---
title: "Beta-blocker continuation during prolonged dobutamine in heart transplant candidates: competing-ri"
id: "plos-one-17-continuation-of-beta-blockers-during-prolonged-dobutamine-infusion-in-heart"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-17-continuation-of-beta-blockers-during-prolonged-dobutamine-infusion-in-heart"
content_type: "clinical_feed_article"
specialty: "Cardiology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0354128"
published_at: "2026-07-21T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Beta-blocker continuation during prolonged dobutamine in heart transplant candidates: competing-ri
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-17-continuation-of-beta-blockers-during-prolonged-dobutamine-infusion-in-heart
- **Specialty:** [Cardiology](https://medichelpline.com/clinical-feed/cardiology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0354128)
- **Published At:** 2026-07-21T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This retrospective single-centre cohort studied adults listed for heart transplantation (HT) who received ≥30 consecutive days of oral **beta-blocker** (BB) therapy concomitant with continuous intravenous **dobutamine** (Jan 2020–Dec 2023). The index date was the first day after this 30-day period, identifying patients who tolerated the combination. - Fifty-three patients met inclusion criteria (mean age 50.8 ± 11.9 years; 64% male; mean LVEF 23.0 ± 6.4%). After the index date, 35 patients continued BB and 18 had BB suspended. Follow-up ended at HT, death, or Dec 31, 2023. - Primary outcome: cumulative incidence of **heart transplantation** treating pre-transplant death as a competing event. Secondary outcome: cumulative incidence of pre-transplant death treating HT as competing event. - To address confounding, inverse probability of treatment weighting (**IPTW**) based on a parsimonious propensity score (age, sex, HF aetiology, hypertension, diabetes, BB class) was applied. Residual imbalance persisted for LVEF and NT-proBNP, favoring greater severity in the BB-suspended group. - IPTW-adjusted Aalen–Johansen analyses showed substantially higher cumulative incidence of HT at ≥270 days with BB continuation (61.1% vs 14.3%; p < 0.001) and lower pre-transplant death (13.3% vs 68.7%; p < 0.001). - Fine–Gray regression with bootstrap confirmed associations: transplantation subdistribution HR (sHR) 8.79 (95% bootstrap CI 2.66–54.31) for BB continuation; pre-transplant mortality sHR 0.077 (95% bootstrap CI 0.014–0.192). - Four pre-specified sensitivity analyses (unweighted Fine–Gray; multivariable Fine–Gray with age, LVEF, HF aetiology; LASSO-penalised PS; doubly robust Fine–Gray) yielded consistent results. Nonparametric bootstrapping (1,500 replications) supported robustness. - Authors caution that the small sample size (N = 53), residual confounding by indication, and persistence of baseline severity imbalance limit causal inference. Findings are hypothesis-generating and suggest need for prospective study of BB continuation in patients tolerating prolonged BB+dubutamine while awaiting HT.
