Genomic Response Analysis of Heart Failure Therapy in African Americans

Condition(s) targeted: Heart Failure

Intervention: FDC I/H (Drug)

Phase: N/A

Status: Not yet recruiting

Sponsored by: University of Pittsburgh

Official(s) and/or principal investigator(s):
Dennis McNamara, MD, Principal Investigator, Affiliation: University of Pittsburgh

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.

Official title: Genomic Analysis of the Enhanced Response to Heart Failure Therapy in African Americans

Study design: Observational Model: Cohort, Time Perspective: Prospective

Primary outcome: Composite score (CS) no units. (survival, heart failure hospitalization, and change in the raw quality of life score on the Minnesota Living with Heart Failure Questionnaire)

Secondary outcome:

Survival

Survival free from heart failure hospitalization

Change in Quality of Life Assessment by Minnesota Living with Heart Failure Questionnaire

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 18 years and older

- 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).

- New York Heart Association (NYHA) Class II-IV

- 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) Exclusion Criteria:

- No history of intolerance to either nitrates or hydralazine

- No treatment with the combination of hydralazine and nitrates for the previous 3

months

- No revascularization or myocardial infarction within last 90 days

- Can not be enrolled for at least 90 days after receiving cardiac resynchronization

therapy (CRT) AND must have an LVEF (less than OR equal to) < 0. 35 at least 3 months after CRT.

- Presence of clinically significant valvular heart disease, hypertrophic or

restrictive cardiomyopathy, active myocarditis, or uncontrolled hypertension.

- Women who are currently pregnant, planning on becoming pregnant in the next two

years, or those who do not agree to prevent pregnancy.

University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213, United States; Not yet recruiting
Jessica Pisarcik, RN, BSN, Phone: 412-647-4463, Email: pisarcikje2@upmc.edu
Dennis McNamara, MD, Principal Investigator

Starting date: January 2015
Last updated: December 1, 2014