Rationale and design of the AdaptResponse trial: a prospective randomized study of cardiac resynchronization therapy with preferential adaptive left ventricular-only pacing

Gerasimos Filippatos, David Birnie, Michael R Gold, Bart Gerritse, Ahmad Hersi, Sandra Jacobs, Kengo Kusano, Christophe Leclercq, Wilfried Mullens, Bruce L Wilkoff, AdaptResponse Investigators, Gerasimos Filippatos, David Birnie, Michael R Gold, Bart Gerritse, Ahmad Hersi, Sandra Jacobs, Kengo Kusano, Christophe Leclercq, Wilfried Mullens, Bruce L Wilkoff, AdaptResponse Investigators

Abstract

The AdaptResponse trial is designed to test the hypothesis that preferential adaptive left ventricular-only pacing with the AdaptivCRT® algorithm reduces the incidence of the combined endpoint of all-cause mortality and intervention for heart failure (HF) decompensation, compared with conventional cardiac resynchronization therapy (CRT), among patients with a CRT indication, left bundle branch block (LBBB) and normal atrioventricular (AV) conduction. The AdaptResponse study is a prospective, randomized, controlled, single-blinded, multicentre, clinical trial (ClinicalTrials.gov Identifier: NCT02205359), conducted at up to 200 centres worldwide. Following enrolment and baseline assessment, eligible subjects will be implanted with a CRT system containing the AdaptivCRT algorithm, and randomized in a 1:1 fashion to either a treatment ('AdaptivCRT') or control ('Conventional CRT') group. The study is designed to observe a primary endpoint in 1100 patients ('event-driven') and approximately 3000 patients will be randomized. The primary endpoint is the composite of all-cause mortality and intervention for HF decompensation; secondary endpoints include all-cause mortality, intervention for HF decompensation, clinical composite score (CCS) at 6 months, atrial fibrillation, quality of life measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ), health outcome measured by the EQ-5D instrument, all-cause readmission after a HF admission, and cost-effectiveness. The AdaptResponse clinical trial is powered to assess clinical endpoints and is expected to provide definitive evidence on the incremental utility of AdaptivCRT-enhanced CRT systems.

Keywords: Atrioventricular conduction; Cardiac resynchronization therapy; Clinical outcome; Heart failure; Left bundle branch block; Left ventricular pacing; Optimization.

© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.

Figures

Figure 1
Figure 1
AdaptivCRT algorithm. The AdaptivCRT algorithm continuously and dynamically optimizes the cardiac resynchronization therapy pacing method and atrioventricular/interventricular delays depending on the patient's activity levels and conduction status. Adaptive left ventricular pacing makes use of the patient's intrinsic conduction by pre‐pacing the left ventricle to synchronize with intrinsic right ventricular activation and establish fusion. When the patient's heart rate increases or atrioventricular conduction is prolonged, the pacing mode switches automatically to adaptive biventricular pacing. During adaptive biventricular pacing, the atrioventricular delays are updated every minute based on atrioventricular interval and P wave width measurements. Intrinsic atrioventricular intervals are measured every minute, and P wave and QRS widths are measured every 16 h. The atrioventricular delay is adjusted to pace about 30 ms after the end of the P wave but at least 50 ms before the onset of the intrinsic QRS. This provides enough time for atrial contraction, while ensuring biventricular pacing, prior to intrinsic conduction to the ventricles. In addition, the ventricular pacing configuration (right ventricle → left ventricle, left ventricle → right ventricle) and interventricular pace delay are updated every minute based on the atrioventricular interval and QRS width measurements. In patients with normal atrioventricular conduction, as measured intracardially by the device, the AdaptivCRT algorithm will primarily provide adaptive left ventricular pacing. During this pacing operation, the timing of the left ventricular pace is automatically adjusted based on the intrinsic atrioventricular interval measurement that occurs every 60 s. After the left ventricular pace occurs, the intrinsic right ventricular contraction completes the biventricular activation. Every minute, the atrioventricular delays are updated to ensure optimal cardiac resynchronization therapy delivery. When programmed to adaptive biventricular and left ventricular pacing, the device employs adaptive left ventricular‐only pacing when the patient's heart rate is 100 b.p.m. or below, when atrioventricular conduction is normal, and left ventricular capture is confirmed. Normal atrioventricular intervals are defined as less than 200 ms for atrial‐sensed intervals and less than 250 ms for atrial‐paced intervals.16 AV, atrioventricular; BiV, biventricular; HR, heart rate; LV, left ventricular; RV, right ventricular; VV, interventricular; As‐RVs, atrial sensed atrioventricular interval; Ap‐RVs, atrial paced atrioventricular interval.
Figure 2
Figure 2
Study flow from enrolment to planned study visits. AE, adverse event; CRT, cardiac resynchronization therapy; ECG, electrocardiogram; HCU, health care service utilization; M, month; NYHA, New York Heart Association class; QoL, quality of life; S2D, device data.

