Men and women react differently to common drugs used to treat heart failure with reduced ejection fraction (HFrEF), according to findings from a new European study, and women may be able to safely cut their doses in half and get the same level of relief as that provided by larger doses.

“This study ... brings into question what the true optimal medical therapy is for women versus men,” the study authors, led by Bernadet T. Santema, MD, of the University Medical Center Groningen (the Netherlands), wrote in an article published in the Lancet.

Dr. Santema and colleagues noted that current guidelines for the use of ACE inhibitors or angiotensin-receptor blockers (ARBs) and beta-blockers for men and women with heart failure do not differentiate between the genders, despite findings showing that, “with the same dose, the maximum plasma concentrations of ACE inhibitors, ARBs, and beta-blockers were up to 2.5 times higher in women than in men.”

In addition, the researchers wrote, women are much more likely than men to suffer side effects from medications, and the effects tend to be more severe.

HFrEF accounts for an estimated 50% of the 5.7 million patients with heart failure in the United States (Nat Rev Dis Primers. 2017 Aug 24. doi: 10.1038/nrdp.2017.58; Card Fail Rev. 2017;3[1]:7-11.)

For the new study, researchers launched an ad hoc analysis of the findings of a prospective study of HFrEF patients in 11 European countries (1,308 men and 402 women) who took drugs in the three classes. Patients were receiving suboptimal medication doses at the start of the study, and physicians were encouraged to increase their medication. The median follow-up for the primary endpoint was 21 months.

“In men, the lowest hazards of death or hospitalization for heart failure occurred at 100% of the recommended dose of ACE inhibitors or ARBs and beta-blockers, but women showed about 30% lower risk at only 50% of the recommended doses, with no further decrease in risk at higher dose levels,” the researchers wrote. “These sex differences were still present after adjusting for clinical covariates, including age and body surface area.”

The researchers analyzed an Asian registry (3,539 men, 961 women) as a comparison and found the identical numbers.

“Our study provides evidence supporting the hypothesis that women with HFrEF might have the best outcomes with lower doses of ACE inhibitors or ARBs and beta-blockers than do men, and lower doses than recommended in international guidelines for heart failure,” they wrote. However, they added that it was not likely that sex-specific studies analyzing doses would be performed.

In an accompanying editorial, Heather P. Whitley, PharmD, and Warren D. Smith, PharmD, noted that clinical research has often failed to take gender differences into account. They wrote that the study – the first of its kind – was well executed and raises important questions, but the analysis did not take into account the prevalence of adverse effects or the serum concentrations of the various medications. Although those limitations weaken the findings, the study still offers evidence that gender-based, drug-dose guidelines deserve consideration, wrote Dr. Whitley, of Auburn (Ala.) University, and Dr. Smith, of Baptist Health System, Montgomery, Ala (Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736[19]31812-4).

The study was funded by the European Commission. Several study authors reported various disclosures. Dr. Whitley and Dr. Smith reported no conflicts of interest.

SOURCE: Santema BT et al. Lancet. 2019 Aug 22. doi: 10.1016/S0140-6736(19)31792-1.

Drug doses for heart failure could possibly be halved for women