Higher Risk of HF After ACS for Women Previously on Beta-blockers

Prescribing beta-blockers to women with hypertension exposes them to unnecessary risk, say investigators.

Higher Risk of HF After ACS for Women Previously on Beta-blockers

The use of beta-blockers for the treatment of high blood pressure appears to increase the risk of heart failure among women presenting with acute coronary syndromes, according to a new analysis.

Among men and women taking beta-blockers for hypertension prior to hospitalization for ACS, women had an absolute 4.6% higher risk of heart failure compared with men at the time of hospital presentation. The absolute difference in the rate of heart failure was even more pronounced in STEMI, where women taking beta-blockers for their high BP had an absolute 6.1% higher rate of heart failure compared with men taking the drugs.

On the basis of these results, published in Hypertension this week, lead author Raffaele Bugiardini, MD (University of Bologna, Italy), said he believes beta-blockers should not be prescribed to women for the treatment of hypertension in the absence of cardiovascular disease until there is evidence the drugs are safe.

“Professional bodies should alert healthcare professionals of the adverse events associated with beta-blocker use in women with hypertension and no prior history of cardiovascular disease [since] prescribing beta-blockers to a woman with hypertension means exposing her to unnecessary risk,” he told TCTMD. “On the other hand, blood pressure in women may be regulated in a more safe way, such as using other medications and of course through diet and exercise.”

Confirmation of these study findings are important, said Bugiardini, but he noted that beta-blockers are old drugs and there is little interest in spending money on new studies for these agents. A sex-stratified clinical trial testing beta-blocker use in women with hypertension and no prior history of cardiovascular disease or heart failure wouldn’t be considered ethical either, since it would be designed to confirm risk rather than benefit. “Further observational studies may give confirmation, but these should be done soon,” he said.   

The adverse effect of beta-blocker therapy in women with hypertension is a sex-specific risk. Raffaele Bugiardini

The 2017 US guidelines for the treatment of hypertension recommend thiazide diuretics, calcium-channel blockers, and ACE inhibitors or ARBs as first-line agents for the treatment of hypertension. Beta-blockers, in contrast, are not to be used as first-line therapy unless a patient has ischemic heart disease or heart failure. In Europe, it is recommended that patients with hypertension be treated with an ACE inhibitor or ARB plus a calcium-channel blocker or diuretic for initial therapy. Beta-blockers can be used as an add-on or when there is a specific indication for use, according to the European Society of Cardiology guidelines.

Risk of HF After STEMI Higher in Women

To TCTMD, Bugiardini said that it has long been known that, after MI, women are much more likely to develop heart failure than men. In a study the group published in 2019, they showed women were at a much higher risk of developing de novo heart failure after STEMI and that these women with heart failure had significantly worse survival than their male counterparts. This led them to suggest that de novo heart failure might explain the “mortality gap” between men and women after STEMI. Bugiardini also noted that beta-blockers are contraindicated in patients with overt heart failure because of their adverse effects on myocardial contractility. Given all of this, they hypothesized that beta-blocker use may be an acute precipitant of heart failure in women presenting with ACS as the first manifestation of cardiovascular disease.     

The new study focused on 13,764 men and women included in the International Survey of Acute Coronary Syndromes (ISACS), a database that contains patients from research cohorts and clinical trials in ACS. Of these, 2,590 patients were treated with beta-blockers before the index event. In terms of the sex-based differences, women were older than men in the registry, and a larger proportion had a history of diabetes, hypercholesterolemia, and chronic kidney disease. Women were more likely than men to receive standard medical therapy prior to the index ACS.

In total, 21.3% of women treated with beta-blockers prior to admission had heart failure (Killip class ≥ 2) at the time of ACS presentation compared with 16.7% of men (RR 1.35; 95% CI 1.10-1.65). In contrast, there was no difference in the rate of heart failure at the time of ACS presentation between men and women not taking beta-blockers. The test for interaction showed a significant association between beta-blocker therapy and sex (P < 0.034). A significant interaction was also seen when investigators restricted the analysis to patients with mild-to-moderate heart failure and when they included patients with Killip class 2/3 heart failure.    

When the analysis was restricted to patients presenting with STEMI, 24.8% of women who had heart failure at the time of admission were treated with beta-blockers compared with 18.7% of men (RR 1.44; 95% CI 1.12-1.84). There was no difference in the rate of heart failure between men and women presenting with STEMI if they were not taking beta-blockers prior to hospital admission. Again, the interaction between sex and beta-blocker therapy was significant (P = 0.033).

Heart failure at the time of presentation was predictive of mortality at 30 days in both men and women.

Two Key Questions

Franz Messerli, MD (University Hospital Bern, Switzerland), who wasn’t involved in the study, said the new findings raise two important questions. This first: why is a drug class that is the cornerstone of treatment for heart failure harmful when used for its prevention? The second, why is there a sex difference?

“All textbooks and guidelines teach that beta-blocker therapy for heart failure should begin at very low doses and the dose should be doubled at intervals of 2 weeks or more until the target dose is reached or symptoms become limiting,” he commented in an email to TCTMD. “These patients have been on a full dose of beta-blockers for antihypertensive therapy. When there is an acute drop in ejection fraction because of an ACS, the beta-blocker dose is far too excessive. Its powerful negative inotropic effect will override potential benefits from blocking catecholamine surges. Little surprise that beta-blockers accelerate the patient’s demise in this situation, particularly in those with higher Killip classes.” 

When there is an acute drop in ejection fraction because of an ACS, the beta-blocker dose is far too excessive. Franz Messerli

In terms of the mechanisms explaining the increased risk of heart failure in women, Bugiardini said it’s possible there may be an interaction between hormone replacement therapy and beta-blockers, with progestin inhibiting the cardiac expression of beta-1-adrenoreceptors and reducing beta-adrenergic-mediated stimulation. This, in turn, may decrease cardiac output and predispose women to heart failure during ACS, he said. Also, women have higher resting levels of left-sided cardiac work. “This mechanism may be more harmful in women during coronary occlusion and ischemia,” said Bugiardini.

For Messerli, the likeliest explanation for the sex difference, a reason also put forward by Bugiardini and colleagues, is that women may be less tolerant of beta-blockers as they have different bioequivalence to therapy due to enhanced absorption and lower distribution volume given their smaller size and different body composition. “In acute heart failure, the same beta-blocker dose as used for hypertension will exert more of a negative inotropic effect in women than in men,” said Messerli.  

Overall, the study underscores the importance of sex-based analyses in clinical research as the findings might reveal critical differences between men and women, say the researchers. “Failure to include both sexes in therapeutic studies are missed opportunities to uncover underlying sex-specific risks,” said Bugiardini. “The adverse effect of beta-blocker therapy in women with hypertension is a sex-specific risk.”

  • Bugiardini and Messerli report no conflicts of interest.

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