Uric Acid and Hypertension in African Americans

Phase 3

Completed

Conditions: Cardiovascular Diseases
Heart Diseases
Hypertension

Interventions: Drug: Placebo
Drug: Allopurinol
Drug: Chlorthalidone
Drug: Potassium chloride

Registration Number: NCT00241839

Lead Sponsor: University of Florida

Brief Summary: This study will test the hypothesis that the administration of a xanthine oxidase inhibitor (allopurinol) will prevent thiazide-induced hyperuricemia, which will result in better blood pressure (BP) control in African Americans.

Detailed Description: Thiazide diuretics when used in the treatment of hypertension are associated with many metabolic side effects, including hyperuricemia, gout, insulin resistance, and hyperlipidemia. Each of these conditions is already highly prevalent in African Americans. Our hypothesis is that thiazide-induced hyperuricemia decreases the efficacy of thiazides in controlling BP, leads to endothelial dysfunction, and increases the incidence of insulin resistance and impaired glucose tolerance. This hypothesis will be tested in a randomized, double-blind, placebo-controlled clinical trial of 8-10 weeks duration in which a total of 100 African American patients with hypertension will be enrolled, randomized, and treated as follows:

1. Subjects with untreated stage I hypertension will receive chlorthalidone (25 mg/day) and potassium chloride (40 mEq/day) for 4 weeks. Serum potassium levels will be obtained after four weeks on chlorthalidone. If the level is below 3.5 mEg/L, a bolus of 40 mEq potassium 2 to 3 times daily will be given for 2 to 3 days, or as clinically indicated. A maintenance dose of 50 mEq will be initiated. After at least 7 days, they will then be randomized to add-on allopurinol (300 mg/day) or placebo. Treatment will continue for 8-10 weeks with the chlorthalidone, potassium chloride, and allopurinol/placebo regimen.

2. Subjects with hypertension controlled (i.e. BP \<140/90) or no higher than stage 1 hypertension (i.e., \<160/100) on a single antihypertensive agent or two antihypertensive agents will be switched from their prior antihypertensive agent to chlorthalidone 25 mg/day, and potassium chloride (40mEq/day) for 4 weeks. Serum potassium levels will be obtained after four weeks on chlorthalidone. If the level is below 3.5 mEg/L, a bolus of 40 mEq potassium 2 to 3 times daily will be given for 2 to 3 days, or as clinically indicated. A maintenance dose of 50 mEq will be initiated. After at least 7 days, they will then be randomized to add-on allopurinol (300 mg/day) or placebo. Treatment will continue for 8-10 weeks with the chlorthalidone, potassium chloride, and allopurinol/placebo regimen.

The allopurinol (or placebo) dose will be adjusted to achieve serum uric acid levels between 4 and 5.5 mg/dL after 2 weeks on drug. All subjects will receive a low-sodium diet. The primary endpoint is reduction in systolic BP. Secondary endpoints measure endothelial function, ambulatory blood pressure, body composition, systemic inflammation, metabolic parameters, oxidant stress, and renal hemodynamics.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 150

Inclusion Criteria

African American (including black individuals born in the Caribbean, Africa, Canada, etc.)
Are either untreated with any antihypertensive agent, with an average sitting clinic BP of between 140/90 and 159/99 mm Hg OR subjects with hypertension controlled (i.e. BP less than 140/90) or no higher than stage 1 hypertension (i.e., less than 160/100) on a single antihypertensive agent or two antihypertensive agents (individuals on fixed dose ARB-diuretic or ACEI-diuretic combinations will also be considered as being on monotherapy for purposes of the study. Individuals on beta blockade or calcium channel blockade for coronary artery disease and/or arrhythmia will not be eligible for the study)
Random spot urine protein/creatinine ratio of less than 0.5 (approximates a 24-hour urinary protein excretion of 500 mg/day)
Calculated MDRD GFR of greater than or equal to 60 ml/min/1.73/m^2
No allopurinol or probenecid intake for at least one month prior to study entry
Willing and able to cooperate with study procedures
Willing to travel to the GCRC at Shands Hospital for overnight inpatient stays on two separate occasions