## Clinical Analysis & Structured Key Points
SKIP TO MAIN CONTENT Advertisement plos.org Create account Sign in About Browse Publish advanced search 0 Save 0 Citation 37 View 0 Share OPEN ACCESS PEER-REVIEWED RESEARCH ARTICLE Continuation of beta-blockers during prolonged dobutamine infusion in heart transplant–prioritised patients: A competing-risk analysis Joao Manoel Rossi Neto , Victor Bemfica de Mello Mattos, Airton Salviano Sousa Junior, Marco Aurelio Finger, Raphael Machado Rossi, Plinio Jose Whitaker Wolf, Carlo Bonasso Filho, Flavia Potsch Camara Mattos Girard, Carolina Casadei dos Santos Published: July 21, 2026 https://doi.org/10.1371/journal.pone.0354128 Article Authors Metrics Comments Media Coverage Peer Review Abstract Introduction Methods Results Discussion Conclusion Supporting information Acknowledgments References Reader Comments Figures Abstract Background Patients awaiting heart transplantation (HT) frequently require prolonged continuous dobutamine infusion. Whether oral beta-blocker (BB) therapy should be maintained during this period remains controversial and poorly studied, particularly in the context of prolonged concomitant use. The impact of BB continuation on waiting-list outcomes in this specific scenario is unknown. Methods We conducted a retrospective single-centre cohort study including adult patients listed for HT who received ≥ 30 consecutive days of concomitant oral BB therapy and continuous intravenous dobutamine between January 2020 and December 2023. The index date was defined as the first day after completion of this 30-day period, identifying patients who had already demonstrated sustained haemodynamic tolerance to the combination. Patients were classified according to BB continuation or suspension after the index date. Competing-risk analyses were performed using inverse probability of treatment weighting (IPTW), Aalen–Johansen cumulative incidence functions, and Fine–Gray regression. Robustness was assessed through nonparametric bootstrapping (1,500 replications). Results Among 53 eligible patients (mean age 50.8 ± 11.9 years; 64% male), 29 underwent HT and 16 died before transplantation. After IPTW adjustment, BB continuation was associated with a higher cumulative incidence of HT at ≥ 270 days (61.1% vs 14.3%; p < 0.001) and a lower cumulative incidence of pre-transplant death (13.3% vs 68.7%; p < 0.001). Fine–Gray regression confirmed these associations: HT sHR 8.79 (95% bootstrap CI 2.66–54.31) and pre-transplant mortality sHR 0.077 (95% bootstrap CI 0.014–0.192). Results were consistent across four pre-specified sensitivity analyses. Conclusions This study evaluates outcomes in patients sustaining oral beta-blocker therapy during prolonged dobutamine infusion while awaiting heart transplantation, a clinical scenario with limited available data. BB continuation was associated with a higher probability of transplantation, with consistent direction across pre-specified sensitivity analyses. Given the small sample size and the potential for residual confounding by indication, these findings should be interpreted with caution and are best viewed as hypothesis-generating. They may help inform future research, particularly prospective studies in this setting. Figures Citation: Rossi Neto JM, de Mello Mattos VB, Junior ASS, Finger MA, Rossi RM, Wolf PJW, et al. (2026) Continuation of beta-blockers during prolonged dobutamine infusion in heart transplant–prioritised patients: A competing-risk analysis. PLoS One 21(7): e0354128. https://doi.org/10.1371/journal.pone.0354128 Editor: Moises Auron, Cleveland Clinic, UNITED STATES OF AMERICA Received: January 8, 2026; Accepted: July 5, 2026; Published: July 21, 2026 Copyright: © 2026 Rossi Neto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: Due to Brazilian data protection regulations (Lei Geral de Proteção de Dados – LGPD), individual-level clinical data cannot be publicly shared; the small sample size (N = 53) creates a non-negligible risk of patient re-identification. All aggregate data necessary to replicate the reported findings are presented within the manuscript and its Supporting Information files. Researchers meeting criteria for access to confidential data may request the de-identified dataset through the Ethics Committee of the Instituto Dante Pazzanese de Cardiologia (cep@idpc.org.br; CAAE 77180624.6.0000.5462). Funding: The author(s) received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. Introduction Advanced heart failure (HF) remains a major global health burden consistently associated with high morbidity, mortality, and healthcare utilisation. Heart transplantation (HT) is the definitive therapy for eligible patients; however, donor scarcity and prolonged waiting-list times often necessitate extended periods of in-hospital stabilisation [1–3]. Continuous intravenous dobutamine is frequently required to maintain adequate haemodynamics