A systematic review and meta-analysis on oncological radiotherapy in patients with a cardiac implantable electronic device: Prevalence and predictors of device malfunction in 3121 patients.

BACKGROUND: The number of patients with cardiac implantable electronic devices (CIEDs) undergoing radiotherapy (RT) for cancer treatment is growing. At present, prevalence and predictors of RT-induced CIEDs malfunctions are not defined. METHODS: Systematic review and meta-analysis conducted following the PRISMA recommendations. PubMed, Scopus and Google Scholar were searched from inception to 31/01/2022 for studies reporting RT-induced malfunctions in CIEDs patients. Aim was to assess the prevalence of RT-induced CIEDs malfunctions and identify potential predictors. RESULTS: Thirty-two out of 3962 records matched the inclusion criteria and were included in the meta-analysis. A total of 135 CIEDs malfunctions were detected among 3121 patients (6.6%, 95% confidence interval [CI]: 5.1%-8.4%). The pooled prevalence increased moving from pacemaker (PM) to implantable cardioverter defibrillator (ICD), and cardiac resynchronization therapy and defibrillator (CRT-D) groups (4.1%, 95% CI: 2.9-5.8; 8.2% 95% CI: 5.9-11.3; and 19.8%, 95% CI: 11.4-32.2 respectively). A higher risk ratio (RR) of malfunctions was found when neutron-producing energies were used as compared to non-neutron-producing energies (RR 9.98, 95% CI: 5.09-19.60) and in patients with ICD/CRT-D as compared to patients with PM/CRT-P (RR 2.07, 95% CI: 1.40-3.06). On the contrary, no association was found between maximal radiation dose at CIED >2 Gy and CIEDs malfunctions (RR 0.93; 95% CI: 0.31-2.76). CONCLUSIONS: Radiotherapy related CIEDs malfunction had a prevalence ranging from 4% to 20%. The use of neutron-producing energies and more complex devices (ICD/CRT-D) were associated with higher risk of device malfunction, while the radiation dose at CIED did not significantly impact on the risk unless higher doses (>10 Gy) were used.

Cardiac pacing and lead devices management: 25 years of research at EP Europace journal.

AIMS: Cardiac pacing represents a key element in the field of electrophysiology and the treatment of conduction diseases. Since the first issue published in 1999, EP Europace has significantly contributed to the development and dissemination of the research in this area. METHODS: In the last 25 years, there has been a continuous improvement of technologies and a great expansion of clinical indications making the field of cardiac pacing a fertile ground for research still today. Pacemaker technology has rapidly evolved, from the first external devices with limited longevity, passing through conventional transvenous pacemakers to leadless devices. Constant innovations in pacemaker size, longevity, pacing mode, algorithms, and remote monitoring highlight that the fascinating and exciting journey of cardiac pacing is not over yet. CONCLUSION: The aim of the present review is to provide the current 'state of the art' on cardiac pacing highlighting the most important contributions from the Journal in the field.

Ibrutinib and Bruton's Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia: Focus on Atrial Fibrillation and Ventricular Tachyarrhythmias/Sudden Cardiac Death.

BACKGROUND: The natural history of chronic lymphocytic leukemia (CLL) was dramatically improved by the introduction of ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. In this review, we aimed to summarize and critically evaluate the association between first- and second-generation BTK inhibitors and the risk of atrial fibrillation (AF) and ventricular arrhythmias (VA). SUMMARY: Since the first clinical experience, the development of AF was observed as the result of off-target effects that likely combined with patient's predisposing risk factors and concomitant cardiac morbidities. More recently, both ibrutinib dose reduction and arrhythmia management allowed long-term treatment, with positive effects on progression-free survival and reduced all-cause mortality as well. Second-generation BTK inhibitors, acalabrutinib, and zanubrutinib have been tested and validated in CLL. A lower occurrence of AF as compared with ibrutinib has been found, although AF has always been a secondary endpoint of all studies that probed these agents. KEY MESSAGES: For this reason, caution should be exercised before concluding that second-generation BTK inhibitors are safer than ibrutinib. Recent data on the effectiveness of ibrutinib over a follow-up of 8 years show a remarkable benefit on all-cause mortality, which is of great value also for interpreting the clinical impact of the few cases of VA and sudden cardiac death (SCD) reported for ibrutinib, independently of QT lengthening. Since a risk of VA and SCD has been recently reported also during treatment with second-generation BTK inhibitors, it appears that this risk, usually reaching its maximum size effect at long-term follow-up, likely denotes a class effect of BTK inhibitors.

