After the seminal observation of the importance of pulmonary veins to the initiation and maintenance of atrial fibrillation (AF),1Haissaguerre M. Jais P. Shah D.C. et al.Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins.N Engl J Med. 1998; 339: 659-666Crossref PubMed Scopus (6710) Google Scholar pulmonary vein isolation (PVI) emerged as a viable treatment for AF. Indeed, catheter ablation is often the preferred treatment for paroxysmal AF, not only after failed antiarrhythmic drug (AAD) therapy, but also as the initial treatment strategy.2Razzack A.A. Lak H.M. Pothuru S. et al.Efficacy and safety of catheter ablation vs antiarrhythmic drugs as initial therapy for management of symptomatic paroxysmal atrial fibrillation.Rev Cardiovasc Med. 2022; 22: 112Crossref Scopus (9) Google Scholar When so applied, single-procedure, AAD-free, 1-year freedom from recurrent AF, atrial flutter (AFL), and atrial tachycardia (AT) rates are 70% to 75%.2Razzack A.A. Lak H.M. Pothuru S. et al.Efficacy and safety of catheter ablation vs antiarrhythmic drugs as initial therapy for management of symptomatic paroxysmal atrial fibrillation.Rev Cardiovasc Med. 2022; 22: 112Crossref Scopus (9) Google Scholar However, as a propensity to AF matures, electrophysiologic, structural, and neurohumoral remodelling promote automaticity and reentry that can initiate and maintain AF from other sites within the atria. Their ultimate expression is persistent AF (PrAF) for which PVI is less effective, with single-procedure, AAD-free, 1-year freedom from recurrent AF/AFL/AT rates of only 20% to 40%.3Brooks A.G. Stiles M.K. Laborderie J. et al.Outcomes of long-standing persistent atrial fibrillation: a systematic review.Heart Rhythm. 2010; 7: 835-846Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar Accordingly, in PrAF patients, other ablation targets have been proposed, most commonly ablation lines of block within the left atrium (LA) and ablation of LA regions with electrographic characteristics of sites of AF initiation or maintenance, including low voltage (scarred) zones, fast electrographic rate (dominant frequency) zones, complex fractionated atrial electrogram (CFAE) zones, and variably identified zones of AF drivers (focal activity or rotors).4Terrricabras M. Piccini J.P. Verma A. Ablation of persistent atrial fibrillation and solutions.J Cardiovasc Electrophysiol. 2020; 31: 1809-1821Crossref PubMed Scopus (14) Google Scholar Nevertheless, no ablation procedure, alone or in combination, has been conclusively demonstrated to be superior to PVI alone. A recent meta-analysis of catheter ablation for PrAF reported single-procedure, AAD- free, 1-year freedom from AF/AFL/AT rates of 55.8% with PVI alone and 44.1% with any other ablation along with PVI.5Sau A. Kapadia S. Al-Aidarous S. et al.Temporal trends and lesion sets for persistent atrial fibrillation ablation: a meta-analysis with trial sequential analysis and meta-regression.Circ Arrhythmia Electrophysiol. 2023; 16: 536-545Crossref Scopus (5) Google Scholar That analysis also noted a common pattern wherein initial trials of each new approach reported benefits not substantiated by later trials.5Sau A. Kapadia S. Al-Aidarous S. et al.Temporal trends and lesion sets for persistent atrial fibrillation ablation: a meta-analysis with trial sequential analysis and meta-regression.Circ Arrhythmia Electrophysiol. 2023; 16: 536-545Crossref Scopus (5) Google Scholar The Bordeaux stepwise approach6O'Neill M.D. Wright M. Knecht S. et al.Long-term follow-up of atrial fibrillation ablation using termination as a procedural end point.Eur Heart J. 2009; 30: 1105-1112Crossref PubMed Scopus (284) Google Scholar is one of the more aggressive ablations for PrAF. Details of the stepwise approach have evolved but may be summarised as: 1) PVI with documented isolation, 2) electrography-based LA and coronary sinus ablation, 3) LA roof ablation line and LA mitral isthmus ablation line, and, in selected patients, 4) ablation in structures outside the LA, including the right atrium (RA). Each step is followed until all have been completed or until AF spontaneously terminates. If AF terminates to AFL or AT, ablation is then targeted at the new rhythm. In patients with PrAF, intraprocedural AF termination is considered to be a predictor of long-term success.6O'Neill M.D. Wright M. Knecht S. et al.Long-term follow-up of atrial fibrillation ablation using termination as a procedural end point.Eur Heart J. 2009; 30: 1105-1112Crossref PubMed Scopus (284) Google Scholar Using the stepwise approach, for PrAF, the rate of intraprocedural AF termination is ∼85% and the single-procedure, AAD-free, 1-year freedom from AF/AFL/AT rate is ∼48%.6O'Neill M.D. Wright M. Knecht S. et al.Long-term follow-up of atrial fibrillation ablation using termination as a procedural end point.Eur Heart J. 2009; 30: 1105-1112Crossref PubMed Scopus (284) Google Scholar Clearly, results of catheter ablation for PrAF according to the outcome of single-procedure, AAD-free, 1-year freedom from AF/AFL/AT are disappointing. Where to go from here? Some centres have adopted a conservative approach by limiting ablation to PVI while awaiting further revelations. Others offer repeated aggressive procedures and focus on the alternative outcome of multiple-procedure, AAD-assisted, 1-year after the last procedure freedom from AF/AFL/AT—an outcome achievable in 90% of PrAF patients.6O'Neill M.D. Wright M. Knecht S. et al.Long-term follow-up of atrial fibrillation ablation using termination as a procedural end point.Eur Heart J. 2009; 30: 1105-1112Crossref PubMed Scopus (284) Google Scholar Meanwhile, research continues. The Bordeaux group has focused on a new sequential approach termed the Marshall-PLAN (Marshall Bundle Elimination, Pulmonary Vein Isolation, and Line Completion for Anatomical Ablation of Persistent Atrial Fibrillation).7Derval N. Duchateau J. Denis A. et al.Marshall bundle elimination, Pulmonary vein isolation, and Line completion for Anatomical ablation of persistent atrial fibrillation (Marshall-PLAN): prospective, single-center study.Heart Rhythm. 2021; 18: 529-537Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar Other groups are examining modifications of the stepwise approach (COAST-AF8Nery P.B. Wells G.A. Verma A. et al.Characterization of Arrhythmia Substrate to Ablate Persistent Atrial Fibrillation (COAST-AF): Randomized controlled trial design and rationale.Am Heart J. 2022; 254: 133-140Crossref PubMed Scopus (2) Google Scholar [Characterization of Arrhythmia Substrate to Ablate Persistent Atrial Fibrillation]) and/or individualising ablation approaches to specific PrAF patients (see below). In this issue of the Canadian Journal of Cardiology, Xu et al.9Xu C. Zhang F. Chen W. et al.Adjunctive right atrial ablation for persistent atrial fibrillation with right atrial enlargement: a pilot study.Can J Cardiol. 2024; 40: 564-572Abstract Full Text Full Text PDF Scopus (1) Google Scholar report the results of a pilot study, involving 120 patients, for a randomised clinical trial (RCT) assessing an individualised approach to catheter ablation for PrAF in patients with RA enlargement attributed to AF (ie, absence of other causes for RA enlargement) in whom a greater probability of RA drivers for AF might reasonably be expected. Patients were randomised to ablation limited to the LA and adjacent venous structures (LA-only group) or to the same LA ablations that, in the absence of termination of the AF, were followed by adjunctive RA ablations (LA+RA group). Like the Bordeaux stepwise approach, the procedure began with PVI, with documented isolation, followed by electrogram-based ablation, an LA roof line, and a mitral isthmus line. Unlike the stepwise approach, AF substrate ablation was not targeted at CFAE zones but rather at areas of potential AF drivers, including those identified by spatiotemporal electrogram dispersion.10Seitz J. Bars C. Théodore G. et al.AF ablation guided by spatiotemporal electrogram dispersion without pulmonary vein isolation: a wholly patient-tailored approach.J Am Coll Cardiol. 2017; 69: 303-321Crossref PubMed Scopus (156) Google Scholar When RA ablation was required, both lines and AF driver ablations were performed. Intraprocedural AF termination was statistically significantly more likely in the LA+RA group (63.3%) than in the LA-only group (36.7%) (hazard ratio [HR] 0.335; P = 0.003) with the difference accounted for by termination during RA ablation. Procedure-related adverse events were similar (5.0% and 3.3%, respectively; P = 0.648). Nevertheless, a no-difference declaration regarding these low risk rates is clearly power limited. RA ablation added approximately 30 minutes to the ablation procedure. Single-procedure, AAD-free, 1-year freedom from recurrent AF/AFL/AT was statistically significantly more likely in the LA+RA group (70%) than in the LA-only group (51.7%) (HR 0.549; P = 0.034). Some readers may consider these results as "too good to be true." The LA+RA group had nearly twice as many patients with intraprocedural AF termination and nearly half the HR for recurrent AF/AFL/AT than the LA-only group. Nevertheless, the statistical significance of the latter finding in this small trial is fragile: 1 fewer AF/AFL/AT event in the LA-only group would have resulted in loss of statistical significance. The difference in follow-up outcomes does not appear to result from poor outcomes in the LA-only group. As shown in Figure 1A, their freedom from recurrent AF/AFL/AT rate is similar to those of other catheter ablation approaches for PrAF as reported in meta-analysis5Sau A. Kapadia S. Al-Aidarous S. et al.Temporal trends and lesion sets for persistent atrial fibrillation ablation: a meta-analysis with trial sequential analysis and meta-regression.Circ Arrhythmia Electrophysiol. 2023; 16: 536-545Crossref Scopus (5) Google Scholar and by the Bordeaux stepwise ablation approach.6O'Neill M.D. Wright M. Knecht S. et al.Long-term follow-up of atrial fibrillation ablation using termination as a procedural end point.Eur Heart J. 2009; 30: 1105-1112Crossref PubMed Scopus (284) Google Scholar Conversely, outcomes in the LA+RA group of Xu et al.9Xu C. Zhang F. Chen W. et al.Adjunctive right atrial ablation for persistent atrial fibrillation with right atrial enlargement: a pilot study.Can J Cardiol. 2024; 40: 564-572Abstract Full Text Full Text PDF Scopus (1) Google Scholar are exceptional. Indeed, they approach those of patients undergoing the Cox IV surgical maze procedure, the current criterion standard of AF ablation efficacy,11Henn M.C. Lancaster T.S. Miller J.R. et al.Late outcomes after the Cox maze IV procedure for atrial fibrillation.J Thorac Cardiovasc Surg. 2015; 150: 1168-1178Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar and exceed those of other catheter ablation procedures5Sau A. Kapadia S. Al-Aidarous S. et al.Temporal trends and lesion sets for persistent atrial fibrillation ablation: a meta-analysis with trial sequential analysis and meta-regression.Circ Arrhythmia Electrophysiol. 2023; 16: 536-545Crossref Scopus (5) Google Scholar and of the aggressive stepwise procedure.6O'Neill M.D. Wright M. Knecht S. et al.Long-term follow-up of atrial fibrillation ablation using termination as a procedural end point.Eur Heart J. 2009; 30: 1105-1112Crossref PubMed Scopus (284) Google Scholar As discussed below, Xu et al.9Xu C. Zhang F. Chen W. et al.Adjunctive right atrial ablation for persistent atrial fibrillation with right atrial enlargement: a pilot study.Can J Cardiol. 2024; 40: 564-572Abstract Full Text Full Text PDF Scopus (1) Google Scholar propose that the exceptional results in the LA+RA group are due to selection of patients with RA enlargement. Many readers may also have a sense of "déjà vu" in that the first published RCT of many previous approaches to ablation of PrAF were small trials showing substantial improvements in outcomes that were not duplicated by subsequent trials,5Sau A. Kapadia S. Al-Aidarous S. et al.Temporal trends and lesion sets for persistent atrial fibrillation ablation: a meta-analysis with trial sequential analysis and meta-regression.Circ Arrhythmia Electrophysiol. 2023; 16: 536-545Crossref Scopus (5) Google Scholar perhaps because of publication bias. Indeed, to our knowledge, there are no other published RCTs of RA ablation after LA ablation in PrAF patients selected for having RA enlargement. Nevertheless, there are previous RCTs of adjunctive RA ablation in unselected PrAF patients. As illustrated in Figure 1B, these reports include a meta-analysis of RCTs of surgical ablation showing a statistically nonsignificant 9% relative increase in single-procedure, AAD-assisted, 1-year freedom from AF,12Guo Q. Yan F. Ouyang P. et al.Bi-atrial or left atrial ablation of atrial fibrillation during concomitant cardiac surgery: a bayesian network meta-analysis of randomized controlled trials.J Cardiovasc Electrophysiol. 2021; 32: 2316-2328Crossref PubMed Scopus (7) Google Scholar an RCT showing a statistically nonsignificant 25% relative increase in single-procedure, AAD-free, 1-year freedom from AF/AFL/AT,13Oral H. Chugh A. Good E. et al.Randomized evaluation of right atrial ablation after left atrial ablation of complex fractionated atrial electrograms for long-lasting persistent atrial fibrillation.Circ Arrhythmia Electrophysiol. 2008; 1: 6-13Crossref PubMed Scopus (81) Google Scholar and an RCT showing a statistically significant 41% relative increase in single-procedure, AAD-free, 1-year freedom from AF.14Calò L. Lamberti F. Loricchio M.L. et al.Left atrial ablation versus biatrial ablation for persistent and permanent atrial fibrillation: a prospective and randomized study.J Am Coll Cardiol. 2006; 47: 2504-2512Crossref PubMed Scopus (100) Google Scholar In the latter RCT by Calò et al.,14Calò L. Lamberti F. Loricchio M.L. et al.Left atrial ablation versus biatrial ablation for persistent and permanent atrial fibrillation: a prospective and randomized study.J Am Coll Cardiol. 2006; 47: 2504-2512Crossref PubMed Scopus (100) Google Scholar the relative improvement in outcomes in the LA+RA group was similar to that observed by Xu et al.9Xu C. Zhang F. Chen W. et al.Adjunctive right atrial ablation for persistent atrial fibrillation with right atrial enlargement: a pilot study.Can J Cardiol. 2024; 40: 564-572Abstract Full Text Full Text PDF Scopus (1) Google Scholar Nevertheless, the absolute freedom from tachyarrhythmia outcomes was much lower in each of the study arms in the RCT by Calò et al.14Calò L. Lamberti F. Loricchio M.L. et al.Left atrial ablation versus biatrial ablation for persistent and permanent atrial fibrillation: a prospective and randomized study.J Am Coll Cardiol. 2006; 47: 2504-2512Crossref PubMed Scopus (100) Google Scholar Xu et al. also provide data supporting their hypotheses that, in their patients, RA enlargement was the result of PrAF and was associated with RA remodelling important to the genesis of PrAF. They further provide data that successful ablation may reverse these adverse remodelling processes. Successful ablation was associated with reductions in RA size and in severity of tricuspid regurgitation. Reverse structural remodelling was not seen in patients with recurrent AF/AFL/AT. Xu et al. report that, during AF before ablation, the mean RA cycle length was shorter than in the LA in 23% of their patients, suggesting that their dominant driver of AF was in the RA. Furthermore, patients with AF termination during LA ablation were more likely to have an LA cycle length gradient shorter than RA, whereas patients with AF termination during RA ablation were more likely to have an RA cycle length gradient shorter than LA. Although a dominant driver location in the RA has been reported in some patients in other groups, the proportion of patients with RA drivers in this study is high, suggesting that the entry criteria did select patients in whom RA ablation may be required. The authors are congratulated for completion of an interesting pilot study evaluating the important question of the possible benefits of an assertive, biatrial, catheter ablation procedure for the treatment of PrAF in patients selected for having a higher probability of having AF drivers in the RA. The results are encouraging but not conclusive. To the authors' credit, they report that a more definitive trial is underway (NCT05883722). The authors have no funding sources to declare.

