Official Title
Genomic Analysis of the Enhanced Response to Heart Failure Therapy in African Americans
Brief Title
Genomic Response Analysis of Heart Failure Therapy in African Americans
Protocol ID
NCT02305095
Lead Sponsor
University of Pittsburgh
Brief Summary
The response to therapy with a fixed dose combination of isosorbide dinitrate and
hydralazine (FDC I/H) is enhanced in African Americans with heart failure and reduced
ejection fraction (HFrEF) when compared to similar white cohorts. This study will seek to
confirm the previous genetic sub-study from AHeFT which suggested a functional
polymorphism of guanine nucleotide binding protein beta polypeptide 3 subunit (GNB3),
C825T in exon 10, influences the therapeutic efficacy of FDC I/H. This study will
initiate treatment with FDC I/H in 500 self designated African American subjects with
systolic heart failure. They will be followed for up to two years on therapy. Clinical
outcomes (survival, heart failure hospitalizations, and change in quality of life) on FDC
I/H will be compared by GNB3 genotype subset. The hypothesis to be confirmed is that
subjects homozygous for the T allele (those with the GNB3 TT genotype which is present in
approximately 50% of black subjects) demonstrate enhanced therapeutic benefit from FDC
I/H.
Detailed Description
The response to therapy with a fixed dose combination of isosorbide dinitrate and
hydralazine (FDC I/H) is enhanced in African Americans with heart failure and reduced
ejection fraction (HFrEF) when compared to similar white cohorts. Despite the clear
survival benefits of treatment with FDC I/H in the African American Heart Failure Trial
(AHeFT), the drug is prescribed in only 25% of black subjects who would potentially
benefit.
In terms of the enhanced response evident in the A-HeFT investigation, race is likely a
marker of differences in genomic background. Genetic variation of the G protein beta sub
unit GNB3 has been studied extensively for its role in hypertension. A polymorphism
exists at position 825 (T/C) which is functionally silent but tightly linked to a
splicing variant resulting in a truncated protein. The GNB3 T haplotype is far more
prevalent in blacks and associated with low renin hypertension. Evaluation of 350
subjects in the genetic sub-study of AHeFT suggests that the GNB3 TT genotype, found in
50% of African Americans but only 10-15% of whites, was linked to an enhanced therapeutic
response to FDC I/H. This investigation will evaluate the hypothesis that the GNB3 TT
genotype is a marker of enhanced therapeutic response to FDC I/H in African Americans
with HFrEF.
The study will enroll a cohort of 500 African Americans with HFrEF, initiate therapy with
FDC I/H and follow them for up to two years. Subjects will be genotyped at entry for the
GNB3 polymorphism and response to therapy compared by genotype. Therapeutic response will
be quantified using the composite score, the primary endpoint of AHeFT, which
incorporates mortality, heart failure hospitalizations, and a change in quality of life
(QoL) score at six months.
Aim 2 will do a similar analysis of response to therapy by GNB3 genotype using
improvement in left ventricular end diastolic diameter (LVEDD) or left ventricular
ejection fraction (LVEF) by echocardiogram after six months on therapy as the outcomes
measure. Aim 3 will use admixture analysis to determine first how global ancestry (the %
African ancestral DNA for an individual) impacts on the outcome measures of drug
response, and how the global ancestry acts as a modifier for the effect of GNB3.
Study Period
-
Enrollment Count
225 participants
Eligibility Criteria
Inclusion Criteria:
1. 18 years and older
2. History of heart failure with an LVEF (less than OR equal to) < 0.35 for at least 6
months OR an LVEF < 0.45 with left ventricular internal end diastole (defined by a
diameter of more than 2.9 cm per square meter of body surface area OR more than 6.5
cm on the basis of echocardiography). ** Echo must be done within 6 months of
enrollment**
3. New York Heart Association (NYHA) Class II-IV
4. Background heart failure therapy that includes angiotensin converting enzyme
inhibitors (ACEi) or angiotensin receptor blockers (ARBs), and beta blockers (BBs)
for at least 3 months (or documentation of intolerance to ACEi/ARBs and BBs)
5. Self-designated race as African American or black (would include subjects whose
country of origin was outside the USA such as Africa, the Caribbean, or Central
America).
Exclusion Criteria:
1. History of intolerance to either nitrates or hydralazine
2. Treatment with the combination of hydralazine and nitrates for the previous 3 months
3. Revascularization or myocardial infarction within last 90 days
4. Received cardiac resynchronization therapy (CRT) AND did not have an assessment of
cardiac function documenting an LVEF < 35% (less than OR equal to 35%) at least 90
days post CRT
5. Presence of clinically significant valvular heart disease, hypertrophic or
restrictive cardiomyopathy, active myocarditis, or uncontrolled hypertension. (Note
that uncontrolled hypertension is defined as blood pressure consistently greater
than 160 mmHg systolic and 95 mmHg diastolic)
6. Women who are currently pregnant, planning on becoming pregnant in the next two
years, or those who do not agree to prevent pregnancy.
7. Subjects who are on continuous home inotropes, a left ventricular assist device, or
who are post cardiac transplant.
Filters
Heart Failure
COMPLETED
ADULT
OLDER_ADULT