Allopurinol Improves Heart Function in African Americans With Resistant Hypertension (RESIST)

Allopurinol Improves Diastolic Function in African Americans With Resistant Hypertension

African American adults in the United States have the highest prevalence rate of high blood pressure (hypertension) and heart failure in the world. African Americans with treatment resistant hypertension have higher levels of the enzyme - xanthine oxidase compared to Caucasians. This trial will test if administration of the xanthine oxidase inhibitor - Allopurinol (commonly used in the treatment of gout), given over a period of 8 weeks, will improve heart function, exercise ability and quality of life in African American Veterans with resistant hypertension.

Study Overview

• Status: Recruiting
• Conditions: Resistant Hypertension; Heart Failure Preserved Ejection Fraction
• Intervention / Treatment: Drug: Allopurinol

Detailed Description

Hypertension among African American adults in the United States has one of the highest prevalence rates in the world and is related to adverse changes in left ventricular (LV) structure and function. Hypertension is an underlying factor in greater than 50% of African American adults with heart failure and is the strongest risk factor in that population. African American adults have a 50% increased incidence of heart failure, due in large part due to the greater prevalence and severity of hypertension.

Heart failure occurs 8 years earlier in African American adults compared with Caucasians. Further, African American adults with heart failure have worse quality of life and depressive symptoms and have a 5-year mortality rate that is 34% higher than in Caucasians. Although African American adults have the highest death rate for heart failure, they are consistently under-represented in clinical trials. The greater heart failure burden among African Americans calls for further work to discover effective preventive and therapeutic strategies for this higher-risk population with heart failure preserved ejection fraction (HFpEF).

An estimated 10-20% of hypertensive patients have resistant hypertension (RHTN), defined as having controlled or uncontrolled blood pressure with the use of 3 or more medications that includes a diuretic. A recent study reported increased plasma xanthine oxidase (XO) activity and mitochondrial DNA damage associated molecular products (mtDAMPs) levels in African American adults with RHTN, compared with Caucasian adults with RHTN. This supports the consensus that oxidative stress is higher in African American adults. Increased xanthine oxidase in heart muscle cells causes a breakdown of muscle structure and a decrease in calcium sensitivity, resulting in left ventricular (LV) dysfunction. A recent study shows that diastolic blood pressure, and other indices of LV diastolic function positively relate to xanthine oxidase activity among African American but not Caucasian RHTN patients.

Given the higher level of xanthine oxidase activity and mtDAMPs in African Americans, the purpose of this clinical trial is to test whether blockade with Allopurinol (for 8 weeks) will improve LV diastolic function, exercise capacity and quality of life metrics in 50 African American Veterans with resistant hypertension.

• Study Type: Interventional
• Enrollment (Estimated): 50
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Louis J Dellitalia, MD; Phone Number: 4729 (205) 933-8101; Email: Louis.Dellitalia@va.gov
• Study Contact Backup: Name: Betty M Pat, PhD; Phone Number: (205) 612-7339; Email: Betty.Pat@va.gov

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35233-1927
      • Recruiting
      • Birmingham VA Medical Center, Birmingham, AL
      • Contact: Louis J Dellitalia, MD; Phone Number: 4729 205-933-8101; Email: Louis.Dellitalia@va.gov
      • Principal Investigator: Louis J Dellitalia, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Veteran
2. African American
3. Resistant hypertension diagnosis (defined as blood pressure greater than 140/90 mmHg at 2 clinic visits despite the use of 3 antihypertensive medications at pharmacologically effective doses)
4. Locale - Birmingham, AL and surrounding areas

Exclusion Criteria:

1. History of heart failure
2. Chronic kidney disease (estimated creatinine clearance < 60 ml/min)
3. Chronic steroid therapy
4. Known coronary artery disease
5. Known causes of secondary hypertension
6. Already taking Allopurinol

Magnetic Resonance Imaging Exclusion

1. Claustrophobia
2. Cardiac implantable electronic device (permanent pacemaker and/or intracardiac defibrillator)
3. Metal clips and/devices or other item that specifically prohibit safe CMR

