Patients on vitamin K treatment: is switching to direct-acting oral anticoagulation cost-effective? A target trial on a prospective cohort.

AIMS: Direct-acting oral anticoagulants (DOACs) have, to a substantial degree, replaced vitamin K antagonists (VKA) as treatments for stroke prevention in atrial fibrillation (AF) patients. However, evidence on the real-world causal effects of switching patients from VKA to DOAC is lacking. We aimed to assess the empirical incremental cost-effectiveness of switching patients to DOAC compared with maintaining VKA treatment. METHODS: The target trial approach was applied to the prospective observational Swiss-AF cohort, which enrolled 2415 AF patients from 2014 to 2017. Clinical data, healthcare resource utilisation and EQ-5D-based utilities representing quality of life were collected in yearly follow-ups. Health insurance claims were available for 1024 patients (42.4%). Overall survival, quality-of-life, costs from the Swiss statutory health insurance perspective and cost-effectiveness were estimated by emulating a target trial in which patients were randomly assigned to switch to DOAC or maintain VKA treatment. RESULTS: 228 patients switching from VKA to DOAC compared with 563 patients maintaining VKA treatment had no overall survival advantage over a 5-year observation period (HR 0.99, 95% CI 0.45, 1.55). The estimated gain in quality-adjusted life years (QALYs) was 0.003 over the 5-year period at an incremental costs of CHF 23 033 (€ 20 940). The estimated incremental cost-effectiveness ratio was CHF 425 852 (€ 387 138) per QALY gained. CONCLUSIONS: Applying a causal inference method to real-world data, we could not demonstrate switching to DOACs to be cost-effective for AF patients with at least 1 year of VKA treatment. Our estimates align with results from a previous randomised trial.

Real-World Cost-Effectiveness of Pulmonary Vein Isolation for Atrial Fibrillation: A Target Trial Approach.

OBJECTIVES: Randomized controlled trials of pulmonary vein isolation (PVI) for treating atrial fibrillation (AF) have proven the procedure's efficacy. Studies assessing its empirical cost-effectiveness outside randomized trial settings are lacking. We aimed to evaluate the effectiveness and cost-effectiveness of PVI versus medical therapy for AF. METHODS: We followed a target trial approach using the Swiss-AF cohort, a prospective observational cohort study that enrolled patients with AF between 2014 and 2017. Resource utilization and cost information were collected through claims data. Quality of life was measured with EQ-5D-3L utilities. We estimated incremental cost-effectiveness ratios (ICERs) from the perspective of the Swiss statutory health insurance system. RESULTS: Patients undergoing PVI compared with medical therapy had a 5-year overall survival advantage with a hazard ratio of 0.75 (95% CI 0.46-1.21; P = .69) and a 19.8% SD improvement in quality of life (95% CI 15.5-22.9; P < .001), at an incremental cost of 29 604 Swiss francs (CHF) (95% CI 16 354-42 855; P < .001). The estimated ICER was CHF 158 612 per quality-adjusted life-year (QALY) gained within a 5-year time horizon. Assuming similar health effects and costs over 5 additional years changed the ICER to CHF 82 195 per QALY gained. Results were robust to the sensitivity analyses performed. CONCLUSIONS: Our results show that PVI might be a cost-effective intervention within the Swiss healthcare context in a 10-year time horizon, but unlikely to be so at 5 years, if a willingness-to-pay threshold of CHF 100 000 per QALY gained is assumed. Given data availability, we find target trial designs are a valuable tool for assessing the cost-effectiveness of healthcare interventions outside of randomized controlled trial settings.

A worldwide survey on incidence, management, and prognosis of oesophageal fistula formation following atrial fibrillation catheter ablation: the POTTER-AF study.

