Genomic Response Analysis of Heart Failure Therapy in African Americans

Heart Failure Clinical Trial

— GRAHF-2  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02305095
• Other study ID #: 3648634
• Secondary ID: MD009118-01
• Status: Completed
• Start date: May 1, 2015
• Est. completion date: September 30, 2022

Study information

• Verified date: April 2023
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 225
• Est. completion date: September 30, 2022
• Est. primary completion date: December 31, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Heart Failure

Intervention

Drug:
• 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

Locations

Country	Name	City	State
United States	Emory University	Atlanta	Georgia
United States	Morehouse School of Medicine	Atlanta	Georgia
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Massachsetts General Hospital	Boston	Massachusetts
United States	Montefiore Medical Center Bronx New York	Bronx	New York
United States	University of South Carolina	Charleston	South Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	University of Illinois of Chicago	Chicago	Illinois
United States	MetroHealth System	Cleveland	Ohio
United States	Henry Ford Health System	Detroit	Michigan
United States	Stern Cardiovascular Foundation	Germantown	Tennessee
United States	Baylor College of Medicine	Houston	Texas
United States	Ochsner	New Orleans	Louisiana
United States	Tulane University Heart and Vascular Institute	New Orleans	Louisiana
United States	Rutgers University Health Center	Newark	New Jersey
United States	Temple University Medical Center	Philadelphia	Pennsylvania
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	University of Alabama Medical Center	Tuscaloosa	Alabama

Sponsors (1)

Lead Sponsor	Collaborator
University of Pittsburgh

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	The CS combines three outcome variables into a single "score". Composite score adds points for survival over 2 years of follow up (death at any time yields -3 points, survival to end of study results in 0), heart failure hospitalization over 2 years of follow up (yes at any time results in -1 point, no results in 0), and the change in the raw quality of life score on the Minnesota Living with Heart Failure Questionnaire from entry to 6 months (change of ten units or greater=increase +2, decrease-2; change 5 to 9= increase+1, decrease -1; change < 5 units for the raw score yields 0 points). The CS will range from -6 to +2 for each patient.	2 years
Secondary	Survival	Comparison of survival on therapy by GNB3 genotype	2 years
Secondary	Survival free from heart failure hospitalization	Comparison of event free survival by GNB3 genotype.	2 years
Secondary	Change in Quality of Life Assessment by Minnesota Living with Heart Failure Questionnaire	Evaluate the change in the raw score of the Quality of Life questionnaire by GNB3 genotype.	6 months