Clinical complexity and impact of the ABC (Atrial fibrillation Better Care) pathway in patients with atrial fibrillation: a report from the ESC-EHRA EURObservational Research Programme in AF General Long-Term Registry.

BACKGROUND: Clinical complexity is increasingly prevalent among patients with atrial fibrillation (AF). The 'Atrial fibrillation Better Care' (ABC) pathway approach has been proposed to streamline a more holistic and integrated approach to AF care; however, there are limited data on its usefulness among clinically complex patients. We aim to determine the impact of ABC pathway in a contemporary cohort of clinically complex AF patients. METHODS: From the ESC-EHRA EORP-AF General Long-Term Registry, we analysed clinically complex AF patients, defined as the presence of frailty, multimorbidity and/or polypharmacy. A K-medoids cluster analysis was performed to identify different groups of clinical complexity. The impact of an ABC-adherent approach on major outcomes was analysed through Cox-regression analyses and delay of event (DoE) analyses. RESULTS: Among 9966 AF patients included, 8289 (83.1%) were clinically complex. Adherence to the ABC pathway in the clinically complex group reduced the risk of all-cause death (adjusted HR [aHR]: 0.72, 95%CI 0.58-0.91), major adverse cardiovascular events (MACEs; aHR: 0.68, 95%CI 0.52-0.87) and composite outcome (aHR: 0.70, 95%CI: 0.58-0.85). Adherence to the ABC pathway was associated with a significant reduction in the risk of death (aHR: 0.74, 95%CI 0.56-0.98) and composite outcome (aHR: 0.76, 95%CI 0.60-0.96) also in the high-complexity cluster; similar trends were observed for MACEs. In DoE analyses, an ABC-adherent approach resulted in significant gains in event-free survival for all the outcomes investigated in clinically complex patients. Based on absolute risk reduction at 1 year of follow-up, the number needed to treat for ABC pathway adherence was 24 for all-cause death, 31 for MACEs and 20 for the composite outcome. CONCLUSIONS: An ABC-adherent approach reduces the risk of major outcomes in clinically complex AF patients. Ensuring adherence to the ABC pathway is essential to improve clinical outcomes among clinically complex AF patients.

Impact of malignancy on outcomes in European patients with atrial fibrillation: A report from the ESC-EHRA EURObservational research programme in atrial fibrillation general long-term registry.

BACKGROUND: The management of patients with atrial fibrillation (AF) and malignancy is challenging given the paucity of evidence supporting their appropriate clinical management. PURPOSE: To evaluate the outcomes of patients with active or prior malignancy in a contemporary cohort of European AF patients. METHODS: Patients enrolled in the EURObservational Research Programme in AF General Long-Term Registry were categorized into 3 categories: No Malignancy (NoMal), Prior Malignancy (PriorMal) and Active Malignancy (ActiveMal). The primary outcomes were all-cause death and the composite outcome MACE. RESULTS: A total of 10 383 patients were analysed. Of these, 9597 (92.4%) were NoMal patients, 577 (5.6%) PriorMal and 209 (2%) ActiveMal. Lack of any antithrombotic treatment was more prevalent in ActiveMal patients (12.4%) as compared to other groups (5.0% vs 6.3% for PriorMal and NoMal, p < .001). After a median follow-up of 730 days, there were 982 (9.5%) deaths and 950 (9.7%) MACE events. ActiveMal was independently associated with a higher risk for all-cause death (HR 2.90, 95% CI 2.23-3.76) and MACE (HR 1.54, 95% CI 1.03-2.31), as well as any haemorrhagic events and major bleeding (OR 2.42, 95% CI 1.49-3.91 and OR 4.18, 95% CI 2.49-7.01, respectively). Use of oral anticoagulants was not significantly associated with a higher risk for all-cause death or bleeding in ActiveMal patients. CONCLUSIONS: In a large contemporary cohort of AF patients, active malignancy was independently associated with all-cause death, MACE and haemorrhagic events. Use of anticoagulants was not associated with a higher risk of all-cause death in patients with active malignancies.

