ATHENA Trial Research Articles

Effect of dronedarone vs. placebo on atrial fibrillation progression: a post hoc analysis from ATHENA trial.

This post hoc analysis of the ATHENA trial (NCT00174785) assessed the effect of dronedarone on the estimated burden of atrial fibrillation (AF)/atrial flutter (AFL) progression to presumed permanent AF/AFL, and regression to sinus rhythm (SR), compared with placebo. The burden of AF/AFL was estimated by a modified Rosendaal method using available electrocardiograms (ECG). Cumulative incidence of permanent AF/AFL (defined as ≥6 months of AF/AFL until end of study) or permanent SR (defined as ≥6 months of SR until end of study) were calculated using Kaplan-Meier estimates. A log-rank test was used to assess statistical significance. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were estimated using a Cox model, adjusted for treatment group. Of the 4439 patients included in this analysis, 2208 received dronedarone, and 2231 placebo. Baseline and clinical characteristics were well balanced between groups. Overall, 304 (13.8%) dronedarone-treated patients progressed to permanent AF/AFL compared with 455 (20.4%) treated with placebo (P < 0.0001). Compared with those receiving placebo, patients receiving dronedarone had a lower cumulative incidence of permanent AF/AFL (log-rank P < 0.001; HR: 0.65; 95% CI: 0.56-0.75), a higher cumulative incidence of permanent SR (log-rank P < 0.001; HR: 1.19; 95% CI: 1.09-1.29), and a lower estimated AF/AFL burden over time (P < 0.01 from Day 14 to Month 21). These results suggest that dronedarone could be a useful antiarrhythmic drug for early rhythm control due to less AF/AFL progression and more regression to SR vs. placebo, potentially reflecting reverse remodeling. NCT00174785.

Dronedarone as early rhythm control: post-hoc analysis of the ATHENA trial using EAST-AFNET4 criteria

Abstract Introduction The EAST-AFNET4 study found that early, systematic rhythm control reduced cardiovascular (CV) outcomes in patients with early atrial fibrillation/atrial flutter (AF) of ≤12 months compared to guideline-recommended usual care. Purpose This post-hoc analysis aimed to assess whether antiarrhythmic drug therapy alone (i.e. dronedarone 400 mg BID) improved CV outcomes compared to placebo in patients with early AF in the ATHENA trial (NCT00174785; Ref 2) applying the EAST-AFNET4 criteria. Methods All patients in the randomised, placebo-controlled ATHENA trial with ≥2 CV conditions as defined in the EAST-AFNET 4 inclusion criteria and known AF duration at baseline were identified. Patients were split into early AF (≤12 months duration) and late AF (&amp;gt;12 months duration) subgroups. Outcomes were collected over a mean follow-up of 21 months and included a composite of CV death, stroke, or hospitalisation with worsening of heart failure or acute coronary syndrome; nights spent in hospital per year; and a safety composite endpoint comprising death, stroke, or pre-specified serious adverse events. All analyses were conducted in the intention-to-treat population. Results Dronedarone treatment was associated with significantly (p=0.014) fewer CV events vs placebo in patients with early AF (Fig 1). There was no interaction with AF duration (p=0.64). Patients on dronedarone spent numerically fewer nights in hospital vs placebo in early (13.4 vs 14.0) and late AF (13.9 vs 16.3), with no treatment interaction between subgroups (p=NS). Dronedarone was associated with more sinus rhythm (SR) at 12 months vs placebo (early AF: 79.9% vs 70.3%; late AF: 60.6% vs 54.0%), and similar rates of SR at 24 months (early AF: 65.8% vs 65.7%; late AF: 54.7% vs 54.1%). For the safety composite endpoint, estimated events/patients were as follows for the early AF group (dronedarone: 153/135; placebo: 182/165) and the late AF group (dronedarone: 86/81; placebo: 95/89). Conclusions The clinical benefit of early rhythm control found in the EAST-AFNET4 trial can be replicated in this analysis of patients with early AF treated in the ATHENA trial comparing dronedarone to placebo. These data support the use of dronedarone as part of early rhythm control. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi

Effect of dronedarone versus placebo on atrial fibrillation progression: a post-hoc analysis from ATHENA trial