during this period, despite well-recognised limitations including arrhythmic risk, tachyphylaxis, and increased mortality [4–6]. Identifying strategies that optimise stability and improve waiting-list outcomes in patients dependent on long-term inotropes is therefore of direct clinical relevance, particularly in settings without access to durable mechanical circulatory support. Beta-blockers (BBs), a cornerstone of chronic HF therapy, provide neurohormonal blockade, reduce arrhythmic burden, and improve long-term outcomes. Their continuation during continuous dobutamine infusion remains controversial, and clinical practice varies widely among transplant centres in the absence of specific guideline recommendations [2,3,7–10]. Concerns regarding pharmacodynamic antagonism and haemodynamic compromise have led many centres to routinely discontinue BB upon inotrope initiation or during acute decompensation. However, a specific and underexplored clinical scenario exists: patients who have already been receiving oral BB and continuous dobutamine concomitantly for ≥ 30 consecutive days while awaiting transplantation. This population — increasingly encountered in centres where pharmacological bridging is the primary or only available strategy — has not been specifically studied. These patients have, by definition, demonstrated sustained haemodynamic tolerance to the combination, raising the question of whether BB continuation in this adapted state confers prognostic benefit. Furthermore, prior observational studies examining inotrope–BB interactions have relied on traditional Kaplan–Meier survival analyses, which censor death and consequently overestimate the probability of transplantation [11–13]. Competing-risk methods are required when death precludes the event of interest, and their application in transplant populations has revealed important distinctions in waiting-list trajectories [1,14,15]. We therefore hypothesised that, in patients who had already demonstrated tolerance to prolonged concomitant BB and dobutamine therapy, continuation of BB after the index date would be associated with a higher probability of heart transplantation and reduced pre-transplant mortality, compared with BB suspension. Methods Study design and setting We conducted a retrospective, single-centre cohort study at the Instituto Dante Pazzanese de Cardiologia (São Paulo, Brazil). The study included adult patients with advanced HF actively listed for HT who received prolonged, continuous intravenous dobutamine infusion between January 2020 and December 2023. No formal sample size calculation was performed because this was a retrospective study including all eligible patients during the study period. Patient selection Eligible participants were adults (≥ 18 years) listed for HT who received ≥ 30 consecutive days of concomitant oral BB therapy and continuous intravenous dobutamine during hospitalisation. The index date (t = 0) was defined as the first day following completion of this 30-day concomitant period. The 30-day threshold was selected to define a population of patients who had demonstrated sustained haemodynamic tolerance to combined BB and dobutamine therapy — a duration sufficient to exclude transient pharmacodynamic interactions and identify a clinically stable phenotype of concomitant use. This represents a poorly studied and clinically distinct scenario from acute BB initiation during inotrope therapy, which has been the focus of prior literature. Exclusion criteria included: (i) prior heart transplantation; (ii) durable mechanical circulatory support before or during the concomitant therapy period; (iii) inactive listing status; and (iv) death or HT prior to completion of the 30-day concomitant period. Exposure definition BB maintained: documented continuation of oral BB therapy for ≥ 72 hours after the index date, with no interruption recorded in pharmacy or nursing records. BB suspended: permanent discontinuation of oral BB therapy documented ≥ 72 hours after the index date, occurring in the context of acute haemodynamic deterioration (cardiogenic or septic shock), with no subsequent reinitiation at any point during follow-up. Follow-up extended until HT, death, or censoring on December 31, 2023. Data collection and definitions Baseline variables collected at the index date included demographics, left ventricular ejection fraction (LVEF), HF aetiology (ischaemic, dilated, Chagas, and other), vital signs, laboratory data (sodium, creatinine, albumin, NT-proBNP, AST [aspartate aminotransferase]), comorbidities (hypertension, diabetes mellitus, dyslipidaemia, chronic kidney disease [CKD]). Medication data included BB class and doses, initial dobutamine dose, renin–angiotensin–aldosterone system inhibitor use (ARNI [angiotensin receptor–neprilysin inhibitor], ACEI [angiotensin-converting enzyme inhibitor], ARB [angiotensin receptor blocker]), mineralocorticoid