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.

β blockers after myocardial infarction with mildly reduced ejection fraction: an individual patient data meta-analysisof randomised controlled trials

Lancet. 2025 Sep 13;406(10508):1128-1137.

Abstract

Background: The effects of β-blocker therapy on clinicaloutcomes in patients with myocardial infarction and mildly reduced (40-49%) left ventricular ejection fraction (LVEF) are largely unknown. Four recently conducted randomised trials tested the efficacy of β blockers after a recent myocardial infarction in patients without reduced left ventricular ejectionfraction (LVEF ≥40%). However, none were individually powered to assess these effects in the subgroup of patients with mildly reduced left ventricular ejection fraction. We aimed to assess the efficacy of β blockers in patientswith myocardial infarction and mildly reduced left ventricular ejection fraction during the index hospitalisation.

Methods: We conducted an individual patient-levelmeta-analysis of patients with mildly reduced left ventricular ejection fraction and no history or signs of heart failure from four recent clinical trials. These studies were included because they were randomised controlled trials testing long-term effects (median follow-up >1 year) of oral β-blocker therapy in patients who recently had a myocardial infarction(randomisation within 14 days) and had mildly reduced left ventricular ejection fraction. No further studies were found in a systematic review (Jan 1, 2020 to June 26, 2025).A one-stage, fixed-effects, Cox proportional hazards regression model was used to assess the treatment effect of β blockers on the predefined primary composite endpoint of all-cause death, new myocardial infarction, or heartfailure. All endpoints were independently adjudicated. This meta-analysis was registered with PROSPERO (CRD420251023480).

Findings: 1885 patients with myocardial infarction andmildly reduced left ventricular ejection fraction were included in the meta-analysis: 979 from the REBOOT trial, 422 from the BETAMI trial, 430 from the DANBLOCK trial, and 54 from the CAPITAL-RCT trial. Overall, 991 patientswere assigned to β blockers and 894 to control (no β blockers). The primary composite endpoint occurred in 106 patients (32·6 events per 1000 patient-years) in theβ-blocker group and 129 patients (43·0 per 1000 patient-years) in the no β-blocker group (hazard ratio 0·75 [95% CI 0·58-0·97]; p=0·031). No heterogeneity between thetrials (trial-by-treatment pinteraction=0·95) or between countries of enrolment was observed (pinteraction=0·98).

Interpretation: In patients with acute myocardial infarctionwith mildly reduced left ventricular ejection fraction without history or clinical signs of heart failure, β-blocker therapy was associated with a reduction in the composite of all-cause death, new myocardial infarction, or heart failure. These results extend the known benefits of these agents inpatients with myocardial infarction with reduced left ventricular ejection fraction to the subgroup with mildly reduced left ventricular ejection fraction.

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.

ST-elevation myocardial infarction and air pollution: relationship between hourly air pollution and cardiovascular risk factors
J Cardiovasc Med (Hagerstown). 2025 Aug 1;26(8):412-419.

Abstract

Objective: Air pollution contributes to cardiovascular diseases through oxidative stress, inflammation, autonomicnervous system imbalance, and direct particle translocation. This study examines the relationship between air pollution parameters and risk factors in patients presenting with (STEMI).

Methods: This prospective, cross-sectional studyincluded ST-elevation myocardial infarction patients aged at least 18 years in a tertiary ST-elevation myocardial infarction hospital. Demographics, comorbidities, seasonal variations, comorbidities, vital signs, hourly air pollution and weather parameters on admission, hospital length of stay, treatment modalities, and outcomes were recorded.

Results: Among 1413 patients, 75.1% were men. The median age of female patients [65 (IQR: 58-73)] was significantly higher that of than males [55 (IQR: 50-66), P < 0.001].Median air quality index (AQI) [53 (IQR: 37-55)] and particulate matter (PM2.5) levels [18 (IQR: 11-27)] on admission were above Environmental Protection Agency limits. Patients with prior coronary artery disease (P = 0.037)and female patients (P = 0.018) had significantly lower PM10 exposure. PM2.5 levels were significantly higher in patients aged >75 years [20.5 (IQR: 13-29)] than in youngerpatients [18 (IQR: 11-27), P = 0.022]. Those recommended for coronary artery bypass grafting had lower sulfur dioxide levels [6 (IQR: 4-9) vs. 8 (IQR: 5-13), P = 0.003].