Abstract Background Atrial fibrillation (AF) may progress over time, leading to greater AF burden. Data suggest that patients receiving rhythm control drugs are less likely to progress to more severe forms of AF vs those receiving a rate control strategy only. ATHENA (NCT00174785) demonstrated that dronedarone significantly decreased cardiovascular (CV) hospitalization and death [1], but it is unclear whether dronedarone affects progression of AF and atrial flutter (AFL). Purpose This post hoc analysis of ATHENA assessed (1) the effect of dronedarone on estimated AF/AFL burden, and (2) AF progression to presumed permanent AF/AFL or AF regression to sinus rhythm (SR). Methods AF/AFL burden was estimated using a modified Rosendaal method [2] based on status of all ECG assessments at each visit. Cumulative incidence of presumed permanent AF/AFL (defined as ≥6 months of AF/AFL until end of study) or preserved SR (≥6 months of SR until end of study) were calculated using the complement of Kaplan-Meier estimates. Log-rank test was used to assess statistical significance. Results Demographic characteristics in 2231 patients on placebo and 2208 on dronedarone were well balanced between groups. Overall, 304 (13.8%) dronedarone-treated patients progressed to presumed permanent AF/AFL compared with 455 (20.4%) treated with placebo. Patients progressing to presumed permanent AF/AFL tended to have larger left atrial diameters and lower left ventricular ejection fractions irrespective of treatment group. The cumulative incidence of presumed permanent AF/AFL was significantly lower in dronedarone-treated patients over time (log-rank p&amp;lt;0.0001; Figure 1). Estimated AF/AFL burden was lower in dronedarone-treated patients over time (Figure 2). Overall, 1149 (52.0%) dronedarone-treated patients had preserved SR compared with 1021 (45.8%) placebo-treated patients, and cumulative incidence of preserved SR was significantly higher in the dronedarone arm compared with the placebo arm (log-rank p&amp;lt;0.0001). Treatment-emergent adverse events were consistent with the findings in the main ATHENA analysis. Conclusions Dronedarone use was associated with fewer patients progressing to presumed permanent AF/AFL, more patients with AF/AFL regressing to preserved SR, and a lower estimated AF/AFL burden, suggesting a protective benefit against AF disease progression. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Sanofi

Factors affecting prognosis in patients treated with bevacizumab plus paclitaxel as first-line chemotherapy for HER2-negative metastatic breast cancer: an international pooled analysis of individual patient data from four prospective observational studies

BackgroundBevacizumab (BV) plus paclitaxel (PTX) is a treatment option in patients with HER2-negative metastatic breast cancer (mBC). We conducted an international pooled analysis with individual patient data to evaluate the effectiveness of BV + PTX as a first-line treatment for HER2-negative mBC patients under routine practice.MethodsA total of 2,474 mBC patients treated with BV + PTX from four prospective observational studies were analyzed. The primary endpoint was overall survival (OS). The other endpoints including identifying independent prognostic factors and validation of the modified Prognostic Factor Index (PFI) developed in the ATHENA trial.ResultsMedian follow-up time was 10.9 months (M). Median OS were 21.4 M (95% confidential interval 19.8–22.7 M). The seven independent prognostic factors (tumor subtype, age, ECOG performance status (PS), disease-free interval (DFI), liver metastases, number of metastatic organs, and prior anthracycline and/or taxane treatment) for OS found in this analysis included the five risk factors (RFs [DFI < 24 months, ECOG PS 2, liver metastases and/or > 3 metastasis organ sites, TNBC, prior anthracycline and/or taxane therapy]). High- (> 3 RFs [median OS 12.6 M]) and intermediate-risk groups (2 RFs [median OS 18.0 M]) had a significantly worse prognosis than the low-risk group (< 1 RF [median OS 27.4 M]), (p < 0.0001).ConclusionsThis international pooled analysis showed the effectiveness of first-line BV + PTX for HER2-negative mBC patients identifying seven independent prognostic factors as real-world evidence. The usefulness of the modified PFI developed in the ATHENA trial in predicting OS among patients receiving BV + PTX was also verified.

Effect of Dronedarone in the Treatment of Atrial Fibrillation in the Asian Population: Post Hoc Analysis of the ATHENA Trial

PurposeLimited data are available on the impact of dronedarone treatment in Asian patients with atrial fibrillation (AF) or atrial flutter (AFL). This post hoc analysis evaluated the efficacy and safety of dronedarone compared with placebo in populations from Asian and non-Asian regions randomized in the ATHENA trial (A Placebo-Controlled, Double-blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg BID for the Prevention of CV Hospitalization or Death From Any Cause in Patients With AF/AFL). MethodsTime to first hospitalization for cardiovascular events or death from any cause (primary outcome) and time to first AF/AFL event recurrence (secondary outcome) were analyzed by Kaplan-Meier curves and Cox proportional hazards regression. FindingsThe risk of experiencing the primary composite outcome was significantly lower in the dronedarone-treated patients in both the Asian (hazard ratio = 0.541; 95% CI, 0.320–0.914]) and non-Asian (hazard ratio = 0.768; 95% CI, 0.696–0.848) populations than in the placebo-treated patients. The median time to the first AF/AFL event recurrence was longer in the dronedarone-treated population than in the placebo-treated populations: 183 vs 92 days (P = 0.165) in the Asian population and 534 vs 196 days (P < 0.001) in the non-Asian population. Treatment-emergent adverse events in Asian (81.2% vs 78.4%) and non-Asian (71.4% vs 68.7%) populations and serious treatment-emergent adverse events in Asian (14.3% vs 15.7%) and non-Asian (20.3% vs 21.5%) patients were comparable in patients taking dronedarone compared with those taking placebo. ImplicationEfficacy and tolerability of dronedarone were consistent in the Asian population compared with the non-Asian population in the ATHENA trial. These finding may aid Asian health care professionals to select the appropriate first-line treatment for Asian patients with AF/AFL.

