Efficacy and safety of dronedarone versus placebo in patients with atrial fibrillation stratified according to renal function: Post hoc analyses of the EURIDIS‐ADONIS trials

Abstract Background The use of antiarrhythmic drugs (AADs) in patients with chronic kidney disease (CKD) is complex because impaired renal clearance can cause increased drug levels, and risk of intolerance or adverse events. Due to the propensity for CKD to occur alongside atrial fibrillation/atrial flutter (AF/AFL), it is essential that AAD safety and efficacy are assessed for patients with CKD. Hypothesis Dronedarone, an approved AAD, may present a suitable therapeutic option for patients with AF/AFL and concomitant CKD. Methods EURIDIS‐ADONIS (EURIDIS, NCT00259428; ADONIS, NCT00259376) were identically designed, multicenter, double‐blind, parallel‐group trials investigating AF/AFL control with dronedarone 400 mg twice daily versus placebo (randomized 2:1). In this post hoc analysis, the primary endpoint was time to first AF/AFL. Patients were stratified according to renal function using the CKD‐Epidemiology Collaboration equation and divided into estimated glomerular filtration rate (eGFR) subgroups of 30–44, 45–59, 60–89, and ≥90 ml/min. Time‐to‐events between treatment groups were compared using log‐rank testing and Cox regression. Results At baseline, most (86%) patients demonstrated a mild or mild‐to‐moderate eGFR decrease. Median time to first AF/AFL recurrence was significantly longer with dronedarone versus placebo for all eGFR subgroups except the 30 to 44 ml/min group, where the trend was similar but statistical power may have been limited by the small population. eGFR stratification had no significant effect on serious adverse events, deaths, or treatment discontinuations. Conclusions This analysis suggests that dronedarone could be an effective therapeutic option for AF with an acceptable safety profile in patients with impaired renal function.


| INTRODUCTION
Atrial fibrillation (AF) and atrial flutter (AFL) are common cardiac arrhythmias that are often symptomatic and responsible for around one-third of all arrhythmia-related hospitalizations. 1-3 Although anticoagulation medication and heart rate control can significantly improve symptoms and decrease risks, restoration of sinus rhythm can further reduce symptoms and greatly improve exercise capacity and quality of life. 4 One antiarrhythmic drug (AAD), dronedarone, has been proven to reduce cardiovascular hospitalizations or death in people with AF/AFL, complementing the findings of the EAST-AFNET4 trial of early rhythm control, and highlighting an important therapeutic goal for individuals with AF and AFL. 5 While amiodarone is a potent AAD, it can cause serious thyroid and systemic toxic side effects in some patients. 6 A post hoc analysis of the BALKAN-AF survey found that patients with CKD received amiodarone almost exclusively for rhythm control, 7 indicating that there is a need for increased understanding of the safety and efficacy of other available therapeutic options. Dronedarone has a similar pharmacological profile to amiodarone, but demonstrates a reduced risk of toxicities, likely due to its increased water solubility, decreased half-life, and absence of iodine. 3,6,8,9 Compared to the Vaughan Williams class Ic drugs and sotalol, renal elimination of dronedarone is minimal, with just 6% excreted in urine. 10 Various randomized controlled trials and real-world studies have investigated the impact of dronedarone on AF burden and cardiovascular hospitalization. 11,12 These studies include the European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS, NCT00259428) and the American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS, NCT00259376), which were identical trials assessing the safety and efficacy of dronedarone for maintaining sinus rhythm in patients with non-permanent AF or AFL. 13 Both trials demonstrated that dronedarone treatment resulted in significantly increased median time to first AF/AFL recurrence, significantly reduced ventricular rate during first AF/AFL recurrence, and significantly reduced rate of hospitalization or death. 13,14 The European Society of Cardiology has identified a need for research investigating the safety and efficacy of AADs for treating patients also diagnosed with chronic kidney disease (CKD). [15][16][17] AF rates are particularly high in patients with CKD, ranging from 15% to 40% in patients with end-stage renal disease, and 16%-21% in patients with stages 3 or 4 CKD. 18 Additionally, CKD stages 3-5 are present in~30% of patients with AF, 19 and more than 50% of patients with AF have an estimated glomerular filtration rate (eGFR) under 60 ml/min. 20 Comorbid disorders that can facilitate both AF and renal dysfunction, such as hypertension and diabetes mellitus, are commonly represented in AF populations. Typically, patients with CKD are under-represented or excluded from AAD trials due to an increased risk of proarrhythmic events, particularly in patients with concomitant structural heart disease. 15,18 As such, there is a significant need for further research regarding the safety and efficacy of AADs for treating people with AF and CKD.
In the EURIDIS-ADONIS trials, renal function data were collected and eGFR calculated using the Cockcroft-Gault equation, 13 however, the CKD-Epidemiology Collaboration equation (CKD-EPI) has since become recognized as providing a better estimation of GFR than the Cockcroft-Gault equation. 21 Therefore, this post hoc analysis of the EURIDIS-ADONIS trials calculated eGFR using CKD-EPI 22 to investigate the safety and efficacy of dronedarone therapy across a range of eGFR strata.

