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Proposal 1236

Title of the Proposed Research

COPERNICUS re-analysis

Lead Researcher

John Cleland

Affiliation

Magdi Yacoub Institute - Heart Science Centre
National Heart & Lung Institute (Myocardial Function Section)
Harefield Hospital
Hill End Road
Harefield, Middlesex, UB9 6JH

Funding Source

Internal departmental resources

Potential Conflicts of Interest

None

Data Sharing Agreement Date

16 September 2015

Lay Summary

Heart failure with reduced left ventricular ejection fraction (HFrEF) is common causing disability, hospital admission and death. [1]. Half of patients with heart failure will develop clinically observed atrial fibrillation (an irregular heart rhythm) during the course of their disease. One of the cornerstones of treatment for HFrEF is beta-blockers. However, recent re-analyses of several landmark studies suggest that beta- blockers neither reduce the rate of hospitalization for heart failure nor mortality amongst patients who were in atrial fibrillation[2]. There are several explanation of this phenomenon. First, most of the trials were conducted with beta-1-selective agents; trends to improvement with non-selective beta-blockers (carvedilol and bucindolol) were observed. Secondly, the optimal ventricular rate for patients with atrial fibrillation may be different from that for patients in sinus rhythm.[3] COPERNICUS is the only large trial (n = 2,289) conducted with a non-selective beta-blocker (carvedilol) in patients with heart failure. The analysis will start by separating patients into four distinct groups depending on the underlying rhythm (sinus, AF, sinus-paced and AF-paced). We suspect few patients in COPERNICUS had pacemakers or defibrillators, although these data has not been reported, but they may confound analysis if is not taken into consideration. We will investigate relationship between outcome and heart rate at baseline and achieved heart rate at the end of the titration phase. We will report the rate of hospitalization for heart failure or cardiovascular death as the primary composite outcome and all-cause and cardiovascular mortality as secondary outcomes. This study is important because it allows us to study the interactions between beta-blockers, heart rhythm and on-treatment heart rate. This will provide insights into the reasons why beta-blockers fail to improve prognosis in patients with atrial fibrillation.

[1] J. J. V McMurray and M. A. Pfeffer, “Heart failure.,” Lancet, vol. 365, no. 9474, pp. 1877–89, Jan. 2005.
[2] D. Kotecha, J. Holmes, H. Krum, D. G. Altman, L. Manzano, J. G. F. Cleland, G. Y. H. Lip, A. J. S. Coats, B. Andersson, P. Kirchhof, T. G. von Lueder, H. Wedel, G. Rosano, M. C. Shibata, A. Rigby, and M. D. Flather, “Efficacy of ß blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis,” Lancet, vol. 384, no. 9961, pp. 2235–2243, 2014.
[3] D. Castagno, H. Skali, M. Takeuchi, K. Swedberg, S. Yusuf, C. B. Granger, E. L. Michelson, M. a. Pfeffer, J. J. V McMurray, and S. D. Solomon, “Association of heart rate and outcomes in a broad spectrum of patients with chronic heart failure: Results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) program,” J. Am. Coll. Cardiol., vol. 59, no. 20, pp. 1785–1795, 2012.

Study Data Provided

Study GSK-105517/287: Carvedilol Prospective Randomized Cumulative Survival Trial.

Statistical Analysis Plan

The statistical analysis plan will be added after the research is published.

Publication Citation

The publication citation will be added after the research is published.