ESC Congress 2017 In Review -- Main Edition - 12

Late-Breaking Clinical Trials

ORION-1 Shows Inclisiran Provides
Robust and Consistent LDL-C
Lowering
Written by Maria Vinall

Inclisiran is a chemically synthesised small interfering RNA designed to target PCSK9 messenger RNA.
Final primary outcome results from the ORION-1 trial
[NCT02597127], found that after 6 months, inclisiran
(either a 1 or 2-dose regimen) produced dose-dependent
reductions in PCSK9 and low-density lipoprotein cholesterol (LDL-C) levels among patients at high cardiovascular risk with elevated LDL-C levels [Ray KK et al. N Engl
J Med. 2017]. Kausik K. Ray, MB ChB, MPhil, Imperial
College London, London, United Kingdom, reported
extended results from ORION-1 and the impact of inclisiran on LDL-C at 1 year.
ORION-1 enrolled 501 patients aged ≥ 18 years with
atherosclerotic cardiovascular disease (ASCVD) or
high ASCVD risk and in whom LDL-C was > 70 mg/dL or
100 mg/dL, respectively, despite maximally tolerated
statin therapy. Participants were randomised to either a
1-dose starting regimen of 200, 300, or 500 mg of inclisiran or placebo administered subcutaneously (SC) or a
2-dose starting regimen of 100, 200, or 300 mg of inclisiran or matching placebo administered SC on days 1
and 90. LDL-C and other lipoproteins were measured
monthly through to 1 year or until LDL-C had returned to
within 20% of starting levels. A total of 497 patients
were treated and 483 completed the end of study visit
and entered extended follow-up to 360 days.
Participants were a mean age of 63 years, mostly
(65%) men. The use of statins was common (73% of
patients) with about 50% being on a high-dose regimen.
LDL-C at baseline was 128 mg/dL. The 1-dose starting regimen was associated with robust and sustained reductions
in LDL-C. The 300-mg dose was considered optimal with
reductions of 50.9%, 38.4%, and 19.0%, at 60, 180, and
360 days after the first injection on the 1-dose regimen.
The addition of a second 300 mg dose at days 90
was associated with LDL-C reductions of 55.5% at day
150, 52.6% at day 180, and 31.4% at day 360.
Both regimens produced sustained reductions over
time. Time-averaged reductions were -37% and -46%
for the 300 mg dose for the 1- and 2-dose regimens
respectively. Patients returned toward baseline in a stable manner with both regimens. With a single dose, the
time adjusted LDL-C reduction for 6 months was 41%
but with a second dose at day 90 this increased to 51%,

October 2017

in both cases with a tight interquartile range. There was
minimal within-patient variability in LDL-C reduction
over time. The adverse event profile was similar with
both regimens. There were no liver function elevations,
no differences in the incidence of myalgias or creatine
phosphokinase (CPK) enzyme elevations, and no study
drug-related deaths. Injection-site reactions occurred in
5% of the patients who received injections of inclisiran
and no patients on placebo.
Inclisiran provides robust sustained reductions in
LDL-C over 1 year with a low injection burden. The optimal starting dose is 300 mg SC at day 1 and day 90.
The suggested maintenance dose is 300 mg SC at day
270, then every 180 days. This regimen provides a 46%
time-averaged reduction over 12 months and a 51%
time-averaged reduction over 6-month dosing interval.

Results From the COMPASS Study
Written by Maria Vinall

Cardiovascular disease (CVD) affects 300 million persons worldwide, about 4% of the worlds' population.
Aspirin is the most widely used preventive treatment
but it reduces CV events by only 19% long-term. The
ATLAS TIMI-51 trial [Mega JL et al. N Engl J Med. 2012]
established the efficacy of low doses of rivaroxaban, a
selective direct factor Xa inhibitor, in patients with acute
coronary syndrome. John W. Eikelboom, MD, McMaster
University, Hamilton, Ontario, Canada, presented the
primary results of the COMPASS trial [Eikelboom JW
et al. N Engl J Med. 2017], which aimed to extend the
results from ATLAS TIMI-51 by evaluating whether rivaroxaban plus aspirin or rivaroxaban alone is superior
to aspirin alone for prevention of CV death, stroke, or
myocardial infarction (MI) in patients with stable coronary artery disease (CAD) or peripheral arterial disease
(PAD).
COMPASS recruited a selected high-risk population
with CAD or PAD. The definition of CAD was prior MI,
multivessel coronary disease, or prior coronary revascularisation. The definition of PAD was prior peripheral
revascularisation or amputation, claudication with a low
ankle brachial index or asymptomatic carotid disease.

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