Dronedarone vs. placebo in patients with atrial fibrillation or atrial flutter across a range of renal function: apost hocanalysis of the ATHENA trial

AimsUse of antiarrhythmic drugs (AADs) in patients with chronic kidney disease (CKD) is challenging owing to issues with renal clearance, drug accumulation, and increased proarrhythmic risks. Because CKD is a common comorbidity in patients with atrial fibrillation/atrial flutter (AF/AFL), it is important to establish the efficacy and safety of AAD treatment in patients with CKD.Methods and resultsDronedarone efficacy and safety in individuals with AF/AFL and varying renal functionality [estimated glomerular filtration rate (eGFR): ≥60, ≥45 and <60, and <45 mL/min] was investigated in a post hoc analysis of ATHENA (NCT00174785), a randomized, double-blind trial of dronedarone vs. placebo in patients with paroxysmal or persistent AF/AFL plus additional cardiovascular (CV) risk factors. Log-rank testing and Cox regression were used to compare the incidence of endpoints between treatments. Overall, 4588 participants were enrolled from the trial. There was no interaction between treatment group and baseline eGFR assessed as a continuous variable (P = 0.743) for the first CV hospitalization or death from any cause (primary outcome). This outcome was lower with dronedarone vs. placebo across a wide range of renal function. First CV hospitalization and first AF/AFL recurrence were both lower in the two least renally impaired subgroups with dronedarone vs. placebo. Treatment emergent adverse events leading to treatment discontinuation were more frequent with dronedarone vs. placebo and occurred more often in patients with severe renal impairment.ConclusionDronedarone is an effective AAD in patients with AF/AFL and CV risk factors across a wide range of renal function.

The impact of dronedarone on patients with atrial fibrillation and diabetes – a sub-analysis of the ATHENA and EURIDIS/ADONIS trials

Abstract Background Diabetes is a well-established risk factor for the development of atrial fibrillation (AF), and is associated with worse outcomes. Both the ATHENA (NCT00174785) and EURIDIS (NCT00259428)/ADONIS (NCT00259376) were randomized, double-blind, placebo-controlled clinical trials, that evaluated dronedarone 400 mg BID vs placebo (2:1 ratio) in patients with AF and atrial flutter (AFL). The aim of this post-hoc analysis was to evaluate the efficacy and safety of dronedarone in patients with or without diabetes. Methods Patients from the ATHENA trial with diabetes, and from the EURIDIS/ADONIS trials with diabetes, &amp;gt;1 elevated glucose level during trial (unfasted ≥11; fasted ≥7 mmol/L) or presence of diabetes medications were identified and categorized according to diabetes status at baseline. Descriptive analyses of baseline characteristics in patients with and without diabetes receiving dronedarone or placebo were assessed, and time to occurrence of the primary outcomes, CV hospitalization or death in ATHENA and AF/AFL recurrence within 12 months in EURIDIS/ADONIS, were estimated using the Kaplan–Meier method. Log-rank test was used to assess the statistical differences of the survival curves. Results A total of 945 (20.4%; dronedarone [N=482], placebo [N=463]) patients of 4628 patients in ATHENA, and 215 (17.4%; dronedarone [N=148], placebo [N=67]) of 1237 patients in EURIDIS/ADONIS had type 2 diabetes. Patients with diabetes were more likely to have coronary heart disease, hypertension, or structural heart disease in both trials. In ATHENA, there were higher rates of CV hospitalization or death in patients with diabetes (39.5%) than without (34.7%). The proportion of patients with diabetes with first CV hospitalization or death was lower with dronedarone versus placebo (35.1 vs 44.1%) and the time to first event occurred significantly later with dronedarone than placebo (log-rank p=0.005; Figure 1). In ATHENA, median time to first AF/AFL recurrence occurred significantly later with dronedarone vs placebo consistently in patients with diabetes (722 vs 527 days; log-rank p=0.004) or without diabetes (741 vs 492 days; log-rank p&amp;lt;0.001). In EURIDIS/ADONIS, the median time to first AF/AFL recurrence occurred later with dronedarone versus placebo in both patients with diabetes (100 vs 23 days; log-rank p non-significant) and without (120 vs 59 days; log-rank p&amp;lt;0.001; Figure 2). Occurrence of any treatment-emergent adverse event [TEAE] (ATHENA: 74.9 vs 71.2%; EURIDIS/ADONIS: 77.7 vs 68.1%) and serious TEAEs (ATHENA 23.8 vs 18.9%; EURIDIS/ADONIS 25.7 vs 18.5%) with dronedarone were similar for patients with or without diabetes. Conclusion Diabetic patients had shorter time to AF recurrences and higher rates of CV hospitalization than patients without diabetes. Dronedarone was equally safe, decreasing the risk of CV hospitalization or death, and effective, delaying AF/AFL recurrences, in patients with and without diabetes. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Sanofi

