Indapamide shows low incidence of severe hypokalaemia in patients with hypertension

In a territory-wide, 12-year follow-up retrospective study by the University of Hong Kong, indapamide has demonstrated a low incidence of hospitalization for severe hypokalaemia in patients with hypertension. Use of sustained-release (SR) indapamide appears to lower the risk of severe hypokalaemia vs the immediate-release (IR) formulation.

However, female patients and those on indapamide for <1 year had increased risk of hospitalization for severe hypokalaemia, highlighting the importance of regular monitoring of potassium levels. [Intern Emerg Med 2023;18:549-557]

Both international and Hong Kong guidelines recommend thiazide and thiazide-like diuretics as one of the first-line medications for hypertension. [Hypertension 2020;75:1334-1357; Hypertension 2018;71:1269-1324; Eur Heart J 2018;39:3021-3104; https://www.healthbureau.gov.hk/pho/rfs/src/pdfviewer/web/pdf/diabetescare/en/15_en_RF_DM_full.pdf] However, diuretics may induce electrolyte disturbances, such as hypokalaemia, which can lead to life-threatening events. [N Engl J Med 2009;361:2153-2164] “We aimed to examine the incidence of and factors associated with hospitalization for severe hypokalaemia in hypertensive patients on indapamide, a [thiazide-like] diuretic commonly used for hypertension in Hong Kong,” the researchers wrote. [Intern Emerg Med 2023;18:549-557]

Using electronic medical records of the Hospital Authority’s Clinical Data Analysis and Reporting System (CDARS), the researchers evaluated 62,881 patients with hypertension who received indapamide as a single diuretic, with a prescription start date between January 2007 and December 2016. The total follow-up was 147,319 person-years (PYs), and median follow-up was 1.4 years. In the study population, the patients’ median age at indapamide initiation was 66–67 years, and the median duration of indapamide use was 0.9–1.4 years.

From January 2007 to December 2018, 0.8 percent of the indapamide-treated patients (n=509) were admitted to hospital for severe hypokalaemia (incidence rate, 3.5/1,000 PYs). Of these patients, 53 percent and 30 percent had hospital admissions within the first year and first 16 weeks of indapamide treatment, respectively. The median hospital stay was 1 day, and the mortality rate was 0 percent.

Women had a higher incidence rate of hospitalization for severe hypokalaemia vs men (4.2 vs 2.5/1,000 PYs), as did patients treated with indapamide 2.5 mg IR vs 1.5 mg SR (3.8 vs 2.5/1,000 PYs) or those treated with indapamide for <1 year (<1 year, 25.9/1,000 PYs; 1–2 years, 4.6/1,000 PYs; 3–4 years, 1.5/1,000 PYs; ≥5 years, 0.5/1,000 PYs). Higher hospitalization rates were also found in patients started on indapamide at ≥80 years vs ≤79 years of age (5.7 vs 3.0–3.4/1,000PYs).

In multivariable logistic regression analysis, the risk of hospitalization for severe hypokalaemia was associated with gender, treatment duration, and pharmaceutical formulation. Women were found to have a higher hospitalization risk than men (adjusted odds ratio [adjOR], 1.75; 95 percent CI, 1.45–2.12; p<0.001). Hospitalization risks were also higher in patients receiving indapamide 2.5 mg IR vs 1.5 mg SR (adjOR, 1.41; 95 percent CI, 1.14–1.75; p=0.002) and those taking indapamide for <1 year vs ≥5 years (adjOR, 2.75; 95 percent CI, 1.93–3.92; p<0.001). However, patients’ age at indapamide initiation was not significantly associated with hospitalization risk (p=0.92).

“With a reduced risk of hypokalaemia, [1.5 mg] SR indapamide could be the preferred formulation [over 2.5 mg IR indapamide],” the researchers suggested. “Regular monitoring of potassium levels remains essential, particularly in female patients and in the first few months of indapamide treatment.”

“In Hong Kong, the trend of indapamide initiation decreased between 2007 and 2016 … Despite multiple reasons for the declining use of indapamide, our study would redress that [indapamide-associated] severe hypokalaemia is rare [and manageable],” the researchers noted.