“CLICK”ing with Chlorthalidone: Rediscovering an Old Drug for Advanced CKD

“There's something special about chlorthalidone.”

–Rajiv Agarwal, MD, as heard on “Freely Filtered”

The nephrology community was abuzz at ASN Kidney Week 2021 as Rajiv Agarwal presented the results of the Chlorthalidone in Chronic Kidney Disease (CLICK) trial, with simultaneous publication in The New England Journal of Medicine (1).

In an attempt to refute the dogma that thiazide-like diuretics lose effectiveness at low estimated glomerular filtration rate (eGFR) (2), the CLICK trial enrolled 160 patients with stage 4 chronic kidney disease (CKD; eGFR 15 to >30 mL/min/1.73 m²) and uncontrolled hypertension—defined as a mean 24-hour ambulatory blood pressure monitoring (ABPM) of 130 mm Hg or higher (systolic BP [SBP]) or 80 mm Hg or higher (diastolic BP [DBP])—in a double-blind, randomized, placebo-controlled trial of chlorthalidone versus placebo. The primary outcome was a change in 24-hour ABPM from baseline to 12 weeks.

Of the 160 subjects in the trial, the average age was in the mid-60s, 40% were Black race, and about three-quarters were male, with a similar number of subjects with diabetes mellitus. Subjects were taking an average of 3.4 antihypertensives (60% were on a loop diuretic), and the mean eGFR was 23.2 mL/min/1.73 m².

With a starting dose of 12.5 mg once daily, the study dose was doubled every 4 weeks, up to a maximum dose of 50 mg, if the patient had a SBP or DBP ≥135 mm Hg or ≥85 mm Hg, respectively.

After only 4 weeks, with a mean dose of 11.5 mg daily, patients in the chlorthalidone group (n = 81) had a clinic SBP reduction of 9.2 mm Hg (vs. a rise of 2.7 mm Hg in the placebo group [n = 79]), and by 12 weeks, the mean dose was 23.1 mg, resulting in a decrease in SBP of 12.6 mm Hg (vs. a rise of 2.4 mm Hg in the placebo group). As seen in Figure 1, at 12 weeks, patients receiving chlorthalidone had a decrease in 24-hour ABPM—the primary outcome—of SBP 11 mm Hg and DBP 4.9 mm Hg (vs. 0.5 mm Hg and 1 mm Hg, respectively, in placebo). Notably, most of the antihypertensive effect occurred early (within 4 weeks) and at the starting dose (12.5 mg daily).

View Full Size

CLICK: Does chlorthalidone improve blood pressure in patients with chronic kidney disease and hypertension?

Citation: Kidney News 14, 2

• Download Figure
• Download figure as PowerPoint slide

Also notable was the decrease in urinary albumin-to-creatinine ratio by 12 weeks, which was 52% in the chlorthalidone group versus 4% in the placebo group. This was a significant decrease that persisted even 2 weeks after the trial concluded. This finding confirms prior studies that indicate an antiproteinuric effect of thiazide(-like) diuretics as part of an antihypertensive regimen (3, 4).

Although the results of CLICK are practice changing and demonstrate the clear antihypertensive and antiproteinuric efficacy of chlorthalidone in advanced CKD, caution and discretion must be used when initiating this therapy. Subjects receiving chlorthalidone were more likely to have an increase in serum creatinine, hypokalemia, hyponatremia, hypomagnesemia, hyperglycemia, hyperuricemia, and dizziness. The risk of a significant rise in creatinine was much higher for patients already on a loop diuretic, and in current practice, many of these patients may also be on a sodium glucose co-transporter 2 inhibitor, which has a mild diuretic effect. These side effects may be particularly notable for older adults.

CLICK extends the findings of other studies that have shown the BP and cardiovascular benefits of thiazide-like diuretics (i.e., chlorthalidone and indapamide) into a high-risk cohort of advanced CKD patients (5–7). Given the long half-life and potency, consideration of a low dose (e.g., 12.5 mg) and less frequent dosing (every other day or thrice weekly) may mitigate some concerns or side effects. Although CLICK did not establish an outcome benefit—such as a reduction in mortality or major adverse events—given its impressive BP-lowering results, it is time that treatment of hypertension in advanced CKD clicked with chlorthalidone.