Dronedarone vs placebo in patients with atrial fibrillation or atrial flutter across a range of renal function: a post hoc analysis of the ATHENA trial

Abstract Background The use of antiarrhythmic drugs in patients with chronic kidney disease (CKD) is challenging due to issues with renal clearance, drug accumulation and increased proarrhythmic risks. Since CKD is a common comorbidity with atrial fibrillation (AF), it is important to establish the efficacy and safety for antiarrhythmic drug treatment in patients with CKD. Purpose To evaluate the efficacy and safety of dronedarone in patients with AF or atrial flutter (AFL) across different stages of renal impairment. Methods In this post-hoc analysis of ATHENA (NCT00174785), a randomised, double-blind trial of dronedarone 400 mg BID vs placebo in patients with AF or AFL plus additional risk factors for death and a calculated glomerular filtration rate ≥10 mL/min, the primary outcome was time to first cardiovascular (CV) hospitalisation or death. Renal function (estimated glomerular filtration rate [eGFR]) was assessed using CKD Epidemiology Collaboration equation and patients were grouped by eGFR (10–44, 45–59, ≥60 mL/min). Log-rank testing and Cox regression were used to compare time to events between treatment groups. Results In ATHENA, 43.6% of placebo and 42.2% of dronedarone patients had mild-to-moderate CKD (Table). Median time to CV hospitalisation/death was longer in all strata for dronedarone vs placebo, reaching significance in the 45–59 and ≥60 mL/min groups (Figure 1). There was a trend towards more treatment-emergent adverse events (TEAEs), deaths and discontinuations due to TEAEs in patients with eGFR 10–44 mL/min. No clear difference in safety was seen between treatment arms except for discontinuations, which were higher with dronedarone. Conclusions This analysis confirms the efficacy of dronedarone, demonstrated in ATHENA, across different stages of renal impairment. Further assessment of safety will require larger populations of patients with CKD. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi

Low Incidence of Postoperative Respiratory Depression with Oliceridine Compared to Morphine: A Retrospective Chart Analysis.

Background Oliceridine, an investigational IV opioid, is a first-in-class G-protein selective agonist at the μ-opioid receptor. The G-protein selectivity results in potent analgesia with less recruitment of β-arrestin, a signaling pathway associated with opioid-related adverse events (ORAEs). In randomized controlled studies in both hard and soft tissue models yielding surgical pain, oliceridine provided effective analgesia with a potential for an improved safety and tolerability profile at equianalgesic doses to morphine. The phase 3, open-label, single-arm, multicenter ATHENA trial demonstrated the safety, tolerability, and effectiveness of oliceridine in moderate to severe acute pain in a broad range of patients undergoing surgery or with painful medical conditions warranting use of an IV opioid. This retrospective, observational chart review study compared respiratory depression events associated with oliceridine administration as found in the ATHENA trial to a control cohort treated with conventional opioids. Methods Patients at 18 years of age or older, who underwent colorectal, orthopedic, cardiothoracic, bariatric, or general surgeries between June 2015 and May 2017 in 11 sites participating in the ATHENA trial who received postoperative analgesia either with IV oliceridine or with IV conventional opioids (e.g., morphine alone or in combination with other opioids) (CO cohort); and had a hospital stay >48 hours, were included in this retrospective analysis. Data from the ATHENA trial was used for the oliceridine cohort; and additional baseline characteristics were collected from medical charts. Data from medical charts were collected for all CO cohort patients. The two cohorts were balanced using an inverse probability weighting method. The primary outcome was the incidence of operationally defined opioid-induced respiratory depression (OIRD) in the two cohorts. Secondary outcomes included between-group comparison of the incidence of OIRD events among a subset of high-risk patients. Results OIRD was significantly less in the oliceridine cohort compared to the CO cohort (8.0% vs. 30.7%; odds ratio: 0.139) (95% confidence interval [CI] 0.09–0.22; P < 0.0001). Likewise, the incidence of OIRD was lower among high-risk patients in the oliceridine cohort (9.1% vs. 34.7%; odds ratio: 0.136) (95% CI [0.09–0.22]; P < 0.0001) compared to the CO cohort. Conclusion In this retrospective chart review study, patients receiving IV oliceridine for moderate to severe acute pain demonstrated a lower incidence of treatment emergent OIRD compared to patients who were treated with IV morphine either alone or with concomitant administration of other opioids.

