Long-term indapamide helps prevent death, cardiac events in at-risk patients

Long-term treatment with indapamide with or without perindopril-based therapy results in a significant reduction in the risk of all-cause mortality, cardiovascular death, fatal stroke, and total stroke among patients with medium to high cardiovascular risk, according to a pooled analysis of four trials.

“Across medium to high cardiovascular risk population, long-term indapamide, mostly combined with perindopril-based treatment, provided evidence of benefit on mortality and morbidity,” the researchers said.

Data were pooled from four randomized controlled trials conducted with matching placebo: PATS (indapamide), PROGRESS (indapamide and perindopril), ADVANCE (single-pill combination perindopril/indapamide), and HYVET (indapamide and an option of perindopril).

The researchers reported the pooled effect (fixed and random) estimate (hazard ratio, with corresponding 95 percent confidence intervals and p values). They also analysed treatment discontinuations to determine the net benefit of indapamide.

A total of 24,194 patients were included (12,113 active and 12,081 placebo). Low statistical heterogeneity was observed on fixed-effects meta-analysis of the three mortality endpoints (I²=0). [J Hypertens 2023;41:508-515]

Compared with placebo, indapamide with or without perindopril-treatment led to statistically significant risk reductions for all-cause death (‒15 percent), cardiovascular death (‒21 percent), fatal stroke (‒36 percent), and all strokes (‒27 percent). Improvements were also noted in other cardiovascular outcomes (risk reduction, 22‒36 percent).

Treatment discontinuation for safety reasons were almost twofold higher in the active group (6.4 percent vs 3.9 percent). However, discontinuation for any reason was comparable between treatment groups (18.4 percent vs 18.0 percent).

The findings on aggregate risk reduction with indapamide were consistent with the effect of the thiazide-like diuretic class on major cardiovascular and mortality outcomes. [JAMA 2003;289:2534-2544; J Hypertens 2015;33:195-211; Cochrane Database Syst Rev 2018;4:CD001841]

“Although the positive benefits demonstrated by the meta-analysis of these four randomized trials might seem obvious to some readers familiar with all four studies, it should be noted that they were published over a span of many years, ranging from 1995 to 2014,” the researchers said.

“Furthermore, two trials deal with poststroke events, two reports concern a population with type 2 diabetes, and one deals with very elderly patients, over 80 years of age, so that many readers may have missed the main results of some of these trials,” they added. [Lancet 2001;358:1033-1041; Eur Heart J 2003;24:475-484; Lancet 2007;37:829-840; N Engl J Med 2008;358:1887-1898]

Two other meta-analysis reported the cardiovascular benefit of thiazide-like diuretics, particularly the protective effect against cardiac events, heart failure, and stroke or coronary events and all-cause mortality. [Am J Hypertens 2015;28:1453-1463; Hypertension 2015;65:1033-1040]

“Many publications suggest that indapamide is an effective and well tolerated diuretic for hypertensive patients, in particular in improving micro-albuminuria (in diabetic individuals), reducing left ventricular mass index, inhibiting platelet aggregation, and reducing oxidative stress,” the researchers said. [Drugs 2006;66:257-271; Hypertension 2015;65:983-984; Am J Cardiol 2011;107:1178-1184]

The present meta-analysis was limited by the use of aggregate and not individual patient data. Additionally, some unpublished data or previously published data were obtained from the investigators to reinforce the robustness of the results, according to the investigators.