ORIGINAL ARTICLE Controlled release metoprolol for aortic regurgitation: a randomised clinical trial Kaspar Broch, 1,2 Stig Urheim, 1,3 Mai Tone Lønnebakken, 4,5 Wenche Stueflotten, 1 Richard Massey, 1 Kristian Fosså, 6 Einar Hopp, 6 Svend Aakhus, 1 Lars Gullestad 1,2 1 Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway 2 Faculty of Medicine, K. G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, University of Oslo, Oslo, Norway 3 Institute for Surgical Research, Oslo University Hospital Rikshospitalet, Oslo, Norway 4 Department of Clinical Science, University of Bergen, Bergen, Norway 5 Department of Heart Disease, Haukeland University Hospital, Bergen, Norway 6 Department of Radiology and Nuclear Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway Correspondence to Dr Kaspar Broch, Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo 0027, Norway; kaspar.broch@ ous-hf.no KB and SU contributed equally to this study. Received 17 July 2015 Revised 11 November 2015 Accepted 12 November 2015 Published Online First 9 December 2015 ▸ http://dx.doi.org/10.1136/ heartjnl-2015-308955 To cite: Broch K, Urheim S, Lønnebakken MT, et al. Heart 2016;102:191–197. ABSTRACT Objective Chronic aortic regurgitation (AR) creates a volume load on the left ventricle, which induces adaptive responses. With time, excessive left ventricular (LV) dilatation may precipitate heart failure. β-adrenergic receptor antagonists (β-blockers) are beneficial in patients with heart failure, but their effect in AR is unclear. This trial was designed to evaluate the effect of controlled release metoprolol on LV remodelling in patients with AR. Methods In this double blind trial, 75 asymptomatic patients aged 44±14 years, 89% males, fulfilling at least two echocardiographic criteria for moderate or severe chronic AR, were randomised to receive metoprolol CR/ XL up-titrated to 200 mg/day, or matching placebo. The primary endpoint was LV end diastolic volume, measured by MRI after 6 months of treatment. Results After 6 months, the difference in the baseline- adjusted LV end diastolic volume between patients allocated to metoprolol and those allocated to placebo was 8 (95% CI -8 to 25) mL (p=0.32). The adjusted LV ejection fraction was 2.7 (95% CI 0.1 to 5.3) percentage points higher in the metoprolol group than in the placebo group (p=0.04). The exercise capacity and peak oxygen consumption did not differ between treatment arms. Serum concentrations of N-terminal pro- B-type natriuretic peptide were 138 (95% CI 71 to 205) pg/mL higher in the metoprolol group (p<0.001). There were no serious adverse events in either treatment arm. Conclusions Treatment with metoprolol of adults with chronic, moderate to severe AR had no effect on LV volumes. Trial registration number ClinicalTrials.gov Identifier: NCT01157572-results. INTRODUCTION Aortic regurgitation (AR) affects approximately 0.5% of the population 1 and is the third most common valvular heart disease in the developed world. 12 The clinical course of chronic AR is char- acterised by a prolonged phase of stability, during which the left ventricle adapts to the volume over- load and patients remain asymptomatic. 3–5 However, if left ventricular (LV) dilatation pro- gresses, the probability of death, overt heart failure, or LV dysfunction increases sharply. 3–5 Today, the only effective treatment is aortic valve replacement or repair. 6 The role of pharmacological treatment in asymp- tomatic patients with haemodynamically significant AR remains unclear. The time to surgical intervention can be delayed by calcium antago- nists, 7 8 ACE inhibitors, 9 10 and hydralazine. 11 However, a more recent study did not find any effect of nifedipine or enalapril on either time to surgery or LV size and function. 12 Treatment with β-adrenergic receptor antagonists (β-blockers) can attenuate or even reverse LV remodelling 13 and improve survival 14 15 in heart failure. Nevertheless, β-blocker therapy has traditionally been discour- aged in patients with incipient heart failure due to severe AR. The relative duration of diastole increases when heart rate is reduced, theoretically aggravating the LV volume load in these patients. On the other hand, animal experiments 16–19 and observational data 20 suggest that β-blockers may be cardioprotective in AR. The effect of β-blockers in AR has not been evaluated in controlled trials in humans. We examined the effect of controlled release metoprolol succinate (metoprolol CR/XL) in asymptomatic patients with chronic, moderate to severe AR, hypothesising that the β-blockade would reverse LV remodelling in these patients. PATIENTS AND METHODS This randomised, double blind, placebo-controlled study was designed to assess the effect of metoprolol CR/XL on LV size and function in patients with chronic AR (ClinicalTrials.gov Identifier: NCT01157572). It was conducted at two sites in Norway and one in Copenhagen, Denmark. The trial complies with the Declaration of Helsinki and was approved by the appropriate Regional Committees for Medical and Health Research Ethics and the Norwegian Medicines Agency. All patients provided written informed consent. The study was performed in accordance with the Consolidated Standards of Reporting Trials (CONSORT) statement. 21 Patient population Patients aged between 18 and 70 years with asymp- tomatic, haemodynamically significant AR, an LV ejection fraction (LVEF) >50%, and an LVend dia- stolic internal diameter >5.0 cm (or an indexed value >3.0 cm/m 2 ) were eligible. Criteria for exclu- sion were: symptoms of heart failure; a history of myocardial infarction or symptomatic coronary heart disease; significant aortic stenosis (valvular area <1.5 cm 2 ); additional haemodynamically sig- nificant valvular or congenital heart disease; an indication for aortic valve surgery (severe AR in conjunction with either symptoms of heart failure, an LVEF <50%, or an LVend diastolic/end systolic internal diameter >7.0/5.0 cm); 22 a second- or Editor’s choice Scan to access more free content Broch K, et al. Heart 2016;102:191–197. doi:10.1136/heartjnl-2015-308416 191 Valvular heart disease on May 29, 2020 by guest. Protected by copyright. http://heart.bmj.com/ Heart: first published as 10.1136/heartjnl-2015-308416 on 9 December 2015. Downloaded from