The use of beta-blockers for heart failure with reduced ejection fraction in the era of SGLT2 inhibitors - are westill afraid to up-titrate?

Heart Vessels . 2025 Sep;40(9):797-804.doi: 10.1007/s00380-025-02525-7.

Abstract

Beta-blockers are one of the four major pillars of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF). The therapy has presented the best effects when up-titrated to evidence-based target doses. Despite their proven benefits, physicians have traditionally shown reluctance to up-titrate beta-blockersbecause of their negative inotropic and chronotropic effects. The effects of newly introduced sodium-glucose cotransporter 2 inhibitors (SGLT2I) in treating heart failure with reduced ejection fraction might open more room for adequate beta-blockers up-titration. The goal of this study was to evaluate the up-titration practice, and impact of target doses of beta-blockers in patients with heart failure with reduced ejection fraction receiving SGLT2I. This is aprospective cohort study involving patients with heart failure with reduced ejection fraction receiving SGLT2I therapy. Baseline use and dosing to the evidence-based targets were examined. We compared the groups of patientsreceiving maximally titrated beta-blockers versus incompletely titrated. Primary outcome was composite of (1) rehospitalization or revisit to emergency unit due to the heart failure; (2) all-cause death and major adverse cardiacevents (MACE). Secondary outcomes were heart rate at rest, left ventricular ejection fraction, NT-proBNP, and NYHA status at 6 and 12 months of follow-up. Study endpoints were documented via telephone interviews, regular outpatientfollow-up, or by electronic hospital records. This study included a total of 458 patients with median follow-up time of 365 (186-502) days. A total of 122 (26.6%) patients hadbeta-blockers maximally up-titrated. The results show that adherence to maximal target doses of β-blocker therapy significantly reduces hazard of death or major adverse cardiac events comparing to not using maximal doses of β-blocker (factor 0.43). Hazard reduction was not statistically significant for composite of rehospitalization or revisit to emergency unit due to HF. Maximal doses of beta-blockers did not result in a significant decrease in resting heart rate. Our real-world data have highlighted the prevalence of incomplete titration of beta-blockers. Although it has been shown that evidence-based target dosing of beta-blockersreduces death and major adverse cardiac events, there is still room for improvement with up-titrating beta-blockers in eligible patients.

Disclaimer:

Lupin makes no representation or warranty of any kind, expressed or implied, regarding the accuracy, adequacy, validity, reliability, availability, or completeness of any scientific information shared by the HCP on the ­­­STARUPDATE podcast. You should not allow the contents of this to substitute for your own medical judgment, which you should exercise in evaluating the information on this website.

Angiotensin receptor-neprilysin inhibitors and mortality among patients with heart failure with reducedejection fraction

https://doi.org/10.1016/j.amjcard.2025.08.063

Abstract

Background

While trial evidence supports the benefit of angiotensin receptor-neprilysin inhibitor (ARNI) therapy in heart failurewith reduced ejection fraction (HFrEF), its effectiveness in routine clinical practice is less explored. This study investigated the relative and absolute effectiveness of ARNI in patients with heart failure with reduced ejectionfraction.

Methods

This nationwide Danish database study included patients with left ventricular ejection fraction (LVEF) ≤40%,2018–2023. Using a prevalent new user design, 2,446 ARNI initiators were matched 1:2 to 4,892 users of angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) based on propensity scores, age, LVEF,and NT-proBNP. The primary outcome was all-cause mortality; secondary outcomes were cardiovascular mortality and hospitalization.

Results

There were 279 deaths among ARNI initiators(5.6/100 person-years) and 533 among ACE-I/ARB users (6.7/100 person-years), yielding a hazard ratio (HR) of 0.85 (95% CI, 0.74–0.98) for all-cause mortality. A significant interaction was observed for recent hospitalization (p=0.04),with ARNI yielding a lower hazard ratio in this group. hazard ratios were otherwise consistent across age, sex, left ventricular ejection fraction, NT-proBNP, NYHA class, ischemic heart disease, chronic kidney disease, and type2 diabetes. The largest absolute mortality reductions were seen in subgroups with recent hospitalization, NYHA class III–IV, and severely elevated NT-proBNP. ARNI was also associated with a lower risk of cardiovascular death (HR, 0.81; 95% CI, 0.65–0.99), but not with other secondary outcomes.

