R1. 이정미 / prof. 김우식

INTRODUCTION Reduction in low-density lipoprotein (LDL) cholesterol levels has proved to be highly effective in reducing rates of major cardiovascular events. Evolocumab –Fully human monoclonal antibodies that inhibit proprotein convertase subtilisin–kexin type 9 (PCSK9) –New class of drugs that very effectively lower LDL cholesterol levels –approximately a 60% reduction in LDL cholesterol levels when administered at the doses that were studied in phase 3 trials

INTRODUCTION OSLER-1 trial & OSLER-2 trial –Open-Label Study of Long-Term Evaluation against LDL Cholesterol –Primary GOAL Gathering of longer-term data on safety, side-effect profile, and LDL cholesterol reduction Included a prespecified exploratory analysis on adjudicated cardiovascular outcomes we report on the combined results of the OSLER-1 and OSLER-2 trials.

METHODs (1) STUDY DESIGN AND OVERSIGHT OSLER-1 trial : open-label, randomized, controlled study conducted at 190 centers that participated in at least one of five phase 2 studies OSLER-2 trial : open-label, randomized, controlled study conducted at 305 centers that participated in at least one of seven phase 3 studies

METHODs (1) PATIENTS –Variation in the clinical characteristics of the patients –Completed one of the parent studies –Not have an adverse event that led to the discontinuation of a study –Not have an unstable medical condition –Not expected to need unblinded lipid measurements or adjustment of background lipid-regulating therapy

METHODs (1) RANDOMIZATION, STUDY TREATMENT, AND FOLLOW-UP –patients were randomly assigned. –receive either evolocumab plus standard therapy (evolocumab group) or standard therapy alone (standard-therapy group) in a 2:1 ratio –Evolocumab : S.C OSLER-1 : dose of 420 mg once a month OSLER-2 : dose of either 140 mg every 2 weeks or 420 mg once a month Both regimens have been shown to reduce LDL cholesterol levels by approximately 60% in this patient population. –Visits on day 1 and then at weeks 12, 24, 36, and 48.

METHODs (1) END POINTS –Primary end point : Incidence of adverse events –Secondary end point : Percent change in the LDL cholesterol level

RESULTs PATIENTS –From October 2011 through June 2014 –Total of 4465 patients : randomly assigned 2976 patients : receive evolocumab plus standard therapy 1489 patients : receive standard therapy alone –Median duration of follow-up was 11.1 months

→ 3128 patiens

RESULTs LIPID CHANGES

RESULTs SAFETY AND SIDE-EFFECT PROFILE Neurocognitive adverse events did not appear to be related to the LDL cholesterol level during treatment

RESULTs CARDIOVASCULAR EVENTS –Include death, myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, stroke, transient ischemic attack, and hospitalization for heart failure

RESULTs CARDIOVASCULAR EVENTS –All cardiovascular events, patients in the evolocumab group had a significantly lower rate of all cardiovascular events than patients in the standard-therapy group.