Hello, everyone. My name is John Jarcho. I'm a cardiologist and a deputy editor at
the New England Journal of Medicine. I'm very happy to be with you here today on
the floor of the American Heart Association's Scientific Sessions to talk
with you a little bit about some of the papers that we're publishing in
conjunction with the meeting. One clinical trial that has certainly
attracted a lot of attention here at the meeting is the REDUCE-IT trial. There
have been a number of trials in the past of various preparations of omega-3 fatty
acids for the reduction of cardiovascular events. Most of those
trials have not shown a significant benefit of such agents; however, there was
one recent trial, the JELIS trial, which showed significant cardiovascular event
reduction in particular with eicosapentaenoic acid which is one of the
omega-3 fatty acids, and that trial helped to provide part of the rationale
for the REDUCE-IT trial. In REDUCE-IT, a highly purified ethyl ester of
eicosapentaenoic acid, called icosapent ethyl, was compared to placebo in 8,000
patients who had either established cardiovascular disease or diabetes
mellitus plus at least one other cardiovascular risk factor. The dose of
icosapent ethyl that was used in the trial was four grams daily, which is a
considerably larger dose than in most omega-3 fatty acid trials in the past.
The primary endpoint of the trial was a composite of cardiovascular death,
myocardial infarction, stroke, coronary revascularization, and unstable angina.
At a median of five years of follow-up, there was a significant reduction in
this primary endpoint with icosapent ethyl.
It is not entirely clear how icosapent ethyl produced this effect
on cardiovascular outcomes. There was a significant reduction in serum
triglyceride levels with the study drug; however, the benefit on cardiovascular
outcomes did not correlate with either baseline triglyceride levels or the
reduction in triglyceride levels. A second trial for which we published the
paper yesterday is the DECLARE–TIMI 58 trial. This was a trial of the drug dapagliflozin
versus placebo in patients with diabetes. Dapagliflozin is a
selective inhibitor of the sodium-glucose cotransporter 2, or
SGLT2, and this was actually the third trial of an agent in the SGLT2 class for
cardiovascular outcomes following empagliflozin in the EMPA-REG OUTCOME trial,
and canagliflozin in the CANVAS trial. Drugs in the SGLT2 inhibitor class reduce
hyperglycemia in patients with type 2 diabetes mellitus by decreasing renal
glucose absorption. In EMPA-REG OUTCOME and CANVAS, there was a
significant benefit on cardiovascular outcomes with the SGLT2 inhibitor. In
the DECLARE trial, dapagliflozin was compared to placebo in 17,000 patients
who had diabetes mellitus and either known cardiovascular disease or multiple
cardiovascular risk factors. The primary outcome of the trial was a composite of
cardiovascular death, myocardial infarction, or stroke.
Dapagliflozin compared to placebo was non-inferior for this primary trial
outcome; however, it was not statistically superior. But there was a benefit with
regard to an important secondary outcome, the composite of cardiovascular death or
hospitalization for heart failure. This benefit was primarily due to a reduction
in hospitalization for heart failure. The results of the DECLARE trial may help
cardiologists to become more comfortable with prescribing SGLT2 inhibitors for
their patients with diabetes. Recent evidence suggests that despite the
available trial evidence, most cardiologists are not comfortable
prescribing these drugs, and the use of these drugs is relatively low in
cardiovascular practice. The final study that I'd like to talk to you about today
is called the PIONEER-HF trial. This is a very interesting trial of the drug
sacubitril–valsartan in patients with acute decompensated heart failure.
Sacubitril–valsartan is a combination drug with two potentially beneficial
effects. Valsartan is an angiotensin-receptor blocker, and sacubitril is a
neprilysin inhibitor which blocks the metabolic breakdown of natriuretic
peptides. In a previous large randomized trial
called PARADIGM-HF, sacubitril–valsartan,
when compared to the ACE inhibitor enalapril, was found to significantly
reduce the outcome of cardiovascular death or hospitalization for heart
failure in patients with heart failure. PARADIGM was a very important trial, but
it did have the limitation that patients were required to be very stable
clinically before they could be randomized. The trial required that all
patients tolerate a dose of enalapril of at least 10 milligrams daily,
or a comparable dose of another ACE inhibitor, or ARB. Then it required that
patients enter an open-label phase with enalapril when they had to tolerate
this drug and patients with adverse events were excluded. And finally,
patients had to enter an open-label phase with sacubitril–valsartan,
and again had to tolerate this drug before they could go on to randomization.
Therefore, the population in PARADIGM-HF, while in general representative of
patients with heart failure, was selective for those that were quite
stable and excluded many of the patients who were originally considered for
randomization. Therefore, the PIONEER-HF trial was designed to try to evaluate
whether sacubitril–valsartan could be initiated in a population of patients
who were much less stable than those seen in PARADIGM-HF, particularly
patients who were hospitalized with acute decompensated heart failure, a
group that had specifically been excluded from the PARADIGM trial. In
PIONEER-HF the comparator to sacubitril–valsartan, as in PARADIGM, was
enalapril. Eight hundred and eighty-one patients were enrolled and randomized.
The primary outcome was the
reduction in N-terminal-proBNP levels at 8 weeks.
And indeed, in this trial, there was a greater reduction in N-terminal-proBNP
levels at eight weeks with sacubitril–valsartan than with enalapril. However,
perhaps at least as interesting, if not more interesting, than these primary
outcome results, were the results with regard to safety in this trial. There was
no significant difference between the two groups with regard to rates of
symptomatic hypotension, hyperkalemia, worsening renal function, or angioedema.
These data thus suggest that, with appropriate precautions,
sacubitril–valsartan can be safely initiated in patients who have been
hospitalized for acute decompensated heart failure. There are a number of
other major trials that the New England Journal has published to coincide with
the AHA at this meeting. but I think I will stop there. It has been my pleasure
to discuss these interesting studies with you. If you'd like to read any of
the papers that NEJM has published together with the AHA, let me suggest
that you check out the AHA webpage at NEJM.org. Thank you very much.