NEW HORIZON IN HEART FAILURE, INVESTIGATIONAL DRUG POISED TO CHANGE CARDIOLOGY
An investigational new
heart failure drug could be poised to change the face of cardiology based on
Hot Line results presented today at ESC Congress 2014
Findings from the
PARADIGM-HF trial, published simultaneously in the New England Journal
of Medicine, "are extraordinarily powerful and compelling; they are
destined to change the management of patients with chronic heart failure for
years to come," said Milton Packer, MD, co-primary author of the study
from University of Texas Southwestern Medical Center, in Dallas, Texas USA.
"This really is
an astonishing result and a real breakthrough for patients with heart
failure," added John McMurray, MD, the other co-primary author, from the
University of Glasgow, UK.
The new agent, an
angiotensin receptor-neprilysin inhibitor (ARNI) known as LCZ696, has already
been granted Fast Track status by the United States Food and Drug
Administration (FDA) -- a designation which can expedite the review of new
medicines intended to treat serious or life-threatening conditions. Fast Track
designation also allows for rolling submission in the US, which Novartis said
it expects to complete by the end of 2014. The company said it aims to file in
Europe in early 2015.
"To say that we
are excited is an understatement. We are absolutely thrilled," said Dr.
Packer.
"Given the
survival advantage of LCZ696 over currently available drugs, once this drug
becomes available, it would be difficult to understand why physicians would
continue to use traditional angiotensin converting-enzyme inhibitors (ACEI) or
angiotensin receptor blockers (ARB) for the treatment of heart failure."
PARADIGM-HF
(Prospective comparison of ARNI with ACEI to Determine Impact on Global
Mortality and morbidity in Heart Failure) first made headlines this spring when
the trial was stopped early by an independent data monitoring committee based
on evidence of the "overwhelming benefit" of LCZ696 compared to
enalapril, an ACE inhibitor.
"We were
surprised and delighted that the magnitude of the superiority was so great that
the trial was stopped early by the ethical committee. That was an amazing
event," said Dr. Packer.
Today, full details of
the findings are being released for the first time.
"The magnitude of
the advantage of LCZ696 over enalapril on cardiovascular mortality was at least
as large as that of enalapril over placebo during long-term treatment,"
Dr. Packer reported. "This robust finding provides strong support for
using this new approach instead of ACE inhibitors or ARBs in the treatment of
chronic heart failure."
PARADIGM-HF randomized
8,399 patients with class II to IV heart failure and an ejection fraction if
40% or less to either LCZ696 200 mg twice daily (n=4,187), or enalapril 10 mg
twice daily (n=4,212), in addition to recommended therapy.
When the trial was
stopped early, after a median follow-up of 27 months, death from cardiovascular
causes or hospitalisation for heart failure (the primary composite outcome) had
occurred in 21.8% of the LCZ696 group and 26.5% of the enalapril group (hazard
ratio [HR] 0.80; p=0.0000002).
Compared to enalapril,
LCZ696 reduced the risk of death from cardiovascular causes by 20% (13.3% vs
16.5%; HR 0.80; p<0.0001), and the risk of hospitalisation for heart failure
by 21% (12.8% vs 15.6%; HR 0.79; p<0.0001), noted Dr. Packer. This effect
was consistent across all prespecified subgroups.
Secondary outcomes
were also significantly improved by LCZ696, including all-cause mortality
(17.0% vs 19.8%; HR 0.84; p<0.001) and symptoms and physical limitations of
heart failure measured on the Kansas City Cardiomyopathy Questionnaire
(p=0.001).
"The superiority
of LCZ696 over enalapril was not accompanied by important safety
concerns," added Dr. Packer. The LCZ696 group had more symptomatic
hypotension compared to the enalapril group (14% vs 9.2%, p< 0.001) however
this rarely required the discontinuation of treatment. In fact, fewer patients
in the LCZ696 group stopped their study medication for any adverse event (10.7%
vs 12.3%, P=0.03).
Importantly, LCZ696
was not associated with an increased risk of serious angioedema, which was the
main safety concern observed with a related medication -- omapatrilat -- in the
OVERTURE trial.
Omapatrilat's
association with life-threatening angioedema is related to its inhibition of
ACE, neprilysin and aminopeptidase P, whereas LCZ696 avoids inhibition of ACE
and aminopeptidase P. "LCZ696 was specifically designed to minimise the
risk of serious angioedema by combining the neprilysin inhibitor sacubitril
(AHU377) and the ARB valsartan," explained Dr. Packer.
Findings of the PARADIGM-HF
trial are particularly striking when considered in the context of the current
standard of care in heart failure, concluded Professor McMurray.
"The superiority
of LCZ696 wasn't over placebo -- it was over the gold-standard dose of the
gold-standard ACE inhibitor, the absolute corner-stone of
guideline-recommended, conventional therapy," he said. "On top of
that, these incremental benefits were obtained in patients fully treated with
the other key pharmacological therapies for this condition such as
beta-blockers and mineralocorticoid receptor antagonists. All that you can ask
of any new therapy in heart failure (or other chronic diseases) is to make
patients live longer, stay out of hospital and feel better -- and those are
exactly the benefits we demonstrated with LCZ696."
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