ODYSSEY OPTIONS I and II - ODYSSEY OPTIONS I and II

Nov 19, 2014
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Sanofi and Regeneron Pharmaceuticals, Inc.
Date Presented:
01/01/2014
Date Updated:
11/19/2014
Original Posted Date:
11/19/2014
References

Description:

The current trial sought to study the safety and efficacy of alirocumab, a PCSK9 inhibitor, compared with other lipid control strategies in patients who had low-density lipoprotein cholesterol (LDL-C) levels above goal with coronary heart disease/risk equivalents.

Hypothesis:

Alirocumab would be superior to other lipid-lowering strategies in reducing LDL-C levels in high cardiovascular (CV) risk patients with suboptimal LDL-C control despite being on a statin.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Patients with prior CV disease + LDL-C ≥70 mg/dl, or CV risk factors + LDL-C ≥100 mg/dl

    Number of enrollees: 355 (OPTIONS I), 305 (OPTIONS II)
    Duration of follow-up: 24 weeks
    Mean patient age: 63 years
    Percentage female: 33%

Primary Endpoints:

  • Percent LDL-C change from baseline at 24 weeks

Drug/Procedures Used:

Patients meeting LDL-C criteria were considered in two separate strata:

OPTION 1:
- Entry statin atorvastatin 20 mg daily: randomized to receive alirocumab with atorva 20 mg vs. ezetimibe with atorva 20 mg vs. atorva 40 mg
- Entry statin atorva 40 mg daily: randomized to receive alirocumab with atorva 40 mg vs. ezetimibe with atorva 40 mg vs. atorva 80 mg vs. rosuva 40 mg

OPTION 2:
- Entry statin rosuva 10 mg daily: randomized to receive alirocumab with rosuva 10 mg vs. ezetimibe with rosuva 10 mg vs. rosuva 20
- Entry statin rosuva 20 mg daily: randomized to receive alirocumab with rosuva 20 mg vs. ezetimibe with rosuva 20 mg vs. rosuva 40

Alirocumab was administered in a dose of 75 mg subcutaneous Q2W, with uptitration to 150 mg Q2W at week 8 if LDL levels were not at goal.

Principal Findings:

A total of 660 patients were randomized, 355 in OPTIONS I and 305 in OPTIONS II. Baseline characteristics were fairly similar. The mean baseline LDL-C ranged between 99 and 119 mg/dl.

OPTIONS I:
Entry statin atorva 20 mg: Alirocumab significantly reduced LDL-C at 24 weeks compared with ezetimibe and double-dose statin at 24 weeks; percent decrease from baseline was 44.1% vs. 20.5% vs. 5.0%, p < 0.0001. The absolute reduction in LDL-C values at 24 weeks was also significantly lower (48.4 vs. 22.6 vs. 8.5 mg/dl). Percent achieving LDL-C levels <70 mg/dl were highest in the alirocumab arm (79.2% vs. 50.3% vs. 16%).

Entry statin atorva 40 mg: Alirocumab significantly reduced LDL-C at 24 weeks compared with ezetimibe, double-dose statin and rosuva 40 mg/day at 24 weeks; percent decrease from baseline was 54% vs. 22.6% vs. 4.8% vs. 21.4%, p < 0.0001. The absolute reduction in LDL-C values at 24 weeks was also significantly lower (50.5 vs. 29.7 vs. 14.5 vs. 23.3 mg/dl). Percent achieving LDL-C levels <70 mg/dl were highest in the alirocumab arm (77.2% vs. 54.2% vs. 10.2% vs. 42.2%).

OPTIONS II:
Entry statin rosuva 10 mg: Alirocumab significantly reduced LDL-C at 24 weeks compared with ezetimibe and double-dose statin at 24 weeks; percent decrease from baseline was 50.6% vs. 14.4% vs. 16.3%, p < 0.0001. The absolute reduction in LDL-C values at 24 weeks were also significantly lower (49.6 vs. 17.4 vs. 17.1 mg/dl). Percent achieving LDL-C levels <70 mg/dl were highest in the alirocumab arm (77.8% vs. 43.1% vs. 31.3%).

Entry statin rosuva 20 mg: Alirocumab significantly reduced LDL-C at 24 weeks compared with ezetimibe, and double-dose statin at 24 weeks; % decrease from baseline was 36.3% vs. 11.0% vs. 15.9% vs. 21.4%, p < 0.0001. The absolute reduction in LDL-C values at 24 weeks was also significantly lower (32.3 vs. 22.1 vs. 19.3 mg/dl). Percent achieving LDL-C levels <70 mg/dl were highest in the alirocumab arm (60.1% vs. 43.6% vs. 29.9%).

Injection-site reactions were numerically higher in the alirocumab arm. On safety analysis, adjudicated CV events were similar (1% vs. 1% vs. 0% [OPTIONS I]; 0% vs. 1% vs. 1% [OPTIONS II]). Incidences of transaminitis and creatine kinase >3 x upper limit of normal were low.

Interpretation:

The results of this trial indicate that alirocumab is superior to ezetimibe and double-dose statin therapy in lowering LDL-C levels and achieving target levels in high CV risk patients already on high-potency statins. This trial adds to the growing body of literature with PCSK9 inhibitors, and is probably one of the boldest in terms of study design, in that it directly compares the efficacy of alirocumab to ezetimibe and higher-dose statin (the latter being the most common clinical strategy currently). Other large outcomes-based trials are ongoing.

Another interesting observation from this trial is that, although not as good as alirocumab, ezetimibe when added to high-potency statins, lowered LDL-C levels better than double-dose statin therapy. In conjunction with the results of the recent IMPROVE-IT trial, it may signal a possibly greater role for ezetimibe in clinical practice, pending approval of the PCSK9 inhibitors. The “lower is better” hypothesis with LDL-C will be also reaffirmed if the outcomes-based trials with PCSK9 inhibitors are positive. Indeed, against the backdrop of the recently presented IMPROVE-IT trial, it may require revisiting the recent move by the lipid guidelines committee to do away with LDL-C directed lipid-lowering therapy.

References:

Presented by Dr. Harold Bays at the American Heart Association Scientific Sessions, Chicago, IL, November 19, 2014.

Keywords: Pyrroles, Creatine Kinase, Cholesterol, LDL, Azetidines, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Coronary Disease, Heptanoic Acids, AHA Annual Scientific Sessions


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