Chlorthalidone Improves Blood Pressure Control in Advanced CKD With Hypertension

Rajiv Agarwal, MD

Although there is a lack of evidence regarding the efficacy and safety of the thiazide-like diuretic chlorthalidone among patients with advanced chronic kidney disease (CKD), some studies have suggested its potential effectiveness for treating hypertension in patients with CKD.

A recent study hypothesized that chlorthalidone would decrease the 24-hour ambulatory systolic blood pressure and the degree of albuminuria over 12 weeks, as well as provide evidence the drug is renoprotective and cardioprotective.

Led by Rajiv Agarwal, MD, Richard L. Roudebush Veterans Affairs Medical Center, a team of investigators observed chlorthalidone therapy, in fact, improved blood pressure control in patients with advanced CKD and poorly controlled hypertension compared to placebo

Methods

Data was collected from the double-blind, randomized, placebo-controlled trial Chlorthalidone in Chronic Kidney Disease (CLICK) Trial.

Eligible patients had stage 4 chronic kidney disease (estimated glomerular filtration rate, eGFR: 15 - <30 ml per minute per 1.73 m2 of body surface area) and uncontrolled hypertension, confirmed by 24-hour ambulatory blood pressure monitoring defined as a mean of ≥130 mm Hg for systolic or ≥80 mm Hg for diastolic, while receiving ≥1 antihypertensive drug.

A total of 9 prespecified trial visits were utilized, with 4 over a 3-week period before randomization and 4 over a 12-week period following randomization, with a final visit 2 weeks after the regimen was discontinued.

Patients were randomly assigned in a 1:1 ratio to receive either chlorthalidone or placebo, of 12.5 mg per day, stratified according to previous use of loop diuretics. The dose was doubled every 4 weeks to 25 mg once daily at week 4 and 50 mg once daily at week 8.

The primary outcome was considered the change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks, with secondary outcomes including 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.

Findings

From 2849 patients who underwent screening, 403 patients provided consent and 160 (40%) underwent randomization to the chlorthalidone group (n = 160) and the placebo group (n = 79). Data show a total of 140 patients (88%) completed the 12-week trial period.

At baseline, 96 patients (60%) were receiving loop diuretics, all patients were receiving 3.4±1.4 antihypertensive medications, and had an eGFR of 23.2±4.2 ml per minute per 1.73 m2 of body- surface area.

Then, 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. The mean 24-hour ambulatory diastolic blood pressure was 74.6±10.1 mm Hg in the chlorthalidone group and 72.8±9.3 mm Hg in the placebo group.

Data show the adjusted change in 24-hour systolic blood pressure from baseline to 12 weeks was -11.0 mm Hg (95% 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. A between group difference of -10.5 mm Hg (95% CI, -14.6 to -6.4, P <.001) was observed.

Further, the adjusted change in the 24-hour ambulatory diastolic blood pressure from baseline to 12 weeks was -4.9mm Hg in the chlorthalidone group and -1.0 mm Hg in the placebo group, for a mean difference of -3.9 mm Hg (95% CI, -6.3 to -1.5).

Lastly, the percent change in the urinary albumin-to-creatinine ratio from baseline to 12 weeks had a between-group difference of -50 percentage points, 95% CI, -60 to -37). Adverse events including hypokalemia, reversible increases in serum creatinine level, dizziness, hyperglycemia, and hyperuricemia associated with chlorthalidone therapy occurred more frequently in the chlorthalidone group, compared to the placebo group.

Takeaways

“In this placebo-controlled trial involving patients with advanced chronic kidney disease and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure control at 12 weeks as compared with placebo,” investigators wrote.

The study, “Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease,” was published in the New England Journal of Medicine.