Catheter Ablation Versus Antiarrhythmic Medication in Patients with Atrial Fibrillation: a Propensity-Matched Analysis Based on a German Claims Data Set

Aims: Main objective of our analysis was to assess the long-term clinical and health economics outcomes of catheter ablation versus antiarrhythmic medication therapy in Germany. Methods: We conducted a retrospective analysis of anonymized claims data covering the years 2010-2014. Patients with at least one diagnosis of AF and a minimum follow-up period of twelve months (excluding death) were included and assigned into two treatment groups: AF ablation and antiarrhythmic medication. To balance different patient characteristics in both groups, the final analysis was based on propensity score-matched (PSM) cohorts. Results: Of 498,253 AF patients, 2,404 could be assigned to the final analysis population – 1,202 patients in each group. The difference in the all-cause mortality rate reached statistical significance after 24 months of observation (1.5% versus 3.1% (p=0.015)) and after 36 months (1.7% versus 4.8% (p=0.005)). We could not identify any significant difference between the groups in cardiovascular events (amongst others stroke, TIA, myocardial infarction) over the three-year observation period. Direct cardiology-associated healthcare costs after index date (excluding catheter ablation procedure) were significantly different between the groups in the first and third observational year (third-year costs of €1,618 in the ablation group versus €2,462 in the medication group; p<0.007). Conclusion: Over a period of 36 months, all-cause mortality in AF patients who underwent catheter ablation was found to be significantly lower compared to AF patients who received antiarrhythmic medication. Direct cardiology healthcare costs after the ablation procedure proved to be consistently and significantly lower in comparison with medication therapy.


Introduction
Atrial fibrillation (AF) is the most common significant cardiac rhythm disorder [1]. It is associated with substantial morbidity and mortality from stroke and thromboembolism [1,2]. An effective and important treatment option for many AF patients is catheter ablation [3][4][5]. Clinical trials have shown that catheter ablation (as a second-line or even firstline treatment option) maintains sinus rhythm more effectively than antiarrhythmic medication [6][7][8][9][10]. However, most of these trials were based on small samples of patients who were treated in specialized centres, and the follow-up periods on which the studies were based were short.
Consequently, the potential health benefits of catheter ablation in terms of long-term real-world cardiovascular outcomes such as stroke, TIA, myocardial infarction and/or systemic non-CNS embolism have been demonstrated only rarely. Similarly, little is known with regard to the long-term health-economic evaluation of catheter ablation in a real-world scenario. A published study with data from Swedish health registries compared propensity-matched cohorts of ablated with non-ablated AF patients: ablation was associated with lower risk of ischemic stroke and lower mortality risk [11]. Another one of the rare analyses in this respect, a US claims data-based analysis of propensity-matched samples of AF patients who either underwent catheter ablation or received antiarrhythmic medication concluded that catheter ablation patients had a significantly lower risk of stroke, TIA and heart failure-associated hospitalizations [12].
Building on the methodology developed in the publication cited above, the main objective of our analysis was to assess the long-term clinical and health economics outcomes of catheter ablation versus antiarrhythmic medication therapy in Germany.

Sample
We conducted a retrospective analysis of anonymized claims data which were provided by two German statutory health insurance (SHI) funds-AOK PLUS and Techniker Krankenkasse (TK). Both SHI funds together insure 13 million people: more than 17% of the statutorily insured population in Germany. The database covered the years 2010-2014 and included information on patients' demographics, outpatient treatments (diagnosis codes and visits to general practitioners and/or specialists), inpatient treatments (dates, diagnoses, procedures, length of stay) and claims filled for prescription medications.
A patient was included in our analysis if at least one outpatient or inpatient diagnosis of AF was recorded during the inclusion period from 01/01/2010 to 31/12/2013 (until 2012: For all patients, the minimum follow-up period was defined as twelve months; only in case of death, this period was shorter. We divided the patients into two groups. Those who had undergone catheter ablation in the left atrium between 2011 and 2013 were assigned to the AF ablation group. Patients who received at least two prescriptions for at least two different antiarrhythmic agents in at least one of the antiarrhythmic drug classes Ia, Ic or III (according to the Singh Vaughan Williams classification) were assigned to the antiarrhythmic medication group (the detailed algorithm for group assignment is available in Supplemental Figure 1). Information about the prescribed dosages were not reported within the claims dataset. Since prescriptions for two different antiarrhythmic drugs were mandatory in this group, one requirement was that these patients had experienced at least one antiarrhythmic drug treatment failure.
If a patient underwent catheter ablation treatment between 2010 and 2013, but had received prescriptions of two antiarrhythmic medications before that procedure, he/she was assigned to the ablation group. The start date (index date) of observation for the ablation group was the date of the ablation procedure; for the medication group, the start date was the date of the first observed prescription of the second antiarrhythmic agent. All patients were followed for a period of twelve months and, in subsets, for a period of 24/36 months, whichever their enrolment allowed.
Patients were generally excluded if at least one of the following criteria was fulfilled, based on the respective procedure codes:

Outcomes
The following outcomes were defined (all referring to either 12/24/36 months of patient-specific observation); events were considered only if they led to an inpatient hospital stay. Detailed information regarding event definition is available in Supplemental

Statistical analysis
All statistical analyses were done with MySQL and SPSS (most current versions). Comparisons of event rates between treatment groups were performed with Fisher's exact test or t-test. For our primary outcome, we additionally plotted a Kaplan-Meier curve and compared time to event as well as the percentage of event-free patients over time between groups with the log-rank test, based on an unadjusted Cox regression analysis.
The application of inclusion and exclusion criteria, propensity score-based matching procedure, identification of events and cost calculation were conducted separately for the two datasets. The results were aggregated and statistically analyzed.
Due to the anonymized nature of the used dataset, no ethical approval was needed. However, the study protocol was reviewed and approved by a Scientific Steering Committee to which all authors belonged.