AIMS: Oesophageal fistula represents a rare but dreadful complication of atrial fibrillation catheter ablation. Data on its incidence, management, and outcome are sparse. METHODS AND RESULTS: This international multicentre registry investigates the characteristics of oesophageal fistulae after treatment of atrial fibrillation by catheter ablation. A total of 553 729 catheter ablation procedures (radiofrequency: 62.9%, cryoballoon: 36.2%, other modalities: 0.9%) were performed, at 214 centres in 35 countries. In 78 centres 138 patients [0.025%, radiofrequency: 0.038%, cryoballoon: 0.0015% (P < 0.0001)] were diagnosed with an oesophageal fistula. Peri-procedural data were available for 118 patients (85.5%). Following catheter ablation, the median time to symptoms and the median time to diagnosis were 18 (7.75, 25; range: 0-60) days and 21 (15, 29.5; range: 2-63) days, respectively. The median time from symptom onset to oesophageal fistula diagnosis was 3 (1, 9; range: 0-42) days. The most common initial symptom was fever (59.3%). The diagnosis was established by chest computed tomography in 80.2% of patients. Oesophageal surgery was performed in 47.4% and direct endoscopic treatment in 19.8% and conservative treatment in 32.8% of patients. The overall mortality was 65.8%. Mortality following surgical (51.9%) or endoscopic treatment (56.5%) was significantly lower as compared to conservative management (89.5%) [odds ratio 7.463 (2.414, 23.072) P < 0.001]. CONCLUSION: Oesophageal fistula after catheter ablation of atrial fibrillation is rare and occurs mostly with the use of radiofrequency energy rather than cryoenergy. Mortality without surgical or endoscopic intervention is exceedingly high.

Assessment of the atrial fibrillation burden in Holter electrocardiogram recordings using artificial intelligence.

Background: Emerging evidence indicates that a high atrial fibrillation (AF) burden is associated with adverse outcome. However, AF burden is not routinely measured in clinical practice. An artificial intelligence (AI)-based tool could facilitate the assessment of AF burden. Objective: We aimed to compare the assessment of AF burden performed manually by physicians with that measured by an AI-based tool. Methods: We analyzed 7-day Holter electrocardiogram (ECG) recordings of AF patients included in the prospective, multicenter Swiss-AF Burden cohort study. AF burden was defined as percentage of time in AF, and was assessed manually by physicians and by an AI-based tool (Cardiomatics, Cracow, Poland). We evaluated the agreement between both techniques by means of Pearson correlation coefficient, linear regression model, and Bland-Altman plot. Results: We assessed the AF burden in 100 Holter ECG recordings of 82 patients. We identified 53 Holter ECGs with 0% or 100% AF burden, where we found a 100% correlation. For the remaining 47 Holter ECGs with an AF burden between 0.01% and 81.53%, Pearson correlation coefficient was 0.998. The calibration intercept was -0.001 (95% CI -0.008; 0.006), and the calibration slope was 0.975 (95% CI 0.954; 0.995; multiple R2 0.995, residual standard error 0.017). Bland-Altman analysis resulted in a bias of -0.006 (95% limits of agreement -0.042 to 0.030). Conclusion: The assessment of AF burden with an AI-based tool provided very similar results compared to manual assessment. An AI-based tool may therefore be an accurate and efficient option for the assessment of AF burden.

Prevalence and Management of Atrial Thrombi in Patients With Atrial Fibrillation Before Pulmonary Vein Isolation.

