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GALACTIC Trial Reveals Less Successful RAAS Inhibitor Uptitration in Women Than Men


Uptitration of renin-angiotensin-aldosterone system (RAAS) inhibitors was less successful in women than men with acute heart failure (AHF), especially in those with HF with reduced ejection fraction.

Among patients with acute heart failure (AHF), rapid uptitration of renin-angiotensin-aldosterone system (RAAS) inhibitors was not as effectively executed in women compared with men, which may help explain women’s increased risk of all-cause mortality and readmission for AHF.

These findings were published in the European Journal of Heart Failure and are based on the results of the GALACTIC randomized controlled trial.

“Sex-specific differences in AHF are both relevant and underappreciated,” the study investigators said. “Therefore, it is crucial to evaluate the risk/benefit ratio and the implementation of novel AHF therapies in women and men separately.”

The investigators randomized 781 patients with AHF into 2 groups, with one group receiving an early, intensive, and sustained vasodilation strategy and the other receiving standard care. Inclusion criteria required patients with AHF to also have elevated plasma natriuretic peptide levels, systolic blood pressure of at least 100 mmHg, and a plan for treatment in a general ward. Of the 781 eligible patients, 288 (37%) were women, and these women were generally older than the men in the study, with a median age of 83 years vs 76 years. Compared with men, women also had a lower body weight with a median of 64.5 kg vs 77.6 kg, as well as a lower estimated glomerular filtration rate with a median of 48 ml/min per 1.73 m2 vs 54 ml/min per 1.73 m2.

Generic pills | Image Credit: Mr.Ilkin – stock.adobe.com

Generic pills | Image Credit: Mr.Ilkin – stock.adobe.com

The primary outcome was a combination of all-cause mortality or rehospitalization for AHF within 180 days, and the study revealed a significant interaction between the treatment strategy and sex when adjusted for female sex (adjusted HR, 1.62; 95% CI, 1.05-2.50; P = .03). The combined endpoint of mortality and rehospitalization occurred in 53 women (38%) in the intervention group and 35 women (24%) in the standard care group. This included 23 deaths among women receiving higher doses of vasodilators and 17 deaths among women receiving standard care.

Additionally, RAAS inhibitor uptitration was less successful in women than men in the overall patient cohort, especially in those with HF with reduced ejection fraction (HFrEF). The median discharge percentage target dose in patients randomized to intervention was 50% in women and 75% in men.

This study yielded 5 key findings highlighted by the investigators. First, women in the study tended to be older, have lower body weight, have more advanced renal dysfunction, and be more frequently affected by hypertensive HF with preserved ejection fraction (HFpEF) compared with men—all of which are characteristics consistent with prior HF trials.

Second, women who received early intensive and sustained vasodilation exhibited a higher likelihood of experiencing the combined primary endpoint of all-cause mortality and HF rehospitalization at 180 days compared to the control group. This suggests a more pronounced effect of chronic HF treatment such as RAAS inhibitor use on mortality and HF readmission in women, rather than a delayed response to vasodilators.

Third, the implementation of early vasodilation and afterload reduction was successful for both men and women. However, the rapid uptitration of RAAS inhibitors was less effective in women, even though they presented significantly higher systolic blood pressure values during hospitalization.

Fourth, when considering patients with HFrEF, women received a significantly lower percentage of the target dose of RAAS inhibitors at discharge compared with men, as women with HFrEF who received less than or equal to 50% of the target dose had worse outcomes. In contrast, men randomized to vasodilation underwent faster uptitration of RAAS inhibitors and achieved a higher percentage of the target dose at discharge, potentially explaining the modest benefit observed in the treatment arm.

Finally, women in the intervention group had a higher heart rate compared with those in the control group, which could indicate either undertreatment—particularly with beta blockers—or that their treatments are contributing to worsened outcomes. The unfavorable outcomes observed in women during this clinical trial may also be linked to sex-specific treatment variations, side effects, and distinctions in the fundamental characteristics of AHF in women.

“Despite having similar hemodynamic profiles, the rapid up-titration of RAAS inhibitors was less successfully implemented in women, possibly resulting in a higher rate of death or AHF readmission versus usual care,” the investigators concluded. “Additionally, sex-specific dosages of current and future HF therapies warrant further studies and increased attention, as this trial rather discourages the use of lower and sex-specific doses of RAAS inhibitors in women with HFrEF.”


Wussler D, Belkin M, Maeder MT, et al. Comprehensive vasodilation in women with acute heart failure: novel insights from the GALACTIC randomized controlled trial. Eur J Heart Fail. Published online October 23, 2023. doi:10.1002/ejhf.3065

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