Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease

Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease
Erica Hanson, PharmD, Cash Wise Clinic Pharmacy

Background: Thiazide diuretics are a first line pharmacologic treatment for hypertension, but limited studies exist to demonstrate the efficacy and safety of thiazide diuretics in patients with advanced chronic kidney disease (CKD). The National Kidney Foundation Kidney Disease Outcomes Quality Initiative recommends the use of thiazide diuretics in CKD Stages 1-3, but there is limited evidence that the medications remain effective below an estimated glomerular filtration rate (eGFR) of 30 mL/min/1.73 m2.

Purpose: The Chlorthalidone in Chronic Kidney Disease (CLICK) Trial looked to evaluate the antihypertensive efficacy of chlorthalidone in patients with stage 4 CKD, along with evaluating safety and renoprotective properties of the drug.

Study Design: This was a double-blind, randomized, placebo-controlled trial with patients recruited from three different hospitals in Indiana. Eligible patients were those with stage 4 CKD (eGFR 15 to <30 mL/min/1.73 m2 of body surface area) and uncontrolled hypertension. Uncontrolled hypertension was defined as patients taking at least one antihypertensive drug with a mean 24-hour ambulatory blood pressure (BP) >130/80 mmHg over a 2-week period. Patients were excluded from the trial if their mean 24-hour ambulatory BP over the 2-week period was greater than 160/100 mmHg. Additionally, patients were excluded if they had a history of stroke or myocardial infarction, used high-dose loop diuretics (>100 mg torsemide daily or >200 mg furosemide daily), or if in the 12 weeks prior to randomization they used a thiazide or thiazide-like diuretic or were hospitalized for heart failure. Nine prespecified follow up visits occurred prior to, throughout, and after the study. During each follow up, labs and vitals were monitored to evaluate electrolyte levels, glucose, renin, aldosterone, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and renal function. Additionally, patients were instructed to limit sodium intake and were standardized to receive a preferred drug within each drug class based on the patient’s current hypertension regimen (angiotensin-converting-enzyme inhibitors changed to lisinopril 20-40 mg daily; angiotensin-receptor blockers changed to losartan 50-100 mg daily; dihydropyridine calcium-channel blockers changed to amlodipine 10 mg daily; beta-blockers changed to atenolol 25-100 mg daily; loop diuretics changed to torsemide 10-20 mg daily). Randomization occurred in a 1:1 ratio for patients to receive chlorthalidone or placebo and was stratified based on use of a loop diuretic. Chlorthalidone doses were increased throughout the study based on BP measurements to a maximum dose of 50 mg once daily. The primary outcome was change in 24-hour ambulatory systolic BP from baseline to 12 weeks. The secondary outcomes were the change in urinary albumin-to-creatinine ratio (UACR), NT-proBNP level, plasma renin and aldosterone levels, and total body volume from baseline to 12 weeks.

Results: A total of 160 patients underwent randomization with 140 patients completing the full 12-week trial. 81 patients received chlorthalidone and 79 patients received placebo. The mean dose of chlorthalidone used in the treatment arm was 11.5 mg at 4 weeks, 18.3 mg at 8 weeks, and 23.1 mg at 12 weeks. For the primary outcome, baseline BP readings from the 24-hour ambulatory monitor for chlorthalidone were 142.6 ± 8.1 mmHg systolic and 74.6 ± 10.1 mmHg diastolic. For placebo, baseline readings were 140.1 ± 8.1 mmHg systolic and 72.8 ± 9.3 mmHg diastolic. After the 12-week trial, ambulatory systolic blood pressures were reduced by 11.0 mmHg in the chlorthalidone group and 0.5 mmHg in the placebo group (mean difference =10.5 mmHg [95% CI -14.6 – -6.4]). Diastolic blood pressures were reduced by 4.9 mmHg in the treatment group versus 1.0 in the placebo group (mean difference =3.9 mmHg [95% CI -6.3 – -1.5]). For secondary outcomes, the percent reduction in the UACR was 52% for chlorthalidone and 4% for placebo after 12 weeks. However, some of the reductions in UACR were lost following discontinuation of chlorthalidone (change from baseline [38% for chlorthalidone and 6% for placebo]). The percent decrease in NT-proBNP level was 30% for chlorthalidone and 11% for placebo after 12 weeks. Changes in plasma renin and aldosterone levels, along with changes in body volume, decreased during the treatment period and increased when chlorthalidone was discontinued. Adverse events were reported in 91% of patients receiving chlorthalidone and 86% receiving placebo, which included hypokalemia, hypomagnesemia, hyponatremia, hyperglycemia, hyperuricemia, increased serum creatinine, and dizziness. Increases in serum creatinine greater than 25% of baseline were observed in 45% of chlorthalidone patients and 13% of placebo patients. 

Conclusion: Chlorthalidone was shown to improve BP control in patients with stage 4 CKD disease after twelve weeks of treatment when compared to placebo. The degree of albuminuria was reduced in patients receiving chlorthalidone but did increase slightly two weeks after discontinuation of treatment, suggesting that chlorthalidone may provide both cardiovascular and renal protection. There was a high number of adverse events and electrolyte level changes in the chlorthalidone group, which the study concluded to be similar adverse events to those reported in other chlorthalidone trials in patients without CKD. Phase 3 trials are recommended to further support using chlorthalidone in advanced chronic kidney disease patients.

Key Point: The use of chlorthalidone in patients with an eGFR<30 mL/min/1.73 m2 improved blood pressure control. Close monitoring is recommended to evaluate for electrolyte and renal function changes.

Reference

  1. Agarwal R, Sinha AD, Cramer AE, et al. Chlorthalidone for hypertension in advanced chronic kidney disease. N Engl J Med. 2021;385(27):2507-2519. doi:10.1056/NEJMoa2110730