Performance-based risk-sharing arrangements for devices and procedures in cardiac electrophysiology: an innovative perspective.

There is an increasing pressure on demonstrating the value of medical interventions and medical technologies resulting in the proposal of new approaches for implementation in the daily practice of innovative treatments that might carry a substantial cost. While originally mainly adopted by pharmaceutical companies, in recent years medical technology companies have initiated novel value-based arrangements for using medical devices, in the form of 'outcomes-based contracts', 'performance-based contracts', or 'risk-sharing agreements'. These are all characterized by linking coverage, reimbursement, or payment for the innovative treatment to the attainment of pre-specified clinical outcomes. Risk-sharing agreements have been promoted also in the field of electrophysiology and offer the possibility to demonstrate the value of specific innovative technologies proposed in this rapidly advancing field, while relieving hospitals from taking on the whole financial risk themselves. Physicians deeply involved in the field of devices and technologies for arrhythmia management and invasive electrophysiology need to be prepared for involvement as stakeholders. This may imply engagement in the evaluation of risk-sharing agreements and specifically, in the process of assessment of technology performances or patient outcomes. Scientific Associations may have an important role in promoting the basis for value-based assessments, in promoting educational initiatives to help assess the determinants of the learning curve for innovative treatments, and in promoting large-scale registries for a precise assessment of patient outcomes and of specific technologies' performance.

Epidemiology and impact of frailty in patients with atrial fibrillation in Europe.

BACKGROUND: Frailty is a medical syndrome characterised by reduced physiological reserve and increased vulnerability to stressors. Data regarding the relationship between frailty and atrial fibrillation (AF) are still inconsistent. OBJECTIVES: We aim to perform a comprehensive evaluation of frailty in a large European cohort of AF patients. METHODS: A 40-item frailty index (FI) was built according to the accumulation of deficits model in the AF patients enrolled in the ESC-EHRA EORP-AF General Long-Term Registry. Association of baseline characteristics, clinical management, quality of life, healthcare resources use and risk of outcomes with frailty was examined. RESULTS: Among 10,177 patients [mean age (standard deviation) 69.0 (11.4) years, 4,103 (40.3%) females], 6,066 (59.6%) were pre-frail and 2,172 (21.3%) were frail, whereas only 1,939 (19.1%) were considered robust. Baseline thromboembolic and bleeding risks were independently associated with increasing FI. Frail patients with AF were less likely to be treated with oral anticoagulants (OACs) (odds ratio 0.70, 95% confidence interval 0.55-0.89), especially with non-vitamin K antagonist OACs and managed with a rhythm control strategy, compared with robust patients. Increasing frailty was associated with a higher risk for all outcomes examined, with a non-linear exponential relationship. The use of OAC was associated with a lower risk of outcomes, except in patients with very/extremely high frailty. CONCLUSIONS: In this large cohort of AF patients, there was a high burden of frailty, influencing clinical management and risk of adverse outcomes. The clinical benefit of OAC is maintained in patients with high frailty, but not in very high/extremely frail ones.

Prevalence, management and impact of chronic obstructive pulmonary disease in atrial fibrillation: a systematic review and meta-analysis of 4,200,000 patients.

AIM: Prevalence of chronic obstructive pulmonary disease (COPD) in atrial fibrillation (AF) patients is unclear, and its association with adverse outcomes is often overlooked. Our aim was to estimate the prevalence of COPD, its impact on clinical management and outcomes in patients with AF, and the impact of beta-blockers (BBs) on outcomes in patients with COPD. METHODS AND RESULTS: A systematic review and meta-analysis was conducted according to international guidelines. All studies reporting the prevalence of COPD in AF patients were included. Data on comorbidities, BBs and oral anticoagulant prescription, and outcomes (all-cause death, cardiovascular (CV) death, ischaemic stroke, major bleeding) were compared according to COPD and BB status. Among 46 studies, pooled prevalence of COPD was 13% [95% confidence intervals (CI) 10-16%, 95% prediction interval 2-47%]. COPD was associated with higher prevalence of comorbidities, higher CHA2DS2-VASc score and lower BB prescription [odds ratio (OR) 0.77, 95% CI 0.61-0.98]. COPD was associated with higher risk of all-cause death (OR 2.22, 95% CI 1.93-2.55), CV death (OR 1.84, 95% CI 1.39-2.43), and major bleeding (OR 1.45, 95% CI 1.17-1.80); no significant differences in outcomes were observed according to BB use in AF patients with COPD. CONCLUSION: COPD is common in AF, being found in 13% of patients, and is associated with increased burden of comorbidities, differential management, and worse outcomes, with more than a two-fold higher risk of all-cause death and increased risk of CV death and major bleeding. Therapy with BBs does not increase the risk of adverse outcomes in patients with AF and COPD.

