Is there evidence favoring the use of beta-blockers and dobutamine in acute heart failure?

Abstracts

Diversos estudos relataram os benefícios dos betabloqueadores (BB) para pacientes com insuficiência cardíaca sistólica. No entanto, muitos pacientes hospitalizados em decorrência de insuficiência cardíaca aguda já estão usando os BB e requerem dobutaminas para hipotensão arterial e baixo débito cardíaco. Portanto, deve-se tomar uma decisão a respeito de se o BB deve ser mantido ou até mesmo iniciado nesses casos. O objetivo deste estudo foi determinar se há provas que sustentem a segurança e a eficácia dos BB junto com a dobutamina para pacientes com insuficiência cardíaca aguda descompensada (ICAD). Foi realizada uma pesquisa na literatura de língua inglesa nas bases de dados MEDLINE, ISI Web of Science, Biblioteca Virtual em Saúde, Cochrane Library e o Portal de Revistas Científicas do Capes para identificar estudos relacionados. Literatura adicional foi obtida mediante a análise das respectivas referências encontradas nos artigos identificados. Os resultados esperados incluíram informações sobre o prognóstico (intra-hospitalar e na mortalidade no acompanhamento, número de dias de internação e reinternação), eficácia e segurança (agravamento dos sintomas, choque, intolerância) do uso concomitante desses medicamentos em pacientes hospitalizados com ICAD e baixo débito cardíaco. Esta análise incluiu nove estudos. No entanto, não foram encontrados ensaios clínicos randomizados sobre o assunto. A maioria dos estudos inclui baixo número de pacientes, e não foram encontrados estudos que abordem a segurança do uso concomitante desses medicamentos. Os dados resultantes sugerem que uma cuidadosa revisão da literatura não forneceu evidências para o uso sistemático de BB em pacientes com síndrome de baixo débito cardíaco que necessitam de suporte inotrópico com dobutamina.

Insuficiência cardíaca; baixo débito cardíaco; antagonistas adrenérgicos beta; uso terapêutico; dobutamina; uso terapêutico

REVIEW ARTICLE

Programa de Pós-Graduação em Medicina e Saúde da Universidade Federal da Bahia, Salvador, BA - Brasil

Mailing Address

ABSTRACT

Several studies have reported the benefits of beta-blockers (BB) for patients presenting with systolic heart failure. however, many patients hospitalized as a result of acute heart failure are already using BB and require dobutamine for arterial hypotension and low cardiac output. Therefore, a decision must be made regarding whether BB should be maintained or even started in such cases. The aim of this study was to establish whether there is evidence supporting the safety andyeffectiveness of BB together with dobutamine for patients presenting with acute decompensated heart failure (ADHF). We conducted a search of the English-language literature in the databases MEDLINE, ISI Web of Science, Virtual Health Library, Cochrane Library and the CAPES Portal of Scientific Journals to identify related studies. Additional literature was obtained through the review of relevant references in the identified articles. The expected outcomes included information on the prognosis (in-hospital and on follow-up mortality, number of days of hospitalization and readmission),yeffectiveness and safety (worsening of symptoms, shock, intolerance) of the concomitant use of these drugs in hospitalized patients with ADHF and low cardiac output. This review included nine studies. however, no randomized clinical trials on this subject were found. Most studies include a low number of patients, and no studies addressing the safety of the concomitant use of these drugs were found. The resulting data suggest that a careful literature review did not supply evidence for the systematic use of BB in patients with low cardiac output syndrome who require dobutamine for inotropic support.

Keywords: Heart Failure; cardiac output, low; adrenergic beta-agonists, therapeutic use; Dobutamine, therapeutic use.