P1034Impact of ablation status on the efficacy and safety of dronedarone in patients with atrial fibrillation/flutter: a post-hoc analysis of the ATHENA trial

Abstract Background Despite increasing use of ablation for atrial fibrillation/flutter (AF/AFL), few systematic data exist on the use of dronedarone and other antiarrhythmic drugs after ablation. Purpose To assess efficacy and safety of dronedarone after ablation in patients with paroxysmal/persistent AF/AFL randomized to dronedarone or placebo in the ATHENA trial (NCT00174785). Methods In ATHENA, 196 patients (dronedarone 90, placebo 106) had an ablation for AF/AFL prior to study entry. AF/AFL recurrence was evaluated in patients in sinus rhythm at baseline (dronedarone 63, placebo 65) by ECG during study visits or symptom recurrence. Results Ablated vs non-ablated patients were more likely to be male, have an implantable cardioverter defibrillator or pacemaker implanted, or be receiving an oral anticoagulant. Fewer ablated patients had an AF/AFL recurrence with dronedarone (36 [57%]) than with placebo (46 [71%]). Median time to first AF/AFL recurrence was significantly longer with dronedarone versus placebo (561 versus 180 days; hazard ratio 0.65 [95% CI 0.42–1.00], p&lt;0.05; Fig 1). Time to first cardiovascular hospitalization or death was similar with dronedarone versus placebo (hazard ratio 0.98 [0.62–1.53]). On-treatment rates of treatment-emergent adverse events with dronedarone versus placebo were 83.1 versus 75.5%, serious treatment-emergent adverse events were 27.0 versus 18.9%, permanent drug discontinuations were 10.1 versus 15.1%, and deaths were 0 versus 1.9%. Conclusions Dronedarone delayed AF/AFL recurrence in patients with a prior AF/AFL ablation. Safety outcomes were consistent with the overall ATHENA trial. Adequately sized prospective studies are needed to confirm these observations. Given the sparsity of data for antiarrhythmic drugs after ablation, this retrospective analysis has merit and is useful for hypothesis generation. Acknowledgement/Funding Sanofi, New York, New York, Unites States of America

P4784Efficacy and safety of dronedarone by duration of atrial fibrillation history: a post-hoc analysis of the ATHENA trial

Abstract Background Atrial fibrillation (AF) is known to progress over time and the effectiveness of antiarrhythmic therapy may vary based on the duration of a patient's AF history. Outcomes with dronedarone (DRO) based on duration of AF/atrial flutter (AFL) history have not been previously characterized. Purpose To evaluate the efficacy and safety of DRO by time since first known AF/AFL episode in patients studied in the ATHENA trial. Methods 2859 (61.8%) patients from ATHENA with documented first known AF/AFL episode (of 4628 total patients randomized) were included in the analysis. Among these patients, first AF/AFL episode was reported at &lt;3 months (shorter history), 3 to &lt;24 months (intermediate), and ≥24 months (longer) in 1296 (45.3%), 845 (29.6%) and 718 (25.1%) patients, respectively. AF/AFL recurrence was evaluated in patients in sinus rhythm at baseline by ECG during study visits or symptom recurrence. Results Demographics (age, sex) were similar across all groups. Patients with longer AF/AFL history tended to have higher prevalence of coronary heart disease and structural heart disease; and were more likely to have AF/AFL (by 12-lead ECG) at baseline (30%) compared to 26% and 16% for intermediate and shorter history groups. Patients with a longer AF history likely had a prior ablation for AF/AFL (7%) vs patients with an intermediate (2%) or shorter AF/AFL history (1%), and more likely required cardioversion during the study (24%) vs intermediate (17%) and shorter history groups (11%). Outcomes and efficacy are reported in Table 1. Rates of treatment-emergent adverse events (TEAEs), serious TEAEs, permanent drug discontinuations, and deaths were similar across all AF/AFL groups. Table 1. Outcomes and efficacy summary Relative Risk, dronedarone (DRO) vs placebo (PBO)1 (95% CI)1,2 AF/AFL &lt;3 months AF/AFL 3 to &lt;24 months AF/AFL ≥24 months PBO (n=626) DRO (n=670) PBO (n=429) DRO (n=416) PBO (n=363) DRO (n=355) First CV hospitalization3 or death (any cause) 0.79 (0.65, 0.96) 0.72 (0.56, 0.92) 0.84 (0.66, 1.07) First CV hospitalization 0.78 (0.64, 0.96) 0.70 (0.55, 0.91) 0.82 (0.63, 1.05) Death (any cause) 0.82 (0.54, 1.24) 0.85 (0.43, 1.68) 1.13 (0.61, 2.10) First AF/AFL recurrence4 0.80 (0.65, 0.97) 0.67 (0.53, 0.84) 0.81 (0.65, 1.02) 1Cox regression model. 2On study period, all randomized patients. 3Main reason was AF/other supraventricular rhythm disorders. 4On selected patients in sinus rhythm at baseline (AF/AFL &lt;3 months: PBO n=514, DRO n=529; 3 to &lt;24 months: PBO n=288, DRO n=312; ≥24 months: PBO n=252, DRO n=250). CV = Cardiovascular. Conclusions Nearly half the patients in ATHENA had a shorter history (&lt;3 months) of AF/AFL prior to randomization. Patients with a longer history of AF/AFL had a greater burden of AF/AFL based on baseline rhythm status, ablation history, and cardioversions required post randomization. Despite these differences, clinical outcomes, efficacy, and safety of DRO appeared to be generally consistent irrespective of duration of AF/AFL history. Acknowledgement/Funding Sanofi, New York, New York, United States of America