Impact of clinical phenotypes on management and outcomes in European atrial fibrillation patients: a report from the ESC-EHRA EURObservational Research Programme in AF (EORP-AF) General Long-Term Registry.

BACKGROUND: Epidemiological studies in atrial fibrillation (AF) illustrate that clinical complexity increase the risk of major adverse outcomes. We aimed to describe European AF patients' clinical phenotypes and analyse the differential clinical course. METHODS: We performed a hierarchical cluster analysis based on Ward's Method and Squared Euclidean Distance using 22 clinical binary variables, identifying the optimal number of clusters. We investigated differences in clinical management, use of healthcare resources and outcomes in a cohort of European AF patients from a Europe-wide observational registry. RESULTS: A total of 9363 were available for this analysis. We identified three clusters: Cluster 1 (n = 3634; 38.8%) characterized by older patients and prevalent non-cardiac comorbidities; Cluster 2 (n = 2774; 29.6%) characterized by younger patients with low prevalence of comorbidities; Cluster 3 (n = 2955;31.6%) characterized by patients' prevalent cardiovascular risk factors/comorbidities. Over a mean follow-up of 22.5 months, Cluster 3 had the highest rate of cardiovascular events, all-cause death, and the composite outcome (combining the previous two) compared to Cluster 1 and Cluster 2 (all P < .001). An adjusted Cox regression showed that compared to Cluster 2, Cluster 3 (hazard ratio (HR) 2.87, 95% confidence interval (CI) 2.27-3.62; HR 3.42, 95%CI 2.72-4.31; HR 2.79, 95%CI 2.32-3.35), and Cluster 1 (HR 1.88, 95%CI 1.48-2.38; HR 2.50, 95%CI 1.98-3.15; HR 2.09, 95%CI 1.74-2.51) reported a higher risk for the three outcomes respectively. CONCLUSIONS: In European AF patients, three main clusters were identified, differentiated by differential presence of comorbidities. Both non-cardiac and cardiac comorbidities clusters were found to be associated with an increased risk of major adverse outcomes.

Integrated care and outcomes in patients with atrial fibrillation and comorbidities.

BACKGROUND: Integrated care for management of atrial fibrillation (AF) patients has been associated with a reduction in adverse events. The 'Atrial fibrillation Better Care (ABC) pathway' has been proposed to streamline such integrated management. In this paper, we analysed the impact of ABC pathway adherent clinical management on outcomes in AF patients with high-risk 'metabolic' comorbidities (i.e. diabetes mellitus [DM], chronic kidney disease [CKD], metabolic syndrome [MetS]. METHODS: Patients from the SPORTIF III and V trials and with available data to evaluate ABC criteria were analysed. DM, CKD and MetS were evaluated according to baseline data. A composite of major adverse cardiovascular events and all-cause death was the study outcome. RESULTS: A total of 3637 patients (median age 72 [IQR 66-77], 30.3% female) were analysed. DM was evident in 23.4%, CKD in 25.8% and MetS in 31.5% among the overall cohort. Respectively, 23.2% were ABC pathway adherent in the DM subgroup, 21.2% in CKD and 23.7% in MetS subgroups. Composite outcome occurred less frequently in patients managed adherent to ABC pathway than those nonadherents, in all three groups. In the final multivariate model, ABC adherent care was inversely associated with a lower risk of composite outcome in the DM (HR 0.45, 95% CI 0.23-0.88), CKD (HR 0.60, 95% CI 0.36-0.98) and MetS (HR 0.37, 95% CI 0.19-0.71) subgroups. CONCLUSIONS: In high-risk AF patients with DM, CKD and MetS, ABC pathway adherent management was associated with a lowered risk of the composite outcome of cardiovascular events, cardiovascular and all-cause death.