Introduction

Several studies have reported the benefits of beta-blockers (BB) for patients presenting with systolic heart failure. however, many patients hospitalized as a result of acute heart failure are already using BB and require dobutamine for arterial hypotension and low cardiac output. Therefore, a decision must be made regarding whether BB should be maintained or even started in such cases. The aim of this study was to establish whether there is evidence supporting the safety andyeffectiveness of BB together with dobutamine for patients presenting with acute decompensated heart failure (ADHF). We conducted a search of the English-language literature in the databases MEDLINE, ISI Web of Science, Virtual Health Library, Cochrane Library and the CAPES Portal of Scientific Journals to identify related studies. Additional literature was obtained through the review of relevant references in the identified articles. The expected outcomes included information on the prognosis (in-hospital and on follow-up mortality, number of days of hospitalization and readmission),yeffectiveness and safety (worsening of symptoms, shock, intolerance) of the concomitant use of these drugs in hospitalized patients with ADHF and low cardiac output. This review included nine studies. however, no randomized clinical trials on this subject were found. Most studies include a low number of patients, and no studies addressing the safety of the concomitant use of these drugs were found. The resulting data suggest that a careful literature review did not supply evidence for the systematic use of BB in patients with low cardiac output syndrome who require dobutamine for inotropic support.

Acute Heart Failure (AHF) is one of the main causes of hospitalization in adult^1,2. Despite advancements in modern treatment, many patients progress to a potentially terminal phase of the disease, namely heart failure (HF) stage D, which comprises symptoms refractory to conventional treatmen^3,4. In large case-series studies, approximately 20 - 30% of hospitalized patients required an intravenous inotropic agen^5-7. In several Western countries, dobutamine is the most frequently used agen⁸.

After several decades of clinical research resulted in conflicting data on the effectivenesy of beta-blockers (BB) in heart failur^9-13, clinical trials on the use of carvedilol, metoprolol and bisoprolol showed a remarkable reduction in mortality and hospitalization in patients with systolic H ^14-18. BBs are negative inotropic and chronotropic agents, whereas dobutamine is a positive inotropic drug with agonistic effects on the α1, α2 and (partially) α1 receptors in the hear¹⁹. Although they are physiologically incompatible, these agents have been used concomitantly in clinical practic^20-24. Some studies suggest that carvedilol mightgdecrease the response to intravenous infusion of dobutamine. This interaction necessitates dosage increases to achieve significant effects in patients with chronic HF and continuing use of carvedilo^{25, 26}.

The first studies on BB in HF were restricted to compensated patients, who did not require additional or intravenous doses of diuretics. Recently, however, observational studies have suggested that the early introduction of BB might be safe in the short term and beneficial in the long ter^{20, 24, 27-29}.

In clinical practice, many patients admitted for AHF are already using BB. Under these circumstances, clinicians must decide whether to maintain or start BB in patients who still require an inotropic catecholamine agent to maintain an appropriate cardiac output.

The international guidelines regarding the use of BB in acute decompensation are conservative. They recommend discontinuation in cases requiring inotropic suppor^{2, 30, 31}. Alternatively, the guidelines recommend against discontinuing BB whenever possible and favor dosage reductions even during the use of inotropic agents, especially dobutamin⁸.

In this study, we performed a literature review to establish whether evidence supports the safety andyeffectiveness of the joint use of BB and dobutamine in this clinical setting.

Methods

The relevant studies were found by searching for original articles, clinical trials and observational studies in the following databases: MEDLINE, ISI Web of Science, Virtual Health Library (Biblioteca Virtual em Saúde - BVS; Brazilian Ministry of Health - MS), Cochrane Library and CAPES journals (Portal periódicos CAPES). The latter is a database developed by the Brazilian government for researchers in Brazilian universities.

The following textual and MeSH search terms were used in different combinations: heart failure, beta-blocker, beta-blockade, adrenergic beta antagonist, carvedilol, inotropic agent, and dobutamine. The search was designed to select original clinical trials assessing the use of BB in patients with severe HF being treated with dobutamine. Expected outcomes included information on the prognosis (in-hospital and follow-up mortality, number of days of hospitalization and rehospitalization) and theyeffectiveness and safety (worsening of symptoms, shock or intolerance) of the concomitant use of these agents in hospitalized patients diagnosed with acute decompensated HF and low cardiac output.

The references in the located articles were searched manually to find further studies on this subject. Four independent researchers performed the review and subsequently selected the relevant articles. Data extraction was performed by two authors.

Inclusion criteria: Qualifying original studies were defined as clinical trials or observational studies on patients hospitalized for AHF and treated with dobutamine and BB and that contained information on the outcomes of interest.

