In the analysis of more than 13,000 patients with ACS and no history of cardiovascular (CV) disease, the women who had taken beta blockers for hypertension showed about a one-third increased risk for heart failure (HF) at the time of their ACS presentation.
The difference between women and men was especially pronounced among patients with ST-segment-elevation myocardial infarction (STEMI), compared with those with non-ST-segment-elevation myocardial infarction (NSTEMI).
No such relationship between sex and risk for HF with ACS was observed among the larger portion of the cohort that had not previously been treated with beta blockers, according to a report published July 13 in Hypertension, with lead author Raffaele Bugiardini, MD, University of Bologna, Italy.
Mortality at 30 days was sharply higher for patients with than without HF at their ACS presentation, by more than sevenfold for women and more than ninefold for men.
“Our study provides robust evidence of an interaction between sex and beta blocker therapy and suggests an increased risk of HF among women presenting with incident myocardial infarction,” Bugiardini told theheart.org | Medscape Cardiology.
Given their novelty, “our findings raise strong concern about the appropriate role of beta blockers in the therapy of hypertension in women with no prior history of cardiovascular diseases. Beta blocker use may be an acute precipitant of heart failure in women presenting with incident ACS as first manifestation of coronary heart disease.” Bugiardini and his colleagues write.
“There is one main implication for clinical practice. Discontinuing a beta blocker in an otherwise healthy woman with hypertension and no prior CV disease is not harmful and could be wise,” Bugiardini said when interviewed. “Blood pressure in women may be regulated in a safer way, such as using other medications and, of course, through diet and exercise.”
Rationale for the Study
Men and women “differ with respect to the risk, causes, and prognosis of HF,” Bugiardini and colleagues write, and current guidelines “do not differentiate between the use of beta blockers in men and in women.”
However, they propose, “Because prior trials and meta-analyses enrolled nearly 5 men for every woman, any differences in the effect of beta blockers among women would have been concealed by the effect of beta blocker therapy among men.”
The current study looked at data from October 2010 to July 2018 in the ISACS ARCHIVES, ISACS-TC, and the EMMACE-3X registries, covering 13,764 patients, from 12 European countries, who had a history of hypertension and presented with confirmed ACS.
Of the combined cohort, 2590 (19%) had been treated with beta blockers prior to their ACS presentation. They were similar to those without a history of beta blocker use with respect to baseline features and use of other medications in an adjusted analysis.
In the group with prior beta blocker use, 21.3% of the women and 16.7% of the men had HF of Killip class 2 or higher, a 4.6% absolute difference that worked out to a relative risk (RR) ratio of 1.35 (95% CI, 1.10 – 1.65).
The corresponding rates for women and men without prior beta blocker use were 17.2% and 16.1%, respectively, for an absolute difference of only 1.1% and an RR ratio 1.09 (95% CI, 0.97 – 1.21).
The interaction between sex and beta blocker therapy for the HF outcome was significant (P < .034).
An analysis that excluded patients in cardiogenic shock at their ACS presentation produced similar results.
In an analysis only of patients with STEMI, the RR ratio for HF in women vs men was 1.44 (95% CI, 1.12 – 1.84) among those with a history of beta blocker use, and 1.11 (95% CI, 0.98 – 1.26) among those who hadn’t used the drugs. The interaction between sex and beta blocker use was significant (P = .033).
No such significant interaction was seen for the subgroup with NSTEMI as their index ACS (P = .14).
Heart failure at ACS was the most powerful observed predictor of 30-day mortality in women and in men in multivariate analysis; the odds ratios were 7.54 (95% CI, 5.78 – 9.83) and 9.62 (95% CI, 7.67 – 12.07), respectively.
“Our study underscores the importance of sex analyses in clinical research studies, which may provide further actionable data,” Bugiardini stated. “Failure to include both sexes in therapeutic studies is a missed opportunity to uncover underlying sex-specific risks. The adverse effect of beta blocker therapy in women with hypertension is a sex-specific risk,” he said.
Not Just a Male Disease
Part of the study’s conclusions are “really not that surprising, because we have known for a long time that women who have an MI are much more likely to develop HF than men, and we also know that HF raises mortality after MI,” Ileana L. Pina, MD, MPH, Wayne State University, Detroit, told theheart.org | Medscape Cardiology.
But what surprised her, she said, was that women taking beta blockers were at greater risk for HF. “This association needs to be proven in a prospective study and confirmed in another dataset,” said Pina, who was not involved with the current study.
“The most important message is to remember that HF is not just a ‘male’ disease and to pay attention to the symptoms of women and not discount or relegate them to anxiety or gastric problems.”
The study was observational, Bugiardini noted, so “the results may have some variance and need confirmation. However, a sex-stratified, randomized controlled trial of beta blocker therapy in patients with hypertension but no prior history of coronary heart disease or HF may not be considered ethical, since it would be designed to confirm risk…and not benefit.”
“Further observational studies may give confirmation,” he added. “In the meantime, the Food and Drug Administration should alert healthcare professionals of the adverse events associated with beta blocker use in women with hypertension and no prior history of CV disease, [because] prescribing beta blockers to a woman with hypertension means exposing her to unnecessary risk.”
Bugiardini and the other authors had no disclosures. Pina reported no relevant financial relationships.
Hypertension. Published online June 13, 2020. Abstract