ERJ Express. Published on July 7, 2016 as doi: 10.1183/13993003.00090-2016 ORIGINAL ARTICLE IN PRESS | CORRECTED PROOF Bisoprolol in idiopathic pulmonary arterial hypertension: an explorative study Jasmijn S.J.A. van Campen 1,7, Karin de Boer2,7, Mariëlle C. van de Veerdonk1,2, Cathelijne E.E. van der Bruggen1, Cor P. Allaart2, Pieter G. Raijmakers3, Martijn W. Heymans4,J.TimMarcus5, Hendrik J. Harms1,3,M.LouisHandoko2, Frances S. de Man1,6, Anton Vonk Noordegraaf1 and Harm-Jan Bogaard1,6 Affiliations: 1Dept of pulmonary medicine, Institute for cardiovascular research, VU University medical center, Amsterdam, The Netherlands. 2Dept of cardiology, Institute for cardiovascular research, VU University medical center, Amsterdam, The Netherlands. 3Dept of nuclear medicine and PET-research, VU University medical center, Amsterdam, The Netherlands. 4Dept of epidemiology, VU University medical center, Amsterdam, The Netherlands. 5Dept of physics and medical technology, VU University medical center, Amsterdam, The Netherlands. 6Dept of physiology, Institute for cardiovascular research, VU University medical center, Amsterdam, The Netherlands. 7Both authors contributed equally. Correspondence: Harm-Jan Bogaard, Dept of pulmonary medicine, VU University Medical Center, ZKH 4f.010, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. E-mail: [email protected] ABSTRACT While beta-blockers are considered contraindicated in pulmonary arterial hypertension (PAH), the prognostic significance of sympathetic nervous system over-activity suggests a potential benefit of beta-blocker therapy. The aim of this randomised, placebo-controlled, crossover, single centre study was to determine the effects of bisoprolol on right ventricular ejection fraction (RVEF) in idiopathic PAH (iPAH) patients. Additional efficacy and safety parameters were explored. Patients with optimally treated, stable iPAH (New York Heart Association functional class II/III) were randomised to placebo or bisoprolol. Imaging and functional measurements were performed at baseline, crossover and end of study. 18 iPAH patients were included, because inclusion faltered before enrolment of the targeted 25 patients. 17 patients completed 6 months of bisoprolol, 15 tolerated bisoprolol, one patient required intravenous diuretics. Bisoprolol was associated with a lower heart rate (17 beats per minute, p=0.0001) but RVEF − − remained unchanged. A drop in cardiac index (0.5 L·min 1·m 2, p=0.015) was observed, along with a trend towards a decreased 6-min walking distance (6MWD). Although careful up-titration of bisoprolol was tolerated by most patients and resulted in a decreased heart rate, no benefit of bisoprolol in iPAH was demonstrated. Decreases in cardiac index and 6MWD suggest a deteriorated cardiac function. The results do not favour the use of bisoprolol in iPAH patients. @ERSpublications A bisoprolol dose that significantly reduced heart rate was not associated with a significant change in RVEF in PAH http://ow.ly/j5D0300OgGz This article has supplementary material available from erj.ersjournals.com Received: Sept 21 2015 | Accepted after revision: May 21 2016 Clinical trial: The study was registered at clinicaltrials.gov with identifier number NCT01246037 and clinicaltrialsregister.eu (EudraCT) with identifier number 2010-020424-21. Support statement: This research was financially supported by a ZonMW grant (number: 95110079). Funding information for this article has been deposited with the Open Funder Registry. Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com Copyright ©ERS 2016 Eur Respir J 2016; In press | DOI: 10.1183/13993003.00090-2016 1 Copyright 2016 by the European Respiratory Society. PULMONARY VASCULAR DISEASE | J.S.J.A. VAN CAMPEN ET AL. Introduction Idiopathic pulmonary arterial hypertension (iPAH) is a rare disease with a prevalence of 5–15 per million adults [1, 2]. iPAH is characterised by progressive pulmonary vascular remodelling and the associated increase in right ventricular (RV) afterload eventually leads to right heart failure and premature death. Even with the best available treatment, prognosis remains poor [3]. Current medical treatments aim to dilate small pulmonary arteries, but recent data suggest that, even if treatment reduces RV afterload, RV function in many iPAH patients continues to deteriorate, which then predicts a poor outcome [4]. Therefore, directly targeted RV therapy may be of additional benefit. Despite the importance of beta-blockers in left heart failure management, current guidelines advise against their use in pulmonary arterial hypertension (PAH) patients [5, 6]. This recommendation is based on the premise that the immediate negative inotropic and chronotropic effects of beta-blockers will