Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease

Abstract

Background: Little evidence has been available to support the use of thiazide diuretics to treat hypertension in patients with advanced chronic kidney disease.

Methods: We randomly assigned patients with stage 4 chronic kidney disease and poorly controlled hypertension, as confirmed by 24-hour ambulatory blood-pressure monitoring, in a 1:1 ratio to receive chlorthalidone at an initial dose of 12.5 mg per day, with increases every 4 weeks if needed to a maximum dose of 50 mg per day, or placebo; randomization was stratified according to previous use of loop diuretics. The primary outcome was the change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks. Secondary outcomes were the change from baseline to 12 weeks in the urinary albumin-to-creatinine ratio, N-terminal pro-B-type natriuretic peptide level, plasma renin and aldosterone levels, and total body volume. Safety was also assessed.

Results: A total of 160 patients underwent randomization, of whom 121 (76%) had diabetes mellitus and 96 (60%) were receiving loop diuretics. At baseline, the mean (±SD) estimated glomerular filtration rate was 23.2±4.2 ml per minute per 1.73 m² of body-surface area and the mean number of antihypertensive medications prescribed was 3.4±1.4. At randomization, the mean 24-hour ambulatory systolic blood pressure was 142.6±8.1 mm Hg in the chlorthalidone group and 140.1±8.1 mm Hg in the placebo group and the mean 24-hour ambulatory diastolic blood pressure was 74.6±10.1 mm Hg and 72.8±9.3 mm Hg, respectively. The adjusted change in 24-hour systolic blood pressure from baseline to 12 weeks was -11.0 mm Hg (95% confidence interval [CI], -13.9 to -8.1) in the chlorthalidone group and -0.5 mm Hg (95% CI, -3.5 to 2.5) in the placebo group. The between-group difference was -10.5 mm Hg (95% CI, -14.6 to -6.4) (P<0.001). The percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks was lower in the chlorthalidone group than in the placebo group by 50 percentage points (95% CI, 37 to 60). Hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia occurred more frequently in the chlorthalidone group than in the placebo group.

Conclusions: Among patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo. (Funded by the National Heart, Lung, and Blood Institute and the Indiana Institute of Medical Research; CLICK ClinicalTrials.gov number, NCT02841280.).

Figure 1.. Systolic Blood Pressure and Body Weight in the Trial Groups over the Trial Period.

Shown are the changes in the least-squares mean seated clinic systolic blood pressure (Panel A) and body weight (Panel B) over the 14-week trial period. At 12 weeks, the assigned regimen was discontinued. I bars indicate 95% confidence intervals. The between-group difference was calculated as the value in the chlorthalidone group minus the value in the placebo group. Values are offset from each other at each time point for readability.

Figure 2.. Changes in Urinary Albumin-to-Creatinine Ratio and Estimated GFR in the Trial Groups over the Trial Period.

Shown are the changes in the geometric mean of the urinary albumin-to-creatinine ratio (Panel A) and the least-squares mean estimated glomerular filtration rate (GFR) (Panel B) over the 14-week trial period. At 12 weeks, the assigned regimen was discontinued, and the measurements at week 14 were taken after the patients had been off their assigned regimen for 2 weeks. I bars indicate 95% confidence intervals. The between-group difference was calculated as the value in the chlorthalidone group minus the value in the placebo group. The percent changes in urinary albumin-to-creatinine ratio were back-transformed and may not total to the percentage-point difference because of rounding. Values are offset from each other at each time point for readability.