BACKGROUND:The RAID (Ranolazine Implantable Cardioverter-Defibrillator) randomized placebo-controlled trial showed that ranolazine treatment was associated with reduction in recurrent ventricular tachycardia (VT) requiring appropriate implantable cardioverter-defibrillator (ICD) therapy. OBJECTIVES:This study aimed to identify groups of patients in whom ranolazine treatment would result in the highest reduction of ventricular tachyarrhythmia (VTA) burden. METHODS:Andersen-Gill analyses were performed to identify variables associated with risk for VTA burden among 1,012 patients enrolled in RAID. The primary endpoint was VTA burden defined as VTA episodes requiring appropriate treatment. RESULTS:Multivariate analysis identified 7 factors associated with increased VTA burden: history of VTA, age ≥65 years, New York Heart Association functional class ≥III, QRS complex (≥130 ms), low ejection fraction (<30%), atrial fibrillation (AF), and concomitant antiarrhythmic drug (AAD) therapy. The effect of ranolazine on VTA burden was seen among patients without concomitant AAD therapy (HR [HR]: 0.68; 95% CI: 0.55-0.84; P < 0.001), whereas no effect was seen among those who are concomitantly treated with other AADs (HR: 1.33; 95% CI: 0.90-1.96; P = 0.16); P = 0.003 for interaction. In patients with cardiac resynchronization therapy (CRT) ICDs, ranolazine treatment was associated with a 36% risk reduction for VTA recurrence (HR: 0.64; 95% CI: 0.47-0.86; P < 0.001), whereas among patients with ICDs without CRT no significant effect was noted (HR: 0.94; 95% CI: 0.74-1.18; P = 0.57); P = 0.047 for interaction. CONCLUSIONS:In patients with high risk for VTA, ranolazine is effective in reducing VTA burden, with significantly greater effect in CRT-treated patients, those without AF, and those not treated with concomitant AADs. In patients already on AADs or those with AF, the addition of ranolazine did not affect VTA burden. (Ranolazine Implantable Cardioverter-Defibrillator Trial [RAID]; NCT01215253).