Secondary study objectives
All-cause mortality rate after twelve months was 0.6%  Table 2)).
Event rates for stroke, TIA, heart failure/myocardial infarction, arterial embolism, pacemaker/ICD implantation and syncope were almost evenly distributed between the compared groups; none of the observed differences reached statistical significance (   Finally, the event rate for pneumonia was found to be nearly identical between the two groups in all tested follow-up intervals. This indicates that the quality of our matching procedure was reasonable.

Discussion
Rhythm control therapy is an essential part of AF management. Antiarrhythmic medication is the first choice for restoring sinus rhythm to improve symptoms in AF patients who remain symptomatic on adequate rate control therapy. In addition, catheter ablation has become established over time as a common treatment option for patients with symptomatic paroxysmal and persistent AF [4,5]. However, the effect of rhythm control via different treatment options on the reduction of major cardiovascular event risk in real-world contexts has not been investigated broadly and is therefore under investigation [13,14].
Our study contributes to this research. Its main strengths were absence of any patient selection bias or cluster effects that may have influenced previous studies. Furthermore, we covered an exceptionally large sample of German patients. non-ablated AF patients, data from Swedish registries; HR 0.50, 95% CI 0.37-0.62) [11] and (3) death rate to be significantly lower in the ablation cohort (0.5% per patient-year) compared with the medically treated cohort in the Euro Heart Survey [15].
In contrast to the results reported by Friberg et al. [11], Reynolds et al. [12] and Chang et al. [16], differences between event rates with stroke/TIA, myocardial infarction/heart failure and arterial embolism were not statistically significant between the treatment groups. We assume that, due to the strict definitions and despite the large datasets, our sample sizes and the associated frequency of event occurrence may not have been high enough.
Regarding direct cardiology healthcare costs, our data show significantly lower follow-up costs in the ablation group in comparison with the medication group. These results confirm the findings of other previous studies [17,18]. The main driver of this cost difference is higher medication costs in the medication group and, additionally in the third observational year, higher hospitalization costs in that group. Interestingly, additional costs in the medication group are not driven by hospitalization frequency among those patients, but by higher costs per hospitalization, indicating a higher severity of cardiovascular events in the medication group.
It needs to be noted that our cost analysis only covered follow-up costs. This means that it did not include costs for the index ablation treatment in the ablation group. Reported costs in this respect vary widely, depending on type and modalities of the procedure and patient-individual risk factors. European studies 10 have reported initial ablation costs varying between €4,715 [17] and €9,600 [19]. These costs are not offset by the reported cost reductions due to catheter ablation as reported in our study if only a three-year follow-up is observed.
We acknowledge some limitations of our study. First, since our dataset provided only limited information, we could not analyze all aspects and potential effects of catheter ablation on clinical/health-economic outcomes. So, for example, quality of life as an important outcome could not be observed. In this respect, previous studies have shown a superiority of catheter ablation to conventional antiarrhythmic medication therapy [9,18].
Second, the underlying data were primarily collected for financial claims and not gathered specifically for research purposes, which is a general weakness associated with claimsbased data studies. Limitations are present in both the level of detail and precision. Despite these weaknesses, a review of existing investigations shows that claims-based data sets can be used as valid research data [20]. Nevertheless, we cannot exclude a possible indication bias related to unknown and/or concealed confounders. In relation to that, additional patient characteristics that could not be incorporated in our PSM procedure could have influenced our results. So, proof of the superiority of catheter ablation in comparison with antiarrhythmic medication needs to be provided by prospective randomized controlled trials, such as the CABANA study which analyzed a composite outcome of allcause death, disabling stroke, severe bleeding and cardiac arrest between randomized AF populations who received either ablation or antiarrythmic medication. To the knowledge of the authors, CABANA showed that above composite outcome did not differ significantly between ablated patients compared to those treated medically, based on an "intention-to-treat" analysis [21].
In summary, over a period of 36 months, all-cause mortality in AF patients who underwent catheter ablation was found to be significantly lower compared to AF patients who received antiarrhythmic medication. We could not identify any significant difference between the groups in the defined cardiovascular events over the three-year observation period. Direct cardiology healthcare costs after the ablation procedure proved to be con-

Funding
This study was supported by Biosense Webster, Inc.
(Diegem, Belgium) and provided to AFNET e.V. Münster that coordinated the study. The study design, the collection/analysis of data and the writing of the manuscript were completed independently of the funding source.
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