(BSPOT04) Comparing the Risk of Metoprolol-Related Adverse Drug Events Between Women and Men with Heart Failure Using Effectiveness Outcomes as a Proxy: a Population-Based Cohort Study using CPRD

Background: Women using cardiovascular drugs have a higher adverse drug event (ADE) risk than men, which may negatively affect the benefit they derive from treatment. This is especially relevant for heart failure (HF) because literature suggests a sex-specific approach to treatment may reduce ADE risk in women.

Objectives: To compare the effectiveness and safety of metoprolol between women and men with HF using carvedilol as an active comparator.
We hypothesize that metoprolol is associated with a higher ADE risk and thus lower effectiveness in women.

Methods: We used a new user active comparator design and data from the United Kingdom Clinical Practice Research Datalink GOLD, which comprises general practitioner data from over 40 million patients. We included all individuals aged ≥ 18 years with an HF diagnosis between 1Jan2012 and 27Jun2023. Index date was the first prescription of either metoprolol or carvedilol. New users were defined as having no beta-blocker prescription 1 year before index date. To ensure treatment was HF-related, we excluded patients whose index date was >3 months away from their HF diagnosis. Treatment episodes were calculated using a permissible gap of 58 days between consecutive prescriptions. Outcomes were (1) all-cause mortality; (2) treatment discontinuation; (3) hypotension, bradycardia, and renal impairment (known ADEs). They were identified with Read codes except treatment discontinuation. Follow-up was 5 years or until data availability, or the first of (1) and (2). We used a Cox proportional hazards model to calculate hazard ratios (HR) and 95% confidence intervals (CI). Confounding by age, comorbidities, concomitant medications, smoking status, alcohol consumption, and body mass index was controlled by propensity score matching. Each outcome was analysed separately.

Results: We included 24,559 patients (49% metoprolol users, 43% women) with an average age of 64.5 years. The metoprolol group had fewer comorbidities and concomitant medications than the carvedilol group . Propensity score matching created a cohort of 6562 women and 8216 men (standard mean difference for all covariates 0.09 and 0.07, respectively). Metoprolol lowered all-cause mortality risk less strongly in women (HR=0.72, 95%CI 0.56-0.91) than in men (HR=0.43, 95%CI 0.33-0.55). Metoprolol was associated with a similar increase in discontinuation risk (HR=1.10,95%CI 1.05-1.16; HR=1.10, 95%CI 1.06-1.16, respectively) but decrease in ADE risk (HR=0.50, 95%CI 0.34-0.73; HR=0.47, 95%CI 0.34-0.64, respectively) in both sexes.

Conclusions: Contrary to our hypothesis, metoprolol was associated with a lower risk of all-cause mortality and ADEs in both women and men. The effect was stronger than expected based on clinical trials, warranting further investigation.