Baseline aldosterone may modify who benefits from MRAs in heart failure

Design

Pooled patient-level cohort analysis with trial-level meta-analysis

Population

Heart-failure cohorts (n = 1019) plus EARLIER (n = 300) and EPHESUS (n = 453)

Primary outcome

Association of MRA use with clinical outcomes by baseline aldosterone

Effect

High aldosterone HR 0.63 (95% CI 0.42 to 0.92); low aldosterone HR 1.66 (1.12 to 2.45); P for interaction 0.005

This analysis pooled patient-level data from heart-failure cohorts with plasma aldosterone measured (DOSE, CARRESS-HF, MDR and TOPCAT; n = 1019) and meta-analysed outcomes with the EARLIER and EPHESUS trials.

MRA use was associated with higher median aldosterone (310 vs 174 pg/mL). In a small cohort measuring mineralocorticoid receptor activity by urine sodium to potassium ratio (n = 136), starting an MRA reduced activity in patients with high baseline aldosterone but increased it in those with low baseline aldosterone.

In the pooled cohorts, the association of MRA use with outcomes depended on baseline aldosterone (P for interaction 0.005): HR 0.63 (95% CI 0.42 to 0.92) with high aldosterone, and HR 1.66 (1.12 to 2.45) with low aldosterone.

The authors themselves describe the findings as hypothesis-generating and state that MRAs remain guideline-directed therapy with population-level benefit. Aldosterone assays are not part of routine heart-failure care, so nothing here changes today's prescribing.

• Continue MRAs as per guidelines; the authors state that they remain guideline-directed therapy.
• Do not order aldosterone levels to decide on MRA treatment; this is an interaction signal from pooled observational data.
• Keep monitoring potassium and creatinine as usual after starting an MRA.
• Watch for prospective trials that stratify MRA therapy by aldosterone.

Why it matters

It raises the possibility that a drug class with established benefit works through a mechanism that fails in some patients.

Don't overread it

Pooled cohorts of mixed design cannot show that withholding an MRA from low-aldosterone patients would help; the authors call the findings hypothesis-generating.

The statistics, in plain English

A significant interaction P value (0.005) means the apparent effect of MRAs differed across aldosterone levels, which is stronger evidence than two separate subgroup results. It is still an association in pooled, partly non-randomised data, and a harmful signal in the low-aldosterone group could be confounded by who received an MRA.

Read the rest in the app

You have read your two free briefings this month. The app carries all 27 specialties, every morning, free — and this finding is waiting in it.

Get Daily Doctor — free

Scan to keep reading on your phone. No account needed to start.