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 AF patients between 2014 and 2017. Resource utilization and cost information was collected through claims data. Quality-of-life was measured with EQ-5D-3L utilities. We estimated incremental cost-effectiveness ratios from the perspective of the Swiss statutory health insurance system. RESULTS Patients undergoing PVI compared to medical therapy had a 5-year overall survival advantage with a hazard ratio of 0.75 (95%CI 0.46-1.21, p=0.69), a 19.8% standard deviation improvement in quality-of-life (95%CI 15.5-22.9%, p<0.001), at an incremental cost of 29,604 (95%CI 16,354-42,855, p<0.001) Swiss Francs (CHF). The estimated incremental cost-effectiveness ratio 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 incremental cost-effectiveness ratio 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 CHF100,000 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 RCT settings

Renal Function and Body Mass Index Contribute to Serum Neurofilament Light Chain Levels in Elderly Patients With Atrial Fibrillation.

Objective: Serum neurofilament light chain (sNfL) is increasingly used as a neuroaxonal injury biomarker in the elderly. Besides age, little is known about how other physiological factors like renal function and body mass index (BMI) alter its levels. Here, we investigated the association of estimated glomerular filtration rate (eGFR) and BMI with sNfL in a large sample of elderly patients with atrial fibrillation (AF). Methods: This is a cross-sectional analysis from the Swiss-AF Cohort (NCT02105844). We measured sNfL using an ultrasensitive single-molecule array assay. We calculated eGFR using the chronic kidney disease epidemiology collaboration (CKD-EPI) creatinine (eGFRcrea) and creatinine–cystatin C (eGFRcrea–cys) formulas, and BMI from weight and height measurements. We evaluated the role of eGFR and BMI as determinants of sNfL levels using multivariable linear regression and the adjusted R2 (R2adj). Results: Among 2,277 Swiss-AF participants (mean age 73.3 years), eGFRcrea showed an inverse curvilinear association with sNfL after adjustment for age and cardiovascular comorbidities. BMI also showed an independent, inverse linear association with sNfL. The R2adj of models with age, eGFRcrea, and BMI alone was 0.26, 0.35, and 0.02, respectively. A model with age and eGFRcrea combined explained 45% of the sNfL variance. Sensitivity analyses (i) further adjusting for vascular brain lesions (N = 1,402 participants with MRI) and (ii) using eGFRcrea–cys yielded consistent results. Interpretation: In an elderly AF cohort, both renal function and BMI were associated with sNfL, but only renal function explained a substantial proportion of the sNfL variance. This should be taken into account when using sNfL in elderly patients or patients with cardiovascular disease

Biomarker, Imaging, and Clinical Factors Associated With Overt and Covert Stroke in Patients With Atrial Fibrillation.

BACKGROUND Atrial fibrillation is a major risk factor for stroke and silent brain infarcts. We studied whether a multimodal approach offers additional insights to the CHA2DS2-VASc score in predicting stroke or new brain infarcts on magnetic resonance imaging (MRI) over a 2-year follow-up. METHODS Swiss-AF is a prospective, multicenter cohort study of patients with known atrial fibrillation. We included patients with available brain MRI both at enrollment and 2 years later. The dates of the baseline and follow-up visits ranged from March 2014 to November 2020. The primary outcome was assessed 2 years after baseline and was defined as a composite of clinically identified stroke or any new brain infarct on the 2-year MRI. We compared a multivariable logistic regression model including prespecified clinical, biomarker, and baseline MRI variables to the CHA2DS2-VASc score. RESULTS We included 1232 patients, 89.8% of them taking oral anticoagulants. The primary outcome occurred in 78 patients (6.3%). The following baseline variables were included in the final multivariate model and were significantly associated with the primary outcome: white matter lesion volume in milliliters (adjusted odds ratio [aOR], 1.91 [95% CI, 1.45-2.56]), NT-proBNP (N-terminal pro-B-type natriuretic peptide; aOR, 1.75 [95% CI, 1.20-2.63]), GDF-15 (growth differentiation factor-15; aOR, 1.68 [95% CI, 1.11-2.53]), serum creatinine (aOR, 1.50 [95% CI, 1.02-2.22]), IL (interleukin)-6 (aOR, 1.37 [95% CI, 1.00-1.86]), and hFABP (heart-type fatty acid-binding protein; aOR, 0.48 [95% CI, 0.31-0.73]). Overall performance and discrimination of the new model was superior to that of the CHA2DS2-VASc score (C statistic, 0.82 [95% CI, 0.77-0.87] versus 0.64 [95% CI, 0.58-0.70]). CONCLUSIONS In patients with atrial fibrillation, a model incorporating white matter lesion volume on baseline MRI and selected blood markers yielded new insights on residual stroke risk despite a high proportion of patients on oral anticoagulants. This may be relevant to develop further preventive measures