References

    1. Brignole M, Auricchio A, Baron‐Esquivias G, Bordachar P, Boriani G, Breithardt OA, Cleland J, Deharo JC, Delgado V, Elliott PM, Gorenek B, Israel CW, Leclercq C, Linde C, Mont L, Padeletti L, Sutton R, Vardas PE; ESC Committee for Practice Guidelines (CPG) , Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S; Document Reviewers , Kirchhof P, Blomstrom‐Lundqvist C, Badano LP, Aliyev F, Bansch D, Baumgartner H, Bsata W, Buser P, Charron P, Daubert JC, Dobreanu D, Faerestrand S, Hasdai D, Hoes AW, Le Heuzey JY, Mavrakis H, McDonagh T, Merino JL, Nawar MM, Nielsen JC, Pieske B, Poposka L, Ruschitzka F, Tendera M, Van Gelder IC, Wilson CM. 2013 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy: the Task Force on cardiac pacing and resynchronization therapy of the European Society of Cardiology (ESC). Developed in collaboration with the European Heart Rhythm Association (EHRA). Eur Heart J 2013;34:2281–2329.
    1. Epstein AE, DiMarco JP, Ellenbogen KA, Estes NA 3rd, Freedman RA, Gettes LS, Gillinov AM, Gregoratos G, Hammill SC, Hayes DL, Hlatky MA, Newby LK, Page RL, Schoenfeld MH, Silka MJ, Stevenson LW, Sweeney MO; American College of Cardiology Foundation ; American Heart Association Task Force on Practice Guidelines; Heart Rhythm Society. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device‐based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. Circulation 2013;127:e283–352.
    1. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, Ellestad M, Trupp RJ, Underwood J, Pickering F, Truex C, McAtee P, Messenger J; MIRACLE Study Group . Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845–1853.
    1. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L; Cardiac Resynchronization–Heart Failure (CARE‐HF) Study Investigators . The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005;352:1539–1549.
    1. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, Abraham WT, Ghio S, Leclercq C, Bax JJ, Yu CM, Gorcsan J 3rd, St John Sutton M, De Sutter J, Murillo J. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation 2008;117:2608–2616.
    1. Boriani G, Gardini B, Diemberger I, Bacchi Reggiani ML, Biffi M, Martignani C, Ziacchi M, Valzania C, Gasparini M, Padeletti L, Branzi A. Meta‐analysis of randomized controlled trials evaluating left ventricular vs. biventricular pacing in heart failure: effect on all‐cause mortality and hospitalizations. Eur J Heart Fail 2012;14:652–660.
    1. Thibault B, Ducharme A, Harel F, White M, O'Meara E, Guertin MC, Lavoie J, Frasure‐Smith N, Dubuc M, Guerra P, Macle L, Rivard L, Roy D, Talajic M, Khairy P; Evaluation of Resynchronization Therapy for Heart Failure (GREATER‐EARTH) Investigators . Left ventricular versus simultaneous biventricular pacing in patients with heart failure and a QRS complex ≥120 milliseconds. Circulation 2011;124:2874–2881.
    1. Boriani G, Kranig W, Donal E, Calo L, Casella M, Delarche N, Lozano IF, Ansalone G, Biffi M, Boulogne E, Leclercq C; B‐LEFT HF study group. A randomized double‐blind comparison of biventricular versus left ventricular stimulation for cardiac resynchronization therapy: the Biventricular versus Left Univentricular Pacing with ICD Back‐up in Heart Failure Patients (B‐LEFT HF) trial. Am Heart J 2010;159:1052–1058.e1.
    1. van Gelder BM, Bracke FA, Meijer A, Pijls NH. The hemodynamic effect of intrinsic conduction during left ventricular pacing as compared to biventricular pacing. J Am Coll Cardiol 2005;46:2305–2310.
    1. Lee KL, Burnes JE, Mullen TJ, Hettrick DA, Tse HF, Lau CP. Avoidance of right ventricular pacing in cardiac resynchronization therapy improves right ventricular hemodynamics in heart failure patients. J Cardiovasc Electrophysiol 2007;18:497–504.