| Study design
The methods for the EURIDIS-ADONIS trials have been described previously. 13 EURIDIS-ADONIS were identical placebo-controlled, multicenter, double-blind, parallel-group trials in which dronedarone efficacy and safety for controlling sinus rhythm in patients with nonpermanent AF/AFL was assessed. Patient eligibility criteria included male or female patients ≥21 years of age, who have had a minimum of one episode of AF/AFL in the preceding 3 months (documented by electrocardiography), and to be in sinus rhythm for at least 1 h before randomization. Exclusion criteria can be found in the supplementary materials. Ethical review boards approved study protocols at each institution and investigations were in accordance with the Declaration of Helsinki.

| Baseline evaluation
Baseline evaluations included a medical history, symptom review, cardiovascular examination, assessment of vital signs, 12-lead electrocardiography (ECG), chest radiography, and laboratory testing.
Left atrial size and left ventricular ejection fraction were determined by two-dimensional echocardiography.

| Study endpoints
The primary endpoint of the study was the time from randomization to the first documented AF/AFL recurrence. An occurrence was classified as an episode lasting for at least 10 min and confirmed by two consecutive 12-lead ECG or transtelephonic recordings taken 10 min apart. The main secondary endpoints were symptoms related to AF/AFL during 12-lead ECG recordings or transtelephonic monitoring and the mean ventricular rate during the first recurrence.

| Statistical analysis
This was a post hoc analysis on pooled data from the geographically distinct but identically designed EURIDIS and ADONIS trials. 13 Renal function (eGFR) was calculated using the Cockcroft-Gault equation in the original publication. In this analysis, it was assessed using the CKD-EPI equation as CKD-EPI provides a better estimation of GFR than the Cockcroft-Gault equation. 21,22 Once eGFR was established, patients were grouped by eGFR strata into 30-44, 45-59, 60-89, and ≥90 ml/min subgroups. Time-to-events between treatment groups were then compared using log-rank testing and unadjusted Cox regression.
Being an exploratory analysis, p values were not adjusted for multiple comparisons. For confirmation purposes, outcomes were also analyzed in eGFR strata classified according to the Modification of Diet in Renal Disease Study Group criteria (Supplementary   Table 1A). No difference was observed between the two and so only CKD-EPI data will be presented herein.

| Baseline characteristics
Patient data from the EURIDIS-ADONIS trials encompassing 1229 patients were analyzed (Table 1A). Most patients (86%) presented with mild (60-89 ml/min) or mild-to-moderate (45-59 ml/min) decreases in eGFR, with females present in higher numbers in groups with worse renal function. As renal function worsened there was a trend towards increasing mean age, and greater prevalence of structural heart disease, coronary heart disease, diabetes, valvular heart disease, presence of pacemakers, and hypertension (Table 1A). Accordingly, CHA 2 DS 2 -VASc scores increased with decreasing renal function (Table 1A). Left atrial diameter was numerically higher in the subgroup with an eGFR of 30-44 ml/min (43-45 mm) than in those with an eGFR of ≥90 ml/min (40-41 mm). Aligned with the observation of higher numbers of comorbidities, increased use of beta-blockers, angiotensin-converting enzyme inhibitors, diuretics, oral anticoagulants, and statins was recorded in groups with greater renal impairment (Table 1B). Digoxin use did not appear to increase with worsening renal function. Amiodarone and sotalol were the most prescribed antiarrhythmic therapies in all eGFR subgroups before randomization, with Vaughan Williams class I AAD use varying between subgroups. No AADs, other than the study drug, were allowed following randomization.

