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The African American Heart Failure Trial (A-HeFT ) is one of the most significant studies of how genes influence a person’s response to particular drugs. Further advancements in pharmacogenetics will help scientists and physicians to individualize drug treatments.
A study published in the November 11,
2004, New England Journal of Medicine simultaneously
generated excitement about a new treatment for heart
failure and touched off a groundswell of controversy
over what some called “race-based” medicine.
And yet, many believe the clinical trial was more about
gene patterns than race, and may be the beginning of
an exciting new age in medicine.
Heart failure is a progressive
condition in which a weakened heart does not pump blood
effectively, reducing blood flow to the body’s
organs. People with heart failure often have such symptoms
as shortness of breath, fatigue when exercising or sometimes
at rest, and a build-up of fluid in the legs and feet.
An estimated 5 million Americans have heart failure,
with 400,000 new cases diagnosed each year. Heart failure
is more than an inconvenience. Depending on the underlying
severity of disease, mortality can range from 50% at
one year to 50% at 5 years. “To slow heart failure
down, prevent it, perhaps to reverse it – what
a tremendous challenge,” says Dr.
Marc Klapholz, director of cardiology at University
Hospital. “Of course, our ultimate goal is to
stop this major killer.”
The medical strategy
for curbing the progression of heart failure includes
lifestyle changes, such as a lower-sodium diet and exercise,
and drugs, such as ACE-inhibitors and beta blockers.
Respectively, these cornerstone treatments can relax
and expand the blood vessels and improve how the heart
pumps. However, cardiologists have found that some these
medicines may not be as effective in African American
as they are for others. And yet, the need for an effective
treatment is significant. African Americans are 2 ½
times as likely as white Americans to develop heart
failure and are more likely to die from the disease.
The
A-HeFT Study
In May 2001, the African
American Heart Failure Trial (A-HeFT) became the first
(and largest) U.S. study on heart failure to enroll
only blacks. A total of 1,050 black men and women with
moderate to severe heart failure participated at 170
clinical sites nationwide. At the time, Dr. Klapholz
was working at one of the sites, St. Vincent Catholic
Medical Center in New York City, and he was one of the
study’s investigators.
Half of the patients
in the study received their standard treatment for heart
failure and a placebo, while the other half were given
their standard treatment plus BiDil®, a combination
of two chemicals, isosorbide dinitrate and hydralazine.
A-HeFT was a double blind study, meaning that neither
the patients nor the investigators knew who was getting
BiDil or placebo. The patients were evaluated every
three months on both clinical and quality of life factors.
Preliminary data surprised even the investigators: Patients
taking BiDil had a 43 percent better chance of survival
than those given placebo. “The study was not designed
to measure mortality alone, but the numbers were very,
very significant,” says Dr. Klapholz. The study
was stopped early (in July 2004) because of the survival
benefit, and the drug was made available to all patients
in the trial.
Technically speaking,
BiDil is not a new drug. Years ago, the Vasodilator
Heart Failure Trial (VHeFT ) study tested the combination
of hydralazine and nitrates in heart failure patients,
but the results were not compelling enough when compared
to other therapies to receive Food and Drug Administration
(FDA) approval. However, retrospective analysis of the
data revealed that the combination of hydralazine and
nitrates seemed to be more effective in blacks. The
combined use of hydralazine and nitrates appears to
enhance levels of nitric oxide, an important molecule
that studies indicate is more deficient in blacks. Nitric
oxide has many essential roles throughout the body;
within the cardiovascular system, it is believed to
help maintain sufficient blood flow to the heart; regulate
heart muscle contractions, and dilate blood vessels.
The advantage of using Bidil, which is owned by the
company Nitromed, is that it combines both hydralazine
and nitrates into a single pill.
Racial
Profiling or a Genetic Pattern?
The
A-HeFT generated tremendous professional and media interest,
but not only because of its very impressive clinical
findings. From some quarters, A-HeFT’s enrollment
of only blacks as study subjects raised troubling questions.
Others noted that, should the FDA approve BiDil as expected,
the drug would be marketed for blacks with heart failure—the
first race-specific drug.
