Clinical outcomes of the AdaptResponse trial – Authors' reply
Authors: Gerasimos Filippatos, Michael R Gold, Wilfried Mullens, Kengo Kusano, Ahmad S Hersi, David Birnie, Bart Gerritse, Christophe Leclercq
Journal: The Lancet (2024)

We thank Kazuo Komamura and Mitsunori Iwase for their interest in our study.1Wilkoff BL Filippatos G Leclercq C et al.Adaptive versus conventional cardiac resynchronisation therapy in patients with heart failure (AdaptResponse): a global, prospective, randomised controlled trial.Lancet. 2023; 402: 1147-1157Summary Full Text Full Text PDF PubMed Google Scholar We agree that the reasons for no significant difference between treatment arms in the primary endpoint are multifactorial, but this is more likely to be due to other factors besides premature study exits and low use of guideline-recommended heart failure medications. The low event rates in both treatment arms, with an overall mortality rate of 16·5% at 5 years, is important to note. This event rate is lower than previous cardiac resynchronisation therapy (CRT) trials and, in our opinion, was probably the main reason for the non-significant findings. With respect to premature study exits, 784 (21·7%) of 3617 patients exited prematurely, but there was still a median 36 months of follow-up in these patients and 11·9% of patients had a primary endpoint event before exiting the trial. The effect of premature study exits on the results was further minimised by the event-driven study design that resulted in longer follow-up of remaining patients to compensate for those who exited prematurely. Of note, the timing of interim analyses was also determined by number of events. With respect to guideline-recommended heart failure medications, we would like to clarify that recommendations at the time of AdaptResponse enrolment (2014–19) included beta-blockers, mineralocorticoid receptor antagonists, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers.2Yancy CW Jessup M Bozkurt B et al.2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.Circulation. 2013; 128: e240-e327Crossref PubMed Scopus (1817) Google Scholar, 3Ponikowski P Voors AA Anker SD et al.2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC.Eur Heart J. 2016; 37: 2129-2200Crossref PubMed Google Scholar The percentage of AdaptResponse participants prescribed beta-blockers, mineralocorticoid receptor antagonists, and angiotensin converting enzyme inhibitors or angiotensin receptor blockers at baseline (90·1%, 48·1%, and 84·7%, respectively) is comparable with percentages reported in PARADIGM-HF and other CRT studies.4McMurray JJ Packer M Desai AS et al.Angiotensin-neprilysin inhibition versus enalapril in heart failure.N Engl J Med. 2014; 371: 993-1004Crossref PubMed Scopus (4904) Google Scholar, 5Friedman DJ Al-Khatib SM Dalgaard F et al.CRT improves outcomes in patients with IVCD but not RBBB: a patient-level meta-analysis of randomized controlled trials.Circulation. 2023; 147: 812-823Crossref PubMed Scopus (0) Google Scholar, 6Cleland JG Abraham WT Linde C et al.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: 3547-3556Crossref PubMed Scopus (409) Google Scholar This finding suggests that heart failure medication use was consistent with guideline recommendations that were applicable during the enrolment period. Komamura and Iwase raise an important question regarding how investigators determined the position of the left ventricular lead for an effective CRT response. The study protocol recommended left ventricular lead placement in a lateral, anterolateral, or posterolateral position; but implantation and placement optimisation were performed at physician discretion. A large majority of AdaptResponse participants received a quadripolar left ventricular lead and methods used to optimise left ventricular lead placement were captured in the study (data not published). Notably, 3350 (92·6%) of 3617 study participants had an improved or unchanged clinical composite score indicating a high CRT response rate (table 2 of the original Article1Wilkoff BL Filippatos G Leclercq C et al.Adaptive versus conventional cardiac resynchronisation therapy in patients with heart failure (AdaptResponse): a global, prospective, randomised controlled trial.Lancet. 2023; 402: 1147-1157Summary Full Text Full Text PDF PubMed Google Scholar). The low overall event rates and high CRT response rate observed in both study arms suggest that the left ventricular leads were in an effective position. The AdaptResponse study was funded by Medtronic. GF reports receiving lecture fees from Bayer, Boehringer Ingelheim, Servier, and Novartis; participating in committees of trials sponsored by Novo Nordisc, Bayer, Boehringer Ingelheim, Servier, Vifor, Cardior, Impulse Dynamics, and Medtronic; and receiving research grants from the EU. CL reports participating in a Medtronic advisory board and receiving honoraria from Medtronic, Biotronik, LivaNova, Boston Scientific, and Abbott. MRG reports being a consultant for Medtronic and Boston Scientific and receiving honoraria from Medtronic, Boston Scientific, and EBR Systems. KK reports receiving speaker's honoraria and research grants from Medtronic Japan and Biotronik Japan; and having received grants from Boston Scientific Japan. BG reports being an employee and is a minority shareholder of Medtronic. DB reports receiving research funding from Medtronic and Boston Scientific, Boehringer Ingelheim, Bayer, Biotronik, Pfizer, and Bristol Myers Squibb. All other authors declare no competing interests. The authors would like to acknowledge their colleague and the first author of the original Article, Dr Bruce L Wilkoff, who passed away on Jan 7, 2024. Clinical outcomes of the AdaptResponse trialIn the largest and longest randomised controlled trial of cardiac resynchronisation therapy (CRT) to date, Bruce L Wilkoff and colleagues showed that adaptive CRT did not significantly reduce the incidence of all-cause death or intervention for heart failure decompensation compared with conventional biventricular CRT.1 The reason for no difference between the two groups might be the number of patients who exited the study prematurely and the low use of guideline-indicated heart failure medications. Full-Text PDF