; Tardif, Jean Claude; Waters, David D.; Shear, Charles L.; Revkin, James H.; Buhr, Kevin A.; Fisher, Marian R.; Tall, Alan R.; Brewer, Bryan.

In: New England Journal of Medicine, Vol. 357, No. 21, 22.11.2007, p. 2109-2122.

Research output: Contribution to journalArticle

Barter, PJ, Caulfield, M, Eriksson, M, Grundy, SM, Kastelein, JJP, Komajda, M, Lopez-Sendon, J, Mosca, L, Tardif, JC, Waters, DD, Shear, CL, Revkin, JH, Buhr, KA, Fisher, MR, Tall, AR & Brewer, B 2007, 'Effects of torcetrapib in patients at high risk for coronary events', New England Journal of Medicine, vol. 357, no. 21, pp. 2109-2122. https://doi.org/10.1056/NEJMoa0706628
Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJP, Komajda M et al. Effects of torcetrapib in patients at high risk for coronary events. New England Journal of Medicine. 2007 Nov 22;357(21):2109-2122. https://doi.org/10.1056/NEJMoa0706628
Barter, Philip J. ; Caulfield, Mark ; Eriksson, Mats ; Grundy, Scott M ; Kastelein, John J P ; Komajda, Michel ; Lopez-Sendon, Jose ; Mosca, Lori ; Tardif, Jean Claude ; Waters, David D. ; Shear, Charles L. ; Revkin, James H. ; Buhr, Kevin A. ; Fisher, Marian R. ; Tall, Alan R. ; Brewer, Bryan. / Effects of torcetrapib in patients at high risk for coronary events. In: New England Journal of Medicine. 2007 ; Vol. 357, No. 21. pp. 2109-2122.
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AU - Barter, Philip J.

AU - Caulfield, Mark

AU - Eriksson, Mats

AU - Grundy, Scott M

AU - Kastelein, John J P

AU - Komajda, Michel

AU - Lopez-Sendon, Jose

AU - Mosca, Lori

AU - Tardif, Jean Claude

AU - Waters, David D.

AU - Shear, Charles L.

AU - Revkin, James H.

AU - Buhr, Kevin A.

AU - Fisher, Marian R.

AU - Tall, Alan R.

AU - Brewer, Bryan

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N2 - 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.)

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