GLAGOV
Doubling Down on Cholesterol Lowering
Now that there are two powerful means of targeting
cholesterol, maybe doubling down makes sense (even
if economically rough). Adding the PCSK9 inhibitor
evolocumab to statin therapy produced more regression of plaque atheroma volume and induced unprecedented plaque regression in a greater percentage of
patients than statin therapy alone.
“We did not regress everybody with a statin
plus evolocumab but we were able to regress about
two-thirds of the patients and we’ve never seen levels
of regression of this magnitude in any previously
conducted study,” said Steven Nissen, MD, from the
Cleveland Clinic, Ohio.
GLAGOV enrolled 968 patients presenting for
coronary angiography, 846 of whom had evaluable
intravascular ultrasound (IVUS) imaging at follow-up.
Those with angiographic disease (20% to 50% stenosis
in a target coronary vessel) were randomly assigned
to monthly evolocumab 420 mg subcutaneously or
matching placebo injection for 18 months, in addition to a stable, optimized statin dose. The trial was
conducted at 197 hospitals on 7 continents.
Mean baseline low-density lipoprotein-cholesterol
(LDL-C) was 92.5 mg/dl. After 18 months of treatment, mean achieved LDL-C in the statin plus evolocumab arm was 36.6 mg/dl (-59.8% from baseline)
compared to 93.0 mg/dl for statin monotherapy (-3.9%
from baseline; p < 0.001).
Almost all patients (99%) were on statins at baseline and about 58% were taking high doses. Nevertheless, compared to placebo, the addition of evolocumab
was associated with plaque regression in a greater percentage of patients for both percent atheroma volume
and tota l atheroma volume (TABLE).
GLAGOV Trial Results
Statin
Monotherapy
Statin +
Evolocumab p Value
Change in percent
atheroma volume
(PAV) (1°)
0.5%
-0.95%
<0.0001
Change in total atheroma volume (2°)
-0.9
-5.8
<0.0001
Percent of patients
showing regression in PAV
47.3%
64.3%
<0.001
Percent of patients
showing progression in PAV
52.7%
35.7%
<0.001
ACC.org/CSWN
Nicholls SJ et al. Effect of evolocumab on progression of coronary disease in statin-treated patients. The GLAGOV randomized
clinical trial. JAMA 2016 Nov 15. [Epub ahead of print]
ORION-1
Hunting for Another Knockout Drug for LDL
The PCSK9 inhibitors are barely out the door, and
there’s already something new that’s come knocking.
Inclisiran (ALN-PCSsc) is a long-acting, subcutaneously delivered, synthetic small interfering ribonucleic acid
(RNA) molecule that inhibits the production of PCSK9,
halting PCSK9 protein synthesis in the liver.
“Targeting intracellular PCSK9 production with
inclisiran offers us the potential for bi or tri-annual
dosing to significantly reduce LDL cholesterol levels,”
Kausik Ray, MD, from the Imperial College London,
London, told attending journalists. That’s right: the
potential is for maybe twice yearly dosing.
The phase II ORION-1 trial tested inclisiran in 501
patients with atherosclerotic cardiovascular disease
(ASCVD) or high ASCVD risk and elevated LDL-C –
>70mg/dl with ASCVD or >100mg/dl if at high risk
– despite maximally-tolerated statin therapy. About
two-thirds of patients had familial hypercholesterolemia and 81% were taking statins at baseline.
Participants were randomly assigned to 1 of 6
doses of inclirisan or matching placebo.
At a 90-day interim analysis, no between-group differences were seen in treatment-related adverse events.
Injection site reactions were seen in 3.2% of inclisirantreated patients.
All doses of inclirisan reduced LDL-C compared
to placebo, with a maximal reduction seen at 15 days
and sustained to about 90 days.
“A single dose of inclisiran reduced LDL cholesterol
by up to 50% at 60 days and maintained levels through
to 90 days while a second dose reduced LDL by about
57% at day 180,” said Dr. Ray.