Conclusions

In this study, ARNI was associated with a 15% reduction in all-cause mortality vs ACE-I/ARB. Patients with advanced orsymptomatic heart failure appeared to experience the greatest absolute benefit.

Disclaimer:

Lupin makes no representation or warranty of any kind, expressed or implied, regarding the accuracy, adequacy, validity, reliability, availability, or completeness of any scientific information shared by the HCP on the ­­­STARUPDATE podcast. You should not allow the contents of this to substitute for your own medical judgment, which you should exercise in evaluating the information on this website.

Comparison between clopidogrel and ticagrelor in CYP2C19 loss-of-function alleles coronary artery disease andstroke patients: a meta-analysis

Eur J Clin Pharmacol. 2025 Sep;81(9):1241-1256.

Abstract

Background: It is suggested that in patientswith coronary artery diseases (CAD) and stroke, the use of ticagrelor and aspirin may perform better than clopidogrel and aspirin regarding the risk of thrombosis/embolism, including recurrent myocardial infarction (MI) andcardiovascular death, especially in those carrying CYP2C19 loss-of-function (LOF) alleles. Therefore, we conducted the present systematic review and meta-analysis to investigate the effect of clopidogrel and ticagrelor in coronaryartery diseases and stroke patients with CYP2C19 LOF alleles (poor metabolizers of clopidogrel).

Methods: We performed the current systematicreview and meta-analysis by searching for all eligible publications on PubMed, Web of Science, and Scopus from inception to November 2024. A search strategyemploying three primary keywords in conjunction with their corresponding Medical Subject Headings (MeSH) terms: "Ticagrelor" AND "Clopidogrel" AND"CYP2C19" (PROSPERO ID CRD420251050533). We implemented the odds ratio (OR) as an effect estimate for the dichotomous variables. The analysis was done at 95% confidence intervals (CI), and the p-value was significant if it was less than or equal to 0.05.

Results: Using clopidogrel was associated withan increased risk of thrombosis/embolism compared with ticagrelor, showing odds ratio = 1.78 (95%CI, 1.08,2.95; p = 0.02). Also, clopidogrel led to an increased risk of stroke, whether when used in stroke or coronary artery diseases patients with CYP2C19 LOF alleles, compared with ticagrelor, with an overall odds ratio = 1.43 (95%CI, 1.23, 1.66; p < 0.00001) and a higher rate of MI with odds ratio = 1.53 (95%CI, 1.22, 1.92; p = 0.0003). No significant difference was observed between the two groups (clopidogrel andticagrelor) in stroke or coronary artery diseases patients with odds ratio = 0.98 (95%CI, 0.79, 1.22; p = 0.87). Also, no significant difference was observed between bothgroups regarding the risk of minor bleeding in stroke or coronary artery diseases patients with odds ratio = 0.66 (95%CI, 0.42, 1.05; p = 0.08) and any types of bleeding (major or minor bleeding) with overall odds ratio = 0.81 (95%CI, 0.54, 1.21; p = 0.3) and I2 = 88%, p < 0.00001.

Conclusion: The meta-analysis of the selected articles indicated a preference for ticagrelor over clopidogrel in patients with stroke or coronary artery diseases possessing CYP2C19 LOF alleles. The reduced incidence of thrombosis/embolism and associated events, such as strokeand MI, was noted in individuals administered ticagrelor in comparison to those receiving clopidogrel. Bleeding remains a concern with ticagrelor; however, current studies indicate its safety since there are no significant changes in therisk of minor and major bleeding and ICH compared to clopidogrel.

Disclaimer:

Lupin makes no representation or warranty of any kind, expressed or implied, regarding the accuracy, adequacy, validity, reliability, availability, or completeness of any scientific information shared by the HCP on the ­­­STARUPDATE podcast. You should not allow the contents of this to substitute for your own medical judgment, which you should exercise in evaluating the information on this website.