Safety and efficacy of dronedarone from clinical trials to real-world evidence: implications for its use in atrial fibrillation.

Efficacy and safety of dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with dronedarone are at acceptable levels, while PK data on the rivaroxaban-dronedarone interaction are unavailable. In RCTs and real-world studies, dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following dronedarone treatment.

Remarkable Improvement of Ejection Fraction in Response to Herbal Decoction Containing High-dose Astragalus Mongholicus: A Case Report

Dronedarone reduced the rate of stroke and transient ischemic attack in patients with paroxysmal atrial fibrillation (AF) in the ATHENA trial. This cannot be explained by its antiarrhythmic effect alone and may involve alternative mechanisms. This study aimed to investigate any direct effect of dronedarone on blood thrombogenicity, independent of its antiarrhythmic effects.Blood samples from patients with cardiovascular disease (n = 30) taking no anticoagulant or antiplatelet medication except aspirin were incubated with dronedarone's active metabolite (SR35021A) at 66 ng/ml (am-L) and 119 ng/ml (am-H), i.e., minimum and maximum mean Cmax reported after repeated 400 mg BID dosing. A third aliquot of blood was incubated with vehicle (Control). Antithrombotic effects of dronedarone were assessed using Coagulation Time (CT), Clot Formation Rate (CFR) and Maximum Clot Firmness (MCF) in ThromboElastoMetry and whole blood platelet aggregation in response to ADP, collagen and TRAP.Compared to Control, mean CT was prolonged by am-L and am-H (164 ± 25 s vs. 180 ± 22 and 182 ± 32 s, respectively, p<0.01 for both). Small but statistically significant reductions were observed in CFR (am-L and am-H) and MCF (am-H). Platelet aggregation induced by ADP and TRAP was also reduced (p<0.05 for both) by am-H.Dronedarone exerts direct anticoagulant and antiplatelet effects on human blood in vitro that are independent of its antiarrhythmic actions. This suggests the reductions in ischemic events reported with dronedarone may not be due to amelioration of AF itself. Additional clinical studies are required to further improve understanding of the mechanisms involved.

Incomplete endothelialization of WatchmanTM Device: Predictors and Implications from Two Cases

Initiation of antiarrhythmic drug therapy (AADx) for atrial fibrillation (AF) on an outpatient basis requires intensive ECG monitoring in order to assess antiarrhythmic efficacy as well as ECG signals of potential proarrhythmia. Dronedarone (DRO) reduces cardiovascular endpoints in AF patients fulfilling criteria of the ATHENA trial [1]. In the present study transtelephonic ECG monitoring was used to guide initiation of AADx in AF patients fulfilling the ATHENA criteria. In 19 consecutive patients (37% female; age 65+10 years; LVEF 62+7%; mean CHA2DS2-VASc score 2.9 + 1.6 (median=2), with symptomatic non-permanent AF and additional cardiovascular risk factors, DRO was prescribed as AADx of first choice. Initiation of therapy and follow-up were monitored by transtelephonic ECG recordings (VITAPHONE™100 IR; Vitaphone GmbH; Germany). In patients with persistent AF, electrical cardioversion was performed on an outpatient basis when DRO was started. Patients were followed for changes in QT intervals as well as AF recurrency. ECGs were transmitted according to a scheduled FU form as well as any time in case of pts symptoms. Patients in whom DRO did not prevent AF recurrence were switched to alternative AADx, or to pulmonary vein isolation (PVI), respectively. At the end of long-term follow-up, DRO alone was successful in preventing AF recurrence in 5 of 19 patients (26%). When pts who responded to AADx of second or third choice or who underwent PVI were included, SR could be maintained in 17/19 pts (89%). No patient required discontinuation of AADx due to ventricular depolarization abnormalities, symptomatic bradycardia or pathologic QT prolongation. In conclusion, transtelephonic ECG transmission is useful for close rhythm monitoring during initiation and follow-up of AADx, also during change from DRO to other AADx. DRO was effective to prevent AF recurrence in 26% of patients during a mean long-term follow-up of more than 30 months - which is well in line with data from the literature.

