Chlorthalidone Could Reduce Hypertension in Patients with Severe CKD, Uncontrolled Hypertension

Rajiv Agarwal, MD

New research presented at the American Society of Nephrology’s Kidney Week 2021 suggests chlorthalidone could reduce blood pressure as well as provide kidney-protective effects in patients with advanced chronic kidney disease (CKD).

A 12-week trial enrolling patients with hypertension and stage 4 CKD, results of the CLICK trial suggest use of chlorthalidone was associated with a between-group difference in systolic blood pressure of −10.5 mmHg compared to placebo therapy in patients with stage 4 CKD and poorly controlled hypertension.

“Besides the adverse effects we commonly see with the use of this drug in people without kidney disease, we saw an increased risk of reversible changes in kidney function, particularly when people were also receiving medications called loop diuretics,” said lead author Rajiv Agarwal, MD, of the Indiana University School of Medicine and the Roudebush VA, in a statement. “Thus, careful monitoring is required when using this medication.”

Based on previous data suggesting chlorthalidone could provide blood pressure-lowering effects in advanced CKD, the Chlorthalidone in Chronic Kidney Disease (CLICK) Trial was designed as a double-blind, randomized, placebo-controlled trial with the intent of assessing the effects on blood pressure and multiple other end points in the aforementioned patient population. The trial included a randomized population of 160 who were recruited from Indiana University Hospitals, Eskenazi Hospital, and the Richard L. Roudebush VA Medical Center.

Specific inclusion criteria for the study included a diagnosis of stage 4 CKD and poorly controlled hypertension. Investigators defined stage 4 CKD as an eGFR from 15 to less than 30 ml/min/1.73m2 and poorly controlled hypertension was defined as a mean 24-hour ambulatory systolic blood pressure of 130 mmHg or greater or diastolic blood pressure of 80 mmHg or greater while receiving at least 1 antihypertensive drug. Of note, presence of poorly controlled hypertension was confirmed by 24-hour ambulatory blood pressure monitoring after a 2-week period during which antihypertensive medications were standardized and patients received a placebo.

The trial included 9 prespecified trial visits, with 4 occurring over a 3-week period before randomization, 4 occurring during a 12-week period following randomization, and a final visit occurring 2 weeks after the assigned regimen was discontinued. Patients included in the trial were randomized in a 1:1 ratio to receive placebo or chlorthalidone at an initial dose of 12.5 mg per day, which was increased, as needed, every 4 weeks up to a maximum dose of 50 mg per day.

The primary outcome of the trial was the change in 24-hour ambulatory systolic blood pressure from baseline to 12 weeks. The secondary outcomes of the trial were change from baseline to 12 weeks in UACR, NT-proBNP level, plasma renin and aldosterone levels, and total body volume. The trial also included a multitude of safety end points.

The 160-person study cohort included 81 randomized to chlorthalidone and 79 randomized to placebo therapy. Of these, 140 (88%) completed the 12-week treatment period. At baseline, the study population had a mean eGFR of 23.2±4.2 ml/min/1.73m2 and the mean number of antihypertensive agents prescribed was 3.4±1.4. Investigators noted 76% of patients who underwent randomization had diabetes mellitus, 60% were receiving loop diuretics, and all but 2 were on an ACE, ARB, or beta-blocker.

At randomization, the mean 24-hour ambulatory systolic blood pressure was 142.6±8.1 mmHg in the chlorthalidone arm and 140.1±8.1 mmHg in the placebo arm and the mean 24-hour ambulatory diastolic blood pressure was 74.6±10.1 mmHg and 72.8±9.3 mmHg among the chlorthalidone and placebo arms, respectively. Upon analysis, results indicated patients in the chlorthalidone arm experienced an adjusted change in 24-hour systolic blood pressure from baseline to 12 weeks of -11.0 mmHg (95% CI, -13.9 to -8.1) compared to a change of -0.5 mmHg (95% CI, -3.5 to 2.5) in the placebo arm, which translated too between-group difference of -10.5 mmHg (95% CI, -14.6 to -6.4) (P <.001).

Analysis of secondary outcomes of interest suggested the percent change in UACR from baseline to 12 weeks was lower among those in the chlorthalidone arm than among those in the placebo arm by 50 percentage points (95% CI, 37 to 60). Additionally, results of the safety analysis indicated hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia occurred more frequently among those in the chlorthalidone arm than in the placebo arm.

This study, “Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease,” was presented at ASN Kidney Week and simultaneously published in The New England Journal of Medicine.