Exclusion criteria: Studies that did not include information on the frequency of dobutamine and BB use and studies in languages other than English were not included.

Results

Selection and assessment of studies:

From 1173 citations identified in databases for inclusion in this systematic review, 54 were eligible (Figure 1). Of these, 13 were excluded because they were reviews, editorials or expert opinions. Two studies were excluded because milrinone was used together with BB; four studies were excluded because they performed echo stress test with dobutamine to assess viability in outpatients using BB; two studies were excluded because they were published only as abstracts in proceedings. Finally, one study was excluded because it addressed the use of medication in patients with postoperative low cardiac output syndrome. In a second round, thirty-two full-text articles were assessed for eligibility. Seven were excluded because they did not report on the frequency of BB and dobutamine use; and 15 were excluded because they did not describe the outcomes of interest. One study was excluded because it was written in French.

Nine studies were included in this review. The data in the included studies are summarized in Tables 1 and 2.

Overall summary of the main results:

• There is a small number of studies addressing the topic of interest;

• Most studies had a small n;

• No clinical trial was specifically designed to answer to the questions of interest (indirect data);

• No studies were found addressing the safety of the concomitant use of these drugs;

• Very heterogeneous population in regard to the inclusion criteria, nonrandomized selection of BB use, and few clinical outcomes of interest to perform summary-measures.

None of the clinical studies on theyeffectiveness of BB in acute HF included patients with low cardiac output (SAP < 90 mmHg). Thus, IMPACT H³², B-CONVINCE³³, COMET³⁴ and OPTIMIZE HF³⁵ were not included in this analysis.

Of 49 studies potentially eligible for analysis, only 9 included data on the use of BB and dobutamine, allowing assessing the outcomes of interest.

Discussion

None of the nine studies assessed used an adequate approach to assess the safety and effectiveness of BB in patients using dobutamine. The direct assessment of this question requires a randomized, double-blind, controlled study comparing a group in which the use of BB is maintained while positive inotropic support is provided with a group in which BB is discontinued. Further assessments include the division of patients who require dobutamine and have no previous use of BB into two randomized groups, one in which BB is started, and a control group maintained without these drugs. Studies should focus on the following outcomes of interest: time of hospitalization, need to discontinue or reduce the dose of BB throughout the study, adverse events and mortality between groups and death or rehospitalization on follow-up.

Among the nine assessed studies, those by Lowes et al²⁵, Metra et al³⁶, Duygu et al³⁷, Bergh et al³⁸ and Triposkiadis et al³⁹ primarily assess short-term hemodynamic improvements by means of invasive or noninvasive measurements in patients who were using BB as well as dobutamine or another intravenous inotropic agent. Despite the small number of cases, these studies did not use controls (patients not using BB) to assess the hemodynamic effectiveness of the inotropic agents. Moreover, none included the group of major clinical interest, namely patients with formal indications for inotropic agents.

In the study LIDO²⁶, patients used dobutamine or levosimendan; 39% of patients in the dobutamine group used BB versus 37% of patients in the levosimendan group. The effects of dobutamine were attenuated by the use of BB. The hemodynamic improvement among BB users was greater in the levosimendan group than in the dobutamine group. Death occurred within 31 days in 8% of patients in the levosimendan group versus 17% of patients in the dobutamine group, and the three in-hospital deaths occurred in the dobutamine group. In general, these findings suggest that there are stronger interactions between BB and dobutamine than between BB and levosimendan. A discussion of the safety and adverse effects associated with the use of BB in the in-hospital phase is not possible because the low number of patients precludes a stratified analysis.

The study by Lima et al⁴⁰ more directly approaches the topic of this study. These authors report results in patients who did or did not use BB and who patently exhibited low cardiac output requiring the use of vasoactive amines. After performing a stratified analysis of BB use in each group, the authors conclude that continued use of BB did not result in worse progression of the disease. The main limitations of the Lima et al⁴⁰ study are that it comprises an observational cohort of surviving patients who were discharged from the hospital and that the choice to use BB or not was not based on explicit criteria, which probably allowed for the use of BB in less severely affected patients.

