Alirocumab as Add-On to Atorvastatin Versus Other Lipid Treatment Strategies: ODYSSEY OPTIONS I Randomized Trial

Abstract

Context: Despite current standard of care, many patients at high risk of cardiovascular disease (CVD) still have elevated low-density lipoprotein cholesterol (LDL-C) levels. Alirocumab is a fully human monoclonal antibody inhibitor of proprotein convertase subtilisin/kexin type 9.

Objective: The objective of the study was to compare the LDL-C-lowering efficacy of adding alirocumab vs other common lipid-lowering strategies.

Design, patients, and interventions: Patients (n = 355) with very high CVD risk and LDL-C levels of 70 mg/dL or greater or high CVD risk and LDL-C of 100 mg/dL or greater on baseline atorvastatin 20 or 40 mg were randomized to one of the following: 1) add-on alirocumab 75 mg every 2 weeks (Q2W) sc; 2) add-on ezetimibe 10 mg/d; 3) double atorvastatin dose; or 4) for atorvastatin 40 mg regimen only, switch to rosuvastatin 40 mg. For patients not achieving protocol-defined LDL-C goals, the alirocumab dose was increased (blinded) at week 12 to 150 mg Q2W.

Main outcome measure: The primary end point was percentage change in calculated LDL-C from baseline to 24 weeks (intent to treat).

Results: Among atorvastatin 20 and 40 mg regimens, respectively, add-on alirocumab reduced LDL-C levels by 44.1% and 54.0% (P < .001 vs all comparators); add-on ezetimibe, 20.5% and 22.6%; doubling of atorvastatin dose, 5.0% and 4.8%; and switching atorvastatin 40 mg to rosuvastatin 40 mg, 21.4%. Most alirocumab-treated patients (87.2% and 84.6%) achieved their LDL-C goals. Most alirocumab-treated patients (86%) maintained their 75-mg Q2W regimen. Treatment-emergent adverse events occurred in 65.4% of alirocumab patients vs 64.4% ezetimibe and 63.8% double atorvastatin/switch to rosuvastatin (data were pooled).

Conclusions: Adding alirocumab to atorvastatin provided significantly greater LDL-C reductions vs adding ezetimibe, doubling atorvastatin dose, or switching to rosuvastatin and enabled greater LDL-C goal achievement.

Trial registration: ClinicalTrials.gov NCT01730040.

Figures

Figure 1.

Primary end point. LS mean (SE) percentage change from baseline in calculated LDL-C to week 24 (ITT analysis). LS mean (SE) percentage difference in calculated LDL-C vs comparator agents at week 24: *, −23.6 (6.6); †, −39.1 (6.4); ‡, −31.4 (6.1); §, −49.2 (6.1); ‖, −32.6 (6.0). LS means, SE, and P value taken from mixed-model with repeated-measures analysis. ATV, atorvastatin; EZE, ezetimibe; LS, least squares; RSV, rosuvastatin.

Figure 2.

Absolute levels and percentage change from baseline in calculated LDL-C over time for patients entering on atorvastatin 20 mg (A and B) and atorvastatin 40 mg (C and D) (ITT analysis). Actual mean LDL-C values are shown for data points at weeks 12 and 24 in panels A and C. ATV, atorvastatin; EZE, ezetimibe; LS, least squares; RSV, rosuvastatin.

Figure 3.

Proportion of patients achieving LDL-C goals at week 24: LDL-C less than 70 mg/dL (very high CVD risk) or less than 100 mg/dL (high CVD risk) (A) or less than 70 mg/dL (regardless of risk) (calculated LDL-C; ITT analysis) (B). Multiple-imputation approach was followed by a stratified exact conditional logistic regression stratified by randomization factor, with treatment group as the main effect and baseline LDL-C as a covariate. ATV, atorvastatin; EZE, ezetimibe; RSV, rosuvastatin.