Hello. I'm Dr. Deepak Bhatt, executive director of interventional cardiovascular programs
at Brigham and Women's Hospital in Boston, Massachusetts, where I'm also a
professor of medicine at Harvard Medical School, and I'm really excited to be
talking here today with a lot of viewers of the New England Journal of Medicine
about the REDUCE-IT trial, which I literally just presented five minutes
ago as a late-breaking clinical trial at the
American Heart Association annual sessions and, I've got to be honest, I'm
extremely excited about this trial and discussing it with all of you.
I've been involved in a lot of different clinical trials through the years and
honestly, I love them all — the ones that are positive, the ones that are negative,
the ones that are somewhere in between, as long as they advance patient care and
contribute in some way to science. With this particular trial, of all the
trials that I've been involved to to date, I think has the greatest potential to be
practice changing and paradigm shifting. And I'm careful in using such
terminology that I typically avoid, because here I believe we might be at
the dawn of a new scientific era with respect to cardiovascular prevention,
akin to what happened decades ago with statins as they were first entering clinical
trials. Why do I say that? Well, let me recap to
you exactly what REDUCE-IT is, and for those of you who want greater detail
that I provide, I should mention just today in the New England Journal of
Medicine, REDUCE-IT was published simultaneously
my presentation that was given here at the AHA, so the paper, and importantly, the
supplement as well, don't forget the supplement, has lots of information — the
protocol, and statistical analysis plan, are posted there as well, so everything
is out there in the open for everyone to take a look.
REDUCE-IT randomized 8,000 patients who had triglycerides between 135 and 500
milligrams per deciliter and had additional cardiovascular risk to
receive either 4 grams a day of icosapent ethyl or placebo. Icosapent
ethyl is a highly-purified EPA, or eicosapentaenoic acid, so 4 grams a day
of that drug versus a placebo in patients with elevated triglycerides and
additionally have cardiovascular risk, defined as follows: about 70 percent of
the patients had secondary prevention-type indications — stable coronary artery
disease, stable cerebrovascular disease, stable peripheral artery disease,
and the remaining 30% or so had what we called primary prevention type
indications, but specifically, it was diabetic patients with at least one
additional cardiovascular risk factor, so a hybrid population of secondary and
higher risk primary prevention. In this population, then we randomized patients
as I mentioned to the study drug or placebo, follow them for a median of
about five years, and examined cardiovascular events, and by
cardiovascular events, I mean a 5-point MACE — cardiovascular death, MI,
stroke, hospitalization for unstable angina, and
coronary revascularisation — and in that endpoint there was a 25% relative risk
reduction, a 4.8% absolute risk reduction, a number needed
to treat of only 21, and that was a highly significant finding. I also see in
the New England Journal of Medicine paper less than 0.001, though, in fact, the
actual p-value, the New England Journal of Medicine truncates the p-values, the actual
p-value was 0.00000001. I might have
forgotten a zero, there might have been an additional zero. There so there's a very
statistically significant finding, but in convention, in keeping with their
convention, it's .001 in New England Journal, so a very robust
finding. Now some doctors might say, well, you know, hospitalization for unstable
angina revascularization procedure, show me
the really hard endpoints, quote unquote. That was our pre-specified key secondary endpoint,
cardiovascular death, MI, stroke, and that was reduced by 26%, again
over 3% absolute risk reduction, number needed to treat 28, so
clinically robust and a p-value there, again the paper <.001,
but in actual fact, <0.000006, so once
more very statistically robust findings. Therefore if we look at subgroups and
there were multiple pre-specified subgroups that I presented and are the
paper in those subgroups a consistency of benefit pretty much across the board
for both the primary and the key secondary endpoint, including key
subgroups such as the secondary and primary prevention cohorts where there
was a consistency of benefit males and females, U.S. and non U.S., diabetes no diabetes,
triglycerides greater than or less than 200, and also triglycerides greater than
or less than 150, as it turned out about 10% of the population enrolled had
triglycerides between 135 and 150. So therefore, very robust
findings consistency of benefit across multiple subgroups. Now we did a