Triposkiadis et al.'s study³⁹ also addresses more directly the aim of this review; however, their assessment was restricted to patients in whom carvedilol exacerbated HF, while excluding patients using any other BB. Although all included patients used low doses of carvedilol, the study showed that the use of dobutamine was associated with a small increase in the left ventricular ejection fraction (1.5%) without alterations of the heart rate, arterial pressure, cardiac output or systemic vascular resistance. This study has severe limitations: the number of patients was small ³¹, randomization was not performed and the control group and the patients were not assessed blindly.

Mebazaa et al⁴¹ and Bohm et al⁴² performed randomized studies to compare two inotropic agents: levosimendan and dobutamine. It is worth noting that one of the limitations of the use of levosimendan is the hypotension occurring in patients with low cardiac output. Therefore, severely affected patients requiring a catecholamine inotropic agent were excluded from the study. In Mebazaa et al⁴¹, 48% of patients were using BB at the time of randomization. These authors indicate a possible advantage of levosimendan over dobutamine regarding short-term mortality by all causes in patients with acute decompensated HF and previous HF who were treated with oral BB. This finding suggests that in patients with AHF and previous history of HF who use oral BB and in whom vasoactive amines are not formally indicated, levosimendan is preferable to dobutamine as an inotropic agent. This conclusion may be related to the potential for an undesirable interaction between BB and dobutamine.

Bohm et al study⁴² is a secondary analysis of SURVIVE data with patients stratified by BB use. The patients were randomized for levosimendan or dobutamine use; thus, previous, in-hospital and post-discharge use of BB was not randomized. Moreover, patients who died during hospitalization, were hospitalized for more than 30 days or lost contact before follow-up (16.8% of the sample) were excluded from the analysis. These authors divided their population into four groups by BB use at admission and upon discharge. They concluded that patients who used BB at admission and continued this use after discharge exhibited higher survival rates at 31 and 180 days compared to the group that used BB neither at admission nor at discharge. These findings reinforce the idea that the patients who tolerate the use of BB, including during acute decompensation, potentially have better prognoses compared to patients that do not tolerate BB neither before nor during hospitalization (study groups no/no and yes/no).

The data described in the present study suggest that a careful literature review did not provide evidence supporting the systematic use of BB in patients with low cardiac output syndrome who require inotropic support in the form of dobutamine. The secondary results of SURVIVE⁴² suggest that patients who have previously used BB and who may continue to use it during decompensation probably have less severe cases. Thus, they will potentially exhibit longer short-term survival. Concomitantly with the findings in LIDO, it might be inferred that patients who require inotropic agents but do not exhibit severe hypotension will benefit more from levosimendan than from dobutamine if they are using BB agents. Currently, very little may be concluded about the safety and effectiveness of starting BB therapy in patients with low cardiac output and arterial hypotension. This question represents a gap in knowledge about AHF management that should be filled soon by studies using the appropriate methods.

Conclusion

There are no conclusive evidence supporting the concomitant use of dobutamine and BB in patients with decompensated HF and low cardiac output.

Author contributions

Conception and design of the research: Passos LCS, Oliveira MG, Barbosa ACC; Acquisition of data, analysis and interpretation of the data and writing of the manuscript: Passos LCS, Oliveira MG, Barbosa ACC, Santos Jr. EG; Statistical analysis: Passos LCS, Barbosa ACC, Santos Jr. EG; Critical revision of the manuscript for intellectual content: Passos LCS, Barbosa ACC.

Potential Conflict of Interest

No potential conflict of interest relevant to this article was reported.

Sources of Funding

There were no external funding sources for this study.

Study Association

This article is part of the thesis of doctoral submitted by Andréa Cristina Costa Barbosa, from Universidade Federal da Bahia.

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Is there evidence favoring the use of beta-blockers and dobutamine in acute heart failure?

Luiz Carlos Santana Passos; Andréa Cristina Costa Barbosa; Márcio Galvão Oliveira; Edval Gomes Santos Jr

Publication Dates

• Publication in this collection
  11 Mar 2013
• Date of issue
  Feb 2013

History

• Received
  03 May 2012
• Accepted
  30 July 2012
• Reviewed
  30 July 2012