Unexpected sudden cardiac death (SCD) remains one of the most common causes of mortality.1Kuriachan V.P. Sumner G.L. Mitchell L.B. Sudden cardiac death.Curr Probl Cardiol. 2015; 40: 133-200Crossref PubMed Scopus (83) Google Scholar The majority of SCDs are caused by ventricular tachycardia (VT) or ventricular fibrillation (VF), with fewer related to asystole, electromechanical dissociation, or sudden hemodynamic catastrophes.1Kuriachan V.P. Sumner G.L. Mitchell L.B. Sudden cardiac death.Curr Probl Cardiol. 2015; 40: 133-200Crossref PubMed Scopus (83) Google Scholar A normally functioning implantable cardioverter defibrillator (ICD) will terminate the vast majority of VT/VF episodes and will preclude asystole, thereby reducing the probability of SCD in high risk patients by ∼50% and of all-cause mortality by ∼25% in comparison with antiarrhythmic drug (AAD) therapy.2Connolly S.J. Hallstrom A.P. Cappato R. et al.Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials.Eur Heart J. 2000; 21: 2071-2078Crossref PubMed Scopus (923) Google Scholar Nevertheless, the placement and subsequent presence of ICDs have risks including surgical complications, system infections, component failures, inappropriate therapies, and death.3Persson R. Earley A. Garlitski A.C. Balk E.M. Uhlig K. Adverse events following implantable cardioverter defibrillator implantation: a systematic review.J Interv Card Electrophysiol. 2014; 40: 191-205Crossref PubMed Scopus (29) Google Scholar Accordingly, ICDs are reserved for patients judged to have higher risks of SCD, a judgement that, at present, is neither sensitive nor specific. Because most SCDs result from VT/VF, the strongest predictors of SCD are predictors of future episodes of VT/VF, the strongest of which is a past episode of VT/VF. Thus, early trials of ICDs focused on patients who had survived life-threatening VT/VF (secondary prevention). In these trials, the incidence of SCD in patients randomized to AAD therapy was 6.1% per year vs 2.8% per year in patients randomized to ICDs.2Connolly S.J. Hallstrom A.P. Cappato R. et al.Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials.Eur Heart J. 2000; 21: 2071-2078Crossref PubMed Scopus (923) Google Scholar Subgroup analyses of these trials suggested that the mortality benefit of an ICD was limited to patients with advanced left ventricular systolic dysfunction.2Connolly S.J. Hallstrom A.P. Cappato R. et al.Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials.Eur Heart J. 2000; 21: 2071-2078Crossref PubMed Scopus (923) Google Scholar Accordingly, subsequent ICD trials in patients without previous VT/VF (primary prevention) focused on patients with cardiomyopathies and left ventricular ejection fractions (LVEFs) ≤ 0.35, wherein the incidence of SCD in patients randomized to conventional therapy was 3.4% per year vs 1.2% per year in patients randomized to ICDs.4Kołodziejczak M. Andreotti F. Kowalewski M. et al.Implantable cardioverter-defibrillators for primary prevention in patients with ischemic or nonischemic cardiomyopathy: a systematic review and meta-analysis.Ann Intern Med. 2017; 167: 103-111Crossref PubMed Scopus (42) Google Scholar Patients with hemodynamically stable VT were excluded from the secondary prevention ICD trials, as they were believed to have low probability of SCD, based on the conviction that, despite being likely to re-experience stable VT, they were not likely to experience life-threatening VT/VF. Observational reports of the probabilities of SCD or rapid, potentially life-threatening VT/VF in patients with hemodynamically stable VT are at odds; some report a low probability,5Brugada P. Talajic M. Smeets J. Mulleneers R. Wellens H.J. The value of the clinical history to assess prognosis of patients with ventricular tachycardia or ventricular fibrillation after myocardial infarction.Eur Heart J. 1989; 10: 747-752Crossref PubMed Scopus (81) Google Scholar,6Sarter B.H. Finkle J.K. Gerszten R.E. Buxton A.E. What is the risk of sudden cardiac death in patients presenting with hemodynamically stable sustained ventricular tachycardia after myocardial infarction?.J Am Coll Cardiol. 1996; 28: 122-129Crossref PubMed Scopus (73) Google Scholar whereas others report a high probability of these events.7Olshansky B. Hahn E.A. Hartz V.L. Prater S.P. Mason J.W. ESVEM Investigators: Clinical significance of syncope in the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial.Am Heart J. 1999; 137: 878-886Crossref PubMed Scopus (68) Google Scholar, 8Olson P.J. Woelfel A. Simpson Jr., R.J. Foster J.R. Stratification of sudden death risk in patients receiving long-term amiodarone treatment for sustained ventricular tachycardia or ventricular fibrillation.Am J Cardiol. 1993; 71: 823-826Abstract Full Text PDF PubMed Scopus (24) Google Scholar, 9Böcker D. Block M. Isbruch F. et al.Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.Br Heart J. 1995; 73: 158-163Crossref PubMed Scopus (45) Google Scholar, 10Glikson M. Lipchenca I. Viskin S. Ballman K.V. Trusty J.M. Gurevitz O.T. Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.J Cardiovasc Electrophysiol. 2004; 15: 658-664Crossref PubMed Scopus (26) Google Scholar Patients in these studies were dominated by those with LVEFs ≤ 0.35. Two studies reported the probabilities of rapid (presumed hemodynamically unstable) VT/VF in patients with previous hemodynamically stable VT who had received ICDs.9Böcker D. Block M. Isbruch F. et al.Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.Br Heart J. 1995; 73: 158-163Crossref PubMed Scopus (45) Google Scholar,10Glikson M. Lipchenca I. Viskin S. Ballman K.V. Trusty J.M. Gurevitz O.T. Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.J Cardiovasc Electrophysiol. 2004; 15: 658-664Crossref PubMed Scopus (26) Google Scholar Böcker et al.9Böcker D. Block M. Isbruch F. et al.Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.Br Heart J. 1995; 73: 158-163Crossref PubMed Scopus (45) Google Scholar studied 50 such patients (82% ischemic cardiomyopathy, mean LVEF 0.39 ± 0.16 ), who had received ICDs after failure to identify predicted effective AAD therapy. Their 2-year actuarial probability of any ICD-treated VT/VF was 77%. Their 2-year actuarial probability of unstable VT/VF (VF or VT with a cycle length both < 250 ms and > 50 ms less than the baseline VT) was 29%. Data specific to patients with relatively preserved LVEF was not provided. Glikson et al.10Glikson M. Lipchenca I. Viskin S. Ballman K.V. Trusty J.M. Gurevitz O.T. Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.J Cardiovasc Electrophysiol. 2004; 15: 658-664Crossref PubMed Scopus (26) Google Scholar studied 82 such patients (89% ischemic cardiomyopathy, mean LVEF 0.32 ± 0.11) who had received ICDs. Their degree of AAD resistance was not specified, although 28% were receiving AADs at the time of their hemodynamically stable VT. Their 2-year actuarial probability of any ICD-treated VT/VF was 67%. Their 2-year actuarial probability of hemodynamically unstable VT/VF (VF or VT with a cycle length > 100 ms less than the baseline VT or 50 ms less than the baseline VT if the resulting cycle length was < 300 ms) was 12%. Seventeen patients had LVEFs ≥ 0.40. They had 4-year actuarial probabilities of any ICD-treated VT/VF of 80% and of hemodynamically unstable VT/VF of 11%. The 56 patients with LVEFs of < 0.40 had 4-year actuarial probabilities of any ICD-treated VT/VF of 76% and of hemodynamically unstable VT/VF of 29%. The difference in rates of hemodynamically unstable VT/VF did not reach statistical significance (P = 0.29), “probably because of the small number of subjects.”10Glikson M. Lipchenca I. Viskin S. Ballman K.V. Trusty J.M. Gurevitz O.T. Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.J Cardiovasc Electrophysiol. 2004; 15: 658-664Crossref PubMed Scopus (26) Google Scholar Guidelines are relatively silent regarding patients with hemodynamically stable VT, ischemic or nonischemic cardiomyopathy, and LVEF ≥ 0.40. European Society of Cardiology (ESC)11Priori S.G. Blomström-Lundqvist C. Mazzanti A. et al.2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.Eur Heart J. 2015; 36: 2793-2867Crossref PubMed Scopus (2437) Google Scholar guidelines provide a Class IIa/Level of Evidence C recommendation for ICDs in such patients, without specifically mentioning patients with hemodynamically stable VT; American Heart Association/American College of Cardiology/Heart Rhythm Society (AHA/ACC/HRS)12Al-Khatib S.M. Stevenson W.G. Ackerman M.J. et al.2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society.J Am Coll Cardiol. 2018; 72: e91-e220Crossref PubMed Scopus (482) Google Scholar guidelines provide a Class I/Level of Evidence B-NR recommendation for ICDs in such patients, without specifically mentioning patients with relatively preserved LVEF; and Canadian Cardiovascular Society (CCS)13Bennett M. Parkash R. Nery P. et al.Canadian Cardiovascular Society/Canadian Heart Rhythm Society 2016 implantable cardioverter defibrillator guidelines.Can J Cardiol. 2017; 33: 174-188Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar,14Deyell M.W. AbdelWahab A. Angaran P. et al.2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society position statement on the management of ventricular tachycardia and fibrillation in patients with structural heart disease.Can J Cardiol. 2020; 36: 822-836Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar guidelines provide a Strong Recommendation/Moderate-Quality Evidence guideline for ICDs in such patients, without specifically mentioning patients with either hemodynamically stable VT or patients with relatively preserved LVEF. In this issue of the Canadian Journal of Cardiology, Gula et al.15Gula L.J. Frydman A. Khan H.R. et al.Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.Can J Cardiol. 2022; 38: 1271-1276Abstract Full Text Full Text PDF Scopus (1) Google Scholar provide additional data relative to recurrence of VT/VF from 64 patients with cardiomyopathy and LVEF 0.36 to 0.49 who had received ICDs after hemodynamically stable VT. The primary outcome variable was the first occurrence of ICD-treated VT/VF following a 7-day blanking period after ICD placement. Their major findings were that such patients have high probability of ICD-treated VT/VF (2-year actuarial probability of 55%); such patients have high probability of shock-treated VT/VF (2-year actuarial probability of 20%); the mean rate of recurrent VT/VF (199 ± 37 beats per minute [bpm]) in the 37 patients with VT/VF recurrence was statistically significantly faster (P = 0.048) than their baseline VT (183 ± 27 bpm); and no clinical variables were identified that independently predicted recurrent VT/VF. Frequent recurrence of VT in the patients of Gula et al.15Gula L.J. Frydman A. Khan H.R. et al.Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.Can J Cardiol. 2022; 38: 1271-1276Abstract Full Text Full Text PDF Scopus (1) Google Scholar is expected, as the arrhythmogenic substrate for hemodynamically stable VT in most patients with cardiomyopathy includes a continuously present re-entrant circuit that will sustain VT when initiated by a trigger. The 2-year actuarial incidence of any ICD-treated VT/VF reported by Gula et al.15Gula L.J. Frydman A. Khan H.R. et al.Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.Can J Cardiol. 2022; 38: 1271-1276Abstract Full Text Full Text PDF Scopus (1) Google Scholar (55%) appears to be less than previously reported by Böcker et al.9Böcker D. Block M. Isbruch F. et al.Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.Br Heart J. 1995; 73: 158-163Crossref PubMed Scopus (45) Google Scholar (77%) and by Glikson et al.10Glikson M. Lipchenca I. Viskin S. Ballman K.V. Trusty J.M. Gurevitz O.T. Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.J Cardiovasc Electrophysiol. 2004; 15: 658-664Crossref PubMed Scopus (26) Google Scholar (67%). This may reflect either interim improvement in patient prognosis and ICD technology or that Gula et al.15Gula L.J. Frydman A. Khan H.R. et al.Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.Can J Cardiol. 2022; 38: 1271-1276Abstract Full Text Full Text PDF Scopus (1) Google Scholar restricted their study to patients with relatively preserved LVEF. The only previous comparable study of patients with both stable VT and relatively preserved LVEF, comprising 17 patients, reported a 4-year actuarial incidence of any ICD-treated VT/VF of 80% (if linearity is assumed, 40% after 2 years).10Glikson M. Lipchenca I. Viskin S. Ballman K.V. Trusty J.M. Gurevitz O.T. Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.J Cardiovasc Electrophysiol. 2004; 15: 658-664Crossref PubMed Scopus (26) Google Scholar Note that the study of Gula et al.15Gula L.J. Frydman A. Khan H.R. et al.Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.Can J Cardiol. 2022; 38: 1271-1276Abstract Full Text Full Text PDF Scopus (1) Google Scholar shares bias of previous studies of having included many patients with demonstrated resistance to AAD. Whether or not these recurrence rates are representative of drug-naïve patients with hemodynamically stable VT and relatively preserved LVEF cannot be determined from available data. Nevertheless, the study of Gula et al.15Gula L.J. Frydman A. Khan H.R. et al.Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.Can J Cardiol. 2022; 38: 1271-1276Abstract Full Text Full Text PDF Scopus (1) Google Scholar nearly triples the number of published patients with hemodynamically stable VT, cardiomyopathy, and relatively preserved LVEF addressing the natural history of VT/VF recurrence. The presence of a continuously present re-entrant circuit capable of supporting stable VT predicts that recurrent VTs should have the same rate as the baseline VT in the absence of therapy changes. Indeed, in patients with LVEF ≥ 0.40 and VT/VF, more than 90% of recurrent VT/VF have a cycle length within 30 msec of the baseline VT/VF.16Mondésert B. Khairy P. Schram G. et al.Impact of revascularization in patients with sustained ventricular arrhythmias, prior myocardial infarction, and preserved left ventricular ejection fraction.Heart Rhythm. 2016; 13: 1221-1227Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar Nevertheless, there remains a worrisome possibility of a recurrent VT/VF with a faster rate that could be life threatening. As discussed earlier, based on 17 patients, the 4-year actuarial probability of hemodynamically unstable ICD-treated VT/VF was 11% in patients with stable VT, cardiomyopathy, and LVEF ≥ 0.40.10Glikson M. Lipchenca I. Viskin S. Ballman K.V. Trusty J.M. Gurevitz O.T. Long-term outcome of patients who received implantable cardioverter defibrillators for stable ventricular tachycardia.J Cardiovasc Electrophysiol. 2004; 15: 658-664Crossref PubMed Scopus (26) Google Scholar Three patients (4.7%) in the study of Gula et al.15Gula L.J. Frydman A. Khan H.R. et al.Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.Can J Cardiol. 2022; 38: 1271-1276Abstract Full Text Full Text PDF Scopus (1) Google Scholar had unstable VT/VF as defined by Böcker et al.9Böcker D. Block M. Isbruch F. et al.Benefits of treatment with implantable cardioverter-defibrillators in patients with stable ventricular tachycardia without cardiac arrest.Br Heart J. 1995; 73: 158-163Crossref PubMed Scopus (45) Google Scholar over a median follow-up of 827 days, translating into a 5-year probability of potentially life-threatening VT/VF of approximately 8.5% (likely an underestimate, as Gula et al.15Gula L.J. Frydman A. Khan H.R. et al.Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.Can J Cardiol. 2022; 38: 1271-1276Abstract Full Text Full Text PDF Scopus (1) Google Scholar only considered first recurrences of VT/VF). This rate is greater than the ≥ 6% estimated 5-year rate of SCD used by ESC11Priori S.G. Blomström-Lundqvist C. Mazzanti A. et al.2015 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death.Eur Heart J. 2015; 36: 2793-2867Crossref PubMed Scopus (2437) Google Scholar guidelines to recommend a Class IIa/Level of Evidence B recommendation for an ICD when considering precision medicine in individualized patients. Nevertheless, we must recognize the dangers of equating presumed life-threatening ICD-treated VT/VF with SCD. Gula et al.15Gula L.J. Frydman A. Khan H.R. et al.Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.Can J Cardiol. 2022; 38: 1271-1276Abstract Full Text Full Text PDF Scopus (1) Google Scholar also provide novel evidence of a statistically significant increase in the rate of VT/VF over time in patients with stable VT, cardiomyopathy, and relatively preserved LVEF. Nevertheless, the extent to which changes in ADD therapy contributed to this observation cannot be determined from available data. The study of Gula et al.15Gula L.J. Frydman A. Khan H.R. et al.Hemodynamically tolerated ventricular tachycardia with mildly impaired ejection fraction: do these patients have VT/VF recurrence and ICD therapies?.Can J Cardiol. 2022; 38: 1271-1276Abstract Full Text Full Text PDF Scopus (1) Google Scholar provides weak support for placement of ICDs in patients with stable VT, cardiomyopathy, and relatively preserved LVEF, particularly in patients with demonstrated resistance to AAD. Nevertheless, further research is clearly required, including prospective observational studies focused on patients early in their course before demonstrated AAD resistance that consider all recurrences of VT/VF following guidelines for high-quality observational trials.17von Elm E. Altman D.G. Egger M. et al.STROBE InitiativeThe Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies.Int J Surg. 2014; 12: 1495-1499Crossref PubMed Scopus (3878) Google Scholar Nevertheless, whether or not such patients truly benefit from ICD placement can only be determined by an appropriately designed randomized clinical trial, if, indeed, such a trial is feasible. Meanwhile, other approaches to reducing the risk of SCD in patients with cardiomyopathy and relatively preserved LVEF are focusing on identifying markers of increased SCD risk other than previous hemodynamically stable VT/VF and randomizing the population, so chosen, in a clinical trial of ICD therapy. One such ongoing study, the Risk Estimation Following Infarction Noninvasive Evaluation-ICD (REFINE-ICD) trial (NCT00673842) is randomizing patients with myocardial infarction (MI) and LVEF 0.36 to 0.49 to usual care vs usual care plus ICDs. Study patients are selected based on both abnormal Holter-based T-wave alternans and abnormal Holter-based heart-rate turbulence, predicting ∼9-fold higher risk of mortality. Enrollment in Refine-ICD is anticipated to be complete in the next 12 months, and it will provide much needed evidence on the optimal care for these patients. No funding has been provided for this article.