OBJECTIVES: This study aimed to investigate the prevalence and management of left atrial (LA) thrombi detected by transesophageal echocardiography (TEE) in patients with atrial fibrillation undergoing pulmonary vein isolation (PVI). BACKGROUND: Little data are available on LA thrombi before PVI. METHODS: All patients scheduled for PVI between April 2010 and April 2018 undergoing pre-procedural TEE were analyzed. Management of LA thrombus was at the discretion of the treating physician. RESULTS: In this study, 1,753 pre-procedural TEE from 1,358 patients (mean age 61 ± 10 years, 28% female) were included. Anticoagulation was used in 86% of all TEE (51% with direct oral anticoagulants [DOAC], 35% with vitamin K antagonists [VKA]). Thrombi were found in 11 TEE (0.6%), all in the LA appendage. Of the 11 patients with a thrombus, 5 (46%) had paroxysmal atrial fibrillation, 2 (18%) had a CHA2DS2-VASc (Congestive Heart Failure, Hypertension, Age ≥75 Years, Diabetes Mellitus, Prior Stroke or Transient Ischemic Attack or Thromboembolism, Vascular Disease, Age 65 to 74 Years, Sex) score of 1, and 5 (46%) were in sinus rhythm at the time of TEE. Of the 8 patients (72%) on anticoagulation therapy, 5 were treated with DOAC and 3 with VKA. Starting anticoagulation (n = 3), switching to VKA with a target international normalized ratio of 2.5 to 3 (n = 3), or switching to a DOAC (n = 1) or a different DOAC (n = 4) resulted in thrombus resolution in 9 of 11 patients (82%). CONCLUSIONS: In patients with atrial fibrillation scheduled for PVI, LA thrombi are rare and present in <1%. Thrombi were found in patients on VKA and DOAC, in low-risk patients, and despite sinus rhythm. Thrombus resolution was achieved in the majority of patients by changing the anticoagulation regimen.

Impact of Female Sex on Clinical Outcomes in the FIRE AND ICE Trial of Catheter Ablation for Atrial Fibrillation.

BACKGROUND: Data on predictors of long-term clinical outcomes after catheter ablation of atrial fibrillation (AF) are limited. We sought to assess the association of baseline covariates with clinical outcomes in the 750 patients with drug-refractory paroxysmal AF enrolled in FIRE AND ICE. METHODS: In a 2-part analysis, univariate and multivariable Cox regression models were first used to identify baseline patient characteristics predictive of catheter ablation efficacy determined by the clinical end points of (1) atrial arrhythmia recurrence (primary efficacy failure), (2) cardiovascular rehospitalization, and (3) repeat ablation. Propensity score stratification methods were then used to account for differences in baseline characteristics between sexes. RESULTS: Female sex (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.08-1.73; P=0.010) and prior direct current cardioversion (HR, 1.40; 95% CI, 1.07-1.82; P=0.013) were independently associated with atrial arrhythmia recurrence. Female sex (HR, 1.36; 95% CI, 1.02-1.80; P=0.035) and hypertension (HR, 1.48; 95% CI, 1.09-2.00; P=0.013) independently predicted cardiovascular rehospitalization. A longer history of AF (HR, 1.03; 95% CI, 1.00-1.06; P=0.039) increased the rate of repeat ablation. Women continued to have higher rates of primary efficacy failure and cardiovascular rehospitalization after propensity score adjustment, with adjusted HRs of 1.51 (95% CI, 1.16-2.18; P<0.05) and 1.40 (95% CI, 1.15-2.17; P<0.05), respectively. CONCLUSIONS: After catheter ablation of paroxysmal AF, female sex was associated with an almost 40% increase in the risks of primary efficacy failure and cardiovascular rehospitalization. Primary efficacy failure was also adversely impacted by a history of direct current cardioversion, whereas hypertension had a negative impact on cardiovascular rehospitalization. History of AF was the only predictor of repeat ablation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01490814.

Prospective Assessment of Sex-Related Differences in Symptom Status and Health Perception Among Patients With Atrial Fibrillation.