Efficacy of different photoprotection strategies in preventing actinic keratosis new lesions after photodynamic therapy. The ATHENA study: a two-center, randomized, prospective, assessor-blinded pragmatic trial

Background: Treatment of actinic keratosis (AK) and field cancerization with photodynamic therapy (PDT) is an effective therapeutic approach with a significant reduction in the number of AK lesions (–75% or more) associated with a significant cosmetic improvement of the photodamaged skin. Recently, also, the daylight PDT (DL-PDT) has proven to be as effective as the conventional PDT (C-PDT), but with a better tolerability. After C-PDT and DL-PDT it is advised to use photoprotection strategies to improve the clinical evolution and prevent the appearance of new AK lesions that usually appear 3–6 months after the last phototherapy session. However, there are no robust clinical data regarding the type of photoprotection to be used (SPF level, duration of treatment, etc.) after successful PDT.Study aim: The present study (ATHENA trial) evaluated the efficacy and tolerability of a topical product based on 0.8% piroxicam and 50+ solar filters (ACTX), applied twice a day as sequential therapy after C-PDT or DL-PDT on the evolution of AK lesions number compared to the use of very high photoprotection products commonly used in this clinical setting (SPF50+ or SPF100+ associated with photolyase) (Standard Sunscreens: SS group). Subjects and methods: This was a multicenter, randomized, two-arm, prospective controlled, assessor-masked outcome evaluation, parallel group (1:1), pragmatic study of 6 months duration in patients with multiple AK lesions suitable for photodynamic therapy. The objectives of the study were the evaluation of the evolution of the number of AK lesions during the period of treatment/application of the study products, and the Investigator global clinical assessment score (IGA score; 4: marked improvement, 3: good, 2: moderate; 1 no improvement; 0: worsening) 2, 3, and 6 months after the last PDT session. A total of 68 subjects (50 men, 18 women; mean age 70 years), 34 assigned to treatment with ACTX and 34 to treatment with SS (17 treated with a SPF50+ and 17 with a photolyase-containing SPF100+ products), were enrolled in the study.Results: The number of AK lesions present before C-PDT/DL-PDT was 11.8 ± 5.8 in the ACTX group and 12.4 ± 6.9 in the SS group. In both groups, there was a progressive reduction of AK lesions observed at baseline (–86% and –87% after 2 months and –88% and –83% at month 3 in ACTX and in the SS group, respectively). At month 6, AK mean lesion number was 1.8 ± 1.6 in the ACTX and 3.2 ± 2.3 in the SS group; this difference was statistically significant (p = 0.03). The IGA score at the end of the study was 3.2 in the ACTX and 2.7 in the SS group (p = 0.05). The percentage of subjects with an IGA score of 4/3 (very good or good) was 81% in the ACTX and 55% in the SS group (p = 0.06).Conclusion: In subjects with AK treated with C-PDT or DL-PDT, a “medicalized” photoprotection treatment is associated with a favorable clinical outcome with progressive reduction of lesions. In contrast to a very high photoprotection (SPF50+ or SPF100+/photolyase), the use of piroxicam 0.8%/SPF 50+ is associated with a significantly greater improvement in clinical evolution of AK lesions.

Significant Anti-CMV/BKV Effect of a Modern Everolimus-Based Regimen Comparted to Standard Tacrolimus-MPA Regimen in de Novo Kidney Transplant Recipients

Athena Study Group. Background The ATHENA trial was designed to compare everolimus [EVR] in combination with tacrolimus [TAC] or cyclosporine A [CyA] vs. a standard regimen of mycophenolic acid [MPA] and TAC in de novo kidney transplant [Tx] recipients. Of specific interest was monitoring of infections with main focus on CMV and BKV. Methods In this randomized 12 months [M] prospective, open-label study with 15 German and 12 French study sites, in total 612 patients [pts] were randomized 1:1:1 at time of Tx to either EVR (target trough: 3-8ng/ml M1-M12) +TAC (target trough: 4-8ng/ml M1-M3; 3-5ng/ml M3-M12), or EVR (3-8ng/ml M1-M12) + CyA (target trough: 75-125 ng/ml M1-M3; 50-100 ng/ml M3-M12) or to control TAC regimen (target trough: 4-8ng/ml M1-M3; 3-5ng/ml M3-M12) with MPA. All pts received ongoing steroids. Here we present M12 data on infections within ITT population with 208 EVR+TAC pts, 199 EVR+CyA pts and 205 TAC+MPA pts. Results From randomization to M12 total incidence of infections was significantly higher in TAC+MPA group with 82% compared to 73% in EVR+TAC and 72% in EVR+CyA treated pts (p<0.05 for both EVR groups). In general, most frequent evet was urinary tract infection with similar incidences across groups: 41% vs 41% vs 40%, respectively. Major differences were seen for viral infections with an incidence of 41% in TAC+MPA vs 26% in EVR+TAC and 12% in EVR+CyA treatment groups (p<0.01). Of specific interest was incidence of BKV and CMV infections: BKV events were reported with 23% in TAC+MPA vs 17% in EVR+TAC vs 9% in EVR+CyA treatment groups (p<0.01) and CMV infections - as well significantly less under EVR treatment - with 21% in TAC+MPA vs 6% in EVR+TAC and 3% in EVR+CyA group (p<0.01). In addition to this more than three-fold difference for CMV infections between TAC+MPA and EVR-treatment, patients with CMV disease and/or recurrent CMV events occurred only in TAC+MPA group, not under EVR-treatment. Matching of CMV-donor/recipient status at baseline was balanced across groups for all risk-constellations and, of note: 3 months CMV-prophylaxis with valganciclovir for D+/R- and D+/R+ pts was requested per protocol. Conclusion ATHENA as largest European KTx study confirmed comparable efficacy and safety of all 3 regimens together with beneficial outcomes on viral infections: significantly less viral infections for EVR-based treatment groups compared to TAC+MPA group and a significant, protective effect of EVR-based regimens vs CMV/BKV events was robustly demonstrated.

