Cardiovascular Diseases, Heart Diseases, Hypertension
Conditions
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.
Interventions
DRUGAllopurinol
Allopurinol (300 mg capsule) was given for 8-10 weeks compared to placebo group after initial baseline testing. After two weeks on the Allopurinol, a serum uric acid level was obtained. If the uric acid level was greater than 5.5, the Allopurinol dosage was increased to 600mg (two 300 mg capsules)for the duration of the trial, 6-8 weeks.
DRUGPlacebo
Placebo capsule (matched in appearance for Allopurinol and labeled 300mg) was given for 8-10 weeks compared to the Allopurinol group after initial baseline testing. After two weeks on the placebo, a serum uric acid level was obtained. If the uric acid level was greater than 5.5, the placebo dosage was increased to 600mg (two 300 mg capsules)for the duration of the study, 6-8 weeks.
DRUGChlorthalidone
Chlorthalidone 25 mg was given daily for 5 weeks before baseline visit for testing and continued through out the study.
DRUGPotassium chloride
Potassium Chloride 40-50meq was given daily for 5 weeks before baseline visit for testing and continued through out the study.
Sponsors
University of Florida
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Recruitment was through flyers and voluntary blood pressure checks and hypertension lectures throughout the county in churches, health fairs, community art festivals, new business openings and celebrations, and in hospital lobbies, business employee lounges, store front spaces at grocery stores and super stores. Individuals also self-refered.
Pre-assignment details
150 subjects signed consents;8 were withdrawn prior to randomization. All participants were placed on chlorthalidone 25mg daily for blood pressure stabilization along with potassium chloride (KCL) 40meq daily. Potassium chloride was increased to 50meq daily for those subjects whose serum potassium was less than 3.5 before baseline visit.
Participants by arm
| Arm | Count |
|---|---|
| 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. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional 300mg allopurinol was added with total dose of 600mg daily. The dosage of allopurinol then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline. | 71 |
| 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, having the same appearance and dosage label(300mg)as allopurinol, was added for 8-10 weeks. Serum uric acid (UA) levels were checked at study visit 2 weeks post baseline. If UA levels were above 5.0 an additional placebo (300mg)was added with total dose of 600mg daily. The dosage of placebo then remained constant throughout the remainder of the study. Testing was repeated at 8-10 weeks after baseline. | 71 |
| Total | 142 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Withdrawal by Subject | 18 | 17 |
Baseline characteristics
| Characteristic | B (Placebo) | A (Allopurinol) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 71 Participants | 70 Participants | 141 Participants |
| Age Continuous | 48.0 years STANDARD_DEVIATION 7.7 | 47.7 years STANDARD_DEVIATION 10.1 | 47.9 years STANDARD_DEVIATION 8.8 |
| Region of Enrollment United States | 71 participants | 71 participants | 142 participants |
| Sex: Female, Male Female | 51 Participants | 51 Participants | 102 Participants |
| Sex: Female, Male Male | 20 Participants | 20 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 26 / 71 | 11 / 71 |
| serious Total, serious adverse events | 4 / 71 | 3 / 71 |
Outcome results
Primary
Change in Diastolic Blood Pressure by Cuff 8-10 Weeks Minus Baseline
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)
Time frame: Measured at 8-10 weeks on allopurinol / placebo
Population: Participants were individuals with essential hypertension (BP 140/90-160/100) on none or up 2 antihypertensive drugs without any other chronic condition or illness. For their data to be included in analysis they had to complete the study (includes baseline to last visit).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A (Allopurinol) | Change in Diastolic Blood Pressure by Cuff 8-10 Weeks Minus Baseline | 3.44 mm Hg | Standard Deviation 12.25 |
| B (Placebo) | Change in Diastolic Blood Pressure by Cuff 8-10 Weeks Minus Baseline | -0.83 mm Hg | Standard Deviation 10.63 |
Comparison: We compared the drop in baseline of diastolic BP for the two treatment groups Allopurinol vs. Placebo by a Satterthwaite corrected t-test.p-value: 0.05995% CI: [-0.17, 8.7]t-test, 2 sided
Primary
Change in Systolic Blood Pressure by Cuff After 8-10 Weeks Minus Baseline
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)
Time frame: Measured at 8-10 weeks on allopurinol or placebo
Population: Participants were individuals with essential hypertension (BP 140/90-160/100) on none or up 2 antihypertensive drugs without any other chronic condition or illness. For their data to be included in analysis they had to complete the study (includes baseline to last visit).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A (Allopurinol) | Change in Systolic Blood Pressure by Cuff After 8-10 Weeks Minus Baseline | 0.21 mm Hg | Standard Deviation 7.37 |
| B (Placebo) | Change in Systolic Blood Pressure by Cuff After 8-10 Weeks Minus Baseline | -0.95 mm Hg | Standard Deviation 8.9 |
p-value: 0.4795% CI: [-2, 4.3]t-test, 2 sided
Secondary
Change in Overall Mean BP From Those Obtained by 24 Hour Ambulatory Blood Pressure Measurements (ABPM) 8-10 Weeks Minus Baseline.
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.
Time frame: Baseline and end of treatment (8-10 weeks on allopurinol / placebo)
Population: We obtained over 90% of those with cuff measures on the 24 hour BP measures (ABPM).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A (Allopurinol) | Change in Overall Mean BP From Those Obtained by 24 Hour Ambulatory Blood Pressure Measurements (ABPM) 8-10 Weeks Minus Baseline. | -5.9 mm Hg | Standard Deviation 11.9 |
| B (Placebo) | Change in Overall Mean BP From Those Obtained by 24 Hour Ambulatory Blood Pressure Measurements (ABPM) 8-10 Weeks Minus Baseline. | 0.90 mm Hg | Standard Deviation 8.91 |
p-value: 0.00295% CI: [-11, -2.6]t-test, 2 sided
Secondary
Change in Uric Acid (UA) Levels: Baseline Less End of Treatment
Subjects on allopurinol are expected to lower their uric acid levels relative to placebo.
Time frame: Baseline UA levels compared to end of treatment levels (8-10 weeks on allopurinol / placebo)
Population: Change in uric acid from baseline to end of treatment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| A (Allopurinol) | Change in Uric Acid (UA) Levels: Baseline Less End of Treatment | 2.29 mg/dl | Standard Deviation 1.29 |
| B (Placebo) | Change in Uric Acid (UA) Levels: Baseline Less End of Treatment | 0.14 mg/dl | Standard Deviation 0.88 |
Comparison: We expected allopurinol to be associated with a decrease in uric acid.p-value: <0.00195% CI: [1.72, 2.59]t-test, 2 sided