Association of pulmonary vein isolation and major cardiovascular events in patients with atrial fibrillation.

BACKGROUND Patients with atrial fibrillation (AF) face an increased risk of adverse cardiovascular events. Evidence suggests that early rhythm control including AF ablation may reduce this risk. METHODS To compare the risks for cardiovascular events in AF patients with and without pulmonary vein isolation (PVI), we analysed data from two prospective cohort studies in Switzerland (n = 3968). A total of 325 patients who had undergone PVI during a 1-year observational period were assigned to the PVI group. Using coarsened exact matching, 2193 patients were assigned to the non-PVI group. Outcomes were all-cause mortality, hospital admission for acute heart failure, a composite of stroke, transient ischemic attack and systemic embolism (Stroke/TIA/SE), myocardial infarction (MI), and bleedings. We calculated multivariable adjusted Cox proportional-hazards models. RESULTS Overall, 2518 patients were included, median age was 66 years [IQR 61.0, 71.0], 25.8% were female. After a median follow-up time of 3.9 years, fewer patients in the PVI group died from any cause (incidence per 100 patient-years 0.64 versus 1.87, HR 0.39, 95%CI 0.19-0.79, p = 0.009) or were admitted to hospital for acute heart failure (incidence per 100 patient-years 0.52 versus 1.72, HR 0.44, 95%CI 0.21-0.95, p = 0.035). There was no significant association between PVI and Stroke/TIA/SE (HR 0.94, 95%CI 0.52-1.69, p = 0.80), MI (HR 0.43, 95%CI 0.11-1.63, p = 0.20) or bleeding (HR 0.75, 95% CI 0.50-1.12, p = 0.20). CONCLUSIONS In our matched comparison, patients in the PVI group had a lower incidence rate of all-cause mortality and hospital admission for acute heart failure compared to the non-PVI group. CLINICALTRIALS GOV IDENTIFIER NCT02105844, April 7th 2014

Serum neurofilament light in atrial fibrillation: clinical, neuroimaging and cognitive correlates

Emerging evidence suggests that atrial fibrillation is associated with cognitive dysfunction independently of stroke, but the underlying mechanisms remain unclear. In this cross-sectional analysis from the Swiss-atrial fibrillation Study (NCT02105844), we investigated the association of serum neurofilament light protein, a neuronal injury biomarker, with (i) the CHA; 2; DS; 2; -VASc score (congestive heart failure, hypertension, age 65-74 or >75 years, diabetes mellitus, stroke or transient ischaemic attack, vascular disease, sex), clinical and neuroimaging parameters and (ii) cognitive measures in atrial fibrillation patients. We measured neurofilament light in serum using an ultrasensitive single-molecule array assay in a sample of 1379 atrial fibrillation patients (mean age, 72 years; female, 27%). Ischaemic infarcts, small vessel disease markers and normalized brain volume were assessed on brain MRI. Cognitive testing included the Montreal cognitive assessment, trail-making test, semantic verbal fluency and digit symbol substitution test, which were summarized using principal component analysis. Results were analysed using univariable and multivariable linear regression. Neurofilament light was associated with the CHA; 2; DS; 2; -VASc score, with an average 19.2% [95% confidence interval (17.2%, 21.3%)] higher neurofilament per unit CHA; 2; DS; 2; -VASc increase. This association persisted after adjustment for age and MRI characteristics. In multivariable analyses, clinical parameters associated with neurofilament light were higher age [32.5% (27.2%, 38%) neurofilament increase per 10 years], diabetes mellitus, heart failure and peripheral artery disease [26.8% (16.8%, 37.6%), 15.7% (8.1%, 23.9%) and 19.5% (6.8%, 33.7%) higher neurofilament, respectively]. Mean arterial pressure showed a curvilinear association with neurofilament, with evidence for both an inverse linear and a U-shaped association. MRI characteristics associated with neurofilament were white matter lesion volume and volume of large non-cortical or cortical infarcts [4.3% (1.8%, 6.8%) and 5.5% (2.5%, 8.7%) neurofilament increase per unit increase in log-volume of the respective lesion], as well as normalized brain volume [4.9% (1.7%, 8.1%) higher neurofilament per 100 cm; 3; smaller brain volume]. Neurofilament light was inversely associated with all cognitive measures in univariable analyses. The effect sizes diminished after adjusting for clinical and MRI variables, but the association with the first principal component was still evident. Our results suggest that in atrial fibrillation patients, neuronal loss measured by serum neurofilament light is associated with age, diabetes mellitus, heart failure, blood pressure and vascular brain lesions, and inversely correlates with normalized brain volume and cognitive function

Association of Heart Rate Variability With Silent Brain Infarcts in Patients With Atrial Fibrillation

Purpose: Silent brain infarcts (SBI) are frequently detected in patients with atrial fibrillation (AF), but it is unknown whether SBI are linked to autonomic dysfunction. We aimed to explore the association of autonomic dysfunction with SBI in AF patients. Methods: 1,358 AF patients without prior stroke or TIA underwent brain MRI and 5-min resting ECG. We divided our cohort into AF patients who presented in sinus rhythm (SR-group, n = 816) or AF (AF-group, n = 542). HRV triangular index (HRVI), standard deviation of normal-to-normal intervals, mean heart rate, root mean square root of successive differences of normal-to-normal intervals, 5-min total power and power in the low frequency, high frequency and very low frequency range were calculated. Primary outcome was presence of SBI in the SR group, defined as large non-cortical or cortical infarcts. Secondary outcomes were SBI volumes and topography. Results: Mean age was 72 ± 9 years, 27% were female. SBI were detected in 10.5% of the SR group and in 19.9% of the AF group (p < 0.001). HRVI <15 was the only HRV parameter associated with the presence of SBI after adjustment for clinical covariates in the SR group [odds ratio (OR) 1.67; 95% confidence interval (CI): 1.03–2.70; p = 0.037]. HRVI <15 was associated with larger brain infarct volumes [β (95% CI) −0.47 (−0.84; −0.09), p = 0.016] in the SR group and was more frequently observed in patients with right- than left-hemispheric SBI (p = 0.017). Conclusion: Impaired HRVI is associated with SBI in AF patients. AF patients with autonomic dysfunction might undergo systematic brain MRI screening to initiate intensified medical treatment

Association of Statin Use and Lipid Levels with Cerebral Microbleeds and Intracranial Hemorrhage in Patients with Atrial Fibrillation: a Prospective Cohort Study.