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Allopurinol - African American Veterans; Subjects will receive Allopurinol (300mg/daily) for 4 weeks. If tolerated, dose will be increased to 600mg/daily for an additional 4 weeks. Subjects will take Allopurinol (300-600mg/daily) for 8 weeks total	Drug: Allopurinol; Single arm of Allopurinol treatment for 300mg/daily for 4 weeks then increased to 600mg/daily for an additional 4 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Normalized peak early diastolic filling rate (E)	Change from baseline in left ventricular diastolic function index: Normalized peak early diastolic filling rate (E) after 8-weeks of treatment with Allopurinol. (Range 1.5 - 3.0 EDV/sec)	8 weeks
Six minute walk test	Change in exercise capacity by six minute walk test after 8-weeks of Allopurinol. Timed activity for distance walked (Distance range approximately 400-800m; Further distance = better outcome)	8 weeks
Self Reported health survey for Heart Failure	Change in self reported quality of life measures using Kansas City Heart Failure Questionnaire (KCCQ-12) after 8-weeks of Allopurinol. Scale (Minimum - 0 ; Maximum - 100; High score = worse outcome)	8 weeks
Self reported Health Survey	Change in self reported quality of life measures using the Quality of Life Medical Outcomes Study Questionnaire (SF 36 QOL) after 8-weeks of Allopurinol. Scale (Minimum - 0; Maximum - 100; High score = worse outcome)	8 weeks
Left ventricular end-diastolic volume index	Change from baseline in left ventricular diastolic function index: left ventricular end diastolic volume normalized to body surface area after 8-weeks of treatment with Allopurinol. (Range 40 - 100 mL/m2)	8 weeks
LV end-diastolic mass index	Change from baseline in left ventricular diastolic function index: LV end-diastolic mass indexed to body surface area after 8-weeks of treatment with Allopurinol. (Range: 40-100 grams/m2)	8 weeks
LV end-diastolic fractional shortening	Change from baseline in left ventricular diastolic function index: LV end-diastolic fractional shortening after 8-weeks of treatment with Allopurinol. (Range: 15-80%)	8 weeks
LV end-diastolic mid-wall radius to wall thickness ratio	Change from baseline in left ventricular diastolic function index: LV end-diastolic mid-wall radius to wall thickness ratio. Ratio (no units; Range: 1.5-4.0).	8 weeks
Normalized peak late diastolic filling rate (A), EDV/s	Change from baseline in left ventricular diastolic function index: Normalized peak late diastolic filling rate (A) after 8-weeks of treatment with Allopurinol. (Range 1.3 - 4.5 EDV/sec)	8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Systolic Blood Pressure	Change in systolic blood pressure after 8 weeks of Allopurinol. Range: 120-200 mmHg	8 weeks
Xanthine Oxidase	Change in systemic levels of xanthine oxidase (range - Xanthine oxidase activity, U/mg protein - Range 0 - 0.1)	8 weeks
mitochondrial DNA damage-associated molecular patterns	Change in systemic levels of mitochondrial DNA damage-associated molecular patterns (range 0-5000 copies/uL)	8 weeks
Brain Natriuretic Peptide	Change in systemic levels of brain natriuretic peptide (BNP) after 8 weeks of Allopurinol (Scale 0 to > 100 pgmL; Minimum 0; Maximum >100).	8 weeks
Diastolic Blood Pressure	Change in diastolic blood pressure after 8 weeks of Allopurinol. Range: 70-110 mmHg	8 weeks

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Louis J Dellitalia, MD, Birmingham VA Medical Center, Birmingham, AL

Study record dates

Study Major Dates

• Study Start (Actual): August 2, 2023
• Primary Completion (Estimated): March 26, 2025
• Study Completion (Estimated): May 30, 2025

Study Registration Dates

• First Submitted: May 2, 2023
• First Submitted That Met QC Criteria: May 23, 2023
• First Posted (Actual): June 5, 2023

Study Record Updates

• Last Update Posted (Actual): August 22, 2023
• Last Update Submitted That Met QC Criteria: August 17, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Heart Failure; Hypertension; African American; Black; Xanthine Oxidase
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Heart Failure; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Allopurinol
• Other Study ID Numbers: F4655-P; I21RX004655-01 (U.S. NIH Grant/Contract: Veterans Affairs)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes