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

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> 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> 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] .)

A Comparison of Bare-Metal and Drug-Eluting Stents for Off-Label Indications

Oscar C. Marroquin, M.D., Faith Selzer, Ph.D., Suresh R. Mulukutla, M.D., David O. Williams, M.D., Helen A. Vlachos, M.Sc., Robert L. Wilensky, M.D., Jean-François Tanguay, M.D., Elizabeth M. Holper, M.D., J. Dawn Abbott, M.D., Joon S. Lee, M.D., Conrad Smith, M.D., William D. Anderson, M.D., Sheryl F. Kelsey, Ph.D., and Kevin E. Kip, Ph.D.

ABSTRACT

Background Recent reports suggest that off-label use of drug-eluting stents is associated with an increased incidence of adverse events. Whether the use of bare-metal stents would yield different results is unknown.

Methods We analyzed data from 6551 patients in the National Heart, Lung, and Blood Institute Dynamic Registry according to whether they were treated with drug-eluting stents or bare-metal stents and whether use was standard or off-label. Patients were followed for 1 year for the occurrence of cardiovascular events and death. Off-label use was defined as use in restenotic lesions, lesions in a bypass graft, left main coronary artery disease, or ostial, bifurcated, or totally occluded lesions, as well as use in patients with a reference-vessel diameter of less than 2.5 mm or greater than 3.75 mm or a lesion length of more than 30 mm.

Results Off-label use occurred in 54.7% of all patients with bare-metal stents and 48.7% of patients with drug-eluting stents. As compared with patients with bare-metal stents, patients with drug-eluting stents had a higher prevalence of diabetes, hypertension, renal disease, previous percutaneous coronary intervention and coronary-artery bypass grafting, and multivessel coronary artery disease. One year after intervention, however, there were no significant differences in the adjusted risk of death or myocardial infarction in patients with drug-eluting stents as compared with those with bare-metal stents, whereas the risk of repeat revascularization was significantly lower among patients with drug-eluting stents.

Conclusions Among patients with off-label indications, the use of drug-eluting stents was not associated with an increased risk of death or myocardial infarction but was associated with a lower rate of repeat revascularization at 1 year, as compared with bare-metal stents. These findings support the use of drug-eluting stents for off-label indications.

The Effect of Aprotinin on Outcome after Coronary-Artery Bypass Grafting

Andrew D. Shaw, M.B., Mark Stafford-Smith, M.D., William D. White, M.P.H., Barbara Phillips-Bute, Ph.D., Madhav Swaminathan, M.D., Carmelo Milano, M.D., Ian J. Welsby, M.B., Solomon Aronson, M.D., Joseph P. Mathew, M.D., Eric D. Peterson, M.D., M.P.H., and Mark F. Newman, M.D.

ABSTRACT

Background Aprotinin has recently been associated with adverse outcomes in patients undergoing cardiac surgery. We reviewed our experience with this agent in patients undergoing cardiac surgery at Duke University Medical Center.

Methods We retrieved data on 10,275 consecutive patients undergoing surgical coronary revascularization at Duke between January 1, 1996, and December 31, 2005. We fit data to a logistic-regression model predicting each patient's likelihood of receiving aprotinin on the basis of preoperative characteristics and to models predicting long-term survival (up to 10 years) and decline in renal function, as measured by increases in serum creatinine levels.

Results A total of 1343 patients (13.2%) received aprotinin, 6776 patients (66.8%) received aminocaproic acid, and 2029 patients (20.0%) received no antifibrinolytic therapy. All patients underwent coronary-artery bypass grafting, and 1181 patients (11.5%) underwent combined coronary-artery bypass grafting and valve surgery. In the risk-adjusted model, survival was worse among patients treated with aprotinin, with a main-effects hazard ratio for death of 1.32 (95% confidence interval [CI], 1.12 to 1.55) for the comparison with patients receiving no antifibrinolytic therapy (P=0.003) and 1.27 (95% CI, 1.10 to 1.46) for the comparison with patients receiving aminocaproic acid (P=0.004). As compared with the use of aminocaproic acid or no antifibrinolytic agent, aprotinin use was also associated with a larger risk-adjusted increase in the serum creatinine level (P<0.001)> with a greater risk-adjusted incidence of dialysis (P=0.56).

Conclusions Patients who received aprotinin had a higher mortality rate and larger increases in serum creatinine levels than those who received aminocaproic acid or no antifibrinolytic agent.

Aprotinin during Coronary-Artery Bypass Grafting and Risk of Death

Sebastian Schneeweiss, M.D., Sc.D., John D. Seeger, Pharm.D., Dr.P.H., Joan Landon, M.P.H., and Alexander M. Walker, M.D., Dr.P.H.

ABSTRACT

Background Aprotinin (Trasylol) is used to mitigate bleeding during coronary-artery bypass grafting (CABG). Accumulating evidence suggests that this practice increases mortality.

Methods Using electronic administrative records of the Premier Perspective Comparative Database, we studied hospitalized patients with operating-room charges for the use of aprotinin (33,517 patients) or aminocaproic acid (44,682 patients) on the day CABG was performed. We tabulated the numbers of patients with a hospital-discharge status of death and performed three types of analyses: a multivariable logistic-regression analysis (primary analysis); propensity-score matching in the highly selected subcohort of patients who received full amounts of the study drug, who underwent CABG by surgeons who performed 50 or more CABG surgeries during the study period, and for whom information on 10 additional covariates was available because the surgery occurred on hospital day 3 or later; and an instrumental-variable analysis of data from patients whose surgeons showed a strong preference for one of the two study drugs.

Results In all, 1512 of the 33,517 aprotinin recipients (4.5%) and 1101 of the 44,682 aminocaproic acid recipients (2.5%) died. After adjustment for 41 characteristics of patients and hospitals, the estimated risk of death was 64% higher in the aprotinin group than in the aminocaproic acid group (relative risk, 1.64; 95% confidence interval [CI], 1.50 to 1.78). In the first 7 days after surgery, the adjusted relative risk of in-hospital death in the aprotinin group was 1.78 (95% CI, 1.56 to 2.02). The relative risk in a propensity-score–matched analysis was 1.32 (95% CI, 1.08 to 1.63). In the instrumental-variable analysis, the use of aprotinin was found to be associated with an excess risk of death of 1.59 per 100 patients (95% CI, 0.14 to 3.04). Postoperative revascularization and dialysis were more frequent among recipients of aprotinin than among recipients of aminocaproic acid.

Conclusions Patients who received aprotinin alone on the day of CABG surgery had a higher mortality than patients who received aminocaproic acid alone. Characteristics of neither the patients nor the surgeons explain the difference, which persisted through several approaches to control confounding.