Conclusion: When air quality index and particulatematter 2.5 levels exceed EPA limits, they may interact with cardiovascular risk factors such as age, sex, and comorbidities, contributing to the development ofST-elevation myocardial infarction. Elderly individuals, women, and those with a history of cardiovascular disease may be more susceptible to the adverse effects of air pollution.

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.

SGLT2 inhibitor with and without ALDosterone AntagonIst for heart failure with preserved ejection fraction:Design paper

ESC Heart Fail. 2025 Aug;12(4):3134-3144. doi: 10.1002/ehf2.15294

Abstract

Background: Sodium glucose co-transporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists(MRA) reduce heart failure (HF) events in patients with heart failure and mildly reduced or preserved ejection fraction (HFmr/pEF). The randomized comparison of Sodium glucose co-transporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists (MRA)combination versus SGLT2i or MRA alone requires further testing in heart failure and mildly reduced or preserved ejection fraction.

Aim: To compare the efficacy (NT-proBNP change as primary outcome) and safety (potassium, creatinine, and blood pressure changes) of dapagliflozin/spironolactone combination versus dapagliflozin alone (primary comparison) and spironolactone alone (exploratory comparison).

Methods: SOGALDI-PEF (SOdium-Glucose cotransporter 2 inhibitor, ALDosterone AntagonIst, or both for heart failure with preserved ejection fraction; NCT05676684), a proof-of-concept investigator-initiated two-centre randomized cross-over trial comparing three arms (dapagliflozin, spironolactone, or both) for three periods of 12 weeks each intercalated by a wash-out period of 4 weeks. After two independent trials demonstrating efficacy of SGLT2i in heart failure and mildly reduced or preserved ejection fraction, amid-trial protocol amendment dropped the spironolactone alone sequence and reduced the wash-out period to 1 week. A sample size of 108 patients was estimated to provide 80% power, at a 0.05 alfa level, to detect a 0.15 LogNT-proBNPdifference between the spironolactone/dapagliflozin combination and dapagliflozin alone sequence.

Results: SOGALDI-PEF included 108 patients with a median age of 76 years, 57% women, 42% with atrial fibrillation, 46% with type 2 diabetes, 33% having an eGFR below 60 mL/min/1.73m2, and 93% having an ejection fraction ≥ 50%. The median serum potassium was 4.3 mmol/L, and the median NT-proBNP was 764 pg/mL. Most patients were treated with renin-angiotensin blockers (68%), beta-blockers(70%) and loop diuretics (69%). Compared to other heart failure and mildly reduced or preserved ejection fraction trials, SOGALDI-PEF patients were older, were more frequently women, had a high prevalence of atrial fibrillation, and had more often a preserved ejection fraction.

Conclusions: SOGALDI-PEF will be the first trial in heart failure and mildly reduced or preserved ejection fraction to test the combination of dapagliflozin/spironolactone vsdapagliflozin alone in a randomized manner. SOGALDI-PEF will provide information on the potential efficacy and safety of concomitant administration of spironolactone with dapagliflozin vs dapagliflozin alone in an elderly population with heart failure and mildly reduced or preserved ejection fraction.

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.

1-Month Versus 12-Month Dual Antiplatelet Therapy for Patients with Chronic Total Occlusion After Successful Percutaneous Coronary Intervention

Drugs Aging. 2025 Aug 2. doi: 10.1007/s40266-025-01235z.

Abstract

Purpose: Compared with long-term dual antiplatelet therapy (DAPT, aspirin with clopidogrel or ticagrelor), short-term DAPT followed by single antiplatelet therapy (SAPT, clopidogrel or ticagrelor) has demonstrated superiority in reducing bleeding risk while maintaining non-inferior in cardiovascular benefits in coronary heart disease (CHD) aftersuccessful percutaneous coronary intervention (PCI). However, no prospective study has explored the benefits of this short-term regimen on patients with chronic total occlusion (CTO) undergoing Percutaneous Coronary Intervention.