receptor antagonists (MRA [mineralocorticoid receptor antagonist]), diuretics, and amiodarone. Variables reflecting the post-index clinical course — including final and mean dobutamine dose, escalation to other vasoactive agents, reason for BB suspension, dialysis initiation, intra-aortic balloon pump (IABP) insertion, and extracorporeal membrane oxygenation (ECMO) initiation — were recorded separately as indicators of haemodynamic deterioration during follow-up. Cardiogenic shock was defined as hypotension (< 90 mmHg systolic or requiring vasoactive support) with evidence of hypoperfusion. Septic shock was defined as sepsis requiring vasopressors to maintain mean arterial pressure ≥ 65 mmHg. No missing data were present for any analysed variable. Outcomes The primary outcome was the cumulative incidence of heart transplantation, treating pre-transplant death as a competing event. The secondary outcome was the cumulative incidence of pre-transplant death, treating HT as the competing event. Statistical analysis Continuous variables were summarised as mean ± SD or median [IQR] and compared using Welch’s t-test or Mann–Whitney U test. Categorical variables were compared using Pearson’s chi-square or Fisher’s exact test. To minimise confounding, IPTW was applied based on a parsimonious logistic regression propensity score (PS). The PS included six a priori selected baseline covariates measured at the index date: age, sex, HF aetiology, hypertension, diabetes mellitus, and BB class. Variables reflecting post-index haemodynamic deterioration — dialysis, IABP, dobutamine dose escalation, and shock episodes — were excluded because chart review confirmed these events occurred after the index date; their inclusion would constitute mediator adjustment bias [16]. Furthermore, with only 18 patients in the smaller treatment group and eight estimated model parameters, the events-per-parameter ratio was low (≈ 2.3), well below the conventional minimum of 10; this justified a parsimonious specification, as adding further covariates would have driven the ratio still lower and produced model instability. Accordingly, LVEF and NT-proBNP were considered baseline markers of disease severity and were therefore evaluated separately in covariate-balance diagnostics (Fig 1) and sensitivity analyses (LVEF in a pre-specified multivariable Fine–Gray model) rather than entered into the primary propensity score. Given the limited sample size and low events-per-parameter ratio, inclusion of additional severity markers in the primary propensity model was considered likely to increase the risk of model instability and overfitting [17]. Download: PNG larger image TIFF original image Fig 1. Covariate balance before and after inverse probability of treatment weighting (IPTW). Absolute standardised mean differences (SMDs) are shown for pre-specified baseline covariates before (unweighted, red circles) and after truncated unstabilised ATE IPTW (teal circles). The dashed vertical line indicates the pre-specified threshold for adequate balance (|SMD| = 0.10). IPTW improved covariate balance across most baseline covariates; residual imbalance in LVEF and NT-proBNP persisted after weighting, in the direction of greater disease severity in the BB-suspended group. Abbreviations: IPTW, inverse probability of treatment weighting; SMD, standardised mean difference; ATE, average treatment effect; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal pro-brain natriuretic peptide; BB, beta-blocker. https://doi.org/10.1371/journal.pone.0354128.g001 Unstabilised average treatment effect (ATE) weights were calculated as the inverse probability of the observed treatment assignment and truncated at the 1st and 99th percentiles to reduce the influence of extreme observations. Stabilised IPTW weights were examined as a sensitivity analysis and yielded materially similar results (range 0.451–2.164). Covariate balance was evaluated using standardised mean differences (SMDs), with |SMD| < 0.10 indicating adequate balance, and visualised using Love plots. Propensity score distributions by group are shown in Supplementary S1 Fig. The primary outcome was defined a priori as cumulative incidence of HT at ≥ 270 days; 90-day and 180-day time points were pre-specified exploratory secondary horizons. Cumulative incidence functions (CIFs) were estimated using the Aalen–Johansen estimator. Subdistribution hazard ratios (sHRs) were estimated using Fine–Gray regression, [12]. incorporated through a Fine–Gray weighted Cox formulation with final weights as the product of Fine–Gray censoring weights and unstabilised IPTW. Robust variance was obtained by clustering on individual patient identifiers. Four pre-specified sensitivity analyses were performed: (i) unweighted Fine–Gray regression; (ii) multivariable Fine–Gray including age, LVEF, and HF aetiology without IPTW; (iii) LASSO-penalised PS with