so-called pre-specified hierarchical statistical analysis, that
is, what that means you can look at one endpoint if it's positive, you keep
going down the list until something's not positive, and if something's not
positive, in general, you shouldn't keep going down further. You can, but then it's
more exploratory as opposed to definitive. What we found here was all of
the secondary endpoints we examine in that statistical hierarchy, things like
fatal or non-fatal heart attack, stroke or fatal or non-fatal stroke, that was reduced
by 28%, hospitalization for unstable angina, and emergent or urgent procedures, all these
different things were significantly reduced, including a 20% relative risk
reduction in death from cardiovascular causes that was statistically
significant and included in that are significant reductions in sudden cardiac
death and also cardiac arrest. Now the final thing on that hierarchy was all
cause mortality that was not significantly reduced but there was a
trend a 13% lower rate of all-cause mortality with a p-value of 0.09 and
there was no difference in non- cardiovascular mortality so that
difference in all cause mortality was driven by the significant reduction in
cardiovascular mortality. So that, really in a nutshell,
is the data that I presented. Now as far as safety, obviously we also examined that, and
in general the drug was as well tolerated as placebo was. The adverse
event rates of note were atrial fibrillation, where adjudicated atrial
fibrillation was significantly higher by about 1% absolute, but importantly stroke,
the most feared complication of atrial fibrillation, was not higher with icosapent
ethyl versus placebo, in fact, there's a 28% reduction in that endpoint with
the study drug versus placebo, so while physicians should be aware of atrial
fibrillation is a possibility, on the other hand, it doesn't seem to be
associated with the most feared complication from atrial fibrillation
which is stroke, at least on the trial-wide level. The other adverse event of note
was serious adverse events lumped together for major bleeding, where there
was a significant ... well, I shouldn't say significant, it was actually a trend, it wasn't significant
p-value of 0.06 when we lumped it all together, and looking at it as GI
bleeding, as serious CNS bleeding, looking at fatal bleeding no significant
differences between the two arms. So again, something doctors should be aware of if
they're using this drug in patients but in absolute terms relatively
modest increases, in strictly speaking, not even statistically significant. So
overall a great tolerability, good safety, and outstanding efficacy such that the
overall benefits, I think. of the drug in this population are quite substantial.
Now there's lots of ongoing analyses as you might imagine we have
planned a cost-effectiveness analysis for the leading academic but as you
might imagine with a number needed to treat of 21, this is probably going to be highly cost
effective. We've also got biomarker and genetic analyses, detailed analyses planned
trying to get at what is the mechanism of benefit here. We saw reductions in
triglycerides about 20%, we saw a reduction in hsCRP about 22%, but the
biggest change was in EPA levels — a 360% increase in EPA levels with
study group, so we're going to try to tease apart, for the sake of science and future
studies, what exactly drove the benefit on multiple endpoints in this trial. I
mentioned a bunch of endpoints but elective revascularisation was
significantly reduced, a tertiary point albeit pre-specified,
stroke, sudden cardiac death, it seems like a lot of different endpoints that
if it were just an anti-inflammatory, or just a triglyceride-lowering
drug, or just a drug with some antithrombotic capabilities,
wouldn't really expect necessarily such a large degree of benefit across multiple
endpoints, so, you know, I think the findings will be practice-changing. You
know, some questions that have been asked to me in the minutes after the
presentation, what about statins? Well our goal was to treat patients with statins
and indeed the LDL coming into the trial on average was 75 so this was
a well-treated patient population with statins. The average LDL is better than
many patients in actual practice so this is truly an incremental advance over
statins. Some have asked about the difference in LDL five milligrams per
deciliter difference between the study drug and placebo at one year
and have asked, you know, oh, the placebo is a mineral oil, you know might that be
causing some harm? I've got to say I think that line of inquiry is flawed but
but even if somebody is really concerned about that I would say that five
milligrams per deciliter in LDL over five years wouldn't cause a 25% relative risk reduction.