Methods: Consecutive patients who underwent successful elective chronic total occlusion Percutaneous CoronaryIntervention were prospectively enrolled from April 2019 to May 2021. After receiving 1-month DAPT, all patients were divided into two groups: SAPT group (followed by clopidogrel or ticagrelor monotherapy) and DAPT group (continued with dual antiplatelet therapy). Detailed baseline characteristics, angiographic and procedural details, and 1-year follow-up data were collected. The endpoints were major adverse cardiovascular events (MACE) and bleeding.

Results: A total of 701 patients who underwent successful chronic total occlusion Percutaneous Coronary Interventionwere enrolled, among whom 330 patients (47.1%) received DAPT and 371 patients (52.9%) received SAPT (clopidogrel or ticagrelor) after 1-month DAPT. Compared with patients receiving DAPT, patients in the SAPT (clopidogrel or ticagrelor) group had a lower rate of previous stroke, fewer left anterior descending coronary artery (LAD) lesions and contrast volume, and fewer lesions per patient, but longer lesion length (P < 0.05). The incidence of MACE (14.5% versus 15.4%; p = 0.742) was not significantly different between the two groups. The DAPT group showed a higher incidence of minor bleeding (BARC types 1 or 2; 12.7% versus 2.3%, p < 0.001) than SAPT (clopidogrel or ticagrelor), while no difference was found for major bleeding (BARC types 3 or 5; 1.2% versus 2.3%, p = 0.261).

Conclusions: Compared with standard 12-month DAPT, 1-month DAPT followed by clopidogrel or ticagrelor monotherapy resulted in lower bleeding risks and similar cardiovascular benefits in chronic total occlusion Percutaneous Coronary Intervention 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.

Beta-blocker interruption effects on blood pressure and heart rate after myocardial infarction: the AβYSS trial
Eur Heart J 2025 Aug 1;46(29):2894-2902. doi: 10.1093/eurheartj/ehaf170.

Abstract

Background and aims: This study aims to report theeffects of β-blocker interruption on blood pressure (BP) and heart rate (HR) in the AβYSS trial where patients were randomized to interruption or continuation of β-blocker treatment after a myocardial infarction (MI).

Methods: Changes in heart rate and blood pressurefrom baseline to post-randomization are reported using linear mixed repeated model, in the 3698 patients of the AβYSS trial with a median follow-up of 3.0 years. Additionally, changes in heart rate and blood pressure and the impact on the primary endpoint (death, MI, stroke, hospitalization for cardiovascular reason) in the pre-specified subgroups of patients with or without history of hypertension were assessed using linear mixed repeated and adjusted Cox proportional hazards model, respectively.

Results: β-blocker interruption was associated withsignificant increase {least square mean difference [95% confidence interval (CI)]} in systolic BP [+3.7 (2.6, 4.8) mmHg, P <.001], diastolic BP [+3.3 (2.6, 4.0) mmHg, P < .001], and resting heart rate [+10 [9, 11) b.p.m., P < .001] at 6 months that persisted over the duration of follow-up despite an increase in antihypertensive drugs in the β-blocker interruptiongroup. The effects were observed in both hypertensive (43% of the population) and non-hypertensive patients. Hypertensive patients were at higher risk of events (25.8% vs. 19.2%) as compared with patients without hypertension (adjusted hazard ratio 1.18, 95% CI 1.01-1.36, P = .03). Patients with hypertension had a particularly marked increase in the primary endpoint (risk difference 5.02%, 0.72%-9.32%, P = .014) when randomized to β-blocker interruption.

Conclusions: Interruption of β-blocker treatment after an uncomplicated myocardial infarction led to a sustained increase in blood pressure and heart rate with potentially deleterious effects on outcomes, especially in patients with history of hypertension.

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.