result in systemic hypotension and a decreased exercise capacity and is supported by several publications [7–9]. However, the sympathetic nerve system (SNS) is excessively active in PAH patients, a phenomenon associated with increased mortality [10] and suggesting a benefit of beta-blocker treatment [11–13]. Preclinical studies demonstrated that beta-blockers improve RV function in experimental pulmonary hypertension in an afterload-independent way [14–17]. Furthermore, PERROS et al. [17] recently provided in vitro and preclinical evidence that beta-blocker treatment may not only improve RV function directly, but also indirectly through improvement of endothelial dysfunction and reversal of pulmonary vascular remodelling. The key question that arises is whether positive effects on myocardial remodelling and oxygen efficiency can negate any acute negative inotropic and chronotropic effects of chronic beta-blocker treatment in PAH. The aim of this randomised, placebo-controlled, crossover, single centre study was to determine the effects of bisoprolol treatment on right ventricular ejection fraction (RVEF) in iPAH patients. A number of additional efficacy and safety parameters were explored. Methods This was a proof-of-concept single centre study with a 12-month prospective, randomised, double-blind, placebo-controlled, crossover design and a half year open-label extension trial. The study was registered at clinicaltrials.gov (NCT01246037) and EudraCT (2010-020424-21). The study was initially designed to detect a 3% difference in RVEF between placebo and bisoprolol, but failed to enrol the targeted 25 study patients. Patients All iPAH patients older than 18 years in New York Heart Association (NYHA) functional class II and III were screened. Eligible patients were in sinus rhythm and clinically stable on PAH specific medication. Inclusion and exclusion criteria are described in the supplementary material. Study protocol After extensive baseline assessments (described later) patients were randomised 1:1 to either bisoprolol or placebo. Treatment was started at a dosage of 1.25 mg (half a tablet), once daily and was gradually increased to achieve the highest tolerated dosage with a maximum dosage of 10 mg (four tablets). Patients were re-examined every 2 weeks and when possible the dosage was increased by 1.25 mg. The dosage was not increased, or was reduced if necessary, in case of a drop in systolic systemic pressure <90 mmHg, progression of heart failure, clinically relevant bradycardia or a heart rate below 60 beats per minute, increased symptoms, or a drop in 6-min walking distance (6MWD) of >10%. Diuretic dose was guided by clinical examination. On a monthly basis blood was drawn and ECG, quality of life (assessed using the Minnesota living with heart failure questionnaire (MLHFQ)) and 6MWD were determined. 4 months into the study, drug doses were not further increased. Patients were re-admitted 6 months after the start of the study to repeat all baseline assessments. Study medication was tapered down and stopped after 2 weeks. Subsequently, patients were crossed over to the alternative medication and in the following 6 months, the same procedures were repeated (figure 1). At baseline, before cross over and after 1 year of study, patients were admitted for assessment of outcome parameters using cardiac magnetic resonance imaging (CMRI), right heart catheterisation, exercise testing, blood sampling, heart rate variability measurements, 11C-acetate positron emission tomography (PET) scans and quality of life questionnaires as described in the supplementary material, which also provides information on clinical deterioration, medical ethical board approval and serious adverse events. 2 DOI: 10.1183/13993003.00090-2016 PULMONARY VASCULAR DISEASE | J.S.J.A. VAN CAMPEN ET AL. t1 t2 t3 t4 t5 t6 n=9 Bisoprolol Bisoprolol Placebo Placebo n=9 4 months 4 months 6 months 2 weeks 6 months FIGURE 1 Study scheme. Clinically stable idiopathic pulmonary arterial hypertension patients were included in the study. At baseline, after 6 months and at the end of the study (t=1, 3 and 6) patients were admitted for extensive testing. Between t1–t2 and t4–t5, patients were examined every 2 weeks for up-titration of bisoprolol or placebo. Between t2–t3 and t5–t6 all patients received a stable drug dose. Medications were tapered and then stopped between t3 and t4, and after t6, unless patients entered the open-label extension study. Statistical analysis Data are presented as mean±SD. To compare the effects of 6 months of bisoprolol and placebo treatment a linear mixed model was used to control for the repeated outcome assessments within patients (see the supplementary material). A 3% change in RVEF was considered a clinically