Prevention of atrial fibrillation by prevention of ventricular pacing?

This editorial refers to ‘The relationship between right ventricular pacing and atrial fibrillation burden and disease progression in patients with paroxysmal atrial fibrillation: the long-MinVPACE study’ by R.A. Veasey et al., on page 815. Atrial fibrillation (AF) is a frequent problem after pacemaker implantation. It is likely that paroxysmal AF had occurred in many patients before pacemaker insertion but was documented for the first time by stored atrial electrograms of dual-chamber devices. On the other hand, pacing from the right atrial appendage may promote the development of AF by mechanisms such as increased dispersion of atrial refractoriness, or scar tissue formation around the implanted atrial lead. The development of permanent AF after pacemaker implantation for sinus node disease even raises the question whether the device is still needed in this situation.1 Randomized controlled trials have demonstrated that the incidence of AF is higher with asynchronous right ventricular pacing in the VVI(R) mode compared with dual-chamber pacing.2 A post hoc analysis of the Mode Selection Trial (MOST) suggested that right ventricular pacing may be responsible for the development of AF, at least in patients with sinus node disease and narrow QRS.3 In this analysis, a linear association between the percentage of right ventricular pacing and the risk of developing AF was observed especially for dual-chamber pacing. Reports on the development of heart failure with right ventricular pacing confirm and extend these concerns on the risks of unnecessary right ventricular pacing. Can this ‘proarrhythmic’ effect of pacing be prevented? It has been suggested that biventricular pacing might reduce the risk of developing AF with pacing.4Post hoc analyses5 and small studies,6 however, did not find a reduction in the incidence of AF with cardiac resynchronization therapy compared with right ventricular pacing or standard medical care. In contrast, the systematic prevention of unnecessary right ventricular pacing, facilitated by the use of dedicated pacing algorithms, seems to be associated with a reduction in the occurrence of AF. In the randomized Search AV Extension and managed ventricular Pacing for Promoting Atrioventricular Conduction (SAVE-PACe) trial, prevention of unnecessary right ventricular pacing (present during an average of 99% of the time in the conventional pacing group) was associated with a 40% relative risk reduction for the development of persistent AF.3 Pacing used to prevent AF has been disappointing in most randomized trials.7–9 In retrospect, this may have been caused by right ventricular pacing that may increase the risk of developing AF. Also biventricular pacing does not seem promising in the prevention of AF.10 It raises the question: can pacing be more effective in the prevention of AFn if right ventricular pacing is prevented? Some analyses suggest that the reduction in right ventricular pacing may enhance the ability of atrial pacing to prevent AF. In the Pacing In Prevention of Atrial Fibrillation (PIPAF) trial, patients paced in the right ventricle for <42% of the time had a significant reduction of the cumulative time in AF during atrial preventive pacing, while this effect was absent in patients paced in the ventricle for more than this.11 In a single-centre experience in 153 patients, right ventricular pacing for <40% of the time after 1 month was associated with a significantly lower mean AF burden during the following 5 years.12 In fact, in these patients, AF burden was 6–11% compared with 22–32% in patients who were paced in the right ventricle for >40% of the time. Other studies did not find this association. In a post hoc analysis in 331 patients from the Atrial Fibrillation Therapy (AFT) trial, AF burden was weakly associated with the percentage of right ventricular pacing with a 0.03% increase in AF burden for every 10% of right ventricular pacing.13 However, the median percentage of right ventricular pacing in this trial was 97%, rendering any extrapolation questionable. In the same report, data from 79 patients of the Pacemaker Atrial Fibrillation Suppression (PAFS) trial showed no association between the percentage of right ventricular pacing and AF burden. However, the PAFS study consisted of four short (4 weeks each) cross-over study periods with different pacing modalities. Likely, these periods were too short, and there might have been significant carry-over effects. An observational study on AF burden and the amount of right ventricular pacing in 62 patients found no statistically significant correlation.14 In the Minimal Ventricular Pacing (MinVPace) study, the group from Eastbourne prospectively investigated if the prevention of right ventricular pacing can reduce the AF burden compared with conventional dual-chamber pacing.15 In this study, 110 patients with paroxysmal AF received dual-chamber pacemakers from different companies for sinus node disease or intermittent atrioventricular block. Similar to the Study of Atrial Fibrillation Reduction (SAFARI),16 ∼40% of patients had no AF recurrence or AF burden <1% with conventional dual-chamber pacing in a 1-month ‘induction phase’, rendering further refinement by dedicated algorithms unnecessary. The remaining 66 patients with AF burden of 1–70% entered the intervention phase and were randomized in a cross-over design to 2 months of conventional dual-chamber pacing, pacing with algorithms to prevent ventricular pacing activated, or pacing with algorithms for the prevention of AF and ventricular pacing activated simultaneously. In the short-term analysis, there was no significant difference in AF burden between the three pacing configurations despite a big difference in the percentage of ventricular pacing (86% with conventional dual-chamber pacing, 2% with minimized ventricular pacing, and 3% with minimized ventricular pacing and atrial preventive pacing algorithms15). However, patients were further randomized to dual-chamber pacing with vs. without algorithms to minimize ventricular pacing for a period of >1 year. In this long-term follow-up,17 a significantly lower AF burden was observed for minimized ventricular pacing (13 vs. 48%, P < 0.001), which maintained the percentage of right ventricular pacing over time at 6% compared with 74% with conventional dual-chamber pacing. Interestingly, the difference in AF burden only emerged after 9 months, similar to Canadian Trial of Physiological Pacing (CTOPP) and other studies on pacing mode selection. The Long-MinVPace trial has strengths and weaknesses: it is the first prospective, randomized study on the prevention of right ventricular pacing within the concept of atrial pacing for prevention of AF. It used devices and algorithms from different manufacturers; therefore, the results will likely apply to atrial preventive pacing and prevention of right ventricular pacing in general. The biggest strength is certainly the follow-up period of 1.4 years, which is much longer than in the Atrial Therapy Efficacy and Safety Trial (ATTEST) and Atrial Septal Pacing Efficacy Clinical Trial (ASPECT) (active phase: 3 months) or the AFT trial (active phases: 2 months each). The use of devices by different manufacturers can, however, also be regarded as a weakness since atrial overdrive pacing algorithms, algorithms for prevention of ventricular pacing, and AF detection algorithms differ. Additionally, the number of patients included in the Long-MinVPace trial is limited. The question whether prevention of unnecessary right ventricular pacing can prevent AF is prospectively assessed in the MINimizE Right Ventricular pacing to prevent Atrial fibrillation and heart failure (MINERVA) trial.18 This trial has enrolled 1300 patients with an indication for permanent pacing and paroxysmal AF in 66 centres worldwide. Patients have been randomized to conventional dual-chamber pacing or pacing with an additional algorithm to minimize ventricular pacing with or without atrial preventive pacing algorithms. In April 2012, the last patient will have completed the 24-month follow-up. Until then, the existing body of evidence tentatively supports the opinion that prevention of unnecessary right ventricular pacing can prevent AF,19,20 strengthened by the Long-MinVPace long-term study results. Since prevention of unnecessary right ventricular pacing may be useful to prevent pacing-induced heart failure (and to prolong battery life), this concept may further improve pacemaker therapy for patients with bradycardia alone or in conjunction with paroxysmal AF. Conflicts of interest: C.W.I. is a member of the Advisory Board of Medtronic Inc., and Sorin Group. He is a member of the speaker's Bureau of Biotronik, Boston-Scientific, Medtronic Inc., sorin Group, and St. Jude Medical. He participates in clinical trials sponsored by Biotronik, Boston-Scientific, and Medtronic Inc.