During a press conference, Borge G. Nordestgaard,
MD, (University of Copenhagen, Norway) commented
on the trial: “Inhibition of PCSK9 synthesis via RNA
interference with 50% to 60% reductions in LDL cholesterol over 3 to 6 months with only 2 to 3 injections a
year looks really, really encouraging.”
PIONEER-AF PCI
NOACs Plus DAPT for Triple Therapy
Among patients with atrial fibrillation (AF) undergoing primary percutaneous coronary intervention (PCI),
rivaroxaban combined with either a thienopyridine
or dual antiplatelet therapy (DAPT) does not increase
bleeding as compared with triple therapy including the
vitamin K antagonist (VKA) warfarin, according to the
long-awaited findings of the PIONEER-AF PCI study.
“You only have to treat 11 to 12 people to prevent
a clinically significant bleed by using one of these alternate regimens with rivaroxaban and you only need
to treat 10 to 15 people to prevent 1 hospitalization,”
reported C. Michael Gibson, MD, Beth Israel Deaconess Medical Center, Boston, MA.
Between 5% and 8% of patients who undergo PCI
have AF. For them, the optimal combination and duration of anticoagulation therapy remain uncertain.
In the open-label PIONEER AF-PCI trial, 2,124 patients with AF who had undergone PCI with stenting
were randomized to 1 of 3 arms:
• Group 1: Rivaroxaban 15 mg once daily plus a
P2Y12 inhibitor for 12 months
• Group 2: Rivaroxaban 2.5 mg twice daily plus a
P2Y12 inhibitor and aspirin for 1, 6, or 12 months;
patients continued on rivaroxaban 15 mg once
daily plus aspirin after DAPT discontinuation
• Group 3: Dose-adjusted warfarin plus DAPT with a
P2Y12 inhibitor and aspirin for 1, 6, or 12 months;
patients continued on warfarin and aspirin after
DAPT discontinuation
The P2Y12 inhibitor prescribed to subjects in all 3
groups was primarily clopidogrel, but was ticagrelor
or prasugrel in ≤15% of patients.
Marijuana use may be linked to temporarily weakened heart muscle
Active marijuana use seems to double the risk of stress cardiomyopathy
that can mimic MI symptoms.
In an analysis of 33,343 patients hospitalized with stress cardiomyopathy in the U.S., 210 were also identified as marijuana users. Despite being
younger and with fewer classic risk factors than non-users, during stress
cardiomyopathy the marijuana users were significantly more likely to go
into cardiac arrest (2.4% vs. 0.8%) and to require an implantable defibrillator (2.4% vs. 0.6%).
Sahil Agrawal, MD, co-author of the paper and chief cardiology fellow
at St. Luke’s University Health Network in Bethlehem, PA: “This development of stress cardiomyopathy in younger patients who used marijuana
suggests a possible link that needs to be further investigated.”
CardioSource WorldNews
COVER UPDATE
For the primary efficacy measure – the nominal
change in PAV through week 78 measured by serial
IVUS imaging – there was a significant difference
(TABLE) and – according to previous evidence – likely
a meaningful difference. At an AHA press conference,
the study’s co-author, Steven J. Nichols, MD, PhD,
from the South Australian Health & Medical Research
Institute, explained that his research has shown that a
0.5% reduction in PAV is associated with a meaningful
reduction in cardiovascular events. So, the 1% reduction in PAV seen in GLAGOV would be expected to
translate into clinical benefit, although he stressed that
the critical determination of risk and benefit will come
from the large outcomes trials underway.
In a post hoc analysis in 144 patients with baseline
LDL-C <70 mg/dl, evolocumab add-on treatment was
associated with a favorable effect on change in PAV
and regression of PAV (p < 0.001 for both), a benefit
seen at LDL-C levels as low as 20 mg/dl.
In the paper, published simultaneously, the authors
noted: “This is the first clinical trial, to our knowledge,
to show incremental effects on regression in patients
who had been treated with mode rate or intensive
statin therapy prior to entry into the study. It is also
the first to our knowledge to demonstrate a reduction
in atherosclerotic disease progression by IVUS for a
nonstatin LDL-C-lowering therapy.”
17