BACKGROUND An increased risk of intracranial hemorrhage (ICH) associated with statins has been reported; but data on the relationship between statin-use and cerebral microbleeds (CMBs) in patients with atrial fibrillation (AF), a population at high bleeding and cardiovascular risk are lacking. AIMS To explore the association between statin-use and blood lipid-levels with the prevalence and progression of CMBs in patients with atrial fibrillation with particular focus on anticoagulated patients. METHODS Data of Swiss-AF, a prospective cohort of patients with established AF were analyzed. Statin-use was assessed during baseline and throughout follow-up. Lipid values were measured at baseline. CMBs were assessed using magnetic resonance imagining (MRI) at baseline and at 2-years follow-up. Imaging data were centrally assessed by blinded investigators. Associations of statin-use and low-density lipoprotein (LDL) levels with CMB prevalence at baseline or CMB progression (at least one additional or new CMB on follow-up MRI at 2-years compared to baseline) were assessed using logistic regression models; the association with ICH was assessed using flexible parametric survival models. Models were adjusted for hypertension, smoking, body mass index, diabetes, stroke/transient ischemic attack, coronary heart disease, antiplatelet use, anticoagulant use and education. RESULTS Of the 1693 patients with CMB data at baseline MRI (mean±SD age 72.5±8.4y, 27.6% women, 90.1% on oral anticoagulants), 802 patients (47.4%) were statin users. The multivariable adjusted odds ratio (adjOR) for CMBs prevalence at baseline for statin users was 1.10 (95% CI, 0.83-1.45). AdjOR for 1 unit increase in LDL-levels was 0.95 (95% CI, 0.82-1.10). At 2-years, 1188 patients had follow-up MRI. CMBs progression was observed in 44 (8.0%) statin users and 47 (7.4%) non-statin users. Of these patients 64 (70.3%) developed a single new CMB, 14 (15.4%) developed 2 CMBs and 13 developed more than 3 CMBs. The multivariable adjOR for statin users was 1.09 (95% CI, 0.66-1.80). There was no association between LDL-levels and CMBs progression (adjOR 1.02, 95% CI, 0.79-1.32). At follow-up 14 (1.2%) statin users had ICH vs 16 (1.3%) non-users. The age and sex adjusted Hazard Ratio (adjHR) was 0.75 (95% CI, 0.36-1.55). Results remained robust in sensitivity analyses excluding participants without anticoagulants. CONCLUSIONS In this prospective cohort of patients with AF, a population at increased hemorrhagic risk due to anticoagulation, the use of statins was not associated with an increased risk of CMBs

Silent brain infarcts impact on cognitive function in atrial fibrillation

Aims: We aimed to investigate the association of clinically overt and silent brain lesions with cognitive function in atrial fibrillation (AF) patients. Methods and results: We enrolled 1227 AF patients in a prospective, multicentre cohort study (Swiss-AF). Patients underwent standardized brain magnetic resonance imaging (MRI) at baseline and after 2 years. We quantified new small non-cortical infarcts (SNCIs) and large non-cortical or cortical infarcts (LNCCIs), white matter lesions (WML), and microbleeds (Mb). Clinically, silent infarcts were defined as new SNCI/LNCCI on follow-up MRI in patients without a clinical stroke or transient ischaemic attack (TIA) during follow-up. Cognition was assessed using validated tests. The mean age was 71 years, 26.1% were females, and 89.9% were anticoagulated. Twenty-eight patients (2.3%) experienced a stroke/TIA during 2 years of follow-up. Of the 68 (5.5%) patients with ≥1 SNCI/LNCCI, 60 (88.2%) were anticoagulated at baseline and 58 (85.3%) had a silent infarct. Patients with brain infarcts had a larger decline in cognition [median (interquartile range)] changes in Cognitive Construct score [-0.12 (-0.22; -0.07)] than patients without new brain infarcts [0.07 (-0.09; 0.25)]. New WML or Mb were not associated with cognitive decline. Conclusion: In a contemporary cohort of AF patients, 5.5% had a new brain infarct on MRI after 2 years. The majority of these infarcts was clinically silent and occurred in anticoagulated patients. Clinically, overt and silent brain infarcts had a similar impact on cognitive decline. Clinical trial registration: ClinicalTrials.gov Identifier: NCT02105844, https://clinicaltrials.gov/ct2/show/NCT02105844. Keywords: Atrial fibrillation; Brain infarction; Cognitive function; Magnetic resonance imaging; Oral anticoagulation