    1. Bertini M, Delgado V, Bax JJ, Van de Veire NR. Why, how and when do we need to optimize the setting of cardiac resynchronization therapy? Europace 2009;11 (Suppl 5):v46–57.
    1. Vidal B, Sitges M, Marigliano A, Delgado V, Diaz‐Infante E, Azqueta M, Tamborero D, Tolosana JM, Berruezo A, Perez‐Villa F, Pare C, Mont L, Brugada J. Optimizing the programation of cardiac resynchronization therapy devices in patients with heart failure and left bundle branch block. Am J Cardiol 2007;100:1002–1006.
    1. Ellenbogen KA, Gold MR, Meyer TE, Fernndez Lozano I, Mittal S, Waggoner AD, Lemke B, Singh JP, Spinale FG, Van Eyk JE, Whitehill J, Weiner S, Bedi M, Rapkin J, Stein KM. Primary results from the SmartDelay determined AV optimization: a comparison to other AV delay methods used in cardiac resynchronization therapy (SMART‐AV) trial: a randomized trial comparing empirical, echocardiography‐guided, and algorithmic atrioventricular delay programming in cardiac resynchronization therapy. Circulation 2010;122:2660–2668.
    1. Brugada Terradellas J, Delnoy PP, Brachmann J, Reynolds DW, Padeletti L, Noelker G, Kantipudi C, Borri‐Brunetto A, Verhees L, Ritter P, Singh JP; RESPOND‐CRT Investigators . Clinical response to cardiac resynchronization therapy with the SonR hemodynamic sensor: the RESPOND‐CRT Randomized Trial. LBCT01‐040 [Abstract]. Heart Rhythm 2016;16:1369–1372.
    1. Ritter P, Delnoy PP, Padeletti L, Lunati M, Naegele H, Borri‐Brunetto A, Silvestre J. A randomized pilot study of optimization of cardiac resynchronization therapy in sinus rhythm patients using a peak endocardial acceleration sensor vs. standard methods. Europace 2012;14:1324–1333.
    1. Krum H, Lemke B, Birnie D, Lee KL, Aonuma K, Starling RC, Gasparini M, Gorcsan J, Rogers T, Sambelashvili A, Kalmes A, Martin D. A novel algorithm for individualized cardiac resynchronization therapy: rationale and design of the adaptive cardiac resynchronization therapy trial. Am Heart J 2012;163:747–752.e1.
    1. Daoud GE, Houmsse M. Cardiac resynchronization therapy pacemaker: critical appraisal of the adaptive CRT‐P device. Med Devices (Auckl) 2016;9:19–25.
    1. Martin DO, Lemke B, Birnie D, Krum H, Lee KL, Aonuma K, Gasparini M, Starling RC, Milasinovic G, Rogers T, Sambelashvili A, Gorcsan J 3rd, Houmsse M; Adaptive CRT Study Investigators . Investigation of a novel algorithm for synchronized left‐ventricular pacing and ambulatory optimization of cardiac resynchronization therapy: results of the adaptive CRT trial. Heart Rhythm 2012;9:1807–1814.
    1. Birnie D, Lemke B, Aonuma K, Krum H, Lee KL, Gasparini M, Starling RC, Milasinovic G, Gorcsan J 3rd, Houmsse M, Abeyratne A, Sambelashvili A, Martin DO. Clinical outcomes with synchronized left ventricular pacing: analysis of the adaptive CRT trial. Heart Rhythm 2013;10:1368–1374.
    1. Singh JP, Abraham WT, Chung ES, Rogers T, Sambelashvili A, Coles JA Jr, Martin DO. Clinical response with adaptive CRT algorithm compared with CRT with echocardiography‐optimized atrioventricular delay: a retrospective analysis of multicentre trials. Europace 2013;15:1622–1628.
    1. Strauss DG, Selvester RH, Wagner GS. Defining left bundle branch block in the era of cardiac resynchronization therapy. Am J Cardiol 2011;107:927–934.
    1. Gheorghiade M, Zannad F, Sopko G, Klein L, Pina IL, Konstam MA, Massie BM, Roland E, Targum S, Collins SP, Filippatos G, Tavazzi L; International Working Group on Acute Heart Failure Syndromes . Acute heart failure syndromes: current state and framework for future research. Circulation 2005;112:3958–3968.
    1. Okumura N, Jhund PS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Swedberg K, Zile MR, Solomon SD, Packer M, McMurray JJ; PARADIGM Investigators and Committees . Importance of clinical worsening of heart failure treated in the outpatient setting: evidence from the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial (PARADIGM‐HF). Circulation 2016;133:2254–2262.