BACKGROUND: We prospectively assessed sex-specific differences in health perception, overall symptom status, and specific symptoms in a large cohort of patients with atrial fibrillation. METHODS AND RESULTS: We performed a prospective multicenter observational cohort study of 1553 patients with atrial fibrillation. Patients completed questionnaires about personal characteristics, comorbidities, and symptoms on a yearly basis. Mean age was 70±11 years among women and 67±12 years among men. Health perception on a visual analogue scale ranging from 0 to 100 (with higher scores indicating better health perception) was significantly lower in women than in men (70 [interquartile range: 50-80] versus 75 [interquartile range: 60-85]; P<0.0001). More women than men had any symptoms (85.0% versus 68.3%; P<0.0001), palpitations (65.2% versus 44.4%; P<0.0001), dizziness (25.6% versus 13.5%; P<0.0001), dyspnea (35.7% versus 21.8%; P<0.0001), and fatigue (25.3% versus 19.1%; P=0.006). At 1-year follow-up, symptoms decreased in both sexes but remained more frequent in women (49.1% versus 32.6%, P<0.0001). In multivariable adjusted longitudinal regression models, female sex remained an independent predictor for lower health perception (ß=-4.8; 95% CI, -6.5 to -3.1; P<0.0001), any symptoms (odds ratio [OR]: 2.6; 95% CI, 2.1-3.4; P<0.0001), palpitations (OR: 2.6; 95% CI, 2.1-3.2; P<0.0001), dizziness (OR: 2.9; 95% CI, 2.1-3.9; P<0.0001), dyspnea (OR: 2.1; 95% CI, 1.6-2.8; P<0.0001), fatigue (OR: 1.6; 95% CI, 1.2-2.2; P=0.0008), and chest pain (OR: 1.8; 95% CI, 1.3-2.6; P=0.001). CONCLUSIONS: Women with atrial fibrillation have a substantially higher symptom burden and lower health perception than men. These relationships persisted after multivariable adjustment and during prospective follow-up.

Longevity of implantable cardioverter defibrillators: a comparison among manufacturers and over time.

AIMS: Longevity of implantable cardioverter defibrillators (ICDs) is crucial for patients and healthcare systems as replacements impact on infection rates and cost-effectiveness. Aim was to determine longevity using very large databases of two teaching hospitals with a high number of replacements and a rather homogeneous distribution among manufacturers. METHODS AND RESULTS: The study population consists of all patients in whom an ICD was inserted in. All ICD manufacturers operating in Switzerland and the Netherlands and all implanted ICDs were included. Implantable cardioverter defibrillator replacements due to normal battery depletion were considered events, and other replacements were censored. Longevity was assessed depending on manufacturers, pacing mode, implant before/after 2006, and all parameters combined. We analysed data from 3436 patients in whom 4881 ICDs [44.2% VVI-ICDs, 27.4% DDD-ICDs, 26.3% cardiac resynchronization therapy (CRT)-ICDs, 2.0% subcutaneous ICDs] were implanted. The four major manufacturers had implant shares between 18.4 and 31.5%. Replacement due to battery depletion (27.4%) was performed for 1339 ICDs. Patient survival at 5 years was 80.1%. Longevity at 5 years improved in contemporary compared with elderly ICDs [63.9-80.6% across all ICDs, of 73.7-92.1% in VVIs, 58.2-76.1% in DDDs, and of 47.1-66.3% in CRT defibrillators, all P value < 0.05]. Remarkable differences were seen among manufacturers, and those with better performance in elderly ICDs were not those with better performance in contemporary ones. CONCLUSION: Implantable cardioverter defibrillator longevity increased in contemporary models independent of manufacturer and pacing mode. Still, significant differences exist among manufacturers. These results might impact on device selection.

Quantitative assessment of a second-generation cryoballoon ablation catheter with new cooling technology-a perspective on potential implications on outcome.

PURPOSE: The purpose of this study was to assess the differences in cooling behavior between the first-generation cryoballoon (CB-1G) and the second-generation cryoballoon (CB-2G) quantitatively to understand the freezing capabilities and to benefit from the improved efficacy of the CB-2G in patients with atrial fibrillation. METHODS: We analyzed quantitatively the ice formation of the CB-1G and CB-2G catheters in vitro in a 37°C warm water bath during freezing for 60, 120, 180, 240, and 300s, respectively. RESULTS: The mean-covered surface area and the relative coverage of the ice spots on the CB-2G were significantly different from the spots on the CB-1G for the 28-mm CBs but not for the 23-mm CBs. Whereas for the CB-1G, the ice formation was discontiguous with four isolated ice spots; the CB-2G showed a contiguous ice cap covering the entire distal part including the pole of the balloon. No homogeneous cooling behavior could be observed at the equatorial level with both catheters. Temporal differences on the ice formation could be observed for the 28-mm CB-2G but not for the 23-mm CB-2G. CONCLUSION: The new-generation CB-2G showed more powerful and homogeneous cooling behavior, especially for the 28-mm CB. Whether this translates into higher long-term success rates is currently unknown. The impact of the more effective cooling and the longer dissolving duration of the ice cap of the new-generation CB-2G on procedural safety needs to be investigated.

