A retrospective analysis of Japanese health records linked esaxerenone with fewer incident cardiovascular events than spironolactone among people with hypertension. The difference was clearest for heart failure and atrial fibrillation, while associations with myocardial infarction and stroke were not statistically significant.
Over a median follow-up of 451 days, 1,060 cardiovascular events occurred. The incidence rate was 10.26 per 100 person-years among people starting esaxerenone and 15.03 among those starting spironolactone. The adjusted analysis estimated a hazard ratio of 0.80 for esaxerenone versus spironolactone, with a 95% confidence interval of 0.70 to 0.91.
How the comparison was made
The primary endpoint, or main outcome, was a composite measure of heart failure, atrial fibrillation, myocardial infarction and stroke. The researchers also examined each component separately and tracked hyperkalemia and acute kidney injury as safety outcomes.
The cohort used nationwide DeSC data from Japan and covered April 2014 through August 2024. It focused on people with hypertension who were new users of either esaxerenone or spironolactone.
Of 7,814 eligible new users, 38 people with missing proteinuria were excluded, along with 1,394 who had prior atrial fibrillation, myocardial infarction or stroke, 418 who had previously received eplerenone or finerenone, and four who received both study drugs. That left a final cohort of 5,960 people.
Esaxerenone is a nonsteroidal mineralocorticoid receptor antagonist, while spironolactone is a steroidal drug in the same class and served as the reference exposure. Because this was an observational comparison of new treatment starts, the findings describe an association rather than proving that one treatment caused the difference.
Among the final participants, 3,776 initiated esaxerenone and 2,184 initiated spironolactone. Median age was 73 years, 2,977 participants were men, median estimated glomerular filtration rate, or eGFR, was 66 ml/min/1.73 m², and 1,210 people, or 20%, had diabetes.
Researchers estimated propensity scores for esaxerenone initiation with logistic regression and used overlap weighting as the primary adjustment. Cox regression estimated hazard ratios with 95% confidence intervals. Subgroup analyses produced generally consistent patterns across age, sex, body mass index, systolic blood pressure, chronic kidney disease and diabetes, while multiple sensitivity analyses supported the robustness of the cardiovascular association.
Where the difference appeared
The clearest numerical difference was in heart failure. Its incidence was 8.49 per 100 person-years after esaxerenone initiation, compared with 12.41 after spironolactone initiation. The weighted hazard ratio was 0.80, with a 95% confidence interval from 0.70 to 0.92.
For atrial fibrillation, incidence was 1.07 per 100 person-years with esaxerenone and 1.84 with spironolactone. The hazard ratio was 0.63, with a 95% confidence interval of 0.44 to 0.91.
The pattern was less clear for myocardial infarction and stroke. Myocardial-infarction incidence was 0.36 per 100 person-years with esaxerenone and 0.37 with spironolactone, with a hazard ratio of 0.97 and a 95% confidence interval of 0.48 to 1.96. Stroke incidence was 1.65 versus 2.18, with a hazard ratio of 0.88 and a 95% confidence interval of 0.64 to 1.19. Neither association was statistically significant.
The study also found lower point estimates for the two safety outcomes with esaxerenone. Hyperkalemia had a hazard ratio of 0.69, with a 95% confidence interval of 0.47 to 1.03. Acute kidney injury had a hazard ratio of 0.33, with a 95% confidence interval of 0.16 to 0.69.
A cautious interpretation
The central limitation is the retrospective cohort design, which leaves potential residual confounding. Differences between the people who started each drug may still have influenced the results, even after the statistical adjustment. The study therefore does not establish that esaxerenone causes fewer cardiovascular events than spironolactone.
The authors interpret the findings as a possible sign of drug-specific differences within the mineralocorticoid receptor antagonist class and recommend further research.
Paper data and sources
Original title: Cardiovascular events with esaxerenone versus spironolactone in hypertension.
Authors: Takashin Nakayama, Hidehiro Kaneko, Yuta Suzuki et al.
Journal/Repository: Journal of human hypertension
Status: Peer-reviewed
First online: 2026-08-20
DOI: 10.1038/s41371-026-01200-2
Original paper · Full text