Research out of the Netherlands suggests current clinical guidelines might recommend overtreatment for women with heart failure, who see maximum benefit from HF drugs at half the dose of men.
Drugs like angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers (ARBs) and beta-blockers are the gold standard for HF therapy, first author Bernadet T. Santema, a PhD candidate at University Medical Center Groningen, and colleagues wrote in The Lancet. But while pharmacological studies have established sex differences in the pharmacokinetics of these medications—at the same dose, maximum plasma concentrations of all three drug classes were up to 2.5 times higher in women than in men—society guidelines still promote sex-neutral target doses.
Santema et al. explained that since women typically have lower bodyweights, a higher proportion of body fat and lower plasma volume than men, they’re more likely to see a longer duration of action of lipophilic drugs and higher peak plasma concentrations of hydrophilic drugs than their male counterparts. And overtreating women can be dangerous—they have a 50% to 70% increased risk of experiencing adverse drug reactions compared to men.
Santema and her team performed a post-hoc analysis of BIOSTAT-CHF, a prospective study of patients in 11 European countries who were recommended for initiation and up-titration of ACE inhibitors or ARBs and beta-blockers. The researchers limited their study to patients with left ventricular ejection fraction of less than 40% and excluded people who died within the first three months of treatment.
Ultimately, Santema and her co-authors’ study population comprised 1,308 men and 402 women with HF with reduced ejection fraction (HFrEF). On average, women in the study were older, shorter and had lower bodyweights than men, but BMI didn’t differ significantly between the sexes.
A similar number of men and women reached guideline-recommended target doses of ACE inhibitors or ARBs (25% vs. 23%, respectively), and beta-blockers (14% vs. 13%, respectively). Santema’s team found that in men, the lowest risks of death or hospitalization for HF occurred at 100% of the recommended dose of ACE inhibitors, ARBs and beta-blockers; in women, risk was 30% lower at 50% of the recommended doses, with no further decrease in risk at higher dose levels.
The authors said their observed sex differences persisted after adjusting for clinical covariates. They validated their results in an independent cohort of 3,539 men and 961 women with HFrEF in the ASIAN-HF study, again finding women achieved 30% reduced risk at half the dose of men.
Santema et al. said their study suggests women with HFrEF might need lower doses of ACE inhibitors, ARBs and beta-blockers than men, seriously calling into question the optimum dosages of the drugs and the accuracy of society guidelines.
“Because of the under-representation of women with HFrEF in all previous clinical drug trials, and in the absence of prospective sex-specific dose-finding clinical trials of current therapies, this is the best available evidence with regards to the optimal dose levels of medication for heart failure in men and women separately,” the authors wrote.
In a related comment, editorialists Heather P. Whitley and Warren D. Smith, both of the Auburn University Harrison School of Pharmacy, called Santema and co-authors’ study a “thoughtful and thorough investigation” that draws attention to something important in HFrEF research.
“This post-hoc analysis sheds light on an area otherwise devoid of data needed to tailor HFrEF pharmacotherapy by sex,” they wrote. “Although adverse drug reaction rates were not directly evaluated in Santema and colleagues’ study, the observation of maximum therapeutic benefits for women being achieved at a lower dose is an important finding.”