…So reflected George on his life and professional career shortly before his passing on January 6, 2022. On that day, the cardiac electrophysiology community lost an iconic pioneer and a great leader. Those of us who knew him well lost a cherished mentor, colleague, and very dear friend.

The Canadian Cardiovascular Society (CCS) atrial fibrillation (AF) guidelines program was developed to aid clinicians in the management of these complex patients, as well as to provide direction to policy makers and health care systems regarding related issues. The most recent comprehensive CCS AF guidelines update was published in 2010. Since then, periodic updates were published dealing with rapidly changing areas. However, since 2010 a large number of developments had accumulated in a wide range of areas, motivating the committee to complete a thorough guideline review. The 2020 iteration of the CCS AF guidelines represents a comprehensive renewal that integrates, updates, and replaces the past decade of guidelines, recommendations, and practical tips. It is intended to be used by practicing clinicians across all disciplines who care for patients with AF. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate recommendation strength and the quality of evidence. Areas of focus include: AF classification and definitions, epidemiology, pathophysiology, clinical evaluation, screening and opportunistic AF detection, detection and management of modifiable risk factors, integrated approach to AF management, stroke prevention, arrhythmia management, sex differences, and AF in special populations. Extensive use is made of tables and figures to synthesize important material and present key concepts. This document should be an important aid for knowledge translation and a tool to help improve clinical management of this important and challenging arrhythmia.

Cardiac tachyarrhythmias are a major cause of morbidity and mortality. Treatments for these tachyarrhythmias include antiarrhythmic drugs, catheter ablation, surgical ablation, cardiac implantable electronic devices, and cardiac transplantation. Each of these treatment approaches is effective in some patients but there is considerable room for improvement, particularly with respect to the most common of the tachydysrhythmias, atrial fibrillation, and the most dangerous of the tachydysrhythmias, ventricular tachycardia (VT) or ventricular fibrillation. Noninvasive stereotactic ablative radiation therapy is emerging as an effective treatment for refractory tachyarrhythmias. Animal models have shown successful ablation of arrhythmogenic myocardial substrates with minimal short-term complications. Studies of stereotactic radioablation involving patients with refractory VT have shown a reduction in VT recurrence and promising early safety data. In this review, we provide the background for the application of stereotactic arrhythmia radioablation therapy along with promising results from early applications of the technology.

