YSM Issue 87.4

As children, we check for monsters under the bed, sharks in the
ocean, and snakes in the garden. Afraid of danger from the outside
world, we rarely consider the potential for destruction within our own
bodies. For 17.3 million people annually, this destruction occurs when
the very organ that pumps their blood fails. In fact, cardiovascular
disease is the world’s leading cause of death. Fortunately, modern
medicine is providing a new hope: a drug called LCZ696.
The drug began clinical trials five years ago, in December 2009.
The company Novartis created it to treat chronic heart failure.
Researchers were astounded by the success of
LCZ696: It performed better in early clinical
trials than any prior heart failure drug has
performed. LCZ696 is effective because
it uses an innovative biological
technique. Rather than relying on the
inhibition of a singular enzyme, it
combines two antihypertensives,
or chemical components that
reduce blood pressure.
Chronic heart failure
occurs when the heart
medicine
FEATURE
Hope for Damaged Hearts
revolutionizing heart failure medication
BY EMMA HEALY
cannot maintain
adequate blood flow,
which leads to fatigue,
shortness of breath,
and increased heart rate.
Long-term effects of the
condition are also serious,
sometimes even fatal. Ischemic
heart disease and cardiac arrest
are not uncommon. Given the
severity of the chronic heart failure
and its high prevalence around the
world, developing effective drugs is an
important medical goal.
The standard treatment for heart failure
right now is enalapril, an angiotensinconverting
enzyme (ACE) inhibitor. ACE is
an enzyme secreted by the lungs and kidneys
that causes the constriction of blood vessels,
thereby increasing blood pressure. By inhibiting ACE, enalapril
reduces constriction and decreases strain on failing hearts.
Up until the clinical trials of LCZ696, enalapril was the best
treatment option for heart failure, and its long-term use decreased
the relative risk of death for patients by about 16 percent. LCZ696
could potentially reduce relative risk of death by 20 percent. This
increase in survival rate is significant, especially considering the
number of people affected by heart failure.
LCZ696 differs from enalapril because it combines two
components: valsartan and sacubitril. Both of these substances
are antihypertensives, meaning that they lower blood pressure, but
each functions differently. Valsartan is similar to enalapril in that it
blocks the functioning of angiotensin. Where enalapril blocks ACE
from converting angiotensin into its active form, valsartan blocks
angiotensin from binding to its receptor. Both approaches reduce
blood pressure by acting on the same molecular pathway.
Sacubitril is entirely unlike valsartan and enalapril—it inhibits
another enzyme, neprilysin, which is normally responsible for
inactivating several peptide hormones in the body. Two of the
hormones that neprilysin inactivates are involved in the natural
reduction of blood volume. In response to
high blood pressure, heart muscle cells
secrete these peptides to reduce blood
volume, but neprilysin prevents this from
happening. By inhibiting neprilysin,
Sacubitril increases the blood level
of these hormones, thereby
decreasing blood pressure. On
their own, neither Valsartan
nor Sacubitril is sufficient
to treat heart failure. But
in combination, they
appear to be extremely
successful.
In trials, LCZ696
was more effective
than other medications,
better preventing
cardiovascular-related
deaths and hospitalizations.
This accomplishment is
monumental because heart failure
has a poor prognosis; even with
modern medications, approximately
50% of individuals with CHF will
die within 5 years of initial diagnosis.
Beyond living longer and undergoing fewer
hospitalizations, LCZ696 subjects were
better able to handle the medication’s side
effects. A common problem with enalapril is
that patients have to discontinue taking the
drug because of severe side effects.
Novartis may change these standards when it releases LCZ696
to the public. Based on the first clinical trial, the drug is extremely
promising and produces significantly better results than enalapril.
It might be too soon for heart failure patients to rejoice, however,
as LCZ696 is not projected to be released to the public until 2015.
Additionally, there are still hurdles to overcome. LCZ696 will
probably be expensive. Analysts have predicted that it might cost a
patient as much as $2,500 a year, as opposed to generic drugs that
could cost as little as $48 per year. Nevertheless, the development of
LCZ696 is a leap forward in the treatment of heart failure.
IMAGE COURTESY OF LIFESTYLES55 WEBSITE
LCZ696 treats heart failure by reducing
blood pressure. Heart failure is a serious
disease, killing millions of people annually.
www.yalescientific.org
October 2014
Yale Scientific Magazine
27