Hypokalemia During Decongestion With Loop Diuretics and Hydrochlorothiazide, a Post Hoc Analysis of the CLOROTIC Trial

Abstract

Background: In patients with acute heart failure, the addition of hydrochlorothiazide (HCTZ) to furosemide increased the diuretic response in the CLOROTIC trial (Combining Loop with Thiazide Diuretics for Decompensated Heart Failure). The aim of this subanalysis was to evaluate the incidence and risk factors for hypokalemia, and its impact on mortality and readmissions.

Methods: This is a post hoc analysis of the CLOROTIC trial that randomized 230 patients with acute heart failure and volume overload to receive HCTZ or placebo in addition to intravenous furosemide. The incidence and risk factors for the development of hypokalemia (K⁺ <3.5 mmol/L) and its association with 30- and 90-day mortality and readmissions were analyzed. The Monte Carlo simulation method was applied to predict the development of hypokalemia.

Results: The incidence of hypokalemia was significantly higher in the HCTZ group (compared with the placebo group) at 48 and 96 hours after randomization, and at discharge (P<0.001). In a multivariate analysis, the following variables were independently associated with the development of hypokalemia: baseline K⁺ values (OR per 0.1 units, 0.82 [95% CI, 0.76-0.87]; P<0.001), treatment with HCTZ (OR, 4.90 [95% CI, 2.50-9.90]; P<0.001), and treatment with a mineralocorticoid receptor antagonist at baseline (OR, 0.42 [95% CI, 0.20-0.84]; P=0.017). There was no association between the development of hypokalemia and 30- and 90-day mortality and readmissions. The Monte Carlo simulation method predicted in patients treated with furosemide alone a higher risk of hypokalemia when baseline K⁺ values are ≤3.7 mmol/L. When HCTZ is added to furosemide, the risk of hypokalemia is present with higher baseline K⁺ values (≤4.3 mmol/L).

Conclusions: Adding HCTZ to intravenous furosemide increases the risk of hypokalemia a especially when baseline K⁺ is ≤4.3 mmol/L and when patients are not treated with a mineralocorticoid receptor antagonist. In patients treated with furosemide and HCTZ, it is advisable to add potassium supplements or a mineralocorticoid receptor antagonist.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01647932.

Keywords: diuretics; heart failure; hypokalemia; potassium; risk factors.