Indianapolis, IN—In general, scant evidence has been available to promote the use of thiazide diuretics to treat hypertension in patients with advanced chronic kidney disease (CKD).
That may have changed with a new study published in the New England Journal of Medicine. Indiana University School of Medicine–led researchers determined that in patients with advanced CKD and poorly controlled hypertension, chlorthalidone therapy improved blood-pressure (BP) control at 12 weeks compared with placebo.
Researchers randomly assigned patients with stage 4 CKD and poorly controlled hypertension, as confirmed by 24-hour ambulatory BP monitoring, in a 1:1 ratio to receive chlorthalidone at an initial dosage of 12.5 mg per day or placebo. The chlorthalidone dosage was increased every 4 weeks, if necessary, to a maximum of 50 mg per day. Randomization was stratified according to previous use of loop diuretics.
The primary outcome was the change in 24-hour ambulatory systolic BP 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 (NT-proBNP) level, plasma renin and aldosterone levels, and total body volume. Safety was also assessed.
The study team randomized 160 patients, of whom 121 (76%) had diabetes mellitus and 96 (60%) were receiving loop diuretics. The mean (±SD) estimated glomerular filtration rate (GFR) was 23.2 ± 4.2 mL per minute per 1.73 m2 of body-surface area at baseline, and the mean number of antihypertensive medications prescribed was 3.4 ± 1.4.
At randomization, the mean 24-hour ambulatory systolic BP was 142.6±8.1 mmHg in the chlorthalidone group and 140.1±8.1 mmHg in the placebo group, with mean 24-hour ambulatory diastolic BP of 74.6 ± 10.1 mmHg and 72.8 ± 9.3 mmHg, respectively.
The adjusted change in 24-hour systolic BP from baseline to 12 weeks was 11.0 mmHg (95% confidence interval [CI], 13.9 to 8.1) in the chlorthalidone group and 0.5 mmHg (95% CI, 3.5 to 2.5) in the placebo group. That means that the between-group difference was 10.5 mmHg (95% CI, 14.6 to 6.4) (P <.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),” the researchers pointed out, adding that hypokalemia, reversible increases in serum creatinine level, hyperglycemia, dizziness, and hyperuricemia occurred more frequently in the chlorthalidone group than in the placebo group.
Background information in the article describes how hypertension, although a common risk factor for both cardiovascular disease and CKD, is often poorly controlled, especially in patients with advanced CKD.
“Thiazide or thiazide-like diuretics are important agents for lowering blood pressure in patients with essential hypertension,” the authors explained. “Chlorthalidone, a thiazide-like diuretic, reduces cardiovascular morbidity, such as the incidence of stroke and heart failure, and cardiovascular mortality. However, its efficacy and safety among patients with advanced chronic kidney disease remain poorly understood.”
On the basis of preliminary evidence of an effect on BP in patients with CKD, the study team hypothesized that in patients with advanced CKD and uncontrolled hypertension, chlorthalidone would decrease the 24-hour ambulatory systolic BP. They also suggested that chlorthalidone would reduce the degree of albuminuria over 12 weeks. The goal was to provide preliminary evidence that chlorthalidone is renoprotective and cardioprotective.
“The time course of the blood-pressure changes suggests that most of the reduction in blood pressure occurred within 4 weeks after therapy with 12.5 mg of chlorthalidone was initiated (in addition to other antihypertensive medications),” the authors wrote. “Reductions in body weight, body volume, and NT-proBNP levels and increases in plasma renin and aldosterone levels within 4 weeks after starting chlorthalidone therapy suggest that the mechanism of blood-pressure reduction is consistent with the changes in effective arterial blood volume over time, which decreased during the treatment period and then increased after the regimen was discontinued.”
Two weeks after chlorthalidone therapy was discontinued, 44% of the reduction in seated clinic systolic BP and 53% of the peak weight loss that was observed at the end of the 12-week treatment period remained.
“The reported half-life of chlorthalidone is 45 to 60 hours, and the duration of action is even longer at 48 to 72 hours,” the researchers noted. “The persistent effects on blood pressure and weight loss are consistent with the long duration of action of chlorthalidone or a modifying effect of the drug on kidney disease. The large reduction in blood pressure is likely to have occurred because chlorthalidone is three times as potent as hydrochlorothiazide.”
The authors also posited, “The reversible changes in the estimated GFR that occurred in the chlorthalidone group were probably due to better blood pressure control, which has been observed in other trials. At 2 weeks after chlorthalidone therapy was discontinued, the blood pressure remained below the baseline value, but the estimated GFR returned to approximately the baseline value, which suggests the additional involvement of tubuloglomerular feedback.”
The researchers advised that chlorthalidone be used with caution in patients receiving loop diuretics, primarily because of the risk of an increase in the serum creatinine level. “The lowest dose of chlorthalidone produced most of the blood-pressure-lowering effect, and this might be the safest dose to use. A reduction in the dose of the loop diuretic might be needed,” they recommended.
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