Open-Label Study of Long-Term Evaluation Against LDL-C Trial - OSLER-1

Nov 05, 2019
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Presenter/Author:
Marc Steven Sabatine, MD, MPH, FACC
Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Amgen
Date Presented:
03/15/2015
Date Published:
10/21/2019
Date Updated:
11/05/2019
Original Posted Date:
03/15/2015
References

Contribution To Literature:

The OSLER-1 study suggests that evolocumab in addition to standard medical therapy results in greater LDL-C reduction and a reduction in 1-year composite cardiovascular outcomes compared with standard medical therapy alone.

Description:

The goal of the trial was to assess the longer-term safety and efficacy of evolocumab, a PCSK9 inhibitor, in addition to standard therapy, compared with standard therapy alone.

Study Design

Patients from five phase 2 trials and seven phase 3 trials were invited to participate in the OSLER extension program. These patients were randomized in a 2:1 fashion to either evolocumab (n = 2,976) or standard of care (n = 1,489). Evolocumab was administered as open-label, subcutaneous injections dosed either 140 mg q 2 weeks or 420 mg q month.

Patient population:

  • Total number of enrollees: 4,465
  • Duration of follow-up: 11.1 months
  • Mean patient age: 58 years
  • Percentage female: 49%
  • Percentage with diabetes: 13%
  • Metabolic syndrome: 34%
  • Known coronary artery disease: 20%; known cardiovascular disease/peripheral arterial disease: 9%
  • Any statin therapy: 70% (high intensity: 27%)

Principal Findings:

The primary composite outcome of death, myocardial infarction, unstable angina, coronary revascularization, stroke, transient ischemic attack, and chronic heart failure hospitalization at 1 year were 0.95% vs. 2.18% (p = 0.003).

Secondary outcomes:

  • Absolute reduction in low-density lipoprotein cholesterol (LDL-C) over 48 weeks in evolocumab vs. standard of care alone: 73 mg/dl (~61%), p < 0.001
  • LDL-C <70 mg/dl at 12 weeks: 73.6% vs. 3.8%, p < 0.0001
  • Change in high-density lipoprotein cholesterol (HDL-C) from baseline: 8.7% vs. 1.7%, p < 0.001
  • 1-year all-cause mortality: 0.14% vs. 0.41%, p = 0.33
  • Coronary events: 0.75% vs. 1.3%, p > 0.05
  • Cerebrovascular accident: 0.14% vs. 0.47%, p > 0.05
  • No adverse events directly related to degree of LDL-C lowering

Long-term results: Total exposure over the course of the trial was 4.951 patient-years (after year 1, control group patient could cross-over). A total of 1,151 patients were thus followed for 2 years or beyond. Evolocumab persistently lowered mean LDL-C by 56-57% between 2-5 years of follow-up. Mean baseline LDL-C decreased from 140 to 61 mg/dl on treatment.

New-onset diabetes mellitus was 2.7% for evolocumab vs. 4.3% for standard of care (SOC). Neurocognitive events were 0.4% for evolocumab vs. 0% for SOC. Two SOC and two evolocumab + SOC patients developed new, transient, binding antidrug antibodies; no neutralizing antibodies were observed.

Interpretation:

The results of this trial indicate that evolocumab significantly reduces LDL-C compared with standard of care, with a significant reduction in composite cardiovascular events at 1 year in a mixed group of patients with hyperlipidemia. Although this was not a dedicated cardiovascular outcomes trial with evolocumab, the clinical safety and efficacy noted in this extension study are encouraging. Other trials with this and other PCSK9 inhibitors are ongoing. Long-term efficacy for LDL-C lowering appears to be maintained out to 5 years. No major safety signals were observed over this time frame.

References:

Koren MJ, Sabatine MS, Giugliano RP, et al. Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia. J Am Coll Cardiol 2019;74:2132-46.

Editorial Comment: Evolocumab Treatment of Hypercholesterolemia in OSLER-1: Enduring Efficacy, Tolerability, and Safety Over 5 Years. J Am Coll Cardiol 2019;74:2147-9.

Sabatine MS, Giugliano RP, Wiviott SD, et al., on behalf of the Open-Label Study of Long-Term Evaluation Against LDL Cholesterol (OSLER) Investigators. Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. N Engl J Med 2015;372:1500-9.

Presented by Dr. Marc S. Sabatine at ACC.15, San Diego, CA, March 15, 2015.

Keywords: ACC Annual Scientific Session, Angina, Unstable, Antibodies, Monoclonal, Cholesterol, HDL, Cholesterol, LDL, Cholesterol, Hypercholesterolemia, Hospitalization, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Risk, Stroke, Subtilisins, Primary Prevention


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