Chlorthalidone was effective in lowering blood pressure in individuals with advanced kidney disease, found a double-blind, placebo-controlled and randomised study from Indiana University in the New England Journal of Medicine.
The study, funded by the National Institutes of Health's National Heart, Lung, and Blood Institute, titled Chlorthalidone in Chronic Kidney Disease (CLICK) was presented also as part of a High Impact Clinical Trials session at the recent international meeting of the American Society of Nephrology.
“Kidneys are key regulators of blood pressure. When an individual has chronic kidney disease, the kidneys are unable to control blood pressure,” said Dr Rajiv Agarwal, professor of medicine and staff physician at the Roudebush VA. “If a person suffers from chronic kidney disease and high blood pressure, it is more likely their kidney disease will advance even further and lead to other health issues such as heart failure.”
The CLICK Study randomly assigned patients with stage 4 chronic kidney disease (CKD) to either a placebo or chlorthalidone group, with dosing at 12.5mg daily. The dose was increased every four weeks, if needed, to a maximum of 50mg per day for patients in the chlorthalidone group. The study was designed to see if blood pressure decreased in the patients treated with chlorthalidone from baseline to 12 weeks, when monitored using a state-of-the-art device called a 24-hour ambulatory blood pressure monitor.
Chlorthalidone was approved by the US Food & Drug Administration in 1960 for treatment of high blood pressure or hypertension. However, it was largely believed to be ineffective in treating high blood pressure in people with advanced chronic kidney disease.
Results from the CLICK study showed chlorthalidone lowered blood pressure by a significant 11 mm Hg at 12 weeks as compared to 0.5 mm Hg reduction with placebo. There was a 50% reduction in albuminuria, a protein that appears in the urine of those suffering from kidney disease, which Agarwal says is remarkable and suggests that chlorthalidone has the potential to reduce kidney failure progression and hospitalisations for heart failure in these patients.
“These results show chlorthalidone is a low-cost solution for the treatment of hypertension in people with chronic kidney disease,” he said. “These are people who are already taking a variety of medicines, so to have one that is cheap and effective is incredibly meaningful. However, the drug is potent, so the lowest therapeutic dose and careful monitoring is needed to avoid complications.”
Study details
Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease.
Rajiv Agarwal, Arjun D. Sinha, Andrew E. Cramer, Mary Balmes-Fenwick, Jazmyn H. Dickinson, Fangqian Ouyang, Wanzhu Tu.
Published in the New England Journal of Medicine on 5 November 2021
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; randomisation 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 randomisation, 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.
NEJA abstract – Chlorthalidone for Hypertension in Advanced Chronic Kidney Disease (Open access)
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