    1. Packer M. Proposal for a new clinical end point to evaluate the efficacy of drugs and devices in the treatment of chronic heart failure. J Card Fail 2001;7:176–182.
    1. Green CP, Porter CB, Bresnahan DR, Spertus JA. Development and evaluation of the Kansas City Cardiomyopathy Questionnaire: a new health status measure for heart failure. J Am Coll Cardiol 2000;35:1245–1255.
    1. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, Estes NA 3rd, Foster E, Greenberg H, Higgins SL, Pfeffer MA, Solomon SD, Wilber D, Zareba W; MADIT‐CRT Trial Investigators . Cardiac‐resynchronization therapy for the prevention of heart‐failure events. N Engl J Med 2009;361:1329–1338.
    1. Linde C, Abraham WT, Gold MR, St John Sutton M, Ghio S, Daubert C; REVERSE (REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction) Study Group . Randomized trial of cardiac resynchronization in mildly symptomatic heart failure patients and in asymptomatic patients with left ventricular dysfunction and previous heart failure symptoms. J Am Coll Cardiol 2008;52:1834–1843.
    1. Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, Hohnloser SH, Nichol G, Birnie DH, Sapp JL, Yee R, Healey JS, Rouleau JL; Resynchronization‐Defibrillation for Ambulatory Heart Failure Trial Investigators . Cardiac‐resynchronization therapy for mild‐to‐moderate heart failure. N Engl J Med 2010;363:2385–2395.
    1. Cleland JG, Abraham WT, Linde C, Gold MR, Young JB, Claude Daubert J, Sherfesee L, Wells GA, Tang AS. An individual patient meta‐analysis of five randomized trials assessing the effects of cardiac resynchronization therapy on morbidity and mortality in patients with symptomatic heart failure. Eur Heart J 2013;34:3547–3556.
    1. Lan KKG, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika 1983;70:659–663.
    1. O'Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549–556.
    1. Hommel G. A stagewise rejective multiple test procedure based on a modified Bonferroni test. Biometrika 1988;75:383–386.
    1. Martin D, Lemke B, Aonuma K, Krum H, Lai‐Fun Lee K, Gasparini M, Starling R, Gorcsan J, Rogers T, Sambelashvili A, Hudnall J, Birnie D. Clinical outcomes with adaptive cardiac resynchronization therapy: long‐term outcomes of the adaptive CRT trial. HFSA Late Breakers [Abstract]. 23 September 2013.
    1. Filippatos G, Anker SD, Bohm M, Gheorghiade M, Kober L, Krum H, Maggioni AP, Ponikowski P, Voors AA, Zannad F, Kim SY, Nowack C, Palombo G, Kolkhof P, Kimmeskamp‐Kirschbaum N, Pieper A, Pitt B. A randomized controlled study of finerenone vs. eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidney disease. Eur Heart J 2016;37:2105–2114.
    1. Gheorghiade M, Pang PS, Ambrosy AP, Lan G, Schmidt P, Filippatos G, Konstam M, Swedberg K, Cook T, Traver B, Maggioni A, Burnett J, Grinfeld L, Udelson J, Zannad F. A comprehensive, longitudinal description of the in‐hospital and post‐discharge clinical, laboratory, and neurohormonal course of patients with heart failure who die or are re‐hospitalized within 90 days: analysis from the EVEREST trial. Heart Fail Rev 2012;17:485–509.
    1. Butler J, Gheorghiade M, Kelkar A, Fonarow GC, Anker S, Greene SJ, Papadimitriou L, Collins S, Ruschitzka F, Yancy CW, Teerlink JR, Adams K, Cotter G, Ponikowski P, Felker GM, Metra M, Filippatos G. In‐hospital worsening heart failure. Eur J Heart Fail 2015;17:1104–1113.
    1. Stockburger M, Moss AJ, Klein HU, Zareba W, Goldenberg I, Biton Y, McNitt S, Kutyifa V. Sustained clinical benefit of cardiac resynchronization therapy in non‐LBBB patients with prolonged PR‐interval: MADIT‐CRT long‐term follow‐up. Clin Res Cardiol 2016;105:944–952.

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