Prospective Evaluation of Malignancy in 17,708 Patients Randomized to Ezetimibe Versus Placebo: Analysis From IMPROVE-IT

Abstract

Background: An increased risk of malignancy was reported with simvastatin/ezetimibe in 1,873 patients in the SEAS (Simvastatin and Ezetimibe in Aortic Stenosis) trial.

Objectives: The purpose of this study was to clarify this unexpected finding in a larger sample size of patients stabilized after acute coronary syndrome, we conducted a prospective systematic analysis of malignancy events in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial).

Methods: Within IMPROVE-IT, 17,708 patients post-acute coronary syndrome were randomized to either ezetimibe 10 mg or matching placebo on a background of simvastatin 40 mg who took ≥1 dose of the study drug. Suspected tumors (benign and malignant) reported by investigators or identified from a review of adverse events were adjudicated by oncologists without knowledge of drug assignment. The primary malignancy endpoint included new, relapsing, or progressive malignancies (excluding nonmelanotic skin malignancies). The secondary endpoint was death due to malignancy.

Results: In this trial, 1,470 patients developed the primary malignancy endpoint during a median 6 years of follow-up. The most common malignancy locations were prostate (18.9%), lung (16.8%), and bladder (8.8%) with no differences by treatment group (p > 0.05 for each location). Kaplan-Meier 7-year rates of malignancies were similar with ezetimibe and placebo (10.2% vs. 10.3%; hazard ratio: 1.03; 95% confidence interval: 0.93 to 1.14; p = 0.56), as were the rates for malignancy death (3.8% vs. 3.6%; hazard ratio: 1.04; 95% confidence interval: 0.88 to 1.23; p = 0.68).

Conclusions: Among 17,708 patients receiving simvastatin 40 mg daily, those randomized to ezetimibe 10 mg daily had a similar incidence of malignancy and deaths due to malignancy compared with those receiving placebo during a median follow-up of 6 years (96,377 patient-years). (IMPROVE-IT: Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin [Ezetimibe/Simvastatin] vs Simvastatin [P04103]; NCT00202878).

Keywords: ACS, acute coronary syndrome; BMI, body mass index; CI, confidence interval; HR, hazard ratio; KM, Kaplan-Meier; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin kexin 9; PH, proportional hazard; RR, risk ratio; acute coronary syndromes; cancer; ezetimibe; hs-CRP, high-sensitive C-reactive protein; lipid-lowering therapy; lipids; malignancy; statin.

© 2020 The Authors.

Figures

Graphical abstract

Central Illustration

Cumulative Incidence Rates for the Primary Malignancy Endpoint by Treatment Arm Simvastatin/ezetimibe (red) and placebo/ezetimibe (blue). The primary malignancy endpoint was defined as new, relapsing, or progressive malignancy (excluding nonmelanotic skin malignancy). The cumulative incidence plots were presented graphically using Kaplan-Meier product-limit method. CI = confidence interval; HR = hazard ratio.

Figure 1

Cumulative Incidence Rates for the Secondary Endpoint of Deaths Due to Malignancy by Treatment Arm Simvastatin/ezetimibe (red) and placebo/ezetimibe (blue). The cumulative incidence plots were presented graphically using Kaplan-Meier product-limit method. CI = confidence interval; HR = hazard ratio.

Figure 2

Primary Malignancy Endpoint by Pre-Specified High-Risk Subgroups The number of events and the 7-year Kaplan-Meier rates are shown. BMI = body mass index; Hs-CRP = high-sensitive C-reactive protein; TC = total cholesterol. Total cholesterol: 25th percentile = 144.0 mg/dl, 50th percentile = 162.4 mg/dl and 75th percentile = 181.0 mg/dl.

Figure 3

Deaths Due to Malignancy Endpoint by Pre-Specified High-Risk Subgroups The number of events and the 7-year Kaplan-Meier rates are shown. Total cholesterol: 25th percentile =144.0 mg/dl, 50th percentile = 162.4 mg/dl and 75th percentile = 181.0 mg/dl. Abbreviations as in Figure 2.