Atrial fibrillation (AF) is a common complication of noncardiac surgery, occurring in 0.8% to 29% of patients within the first postoperative week, depending on the type of surgery performed.1AlTurki A. Marafi M. Proietti R. et al.Major adverse cardiovascular events associated with postoperative atrial fibrillation after noncardiac surgery: a systematic review and meta-analysis.Circ Arrhythm Electrophysiol. 2020; 1e007437Google Scholar Postoperative AF (POAF) has been ascribed to the proarrhythmic effects of surgery (hypoxia, acidosis, electrolyte depletion, fluid shifts, sympathetic activation, systemic inflammation) acting on a susceptible myocardial substrate in a population with comorbidities associated with aging (hypertension, diabetes mellitus, subclinical structural heart disease). The importance of POAF after noncardiac surgery lies in its potential adverse consequences. Associations with a 4-fold increase in thromboembolic stroke events and a 3-fold increase in long-term all-cause mortality impose an important morbidity and mortality burden given the size of the population undergoing noncardiac surgery. Not so long ago, AF was considered to be a relatively benign condition, requiring only a little “dig and quinidine.” However, beginning in the 1970s, growing recognition of its major contributions to stroke and death2Wolf P.A. Dawber T.R. Thomas H.E. Kannel W.B. Epidemiologic assessment of chronic atrial fibrillation and risk of stroke: the Framingham Study.Neurology. 1978; 28: 973-977Crossref PubMed Google Scholar,3Wolf P.A. Abbott R.D. Kannel W.B. Atrial fibrillation: a major contributor to stroke in the elderly. The Framingham Study.Arch Intern Med. 1987; 14: 1561-1564Crossref Scopus (1227) Google Scholar brought about a sea-change in AF management.4Canadian Cardiovascular Society Consensus Conference on Atrial Fibrillation.Can J Cardiol. 1996; 12: 1A-61APubMed Google Scholar Because of its broad impact, therapy of patients with nonvalvular AF (NVAF) has been extensively researched. Thromboembolic prophylaxis has since become a cornerstone of management guidelines the world over, as reflected in current Canadian guidelines.5Andrade J.G. Verma A. Mitchell L.B. et al.2018 focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation.Can J Cardiol. 2018; 34: 1371-1392Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Yet, perhaps because of its seemingly transient impact, POAF following noncardiac surgery has not been as well studied. At the very least, POAF could be taken as evidence that the patient’s devolving cardiac substrate has declined to a threshold that allows AF to occur.6Heijman J. Muna A.P. Veleva T. et al.Atrial myocyte NLRP3/CaMKII nexus forms a substrate for postoperative atrial fibrillation.Circ Res. 2020; 12: 1036-1055Crossref Scopus (28) Google Scholar A patient with a first documented AF event is at higher risk than one with no documented episodes of AF.1AlTurki A. Marafi M. Proietti R. et al.Major adverse cardiovascular events associated with postoperative atrial fibrillation after noncardiac surgery: a systematic review and meta-analysis.Circ Arrhythm Electrophysiol. 2020; 1e007437Google Scholar Given the benefits of anticoagulation therapy in patients with NVAF unrelated to surgery, it is tempting to anticoagulate all AF patients > 65 years of age, even if seemingly provoked by surgery. However, history has taught us that therapeutic assumptions based on studies in one population should not be extrapolated without verification to the treatment of another. The benefits of oral anticoagulation therapy (OAC) in the prevention of thromboembolic events must always be balanced against the risk of major bleeding. What are the relative magnitudes of decreased thromboembolism vs increased major bleeding in the population proposed for OAC prophylaxis? Unfortunately, there are no randomized controlled trial data to guide decision making concerning POAF after noncardiac surgery. Instead, current recommendations are based on evidence from other settings, including POAF after cardiac surgery, which, in turn, are based on recommendations for patients with NVAF not related to surgery. Such tenuous extrapolations are reflected in the class I recommendation for noncardiac thoracic surgery by the American Association for Thoracic Surgery: “for patients who develop POAF lasting > 48 hours, it is recommended that antithrombotic medications are administered similarly to nonsurgical patients … therapy should be based on the benefit of reducing stroke risk vs the risk of bleeding in the postoperative period”7Frendl G. Sodickson A.C. Chung M.K. et al.2014 AATS guidelines for the prevention and management of perioperative atrial fibrillation and flutter for thoracic surgical procedures.J Thorac Cardiovasc Surg. 2014; 14: e153-193Abstract Full Text Full Text PDF Scopus (126) Google Scholar; and the class IIa recommendation by the American College of Cardiology/American Heart Association: “it is reasonable to administer antithrombotic medication in patients who develop postoperative AF as advised for nonsurgical patients.”8January C.T. Wann L.S. Alpert J.S. et al.2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.Circulation. 2014; 130: e199-267Crossref PubMed Scopus (1108) Google Scholar The level of thromboembolic risk assumed in these recommendations is consistent with a study of 1,520,109 noncardiac surgical procedures in the Danish nationwide registries.9Butt J.H. Olesen J.B. Havers-Borgersen E. et al.Risk of thromboembolism associated with atrial fibrillation following noncardiac surgery.J Am Coll Cardiol. 2018; 72: 2027-2036Crossref PubMed Scopus (41) Google Scholar The 0.4% of patients identified with POAF were matched 1:1 with surgical patients not developing POAF. POAF patients had higher risks of thromboembolic events (hazard ratio [HR] 1.89), AF rehospitalization (HR 5.26), and all-cause mortality (HR 1.67). The long-term risk of thromboembolism in these POAF patients was similar to matched patients with nonsurgical AF (3.17% and 2.99% per year, respectively) with similar statistically significant reductions in thromboembolism with anticoagulation (HRs 0.52 and 0.56, respectively). Evidence in Japanese patients from Higuchi et al.10Higuchi S. Kabeya Y. Matsushita K. et al.Perioperative atrial fibrillation in noncardiac surgeries for malignancies and one-year recurrence.Can J Cardiol. 2019; 35: 1449-1456Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar also suggests that AF frequently recurs in POAF patients and is not a benign postoperative complication. Clearly, we need to better understand the benefits and risks of committing POAF patients to long-term anticoagulation. Accordingly, the data from Elharram et al.11Elharram M. Samuel M. AlTurki A. et al.Anticoagulant use and the risk of thromboembolism and bleeding in postoperative atrial fibrillation after noncardiac surgery.Can J Cardiol. 2021; 37: 391-399Abstract Full Text Full Text PDF Scopus (2) Google Scholar in this issue of the Journal are welcome information. The authors set out to quantify the effects of OAC on the frequency of thromboembolic events and the number of major bleeding events in POAF patients after noncardiac surgery. Their retrospective analysis identified 22,007 cases of POAF after noncardiac surgery in a provincial database that was linked to a pharmacy claims funding database. Observations were stratified using CHA2DS2-VASc scores for risk of thromboembolic events, HAS-BLED scores (modified to exclude the nonstable international normalized ratio criterion) for risk of major bleeding events, and by the use or nonuse of OAC. The annual incidences of thromboembolic events in patients not receiving OAC were 0.68% with CHA2DS2-VASc 0-1, 1.09% with CHA2DS2-VASc 2-3, and 1.51% with CHA2DS2-VASc ≥ 4. These annual thromboembolism rates are substantially lower than reported in patients with NVAF without surgery not receiving OAC in the same CHA2DS2-VASc groups from the Danish database (1.5%, 3.82%, and 9.22%, respectively).12Olesen J.B. Lip G.Y.H. Hansen M.L. et al.Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.BMJ. 2011; 3: d124Crossref Scopus (930) Google Scholar The discordance between the lower rate of thromboembolism reported by Elharram et al.11Elharram M. Samuel M. AlTurki A. et al.Anticoagulant use and the risk of thromboembolism and bleeding in postoperative atrial fibrillation after noncardiac surgery.Can J Cardiol. 2021; 37: 391-399Abstract Full Text Full Text PDF Scopus (2) Google Scholar and the higher rate from the Danish database,13Olesen J.B. Lip G.Y.H. Hansen P.R. et al.Bleeding risk in “real world” patients with atrial fibrillation: comparison of two established bleeding prediction schemes in a nationwide cohort.J Thromb Haemost. 2011; 9: 1460-1467Crossref PubMed Scopus (158) Google Scholar suggests that therapeutic choices for patients with POAF after major noncardiac surgery should not be extrapolated from patients who have NVAF without surgery. The Canadian Cardiovascular Society atrial fibrillation guidelines5Andrade J.G. Verma A. Mitchell L.B. et al.2018 focused update of the Canadian Cardiovascular Society guidelines for the management of atrial fibrillation.Can J Cardiol. 2018; 34: 1371-1392Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar suggest that the risk of OAC is warranted when the annual rate of a thromboembolic event exceeds 1.5%. Thus, the data provided by Elharram et al.11Elharram M. Samuel M. AlTurki A. et al.Anticoagulant use and the risk of thromboembolism and bleeding in postoperative atrial fibrillation after noncardiac surgery.Can J Cardiol. 2021; 37: 391-399Abstract Full Text Full Text PDF Scopus (2) Google Scholar would give pause for thought when considering OAC in POAF patients with CHA2DS2-VASc < 4. There is biological rationale for noncardiac surgery POAF patients having less thromboembolic risk than patients with NVAF in the absence of surgery. POAF includes a spectrum of patients. Those with no underlying atrial tissue pathology, in whom the POAF is solely the result of the surgical stress, are unlikely to have AF recurrence and future thromboembolism (“reversible AF”), while those with subclinical atrial cardiomyopathy, in whom surgical stress has prematurely precipitated inevitable AF, are more likely to have recurrence and future thromboembolism (“provoked AF”). Accordingly, the more that reversible AF is included in any given surgical population, the less likely is there to be benefit from OAC. This forces us to confront our clinical instinct to anticoagulate patients for stroke prevention in a POAF population for whom the risk-benefit ratio of anticoagulation is understudied. Elharram et al.11Elharram M. Samuel M. AlTurki A. et al.Anticoagulant use and the risk of thromboembolism and bleeding in postoperative atrial fibrillation after noncardiac surgery.Can J Cardiol. 2021; 37: 391-399Abstract Full Text Full Text PDF Scopus (2) Google Scholar also report annual incidences of major bleeding while receiving OAC of 4.41% in patients with HAS-BLED ≤ 2 and 6.06% with HAS-BLED ≥ 3. These are surprisingly similar to rates reported for patients with NVAF without surgery receiving OAC (4.07% for HAS-BLED ≤ 2 and 8.11% for HAS-BLED ≥ 3).13Olesen J.B. Lip G.Y.H. Hansen P.R. et al.Bleeding risk in “real world” patients with atrial fibrillation: comparison of two established bleeding prediction schemes in a nationwide cohort.J Thromb Haemost. 2011; 9: 1460-1467Crossref PubMed Scopus (158) Google Scholar Furthermore, vitamin K antagonist (VKA; mainly warfarin) therapy posed a higher risk of hemorrhage than direct oral anticoagulant therapy (DOAC), as previously seen in other AF populations.14Eikelboom J. Merli G. Bleeding with direct oral anticoagulants vs warfarin: clinical experience.Am J Med. 2016; 129: S33-40Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar,15Chan Y.-H. See L.-C. Tu H.-T. et al.Efficacy and safety of apixaban, dabigatran, rivaroxaban, and warfarin in Asians with nonvalvular atrial fibrillation.J Am Heart Assoc. 2018; 7e008150Crossref PubMed Scopus (66) Google Scholar Could the pharmacologic properties of VKAs and DOACs explain this? All OACs reduce the rate of new clot formation, shifting the balance away from thromboembolic events and toward bleeding events. However, the pharmacologic differences between agents, summarized in Table 1, determine the pattern of effects on coagulation. Because OAC only increases the duration of bleeding from an active source (but does not cause it), therapy may pose greater risk in postoperative patients with recently damaged blood vessels. VKAs produce a long-lasting 4-coagulation-factor deficiency requiring regular monitoring owing to variable vitamin K availability and VKA pharmacokinetics. VKAs provide constant round-the-clock high-level suppression of clot formation, making them well suited for protecting highly thrombogenic mechanical heart valves, but allow little opportunity for thrombotic repair of a microbleeding source. DOACs impede coagulation immediately upon absorption, but are rapidly eliminated by transport proteins, giving them half-lives of < 12 hours. They produce anticoagulation by selective inhibition of a single rate-limiting clotting factor, which lasts long enough to prevent accumulation of atrial clot, yet not so long as to prevent daily periods of coagulation rebound that reduce bleeding risk. DOAC effects are relatively predictable because much of the population (but not everyone) will achieve concentrations that are within the effective range after standard doses. However, if doses are missed, concentrations will fall relatively rapidly and protection against thrombosis will diminish.16Testa S. Paoletti O. Legnani C. et al.Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants.J Thromb Haemost JTH. 2018; 1: 842-848Crossref Scopus (59) Google ScholarTable 1Comparison of oral anticoagulant propertiesPropertyVitamin K antagonist (VKA)Direct oral anticoagulant (DOAC)MechanismClotting factor depletion, similar effect to hemophiliaClotting factor inhibition, similar effect to lupus anticoagulantElimination pathwayMetabolism: Cytochrome P450 CYP2C9, susceptible to inhibition by food or by drugs such as amiodarone, fluconazole, and sulfamethoxazoleExcretion: rapidly eliminated via transport proteins (p-glycoprotein), proportionately less affected by drugs such as amiodarone and diltiazemOnset of effectDays required for reduced factor production and depletion to achieve full anticoagulationHours (1-2) for systemic absorption to achieve full anticoagulation effectOffset of effectDays to achieve natural factor replacement, somewhat faster with a vitamin K dose; immediate but temporary INR < 1.5 with clotting factor replacement24 hours for DOAC to decline below effective concentration after last dose; all drug eliminated by 48 hours; immediate inactivation with reversal agents (when available)MonitoringAbsolute requirement for INR monitoring and dose adjustment to maintain safe and effective therapy owing to variations over time in dietary vitamin K access and absorption and drug interactions affecting VKA concentrationsMonitoring not standard practice, but DOAC concentration assessment can identify patients with impaired absorption or excretion; dosing requirements usually stable in any given patient and do not require regular adjustmentFavored indicationThromboprophylaxis for highly thrombogenic surfaces needing constant suppression of coagulation, eg, mechanical heart valvesThromboprophylaxis for more moderate clotting stimuli where undulating coagulation suppression is sufficient and consequently lowers risk of bleed, eg, NVAFINR, international normalized ratio of prothrombin times; NVAF, nonvalvular atrial fibrillation. Open table in a new tab INR, international normalized ratio of prothrombin times; NVAF, nonvalvular atrial fibrillation. Elharram et al.11Elharram M. Samuel M. AlTurki A. et al.Anticoagulant use and the risk of thromboembolism and bleeding in postoperative atrial fibrillation after noncardiac surgery.Can J Cardiol. 2021; 37: 391-399Abstract Full Text Full Text PDF Scopus (2) Google Scholar also examined the thromboembolic and major bleeding rates in patients who were prescribed OAC vs those who were not. There was no statistically significant reduction in thromboembolism with OAC (adjusted HR 0.89, 95% confidence interval [CI] 0.73-1.07) although patients with CHA2DS2-VASc ≥ 4 may benefit. Nevertheless, OAC (mainly VKA) was associated with a statistically significant increase in major bleeding (adjusted HR 1.2, 95% CI 1.1-1.32). Of course, these comparisons are likely to be confounded by indication. The chief shortcomings of the report by Elharram et al.11Elharram M. Samuel M. AlTurki A. et al.Anticoagulant use and the risk of thromboembolism and bleeding in postoperative atrial fibrillation after noncardiac surgery.Can J Cardiol. 2021; 37: 391-399Abstract Full Text Full Text PDF Scopus (2) Google Scholar are: 1) its retrospective nature, precluding standardization of therapy or balance of random effects; 2) the 1999-2015 time frame, during which 81% of OAC was with warfarin (VKA), rather than currently recommended DOACs; 3) inability to assess AF pattern or duration; 4) inability to accurately determine time line of OAC; and 5) the database links largely limited to patients > 65 years of age. Nevertheless, patients were exposed to enough OAC to have increased risk of bleeding yet had insufficient benefit to demonstrate a statistically significant reduction in thromboembolic events, except in the highest CHA2DS2-VASc stratification. In this regard, it is noteworthy that the CHADS2 and CHA2DS2-VASc scores predict not only the future probability of thromboembolic events, but also the future probability of AF arrhythmic events unrelated to surgery.17Chao T.-F. Liu C.-J. Chen S.-J. et al.CHADS2 score and risk of new-onset atrial fibrillation: a nationwide cohort study in Taiwan.Int J Cardiol. 2013; 16: 1360-1363Abstract Full Text Full Text PDF Scopus (58) Google Scholar When and how should we anticoagulate POAF patients after noncardiac surgery? Evidence-based recommendations are lacking. Given the improved outcomes in NVAF patients treated with OAC, it may be difficult to accept that much of the POAF population should not be anticoagulated, but we just don’t know. Regardless, these results further argue that only a properly performed randomized controlled trial will establish the relative benefits and risks of OAC in this setting. Such prospective studies may be able to determine which POAF patients should be anticoagulated and which should not. What should we do until the data comes? The report by Elharram et al.11Elharram M. Samuel M. AlTurki A. et al.Anticoagulant use and the risk of thromboembolism and bleeding in postoperative atrial fibrillation after noncardiac surgery.Can J Cardiol. 2021; 37: 391-399Abstract Full Text Full Text PDF Scopus (2) Google Scholar suggests that, other factors being equal, the risks of chronic OAC may be warranted only in patients with POAF after noncardiac surgery who have a CHA2DS2-VASc score ≥ 4. The authors have no funding sources to declare.