Exclusion Criteria

History of malignant or accelerated hypertension
Confirmed total white cell count of less than 2,500/mm^3, anemia, or thrombocytopenia
Known history of liver disease
Known secondary cause of hypertension
Known presence of diabetes or fasting blood glucose greater than or equal to 126 mg/dL
History of heart failure, acute myocardial infarction, or stroke or on a β-blocker or calcium channel blocker for cardiovascular indications other than for lowering blood pressure
Abnormal EKG requiring medical intervention
History of clinical or renal biopsy or evidence of renal parenchymal disease
Acute gout attack within 2 weeks of study entry
History of drug abuse in the last 2 years, including narcotics, cocaine, or alcohol (greater than 21 drinks/week)
Arm circumference of greater than 52 cm, which precludes measurement with a 'thigh' BP cuff
History of a reaction to allopurinol or chlorthalidone
Pregnant or planning to become pregnant during the study, or breastfeeding
History of noncompliance, are unable to comply with the study requirements, or who are currently participating in another study
Not fasting prior to obtaining screening laboratory data. If a participant has clearly not fasted, we will exclude those individuals with casual blood glucose levels of greater than or equal to 200 mg/dL. In the event that a fasting blood sugar exceeds 126 mg/dL, it will be reconfirmed on a blood glucose measurement obtained on a subsequent day, per American Diabetes Association criteria

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
B	Placebo	Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, a Placebo,matched in appearance to Allopurinol, was added daily for 8-10 weeks, at which time testing was repeated.
B	Potassium chloride	Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, a Placebo,matched in appearance to Allopurinol, was added daily for 8-10 weeks, at which time testing was repeated.
A	Chlorthalidone	Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, Allopurinol 300mg daily was added for 8-10 weeks at which time testing was repeated.
A	Allopurinol	Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, Allopurinol 300mg daily was added for 8-10 weeks at which time testing was repeated.
A	Potassium chloride	Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, Allopurinol 300mg daily was added for 8-10 weeks at which time testing was repeated.
B	Chlorthalidone	Chlorthalidone 25 mg and Potassium Chloride 40-50meq were given daily for 5 weeks before baseline visit for testing. After baseline testing was completed, a Placebo,matched in appearance to Allopurinol, was added daily for 8-10 weeks, at which time testing was repeated.

Primary Outcome Measures

Name	Time	Method
Change in Diastolic Blood Pressure by Cuff 8-10 Weeks Minus Baseline	Measured at 8-10 weeks on allopurinol / placebo	The Diastolic BP was taken at Baseline and after 8-10 weeks of treatment or placebo while on chlorthalidone and potassium chloride. The blood pressure was measured according to "Shared Care" protocol: 15 minutes of quiet, undisturbed rest with three BP measurements obtained subsequently at 5 minute intervals. The mean of the second and third reading was the value used for analysis for both the Baseline measurement and the measurement after 8 - 10 weeks of treatment. The dependent variable is baseline value minus ending value. Measures are in millimeters of mercury (mm hg)
Change in Systolic Blood Pressure by Cuff After 8-10 Weeks Minus Baseline	Measured at 8-10 weeks on allopurinol or placebo	The systolic BP was taken at Baseline and after 8-10 weeks of treatment on placebo, while on chlorthalidone and potassium chloride. The blood pressure was measured according to "Shared Care" protocol: 15 minutes of quiet, undisturbed rest with three BP measurements obtained subsequently at 5 minute intervals. The mean of the second and third reading was the value used for analysis for both the Baseline measurement and the measurement after 8 - 10 weeks of treatment. The dependent variable is baseline value minus ending value. Measures are in millimeters of mercury (mm hg)

Secondary Outcome Measures

Name	Time	Method
Change in Overall Mean BP From Those Obtained by 24 Hour Ambulatory Blood Pressure Measurements (ABPM) 8-10 Weeks Minus Baseline.	Baseline and end of treatment (8-10 weeks on allopurinol / placebo)	Subjects had 24 hr blood pressure monitoring (ABPM) at baseline and treatment end. The readings were averaged and the changes from baseline to treatment end were compared.
Change in Uric Acid (UA) Levels: Baseline Less End of Treatment	Baseline UA levels compared to end of treatment levels (8-10 weeks on allopurinol / placebo)	Subjects on allopurinol are expected to lower their uric acid levels relative to placebo.