Dr. Klapholz believes
the racial aspects of A-HeFT have overshadowed the more
significant genetic factors that come into play. “We
must acknowledge what the study shows— that this
therapy is beneficial in black patients. It must also
be recognized that this study did not evaluate this
therapy in non-black patients, and therefore, we don’t
know its effect in that population Research indicates
that specific gene patterns might identify a group of
patients who are more responsive to a particular therapy,”
he says. “Race, in and of itself, is at best a
crude placeholder for explaining genetic differences.”
“There can be a
greater prevalence of genetic patterns in one population,
but that doesn’t mean these gene patterns are
not present in other groups. They could be there but
at a lesser frequency.”
Take Tay-Sachs, a progressive
disease of the central nervous system, for example.
Tay-Sachs is more prevalent among Ashkenazi Jews, but
not everyone who has Tay-Sachs is Jewish. Similarly,
while a deficiency of nitric oxide may be common among
blacks, it is not necessarily exclusive to blacks. The
gene or genes responsible for nitric oxide deficiency
have not yet been identified, but blood was taken from
A-HeFT patients for further analysis. When the nitric
oxide deficiency gene is discovered, its prevalence
in blacks and other racial groups can be studied.
Meanwhile, BiDil is not
a “one race” drug. Doctors will be able
to prescribe it as indicated, for blacks with heart
failure, and as an “off-label” medicine
for anyone with heart failure who is not responding
optimally to standard medical treatments. The study’s
researchers believe BiDil’s potential extends
beyond the black population.
Getting
“Personal”
On a broad level, the
A-HeFT study has significance for everyone, whether
they have heart failure or not and regardless of their
race. Geneticists tell us that all humans have 99 percent
of genes in common, with the remaining 1 percent accounting
for variations. If there are even the most miniscule
genetic variations between populations, then it logically
follows that medicines can be developed that address
those differences.
Pharmacogenomics is the
study of how genetics influence a person’s response
to a drug. When the new specialty emerged in the 1950s,
the emphasis was on how certain ethnic groups metabolized
drugs; today, with advancements such as gene and protein
sequencing, increasingly, the focus will be on the individual.
Just as a person’s
genetic makeup determines his or her predisposition
to developing certain conditions, it also can impact
how an individual’s body responds to a specific
drug. Whether a drug is metabolized slowly or quickly,
or whether the medication has the desired effect or
does not work well, may reflect certain genetic variations.
A person’s genotype,
a specific genetic code, provides all types of information,
including whether there are gene variations that affect
the way the body reacts to certain drugs. Of particular
interest is the Cytochrome P450, a group of enzymes
that process chemicals in the body. The genetic variations
of P450 can affect how a drug is metabolized and how
long it remains in the body. This microscopic information
is important, because if the drug is metabolized too
quickly, the patient might not receive the medicine’s
full effect. Slowly metabolized drugs present a different
problem: otherwise perfectly acceptable doses of a medicine
could build up in a person’s body to toxic levels.
For many medications,
including antidepressants, blood thinners, and beta
blockers, researchers know how the P450 genetic variations
impact drug metabolism. By testing the blood for P450
variations, a doctor can make any necessary adjustments
in dosage or prescribe a different medication altogether.
For example, a person who has the slow-metabolizing
form of Cytochrome P450 2C9 enzyme, which metabolizes
coumadin, may need a lower dose than other people without
the genetic variation. Currently, most people are not
screened for these variations; testing may be recommended
if a person has a severe adverse reaction to a drug
or if they have a poor therapeutic response to a drug
known to be affected by P450 despite optimal dosing.
A
More Individualized Treatment Plan
Today’s
advances in pharmacogenomics are but the tip of the
iceberg. The more that is known about the interrelationship
between human genes and medication, the more reliance
physicians will have on an individual’s genetic
makeup when prescribing drugs.
“It’s definitely
the direction medicine is heading, although we’re
not there yet,” says Dr. Klapholz. “The
time will come when a person’s specific genetic
pattern will have significant influence on which medicine
is prescribed.”
To arrange
for a consultation with an adult onset genetics professional,
call the Adult Onset Genetic Testing program at (973)
972-7859. For an appointment with Dr. Klapholz or any
of University Hospital's cardiac experts, call (973)
972-2574.
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