This article refers to 'Comorbidities and clinical response to cardiac resynchronization therapy: Patient-level meta-analysis from eight clinical trials' by M. Fudim et al., published in this issue on pages 1039-1046.Cardiac resynchronization therapy (CRT) plays a role in the management of patients with heart failure and reduced ejection fraction (HFrEF) and electrical dyssynchrony, conveying a prognostic benefit, improving cardiac function and quality of life. 1 Nevertheless, CRT is largely underutilized, with about two-thirds of potentially eligible patients not receiving the treatment. 2 A recent online survey revealed that one of the most commonly mentioned reasons for not considering CRT is that 'patients are too ill', suggesting that CRT benefit is not perceived among healthcare providers when patients are old and comorbid. 3 This feeling is further confirmed when the analysis is expanded to different stakeholders, including representatives of patient associations, governmental agencies, and industry. Interestingly, the lack of clear evidence supporting a more liberal use of CRT in complex and comorbid patients has recently been identified as the main hurdle in considering this option. 4 Randomized controlled trials (RCTs), indeed, are limited in addressing this issue: specific comorbidities are often presented as exclusion criteria or, at best, reported in a very limited proportion of patients, resulting in underpowered RCTs for certain subgroups. 5 Even the impact of CRT in patients with atrial fibrillation (AF), alone or in combination with other comorbidities, remains a matter of debate 6,7 : most of the landmark trials on this topic, apart from the Resynchronization-Defibrillation for Ambulatory Heart Failure' (RAFT) and Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) trials, excluded patients with permanent AF and enrolled only individuals with sinus rhythm at randomization, who experienced intermittent (paroxysmal or persistent) episodes of AF, prior and/or during the investigation period. 8,9