Genomic Response Analysis of Heart Failure Therapy in African Americans

NCT ID: NCT02305095

Last Updated: 2023-04-20

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 225 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2015-05-01
• Study Completion Date: 2022-09-30

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.

Conditions

Heart Failure

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

GNB3 TT

All subjects with the GNB3 TT genotype for the polymorphism at position 825 (T/C). They will be initiated on therapy with FDC I/H, followed for 2 years and response to therapy quantified by a composite score (CS).

FDC I/H

Intervention Type: DRUG

All subjects in both groups will be initiated on drug, FDC I/H with dose titrated up to target doses based on clinical guidelines

GNB3 C

All subjects with at least one copy of the GNB3 C allele which includes both subjects homozygous for the 825C allele (GNB3 CC genotype) and subjects who are heterozygous (GNB3 TC genotype).They will be initiated on therapy with FDC I/H, followed for 2 years and response to therapy quantified by a composite score (CS).

FDC I/H

Intervention Type: DRUG

All subjects in both groups will be initiated on drug, FDC I/H with dose titrated up to target doses based on clinical guidelines

Interventions

FDC I/H

All subjects in both groups will be initiated on drug, FDC I/H with dose titrated up to target doses based on clinical guidelines

Intervention Type: DRUG

Other Intervention Names

BiDil

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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University of Pittsburgh

OTHER

Sponsor Role: lead

Responsible Party

Dennis M. McNamara, MD, MS

Professor of Medicine and Director, Center for Heart Failure Research

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Dennis McNamara, MD

Role: PRINCIPAL_INVESTIGATOR

University of Pittsburgh Medical Center

Locations

University of Alabama Medical Center

Tuscaloosa, Alabama, United States

Morehouse School of Medicine

Atlanta, Georgia, United States

Emory University

Atlanta, Georgia, United States

Northwestern University

Chicago, Illinois, United States

University of Illinois of Chicago

Chicago, Illinois, United States

Tulane University Heart and Vascular Institute

New Orleans, Louisiana, United States

Ochsner

New Orleans, Louisiana, United States

University of Maryland Medical Center

Baltimore, Maryland, United States

Massachsetts General Hospital

Boston, Massachusetts, United States

Henry Ford Health System

Detroit, Michigan, United States

Rutgers University Health Center

Newark, New Jersey, United States

Montefiore Medical Center Bronx New York

The Bronx, New York, United States

MetroHealth System

Cleveland, Ohio, United States

Temple University Medical Center

Philadelphia, Pennsylvania, United States

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, United States

University of South Carolina

Charleston, South Carolina, United States

Stern Cardiovascular Foundation

Germantown, Tennessee, United States

Baylor College of Medicine

Houston, Texas, United States

University of Virginia

Charlottesville, Virginia, United States

Countries

United States

Other Identifiers

MD009118-01

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

3648634

Identifier Type: -

Identifier Source: org_study_id