cross-validated regularisation; and (iv) doubly robust Fine–Gray combining IPTW with direct covariate adjustment. Confidence intervals for IPTW-weighted CIF differences were derived from percentile-based nonparametric bootstrap resampling (1,500 replications). To quantify robustness to unmeasured confounding, E-values were calculated using the conservative correction for common outcomes [18]. Full results are reported in Supplementary S2 Table. Two-sided p-values < 0.05 were considered statistically significant. All analyses were performed using R version 4.4.1 with the cmprsk and survival packages, and Python 3.11.9 (pandas 2.2.2, matplotlib 3.9.0, numpy 1.26.4) for data preprocessing and visualisation. Ethics approval This retrospective study was approved by the Institutional Ethics Committee of the Instituto Dante Pazzanese de Cardiologia (CAAE 77180624.6.0000.5462). In accordance with institutional and national regulations, attempts were made to obtain written informed consent from participants or their legal representatives whenever feasible. When consent could not be obtained, attempts and reasons were documented in patients’ medical records as instructed by the Ethics Committee. No individual patient-identifiable data are disclosed. All procedures complied with the Declaration of Helsinki. Results Study population Of the 83 patients screened between January 2020 and December 2023, 30 were excluded: 11 who did not receive dobutamine, 9 aged < 18 years, 1 without beta-blocker use, 1 who died before prioritisation, and 8 who received < 30 days of concomitant therapy. The final cohort comprised 53 patients who completed ≥ 30 consecutive days of combined BB and dobutamine therapy. Among these, 29 underwent HT, 16 died before HT, and 8 were censored at study end. Baseline characteristics The mean age was 50.8 ± 11.9 years and 64% were male. Mean LVEF was 23.0 ± 6.4%. Median hospitalisation duration was 110 days (IQR 74–226). The duration of beta-blocker use after the index date had a median of 101 days (IQR 62–211; maximum 442 days), reflecting the prolonged nature of the clinical scenario studied. Table 1 presents baseline characteristics at the index date (Panel A) and variables reflecting the post-index clinical course (Panel B). At baseline, groups were broadly similar in LVEF, HF aetiology, comorbidities, BB class, and initial dobutamine dose, with the exception of age and NT-proBNP. During follow-up, BB suspension was strongly associated with escalation of dobutamine dose, requirement for additional vasoactive agents, cardiogenic or septic shock, dialysis initiation, and IABP insertion — all events that developed after the index date, reflecting progressive haemodynamic deterioration rather than pre-existing baseline differences. Download: PNG larger image TIFF original image Table 1. Baseline and post-index clinical characteristics by beta-blocker exposure group. https://doi.org/10.1371/journal.pone.0354128.t001 Unadjusted outcomes Although unadjusted comparisons demonstrate clinical differences between groups, these associations are descriptive only. Because death precludes transplantation, formal inference required competing-risk methods. Propensity weighting and covariate balance IPTW improved covariate balance across the pre-specified baseline covariates included in the propensity score model. After weighting, 9 of 11 variables (81.8%) achieved an absolute SMD below 0.10. Residual imbalance persisted for LVEF (SMD = 0.28; lower in the BB-suspended group) and NT-proBNP (SMD = 0.47; higher in the BB-suspended group), both in the direction of greater disease severity in the BB-suspended group. Given the modest sample size, some residual imbalance in markers of disease severity cannot be fully excluded; estimates should therefore be interpreted as reflecting both a possible prognostic association and the prognostic advantage conferred by haemodynamic stability itself (Fig 1). Weighted competing-risk outcomes In IPTW-adjusted Aalen–Johansen analyses (Fig 2 and Table 2), BB continuation was associated with substantially higher cumulative incidence of HT and lower pre-transplant mortality: Download: PNG larger image TIFF original image Table 2. IPTW-weighted cumulative incidence of heart transplantation and pre-transplant death at pre-specified time horizons. https://doi.org/10.1371/journal.pone.0354128.t002 Download: PNG larger image TIFF original image Fig 2. IPTW-weighted Aalen–Johansen cumulative incidence functions for heart transplantation (Panel A) and pre-transplant death (Panel B). Curves compare patients in whom beta-blockers were maintained (solid lines, n = 35) versus suspended (dashed lines, n = 18). Pre-transplant death was treated as a competing event for heart transplantation, and vice versa. Dashed vertical lines indicate pre-specified horizons at 90, 180, and ≥ 270 days
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