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IMPORTANCE Catheter ablation is more effective than drug therapy in restoring sinus rhythm in patients with atrial fibrillation (AF), but its incremental effect on long-term quality of life (QOL) is uncertain. OBJECTIVE To determine whether catheter ablation is more beneficial than conventional drug therapy for improving QOL in patients with AF. DESIGN, SETTING, AND PARTICIPANTS An open-label randomized clinical trial of catheter ablation vs drug therapy in 2204 symptomatic patients with AF older than 65 years or 65 years or younger with at least 1 risk factor for stroke. Patients were enrolled from November 2009 to April 2016 from 126 centers in 10 countries. Follow-up ended in December 2017. INTERVENTIONS Pulmonary vein isolation, with additional ablation procedures at the discretion of the investigators, for the catheter ablation group (n = 1108) and standard rhythm and/or rate-control drugs selected and managed by investigators for the drug therapy group (n = 1096). MAIN OUTCOMES AND MEASURES Prespecified co-primary QOL end points at 12 months, including the Atrial Fibrillation Effect on Quality of Life (AFEQT) summary score (range, 0-100; 0 indicates complete disability and 100 indicates no disability; patient-level clinically important difference, >= 5 points) and the Mayo AF-Specific Symptom Inventory (MAFSI) frequency score (range, 0-40; 0 indicates no symptoms and 40 indicates the most severe symptoms; patient-level clinically important difference, <=-1.6 points) and severity score (range, 0-30; 0 indicates no symptoms and 30 indicates the most severe symptoms; patient-level clinically important difference, <=-1.3 points). RESULTS Among 2204 randomized patients (median age, 68 years; 1385 patients [63%] were men, 946 [43%] had paroxysmal AF, and 1256 [57%] had persistent AF), the median follow-up was 48.5 months, and 1968 (89%) completed the trial. The mean AFEQT summary score was more favorable in the catheter ablation group than the drug therapy group at 12 months (86.4 points vs 80.9 points) (adjusted difference, 5.3 points [95% CI, 3.7-6.9]; P <.001). The mean MAFSI frequency score was more favorable for the catheter ablation group than the drug therapy group at 12 months (6.4 points vs 8.1 points) (adjusted difference, -1.7 points [95% CI, -2.3 to -1.2]; P <.001) and the mean MAFSI severity score was more favorable for the catheter ablation group than the drug therapy group at 12 months (5.0 points vs 6.5 points) (adjusted difference, -1.5 points [95% CI, -2.0 to -1.1]; P <.001). CONCLUSIONS AND RELEVANCE Among patients with symptomatic atrial fibrillation, catheter ablation, compared with medical therapy, led to clinically important and significant improvements in quality of life at 12 months. These findings can help guide decisions regarding management of atrial fibrillation.

