Multicenter Randomized Controlled Crossover Trial Comparing Hemodynamic Optimization Against Echocardiographic Optimization of AV and VV Delay of Cardiac Resynchronization Therapy: The BRAVO Trial

Zachary I Whinnett, S M Afzal Sohaib, Mark Mason, Edward Duncan, Mark Tanner, David Lefroy, Mohamed Al-Obaidi, Sue Ellery, Francisco Leyva-Leon, Tim Betts, Mark Dayer, Paul Foley, Jon Swinburn, Martin Thomas, Raj Khiani, Tom Wong, Zaheer Yousef, Dominic Rogers, Paul R Kalra, Vignesh Dhileepan, Katherine March, James Howard, Andreas Kyriacou, Jamil Mayet, Prapa Kanagaratnam, Michael Frenneaux, Alun D Hughes, Darrel P Francis, Zachary I Whinnett, S M Afzal Sohaib, Mark Mason, Edward Duncan, Mark Tanner, David Lefroy, Mohamed Al-Obaidi, Sue Ellery, Francisco Leyva-Leon, Tim Betts, Mark Dayer, Paul Foley, Jon Swinburn, Martin Thomas, Raj Khiani, Tom Wong, Zaheer Yousef, Dominic Rogers, Paul R Kalra, Vignesh Dhileepan, Katherine March, James Howard, Andreas Kyriacou, Jamil Mayet, Prapa Kanagaratnam, Michael Frenneaux, Alun D Hughes, Darrel P Francis

Abstract

Objectives: BRAVO (British Randomized Controlled Trial of AV and VV Optimization) is a multicenter, randomized, crossover, noninferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular delay with a noninvasive blood pressure method.

Background: Cardiac resynchronization therapy including AV delay optimization confers clinical benefit, but the optimization requires time and expertise to perform.

Methods: This study randomized patients to echocardiographic optimization or hemodynamic optimization using multiple-replicate beat-by-beat noninvasive blood pressure at baseline; after 6 months, participants were crossed over to the other optimization arm of the trial. The primary outcome was exercise capacity, quantified as peak exercise oxygen uptake. Secondary outcome measures were echocardiographic left ventricular (LV) remodeling, quality-of-life scores, and N-terminal pro-B-type natriuretic peptide.

Results: A total of 401 patients were enrolled, the median age was 69 years, 78% of patients were men, and the New York Heart Association functional class was II in 84% and III in 16%. The primary endpoint, peak oxygen uptake, met the criterion for noninferiority (pnoninferiority = 0.0001), with no significant difference between the hemodynamically optimized arm and echocardiographically optimized arm of the trial (mean difference 0.1 ml/kg/min). Secondary endpoints for noninferiority were also met for symptoms (mean difference in Minnesota score 1; pnoninferiority = 0.002) and hormonal changes (mean change in N-terminal pro-B-type natriuretic peptide -10 pg/ml; pnoninferiority = 0.002). There was no significant difference in LV size (mean change in LV systolic dimension 1 mm; pnoninferiority < 0.001; LV diastolic dimension 0 mm; pnoninferiority <0.001). In 30% of patients the AV delay identified as optimal was more than 20 ms from the nominal setting of 120 ms.

Conclusions: Optimization of cardiac resynchronization therapy devices by using noninvasive blood pressure is noninferior to echocardiographic optimization. Therefore, noninvasive hemodynamic optimization is an acceptable alternative that has the potential to be automated and thus more easily implemented. (British Randomized Controlled Trial of AV and VV Optimization [BRAVO]; NCT01258829).

Keywords: biventricular pacing; cardiac resynchronization therapy; echocardiographic optimization; heart failure; hemodynamic optimization; optimization.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Flowchart of Study Design Patients visited 4 times and underwent 2 atrioventricular and interventricular delay optimizations according to echocardiographic and hemodynamic protocols. ECG = electrocardiography; QoL = quality of life.
Figure 2
Figure 2
Simplified Schematic of Hemodynamic Optimization Method Continuous noninvasive beat-to-beat measurements are made through the Finometer (Finapres Medical Systems, Amsterdam, the Netherlands). Multiple alternations are carried out between a tested atrioventricular (AV) or ventriculoventricular (VV) delay and reference AV or VV delay. Blood pressures (BPs) before and after a transition in pacing state are measured as an average of 8 to 10 beats, as previously described . The average change in BP is plotted against AV or VV delay to fit a curve. The peak of the curve is used to select the optimum. LV = left ventricular.
Figure 3
Figure 3
Patient Flow Patients were randomized to either optimization method for 6 months before crossing over to the other arm of the trial for a further 6 months. Investigations performed at each stage are listed. HF = heart failure.
Figure 4
Figure 4
Primary Outcome: Change in ΔVo2max, Shown as Mean With 95% Confidence Interval Hemodynamic optimization using beat-to-beat noninvasive blood pressure was noninferior to the conventional established method of echocardiographic optimization. ΔVo2max = change in peak oxygen uptake.
Figure 5
Figure 5
Distribution of AV Delay Identified as Optimal Using the 2 Optimization Methods In approximately one-third of patients, the optimal atrioventricular (AV) delay was found to be more than 40 ms longer or shorter than the commonly used nominal setting of 120 ms. These patients are likely to have the most to gain from AV delay optimization.

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