Functional assessment of the left atrium by real-time three-dimensional echocardiography using a novel dedicated analysis tool: initial validation studies in comparison with computed tomography.

AIMS: A novel real-time three-dimensional echocardiography (RT3DE) analysis tool specifically designed for evaluation of the left atrium enables comprehensive evaluation of left atrial (LA) size, global, and regional function using a dynamic 16-segment model. The aim of this study was the initial validation of this method using computed tomography (CT) as the method of reference. METHODS AND RESULTS: The study population consisted of 34 prospectively enrolled patients with clinical indication for pulmonary vein isolation. A dynamic polyhedron model of the left atrium was generated using RT3DE. LA maximum and minimum volumes (LA(max)/LA(min)) and emptying fraction (LAEF) were determined and compared with the results obtained by CT. High correlations between RT3DE and CT were found for LA(max) (r = 0.92, P < 0.001), LA(min) (r = 0.95, P < 0.001), and LAEF (r = 0.82, P < 0.001). LA(max) and LA(min) were lower by RT3DE than by CT (95.0 ± 44.7 vs. 119.8 ± 50.5 mL, P < 0.001 and 58.1 ± 41.3 vs. 83.3 ± 52.6 mL, P < 0.001, respectively), whereas LAEF was measured higher by RT3DE (42.8 ± 15.2 vs. 34.2 ± 15.4%, P < 0.001, respectively). RT3DE measurements closely correlated in terms of intra-observer (intra-class correlation r = 0.99, r = 0.99, r = 0.96, respectively) and inter-observer variability (r = 0.97, r = 0.98, r = 0.88, respectively). CONCLUSIONS: LA volumes and EF as assessed by RT3DE correlate highly with CT measurements, albeit there is some bias between the imaging modalities. Most importantly, RT3DE measurements using the novel dedicated LA analysis tool are robust in terms of observer variability and thus suitable for follow-up analyses.

A randomized assessment of the incremental role of ablation of complex fractionated atrial electrograms after antral pulmonary vein isolation for long-lasting persistent atrial fibrillation.

OBJECTIVES: This study sought to determine whether ablation of complex fractionated atrial electrograms (CFAEs) after antral pulmonary vein isolation (APVI) further improves the clinical outcome of APVI in patients with long-lasting persistent atrial fibrillation (AF). BACKGROUND: Ablation of CFAEs has been reported to eliminate persistent AF. However, residual pulmonary vein arrhythmogenicity is a common mechanism of recurrence. METHODS: In this randomized study, 119 consecutive patients (mean age 60 +/- 9 years) with long-lasting persistent AF underwent APVI with an irrigated-tip radiofrequency ablation catheter. Antral pulmonary vein isolation resulted in termination of AF in 19 of 119 patients (Group A, 16%). The remaining 100 patients who still were in AF were randomized to no further ablation and underwent cardioversion (Group B, n = 50) or to ablation of CFAEs in the left atrium or coronary sinus for up to 2 additional hours of procedure duration (Group C, n = 50). RESULTS: Atrial fibrillation terminated during ablation of CFAEs in 9 of 50 patients (18%) in Group C. At 10 +/- 3 months after a single ablation procedure, 18 of 50 (36%) in Group B and 17 of 50 (34%) in Group C were in sinus rhythm without antiarrhythmic drugs (p = 0.84). In Group A, 15 of 19 patients (79%) were in sinus rhythm. A repeat ablation procedure was performed in 34 of 100 randomized patients (for AF in 30 and atrial flutter in 4). At 9 +/- 4 months after the final procedure, 34 of 50 (68%) in Group B and 30 of 50 (60%) in Group C were in sinus rhythm without antiarrhythmic drugs (p = 0.40). CONCLUSIONS: Up to 2 h of additional ablation of CFAEs after APVI does not appear to improve clinical outcomes in patients with long-lasting persistent AF.