For 6 decades, health care professionals and patients, felt “in control” of oral anticoagulation. Warfarin dosing was titrated to values of prothrombin time (PT) within a range of international normalized ratios (INRs). Lamentably, this control was, in part, an illusion. Dose adjustments were made according to art and experience to retrospectively correct abnormal INRs that had been out of range for an unknown period of time between the last 2 INR measurements. Too many patients found frequent INR measurements objectionable and often avoided testing. Dose adjustments were not governed by knowledge of the patient’s personal pharmacology and the pharmacodynamic responses to dose adjustments were delayed, because the site of warfarin action is well upstream from the coagulation event in a complex cascade of clotting factors. To achieve appropriate anticoagulation, the initial warfarin dose needed to be found by trial and error to compensate for each patient’s genetically-bestowed profile of warfarin metabolism and vitamin K epoxide sensitivity. When anticoagulation was established, patients’ dose requirements could change abruptly under the influence of disease, drug interaction, or altered vitamin K exposure. This required skilled attention to changes in the patient’s disease-therapy environment or luck in timing INR measurements to guide dose adjustments before outside factors could cause INR shifts and possibly bleeding or thrombosis. Nevertheless, with no alternate oral anticoagulation available, we had no choice but to become moderately adept at INR monitoring. With these challenges, achieving a 50% average time in therapeutic INR range was the norm to be expected. More recently on the market are new medications that act directly on the coagulation cascade (direct oral anticoagulants or DOACs, also known as NOACs or non-vitamin K targeting anticoagulants). These agents eliminate lag in time to onset of anticoagulant effects and greatly reduce interindividual variability in the degree of anticoagulation, properties that permit the use of unadjusted, fixed dosing, and eliminate the requirement for serial monitoring of anticoagulation effects. Massive preregistration trials and a decade of experience have shown that standard-dose DOAC therapy is safe and effective in most patients, the proviso being that those patients do not have pharmacokinetic contraindications (eg, renal failure).1Gong I.Y. Kim R.B. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban.Can J Cardiol. 2013; 29: S24-S33Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar Nonetheless, some health care professionals and patients feel uncomfortably out of control without the ability to monitor their anticoagulant medication. That uncertainty prompts the question, “Couldn’t we just use a laboratory test to be sure that this patient is correctly anticoagulated?” The longing to monitor anticoagulants persists, because the penalty for over- or undertreatment can be major bleeding or thromboembolic events. Clinically, the temptation is to fall back on the familiar coagulation tests, despite the fact that they do not reliably quantify the effects of DOACs. This conundrum is illustrated by the report of Kawabata et al.,2Kawabata M. Goya M. Takahashi Y. et al.Excessive prolongation of coagulation time during treatment with direct oral anticoagulants in patients with nonvalvular atrial fibrillation.Can J Cardiol. 2019; 35: 736-743Abstract Full Text Full Text PDF Scopus (4) Google Scholar in this issue of the Canadian Journal of Cardiology, who retrospectively examined a population of nonvalvular atrial fibrillation patients taking DOACs to determine the prevalence, causes, and consequences of excessively prolonged PT and activated partial thromboplastin time (APTT), defined as PT or APTT > 2 SDs over the median. Of the 1521 patients they identified with records of PT or APTT associated with DOAC therapy, excessive prolongation occurred in 88 (5.8%). Compared with the rest of the population, these patients had a > fourfold increase in major bleeding events after a median follow-up of 8.9 months (5.7% vs 1.3%; P = 0.01). Patients with excessively prolonged PT or APTT measurements were older (69 vs 66 years; P = 0.012), had lower body weights (60 vs 66 kg; P = 0.0001), and had lower creatinine clearance (66 vs 76 mL/min; P = 0.002). Although they also had higher Congestive Heart Failure, Hypertension, Age (≥ 75 years), Diabetes, Stroke/Transient Ischemic Attack, Vascular Disease, Age (65-74 years), Sex (Female) (CHA2DS2-VASc) scores (2.8 vs 2.3; P = 0.011), and higher Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (> 65 Years), Drugs/Alcohol Concomitantly (HAS-BLED) scores (1.6 vs 1.3; P = 0.017), in multivariate analysis only body weight ≤ 60 kg (odds ratio, 2.12; 95% confidence interval, 1.20-3.72; P = 0.016) and the use of higher than recommended DOAC dosages (odds ratio, 2.29; 95% confidence interval, 1.17-4.50; P = 0.016) were independently associated with excessively prolonged PT or APTT. Of the 58 patients investigated for associated coagulation disorders: 47% had no identifiable disorders, 28% had antiphospholipid antibodies; 11% were receiving higher than recommended doses of DOACs; 8% had coagulation factor deficiencies; and 6% had severe liver disease. Could clinical judgement have identified patients with higher bleeding risk during DOAC treatment, or is laboratory screening a valuable option? Kawabata et al.2Kawabata M. Goya M. Takahashi Y. et al.Excessive prolongation of coagulation time during treatment with direct oral anticoagulants in patients with nonvalvular atrial fibrillation.Can J Cardiol. 2019; 35: 736-743Abstract Full Text Full Text PDF Scopus (4) Google Scholar found that only the 2 abnormalities, both easily detected clinically without laboratory screening, were the most commonly identified abnormalities associated with excessive PT or APTT measurements: (1) higher than recommended dose of DOAC; and (2) low body weight.1Gong I.Y. Kim R.B. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban.Can J Cardiol. 2013; 29: S24-S33Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar The independent predictive values of these 2 associations could imply that lower dosing is needed for low body weight and/or reduced renal function. The most commonly associated occult abnormality was the presence of antiphospholipid antibodies. However, none of these patients had a major bleeding or thromboembolic event during follow-up, and no alterations in therapy were required. Therefore, determining this information did not change clinical care. Otherwise, screening for excessively high values of PT or APTT identified only 4 patients with coagulation factor deficiencies and 25 patients with no identifiable associated disorder (0.26% and 1.6% of the total study population). Overall, the clinically actionable results of screening for excessive prolongation of PT or APTT were extremely low. Nonetheless, the nagging question persists as to whether we could implement monitoring to do a better job of determining DOAC dose. Certainly, laboratory monitoring and dose adjustment of DOACs is a topic of discussion in the contemporary literature.3Patel J.P. Byrne R.A. Patel R.K. Arya R. Progress in the monitoring of direct oral anticoagulant therapy.Br J Haematol. 2019; 184: 912-924Crossref PubMed Scopus (27) Google Scholar, 4Wyse D.G. Targeted therapeutic drug monitoring for direct oral anticoagulants: what is its potential place and can it limit black swan events?.Can J Cardiol. 2018; 34: 1393-1395Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar, 5Eikelboom J.W. Quinlan D.J. Hirsh J. Connolly S.J. Weitz J.I. Laboratory monitoring of nonvitamin K antagonist oral anticoagulant use in patients with atrial fibrillation.JAMA Cardiol. 2017; 2: 566-574Crossref PubMed Scopus (85) Google Scholar To be valuable, screening should identify risks that can be corrected by dose adjustment or by choice of other therapy. Such screening should also reduce adverse outcomes sufficiently enough to justify the additional screening costs, or at least increase the number of patients who could be safely and effectively managed with DOACs. If we chose to monitor DOACs, what is the goal of our monitoring? What monitoring parameter best supports that goal? What guidance does that parameter give to adjusting personal dosing? How often does it need to be done? Importantly, we must keep clear in our minds that DOACs are not like warfarin.6Maddison J. Somogyi A.A. Jensen B.P. et al.The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype.Br J Clin Pharmacol. 2012; 75: 208-216Crossref Scopus (30) Google Scholar Whereas DOACs are true anticoagulant agents for which increasing concentrations at the effect site correlate directly with degree of effect,1Gong I.Y. Kim R.B. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban.Can J Cardiol. 2013; 29: S24-S33Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar warfarin does not interfere with clot formation itself, but rather it is an antimetabolite, interfering with the vitamin K supply/regeneration critical to production of several clotting proteins. The effect of this complex interaction cannot be directly predicted by simply knowing warfarin concentration. Next, one must choose the goals of monitoring. Situational monitoring is often used sequentially, with the goal of adjusting dose as often as needed to accommodate for changing responses to medications, especially those with a relatively narrow therapeutic window. However, baseline screening for inherent differences in pharmacokinetics, either genetically imbued or functionally acquired, has the goal of identifying patients in whom the “standard dose” of drug is not optimal. Because of the contemporary focus on personalized medicine, the sum total of individual differences in a patient’s pharmacokinetics could be referred to as “personal pharmacokinetics.” A strategy to adjust personal dose to accommodate the effect of personal pharmacokinetics on drug concentration reduces the incidence of therapeutic misadventure in the population as a whole and, because it does not require frequent repetition, can use fewer resources. Warfarin management uses situational monitoring for frequent verification of drug effect to mitigate its variable interplay with environmental effects on cytochrome P450 2C9 (CYP2C9) metabolism, vitamin K epoxide (VKOR) activity, and vitamin K exposure.6Maddison J. Somogyi A.A. Jensen B.P. et al.The pharmacokinetics and pharmacodynamics of single dose (R)- and (S)-warfarin administered separately and together: relationship to VKORC1 genotype.Br J Clin Pharmacol. 2012; 75: 208-216Crossref Scopus (30) Google Scholar Without guided dose adjustment, rates of bleeding or thrombosis would be unacceptable. This kind of monitoring is also used in assessing whether an acutely bleeding patient is overanticoagulated or a patient needs reversal of anticoagulation before surgery. In these situations, the monitoring parameter must accurately reflect the degree of anticoagulation and have a rapid turnaround. However, because the goal in this situation is a simple decision to continue/hold/reverse warfarin dosing, no guidance regarding magnitude of dose adjustment is actually needed. Such pharmacodynamic monitoring is discussed in a review by Eikelboom et al.5Eikelboom J.W. Quinlan D.J. Hirsh J. Connolly S.J. Weitz J.I. Laboratory monitoring of nonvitamin K antagonist oral anticoagulant use in patients with atrial fibrillation.JAMA Cardiol. 2017; 2: 566-574Crossref PubMed Scopus (85) Google Scholar In contrast, the goal of baseline screening of drug concentrations is to adjust for the naturally occurring population variation in effect site concentration of drug (ie, the intrinsic spread in steady-state peak drug concentrations developed in response to fixed-dose therapy in the population). Adjusting drug dose to optimize concentration is a reasonable strategy for patients starting treatment with a DOAC, because drug effect is proportional to concentration for directly acting medications. A measure of steady-state peak concentration developed after a given dose can guide dose adjustment, moving less typical patients into a band of concentrations associated with successful therapy (Fig. 1). Adding a measure of trough concentration permits calculation of personal elimination rate, commonly expressed as half-life. Because DOACs have linear pharmacokinetics in the clinical dosing range, change in concentration is proportional to change in dose. Successful examples of guided DOAC dose adjustment in patients with unusual pharmacokinetics have been reported.7Pollak P.T. Sun G.R. Kim R.B. Personalized anticoagulation: guided apixaban dose adjustment to compensate for pharmacokinetic abnormalities related to short-bowel syndrome.Can J Cardiol. 2018; 34 (342.e17-e19)Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar, 8Dagan G. Perlman A. Hochberg-Klein S. Kalish Y. Muszkat M. Managing direct oral anticoagulants in patients with antiepileptic medication.Can J Cardiol. 2018; 34 (1534.e1-e3)Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Because pharmacology predicts a graded relationship between effect and drug concentration,9Rang H.P. The receptor concept: pharmacology’s big idea.Br J Pharmacol. 2006; 147: S9-S16PubMed Google Scholar monitoring (screening) at inception of DOAC therapy could offer 3 benefits: (1) screening after initial dosing could identify patients with personal pharmacokinetics atypical enough to make nonstandard dosing optimal; (2) chronic physiological abnormalities or drug-drug interactions affecting DOAC concentration at baseline (or even later on recheck) could be identified and adjusted for early during treatment; and (3) some patients with slow drug elimination, who might otherwise be excluded from DOAC therapy, might be managed with a simple dose adjustment. While convenient to focus on peak concentrations, we must also remember that the effect of DOACs is not constant over the dosing interval. Serum DOAC concentrations might fluctuate anywhere from 2- to 8-fold between doses. Yet, for most patients, the degree of thrombosis inhibition over the course of the day is sufficient to tip the overall balance in favour of clot resolution through natural fibrinolysis. This means that, although no 2 patients have the same concentration profile, most patients achieve successful anticoagulation without excessive bleeding. Because the ratio of change in anticoagulation effect to change in DOAC concentration is relatively modest, the concentration-response curve can be characterized as “flat” (Fig. 1A). The advantage of a flat response is that, even with the population variation in concentrations produced by a fixed-dose drug, acceptable therapy is still achieved in most patients. For example, if a given DOAC provides successful therapy at a range of concentrations within ± 1.5 SDs of the mean produced by fixed-dose therapy, then 87% of the population would be therapeutic with fixed dosing (Fig. 1C). Patients developing concentrations at the lower end of the desirable range would be more prone to clotting, whereas those at the upper end would be more prone to bleeding. How best to identify patients who develop concentrations inconsistent with desirable clinical effect? For most pharmacokinetic problems, the best assessment is to measure drug concentration at steady state at a defined time after a defined dose of drug and compare it to a population standard. Trying to adjust dose according to pharmacodynamic parameters such as PT only adds an extra layer of variability. Pharmacology is founded on the theory that effects are proportional to interactions between receptors and agonist/antagonist molecules, a concept less than a century old.9Rang H.P. The receptor concept: pharmacology’s big idea.Br J Pharmacol. 2006; 147: S9-S16PubMed Google Scholar Modern understanding of a drug’s effects involves knowledge of its pharmacodynamics and pharmacokinetics. Pharmacodynamics is dependent on the expression of genetically encoded receptor proteins and their sensitivity to variations in drug concentration, which in turn are determined by pharmacokinetics. The concentration to which a receptor is exposed is dependent on: (1) drug dose in the context of: (2) personal pharmacokinetics (genetic variations in absorption, distribution, metabolism, and elimination); under the influence of: (3) external modifiers (drug-drug-food interactions, disease-anatomic-drug interactions).