It would be projected to cause maybe a 2, 3% the most optimistic
extrapolation from the cholesterol clinical trial collaboration
would be maybe 4% so again, it wouldn't explain it, and people forget there was
an older trial, JELIS, a Japanese trial, very well done
it showed a 19% relative risk reduction in ischemic events with a
lower dose of EPA, not exactly this drug, but nonetheless somewhat opening the
door to the concept of EPA as a cardiovascular-protective agent, and that
trial was randomized but it was open label, meaning that there was no actual
placebo, patients either got that study drug or they got nothing on a background
of low-dose statin, so that's there for people that don't like the mineral oil placebo,
well that was an open-label trial with no mineral oil placebo and still a
significant 19% relative risk reduction. I'll point out there as well
at the time, many people (I was one of those people) criticized JELIS saying, oh, it's
open-label it should have been double-blind so you know we did a trial
in a rigorous way and if you think about it, what would we use as a placebo? We
could've used a sugar pill, but then obviously the patient would know they're getting a sugar
pill and they'd be unblinded, so that wouldn't have worked. We could have used olive oil but then if the trial was
negative, people would have said, oh, what are you guys, stupid? Why did you use olive oil?
So, you know, we settled on mineral oil because it had to be something with similar
consistency in appearance as icosapent ethyl, so that was the reason for it.
And for folks that aren't satisfied with those degree of answers, and really
think that there's something there which there isn't, we actually did an
analysis it's published in the results section of the New England Journal of
Medicine paper, it's just a line in there but what it alludes to is an analysis of
placebo versus patients ... study drug, rather, versus placebo in patients who either
had an LDL increase in a year or had no LDL increase in a the year and the degree
of benefit was really quite similar in those two arms. So it it really was the
case that mineral oil is this a highly toxic substance, it's raising LDL cholesterol,
it's hurting patients, well, then we wouldn't have expected to see a benefit in
those patients who didn't have an LDL increase. So I think the trial results are robust
and some have then raised the CRP, and oh, the CRP is going up in the
placebo, well that's the reason that there's benefit with the study drug, that
it's placebo harming patients. So first of all, we were very transparent with
the biomarkers that we've analyzed and we're able to present at this time and
many more biomarker analyses are planned, and we had prespecified just
looking at CRP, and that was presented, and we also prespecified looking at
log-transformed CRP and that's also presented in the supplementary table 4.
And what we showed is, first of all, the correct way to look at CRP is really log-
transformed CRP, because that takes out the outliers, and, done that way, there is no
significant increase in CRP in the placebo arm; rather, there's a significant
decrease in CRP with icosapent ethyl, as has been reported previously, such
that comparing the two arms there's a 22% difference in CRP at two years. So I
think the study drug is working, it's working robustly, there's not something
funny that's going on with the placebo comparator for the reasons that I
mentioned and honestly I don't really think this is such an important point I
raise it because it's one of the questions that has sort of been
permeating the Twittersphere, and therefore I thought, let me use this
opportunity to address those sorts of questions head-on. You know, it's
interesting, at the end of the late-breaking clinical trial session the
audience was surveyed to see what they would do in clinical practice based on
REDUCE-IT and I don't remember the exact number, I think was something like 90+ percent, said
that they would use icosapent ethyl in patients who are similar to the REDUCE-IT
population. So, obviously, there's still questions to be answered and we plan to continue
analyzing the REDUCE-IT database, the clinical cost-effectiveness, the biomarkers,
the genetics, and in terms of clinical endpoints we only presented time to
first event, so perhaps if we were to examine total events and recurrent
events there are other potential benefits that we haven't yet seen. So
there's a lot more work to be done but I think as far as the top-line results go
we've established the safety of icosapent ethyl given as a cardiovascular
reducing drug and established a very large degree of efficacy, and my hope is
that this trial really will open up a whole new era in cardiovascular
prevention maybe harkening back to those early days when
statins were first being appreciated not just as LDL-lowering drugs, but as drugs
to reduce cardiovascular events including death from cardiovascular
causes. Well, I hope this perspective has been useful to all of you and again if
something I said was unclear or I misstated something the good news is
that the paper and the supplement which is a pretty long supplement is all in the
New England Journal of Medicine at www.nejm.org. Thank you so much for your attention.