| Time to first AF/AFL (primary outcome)
Median time to first AF/AFL recurrence was significantly longer in the dronedarone versus placebo group for all eGFR subgroups except the most renally impaired (30-44 ml/min) (Table S1B), whether based on first adjudicated (Figures 1 and 2) or symptomatic episodes ( Figure S1). While dronedarone appeared to provide a benefit in time to first adjudicated AF/AFL compared with placebo in all the eGFR subgroups (Figures 1 and   2), this result was only significant in the 45-59, 60-89, and ≥90 ml/min eGFR subgroups, with the most substantial benefit being observed in patients with eGFR ≥90 ml/min. As the hazard ratios for the cumulative incidence of adjudicated first AF/AFL recurrence ( Figure 2) were all <1 and not significantly different from one another, no test for interaction was performed. The 30-44 ml/min subgroup demonstrated a trend towards an increased time to first AF/AFL recurrence, but statistical power was limited by the relatively small patient numbers (n = 70).

| Heart rate
Patients in the 30-44 ml/min eGFR subgroup demonstrated a mean heart rate 3-4 beats-per-minute (bpm) slower than the ≥90 ml/min subgroup at baseline (Table 1A), and the use of betablockers was numerically higher in the 30-44 ml/min eGFR subgroup (Table 1B).
By the time of first adjudicated AF/AFL, dronedarone treatment was associated with a lower mean heart rate in all eGFR subgroups compared with placebo ( Figure 3).

| Safety
No notable differences between dronedarone and placebo were observed for incidences of serious adverse events, deaths, and treatment discontinuations among eGFR strata (  Therefore, this analysis suggests that dronedarone is equally effective in renally impaired patients for treatment of AF/AFL as those without renal impairment.
There was a marked lowering of heart rate by 12-17 bpm during AF/AFL recurrences associated with dronedarone treatment compared with placebo regardless of the severity of renal impairment.
This is consistent with a previous study that reported a heart rate reduction of 11.7 bpm with dronedarone versus placebo (p < .0001) 23 and with the overall data from the EURIDIS-ADONIS trials. 13 Interestingly, there appeared to be an increase in left atrial anteroposterior diameter between the least and the most renally affected subgroups. This trend towards higher left atrial diameter with worse renal function has been reported previously and is associated with more rapid renal decline, increased likelihood of treatment resistance, greater contributory comorbidities, and increased all-cause mortality. [24][25][26][27][28] The data presented in this analysis Competition of dronedarone with creatinine for cation transport channel secretion by renal tubules has been shown to result in a reversible significant reduction in creatinine clearance of about 18%. 29 Whilst typically an indicator of reduced renal function, such inhibition of creatinine secretion has been demonstrated across a range of drugs, 30 which is not necessarily associated with impaired renal function. Similarly, this analysis showed a numerical increase in serum creatinine in patients who received dronedarone, which was maintained until the end of the study. Whilst this is consistent with inhibition of creatinine secretion by dronedarone, which by creatinine-derived glomerular filtration estimations would indicate a reduction in eGFR, it should be noted that in earlier studies no numerical effect of dronedarone on non-creatinine derived GFR estimations was observed. 29 Additionally, it is important to stress that the use of formulas to calculate eGFR based on creatinine level may underestimate renal function following treatment with dronedarone due to various confounders (e.g., muscle mass and dehydration). 31,32 If problematic, creatinine-derived eGFR results can be combined with clinical assessment of cystatin C levels for the most accurate results, although it should be noted that this is a more costly approach. 31,32 No threshold was identified at which dronedarone efficacy or its safety profile was negatively impacted. Neither were any effects observed that might suggest alternative drug interactions introduced by the renal activity of dronedarone. No significant differences in adverse events were observed between any eGFR subgroups, suggesting that renal function does not impact the safety profile of dronedarone. 13 The analysis has some limitations. Primarily, the stratification of patients from the EURIDIS-ADONIS trials into subgroups according to renal function was not predefined and hence resulted in a loss of statistical power, particularly, in the most renally impaired subgroup.
Additionally, having smaller patient groups may have increased the impact of confounders when comparing between eGFR strata, potentially influencing outcomes. As with many trials investigating AF/ AFL at that time, continuous monitoring was not performed. It is, therefore, possible that some recurrent arrhythmia events may have been missed, particularly as the majority of reported events were symptomatic AF/AFL, despite AF/AFL recurrences typically being asymptomatic. 13  Abbreviations: eGFR, estimated glomerular filtration rate; NA, not available (none or one patient with data available); Pt, patient; SD, standard deviation; TEAE, treatment-emergent adverse event.
F I G U R E 3 Mean heart rate at first adjudicated atrial fibrillation/flutter. Heart rate values obtained on only one RR interval were not considered. Error bars represent the standard deviation of the mean. BPM, beats per minute; eGFR, estimated glomerular filtration rate