Personalized medicine: women in heart failure clinical trials, a must!

We read with great interest the paper by Merrill et al. (1) reporting that spironolactone is associated with a reduction in all-cause mortality in women but not in Letters to the Editor JACC: HEART FAILURE VOL. 7, NO. 8, 2019 AUGUST 2019:731 – 4 732 Author's Personal Copy men with heart failure with preserved ejection fraction, enrolled in the TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) trial (2). The authors should be congratulated for exploring differences in clinical response to drugs between men and women. Their analyses highlight the importance of stratified randomization by sex and sample sizes large enough to make conclusions in both men and women. The random assignment of treatment is an essential feature of randomized clinical trials (RCT) that maximizes comparability between treatment groups. Subgroup analyses are often performed to estimate the effect of the drug based on specific characteristics, such as patient sex. However, subgroup analyses have limitations including not adjusting for covariates. Because randomization is not usually stratified by sex, women and men, despite being randomized to treatment, may not have comparable clinical characteristics. In fact, in stratifying by sex, Merrill et al. (1) uncovered how women and men had a significantly different clinical profile. Women were older, with fewer comorbidities (i.e., coronary artery disease and atrial fibrillation), but with higher blood pressure and body mass index. Such imbalances between women and men highlight the need for randomization stratified by sex.