ODYSSEY LONG TERM - ODYSSEY LONG TERM

Description:

The goal of the trial was to evaluate treatment with alirocumab, a monoclonal antibody targeting PCSK9, compared with placebo among participants with heterozygous familial hypercholesterolemia or high cardiovascular risk.

Contribution to the Literature: The ODYSSEY LONG TERM trial showed that alirocumab markedly reduced LDL-C among patients on maximum tolerated statin therapy.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Participants with heterozygous familial hypercholesterolemia or high cardiovascular risk
  • On maximum tolerated statin therapy
  • LDL-C >70 mg/dl
  • Number of enrollees: 2,341
  • Duration of follow-up: 52 weeks
  • Mean patient age: 64 years
  • Percentage female: 37%

Primary Endpoints:

From baseline to 24 weeks, the change in LDL-C

Drug/Procedures Used:

Participants with heterozygous familial hypercholesterolemia or high cardiovascular risk on maximum tolerated statin therapy were randomized to self-administered alirocumab 150 mg subcutaneous injection every 2 weeks (n = 1,553) versus placebo subcutaneous injection every 2 weeks (n = 788).

Concomitant Medications:

Statin: 99.9% (44.4% was high-intensity statin)

Principal Findings:

Overall, 2,341 patients were randomized. The median age was 64 years, 37% were women, mean body mass index was 30 kg/m2, and 35% had diabetes. The mean LDL-C was 123 mg/dl.

The primary outcome was the percentage change in LDL-C at 24 weeks. From baseline to 24 weeks, the change in LDL-C was -61% for alirocumab compared with 0.8% for placebo (p < 0.0001). At 52 weeks; LDL-C 53 mg/dl with alirocumab vs. 123 mg/dl with placebo. From baseline to 78 weeks, the change in LDL-C was -52% for alirocumab compared with 3.6% for placebo (p < 0.0001).

From baseline to 24 weeks, the change in non–high-density lipoprotein-cholesterol (non–HDL-C) was -52% for alirocumab compared with 0% for placebo (p < 0.0001).

Adverse events leading to drug discontinuation occurred in 7.2% of the alirocumab group vs. 5.8% of the placebo group (p = 0.26).

- Myalgias: 5.4% vs. 2.9% (p = 0.006), respectively, for alirocumab vs. placebo

- Neurocognitive events: 1.2% vs. 0.5% (p = 0.17), respectively, for alirocumab vs. placebo

- Ophthalmologic events: 2.9% vs. 1.9% (p = 0.65), respectively, for alirocumab vs. placebo

- Death from coronary heart disease, myocardial infarction, stroke, or unstable angina requiring hospitalization at 78 weeks (post-hoc analysis): 1.7% vs. 3.3% (p = 0.02), respectively, for alirocumab vs. placebo

In a pooled analysis of four alirocumab vs. placebo trials (n = 1,257), alirocumab resulted in a 60% reduction in LDL-C at 52 weeks and a 63% reduction in LDL-C at 78 weeks. Target LDL-C <70 mg/dl was achieved in 56% of subjects. Treatment emergent adverse events leading to death occurred in 0.8%, and to study drug discontinuation in 3.9%.

Interpretation:

Among patients with heterozygous familial hypercholesterolemia or high cardiovascular risk, alirocumab resulted in a large reduction in LDL-C compared with placebo, which was maintained, although slightly attenuated at 78 weeks. Alirocumab appeared to be generally well-tolerated and was associated with low cardiovascular events. Post-hoc analysis suggested a reduction in adverse cardiac events from alirocumab; however, future studies will need to examine the impact of this agent on clinical outcomes.

References:

Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015;Sep 1:[Epub ahead of print].

Editorial: Laufs U, Parhofer KG. Simplified algorithm to facilitate communication of familial hypercholesterolaemia. Eur Heart J 2015;Sep 1:[Epub ahead of print].

Presented by Dr. John Kastelein at the European Society of Cardiology Congress, London, September 1, 2015.

Robinson JG, Farnier M, Krempf M, et al., on behalf of the ODYSSEY LONG TERM  Investigators. Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med 2015;372:1489-99.

Presented by Dr. Jennifer Robinson at the European Society of Cardiology Congress, Barcelona, Spain, August 31, 2014.

Clinical Topics: Diabetes and Cardiometabolic Disease, Clinical Topic Collection: Dyslipidemia, Lipid Metabolism, Nonstatins, Novel Agents, Primary Hyperlipidemia, Statins

Keywords: Lipoproteins, LDL, Body Mass Index, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Injections, Subcutaneous, Hyperlipoproteinemia Type II, Risk Factors, Cholesterol, HDL, Lipoproteins, HDL, Diabetes Mellitus, ESC Congress, ACC Annual Scientific Session


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