Infections associated with cardiac electronic implantable devices: economic perspectives and impact of the TYRX™ antibacterial envelope.

The occurrence of cardiac implantable electronic devices (CIED) infections and related adverse outcomes have an important financial impact on the healthcare system, with hospitalization length of stay (2-3 weeks on average) being the largest cost driver, including the cost of device system extraction and device replacement accounting for more than half of total costs. In the recent literature, the economic profile of the TYRX™ absorbable antibacterial envelope was analysed taking into account both randomized and non-randomized trial data. Economic analysis found that the envelope is associated with cost-effectiveness ratios below USA and European benchmarks in selected patients at increased risk of infection. Therefore, the TYRX™ envelope, by effectively reducing CIED infections, provides value according to the criteria of affordability currently adopted by USA and European healthcare systems.

Red blood cell distribution width in patients undergoing transcatheter aortic valve implantation: Implications for outcomes.

BACKGROUND: Red cell distribution width (RDW) is recently emerging as a prognostic indicator in many cardiovascular diseases. However, less is known about its predictive role in patients undergoing transcatheter aortic valve implantation (TAVI). METHODS: We retrospectively included very high-risk patients with severe aortic valve stenosis undergoing TAVI between February 2012 and December 2019. Patients were classified according to RDW tertiles. Our primary endpoint was long-term all-cause mortality. The secondary endpoint was a composite of in-hospital major adverse events as defined by the Valve Academic Research Consortium 2 criteria and/or long-term all-cause mortality. RESULTS: A total of 424 patients [median age 83.5 years, 52.6% females] were analysed. After a median follow-up of 1.55 years, all-cause mortality was 25.5%. At the multivariate-adjusted Cox regression analysis, patients in the highest RDW tertile were associated with a higher risk for all-cause mortality [hazard ratio [HR] 1.73, 95%confidence interval [CI] 1.02-2.95] compared with the lowest tertile. When considering RDW as a continuous variable, we found an 11% increased risk in overall mortality [HR 1.11, 95% CI 1.00-1.24] for each increased point in RDW. The highest RDW tertile was also independently associated with the occurrence of the composite endpoint [odds ratio [OR] 2.10, 95% CI 1.17-3.76] compared with lower tertiles. CONCLUSIONS: In our cohort, elevated basal RDW values were independent predictors of increased long-term mortality and higher rate of in-hospital adverse events. The inclusion of a routinely available biomarker as RDW, may help the pre-operative risk assessment in potential TAVI candidates and optimise their management.

What do we do about atrial high rate episodes?

Atrial high rate episodes (AHREs) are defined as asymptomatic atrial tachyarrhythmias detected by cardiac implantable electronic devices with atrial sensing, providing automated continuous monitoring and tracings storage, occurring in subjects with no previous clinical atrial fibrillation (AF) and with no AF detected at conventional electrocardiogram recordings. AHREs are associated with an increased thrombo-embolic risk, which is not negligible, although lower than that of clinical AF. The thrombo-embolic risk increases with increasing burden of AHREs, and moreover, AHREs burden shows a dynamic pattern, with tendency to progression along with time, with potential transition to clinical AF. The clinical management of AHREs, in particular with regard to prophylactic treatment with oral anticoagulants (OACs), remains uncertain and heterogeneous. At present, in patients with confirmed AHREs, as a result of device tracing analysis, an integrated, individual and clinically-guided assessment should be applied, taking into account the patients' risk of stroke (to be reassessed regularly) and the AHREs burden. The use of OACs, preferentially non-vitamin K antagonists OACs, may be justified in selected patients, such as those with longer AHREs durations (in the range of several hours or ≥24 h), with no doubts on AF diagnosis after device tracing analysis and with an estimated high/very high individual risk of stroke, accounting for the anticipated net clinical benefit, and informed patient's preferences. Two randomized clinical trials on this topic are currently ongoing and are likely to better define the role of anticoagulant therapy in patients with AHREs.