Background: Physicians treating nonvalvular atrial fibrillation (AF) assess stroke and bleeding risks when deciding on anticoagulation. The agreement between empirical and physician-estimated risks is unclear. Furthermore, the association between patient and physician sex and anticoagulation decision-making is uncertain. Methods: We pooled data from 2 national primary care physician chart audit databases of patients with AF (Facilitating Review and Education to Optimize Stroke Prevention in Atrial Fibrillation and Coordinated National Network to Engage Physicians in the Care and Treatment of Patients with Atrial Fibrillation Chart Audit) with a combined 1035 physicians (133 female, 902 male) and 10,927 patients (4567 female and 6360 male). Results: Male physicians underestimated stroke risk in female patients and overestimated risk in male patients. Female physicians estimated stroke risk well in female patients but underestimated the risk in male patients. Risk of bleeding was underestimated in all. Despite differences in risk assessment by physician and patient sex, > 90% of patients received anticoagulation across all subgroups. There was modest agreement between physician estimated and calculated (ie, CHADS(2) score) stroke risk: Kappa scores were 0.41 (0.35-0.47) for female physicians and 0.34 (0.32-0.36) for male physicians. Conclusions: Our study is the first to examine the association between patient and physician sex influences and stroke and bleeding risk estimation in AF. Although there were differences in agreement between physician estimated stroke risk and calculated CHADS(2) scores, these differences were small and unlikely to affect clinical practice; further, despite any perceived differences in the accuracy of risk assessment by sex, most patients received anticoagulation.

The practice of electrical or pharmacological cardioversion (CV) to restore sinus rhythm in patents with symptomatic atrial fibrillation (AF) or atrial flutter has been a part of clinical practice for more than 100 years. For almost as long as CV has been performed, it has been recognized that the act of restoring sinus rhythm is associated with an increased risk of stroke and systemic embolism, and that oral anticoagulant (OAC) therapy can be used to prevent peri-CV thromboembolism. Although it has been widely accepted that OAC therapy is necessary to prevent thromboembolism in patients with chronic AF/atrial flutter who undergo CV, previous clinical practice recommendations have suggested that OAC therapy may be omitted in patients at low risk of stroke. However, in recent years, evidence has emerged from several sources challenging these historical conventions. In 2018 the Canadian Cardiovascular Society AF guidelines updated the previous recommendations regarding CV of acute onset AF, and the use of peri-CV anticoagulation. In this article we present an extensive review of the evidence informing the previous recommendations, as well as the novel evidence that informed the change in recommendations. In addition, the current Canadian Cardiovascular Society AF guideline recommendations are examined within the context of contemporary international major society guidelines.

Importance Catheter ablation is effective in restoring sinus rhythm in atrial fibrillation (AF), but its effects on long-term mortality and stroke risk are uncertain. Objective To determine whether catheter ablation is more effective than conventional medical therapy for improving outcomes in AF. Design, Setting, and Participants The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation trial is an investigator-initiated, open-label, multicenter, randomized trial involving 126 centers in 10 countries. A total of 2204 symptomatic patients with AF aged 65 years and older or younger than 65 years with 1 or more risk factors for stroke were enrolled from November 2009 to April 2016, with follow-up through December 31, 2017. Interventions The catheter ablation group (n = 1108) underwent pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators. The drug therapy group (n = 1096) received standard rhythm and/or rate control drugs guided by contemporaneous guidelines. Main Outcomes and Measures The primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Among 13 prespecified secondary end points, 3 are included in this report: all-cause mortality; total mortality or cardiovascular hospitalization; and AF recurrence. Results Of the 2204 patients randomized (median age, 68 years; 37.2% female; 42.9% had paroxysmal AF and 57.1% had persistent AF), 89.3% completed the trial. Of the patients assigned to catheter ablation, 1006 (90.8%) underwent the procedure. Of the patients assigned to drug therapy, 301 (27.5%) ultimately received catheter ablation. In the intention-to-treat analysis, over a median follow-up of 48.5 months, the primary end point occurred in 8.0% (n = 89) of patients in the ablation group vs 9.2% (n = 101) of patients in the drug therapy group (hazard ratio [HR], 0.86 [95% CI, 0.65-1.15]; P = .30). Among the secondary end points, outcomes in the ablation group vs the drug therapy group, respectively, were 5.2% vs 6.1% for all-cause mortality (HR, 0.85 [95% CI, 0.60-1.21]; P = .38), 51.7% vs 58.1% for death or cardiovascular hospitalization (HR, 0.83 [95% CI, 0.74-0.93]; P = .001), and 49.9% vs 69.5% for AF recurrence (HR, 0.52 [95% CI, 0.45-0.60]; P < .001). Conclusions and Relevance Among patients with AF, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest. However, the estimated treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers, which should be considered in interpreting the results of the trial. Trial Registration ClinicalTrials.gov Identifier: NCT00911508

Polymorphic ventricular tachycardia (PMVT) is a rapid ventricular tachycardia in which the QRS complexes vary in coupling interval, morphology, and axis on a beat-to-beat basis. PMVT occurs in two distinct forms: PMVT without QT interval prolongation and PMVT with QT interval prolongation. The two types differ in important ways with respect to their differential diagnosis and treatment. PMVT without QT interval prolongation usually emerges in the setting of an unstable structural heart disorder, such as acute ischaemia or decompensated heart failure. Treatment is directed at the underlying heart disorder, correction of acid–base disturbances, hypoxia, and electrolyte abnormalities along with beta-blocking therapy and amiodarone. Invasive antiarrhythmic interventions, such as sympathetic denervation and transcatheter ablation, are occasionally required. Long-term treatment often includes an implantable cardioverter defibrillator. PMVT with QT interval prolongation, known as torsade de pointes VT, occurs when repolarization reserve has been exhausted by either inherited or acquired factors that prolong the QT interval. Classical features of the ‘twisting-of-the-points’ polymorphism and the short–long–short initiation sequence are common but are not universal. Treatment is directed at removal of the cause of the QT interval prolongation, correction of electrolyte disturbances (hypokalaemia and hypomagnesaemia), supplemental magnesium therapy, and treatments to shorten the QT interval such as isoproterenol, pacing, or lidocaine. Long-term treatment is focused on avoidance of QT interval prolonging factors. If the likelihood of subsequent recurrence is not low, consideration is given to placement of a permanent pacemaker or implantable cardioverter defibrillator.

BACKGROUND Ventricular tachycardia (VT) and ventricular fibrillation (VF) remain a challenging problem in patients with implantable cardioverter-defibrillators (ICDs). OBJECTIVES This study aimed to determine whether ranolazine administration decreases the likelihood of VT, VF, or death in patients with an ICD. METHODS This was double-blind, placebo-controlled clinical trial in which high-risk ICD patients with ischemic or nonischemic cardiomyopathy were randomized to 1,000 mg ranolazine twice a day or placebo. The primary endpoint was VT or VF requiring appropriate ICD therapy or death, whichever occurred first. Pre-specified secondary endpoints included ICD shock for VT, VF, or death and recurrent VT or VF requiring ICD therapy. RESULTS Among 1,012 ICD patients (510 randomized to ranolazine and 502 to placebo) the mean age was 64 +/- 10 years and 18% were women. During 28 +/- 16 months of follow-up there were 372 (37%) patients with primary endpoint, 270 (27%) patients with VT or VF, and 148 (15%) deaths. The blinded study drug was discontinued in 199 (39.6%) patients receiving placebo and in 253 (49.6%) patients receiving ranolazine (p = 0.001). The hazard ratio for ranolazine versus placebo was 0.84 (95% confidence interval: 0.67 to 1.05; p = 0.117) for VT, VF, or death. In a pre-specified secondary analysis, patients randomized to ranolazine had a marginally significant lower risk of ICD therapies for recurrent VT or VF (hazard ratio: 0.70; 95% confidence interval: 0.51 to 0.96; p = 0.028). There were no other significant treatment effects in other pre-specified secondary analyses, which included individual components of the primary endpoint, inappropriate shocks, cardiac hospitalizations, and quality of life. CONCLUSIONS In high-risk ICD patients, treatment with ranolazine did not significantly reduce the incidence of the first VT or VF, or death. However, the study was underpowered to detect a difference in the primary endpoint. In pre specified secondary endpoint analyses, ranolazine administration was associated with a significant reduction in recurrent VT or VF requiring ICD therapy without evidence for increased mortality. (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.

Historical forest management practices in the southwestern US have left forests prone to high-severity, stand-replacement fires. Reducing the cost of forest-fire management and reintroducing fire to the landscape without negative impact depends on detailed knowledge of stand composition, in particular, above-ground biomass (AGB). Lidar-based modeling techniques provide opportunities to increase ability of managers to monitor AGB and other forest metrics at reduced cost. We developed a regional lidar-based statistical model to estimate AGB for Ponderosa pine and mixed conifer forest systems of the southwestern USA, using previously collected field data. Model selection was performed using Bayesian model averaging (BMA) to reduce researcher bias, fully explore the model space, and avoid overfitting. The selected model includes measures of canopy height, canopy density, and height distribution. The model selected with BMA explains 71% of the variability in field-estimates of AGB, and the RMSE of the two independent validation data sets are 23.25 and 32.82 Mg/ha. The regional model is structured in accordance with previously described local models, and performs equivalently to these smaller scale models. We have demonstrated the effectiveness of lidar for developing cost-effective, robust regional AGB models for monitoring and planning adaptively at the landscape scale.

A cardiac bradyarrhythmia may be the result of disordered impulse formation, disordered impulse conduction, or both. Human anatomy and physiology of the cardiac electrophysiological system are reviewed to provide a framework for an understanding of the patterns of sinus node, AV node, and His-Purkinje system dysfunction that result in clinical bradyarrhythmias. The important pathologic processes leading to these clinical bradyarrhythmias are discussed. The symptoms of the bradyarrhythmias are considered along with the details of treatment approaches with an emphasis on the indications for and appropriate selection of the platforms of implanted permanent cardiac pacemakers.