Dronedarone exerts anticoagulant and antiplatelet effects independently of its antiarrhythmic actions

Background and aimsDronedarone reduced the rate of stroke and transient ischemic attack in patients with paroxysmal atrial fibrillation (AF) in the ATHENA trial. This cannot be explained by its antiarrhythmic effect alone and may involve alternative mechanisms. This study aimed to investigate any direct effect of dronedarone on blood thrombogenicity, independent of its antiarrhythmic effects. MethodsBlood samples from patients with cardiovascular disease (n = 30) taking no anticoagulant or antiplatelet medication except aspirin were incubated with dronedarone's active metabolite (SR35021A) at 66 ng/ml (am-L) and 119 ng/ml (am-H), i.e., minimum and maximum mean Cmax reported after repeated 400 mg BID dosing. A third aliquot of blood was incubated with vehicle (Control). Antithrombotic effects of dronedarone were assessed using Coagulation Time (CT), Clot Formation Rate (CFR) and Maximum Clot Firmness (MCF) in ThromboElastoMetry and whole blood platelet aggregation in response to ADP, collagen and TRAP. ResultsCompared to Control, mean CT was prolonged by am-L and am-H (164 ± 25 s vs. 180 ± 22 and 182 ± 32 s, respectively, p<0.01 for both). Small but statistically significant reductions were observed in CFR (am-L and am-H) and MCF (am-H). Platelet aggregation induced by ADP and TRAP was also reduced (p<0.05 for both) by am-H. ConclusionsDronedarone exerts direct anticoagulant and antiplatelet effects on human blood in vitro that are independent of its antiarrhythmic actions. This suggests the reductions in ischemic events reported with dronedarone may not be due to amelioration of AF itself. Additional clinical studies are required to further improve understanding of the mechanisms involved.

Triaging HPV-positive women with p16/Ki-67 dual-stained cytology: Results from a sub-study nested into the ATHENA trial

ObjectivesIn addition to genotyping for HPV16/18, dual-immunostaining for p16/Ki-67 has shown promise as a triage of HPV-positive women. We assessed the performance of p16/Ki-67 dual-stained cytology for triaging HPV-positive women undergoing primary HPV screening. MethodsAll women ≥25years with valid cervical biopsy and cobas® HPV Test results from the cross-sectional phase of ATHENA who were referred to colposcopy (n=7727) were eligible for enrolment. p16/Ki-67 dual-stained cytology was retrospectively performed on residual cytologic material collected into a second liquid-based cytology vial during the ATHENA enrolment visit. The diagnostic performance of dual-stained cytology, with or without HPV16/18 genotyping, for the detection of biopsy-confirmed cervical intraepithelial neoplasia grade 3 or worse (CIN3+) was determined and compared to Pap cytology. Furthermore, the number of colposcopies required per CIN3+ detected was determined. ResultsDual-stained cytology was significantly more sensitive than Pap cytology (74.9% vs. 51.9%; p<0.0001) for triaging HPV-positive women, whereas specificity was comparable (74.1% vs. 75.0%; p=0.3198). Referral of all HPV16/18 positive women combined with dual-stained cytology triage of women positive for 12 “other” HPV genotypes provided the highest sensitivity for CIN3+ (86.8%; 95% CI: 81.9–90.8). A similar strategy but using Pap cytology for the triage of women positive for 12 “other” HPV genotypes was less sensitive (78.2%; 95% CI: 72.5–83.2; p=0.0003), but required a similar number of colposcopies per CIN3+ detected. Conclusionsp16/Ki-67 dual-stained cytology, either alone or combined with HPV16/18 genotyping, represents a promising approach as a sensitive and efficient triage for colposcopy of HPV-positive women when primary HPV screening is utilized.

Is there really an HPV genotype difference in African American versus Caucasian women? Insights from the ATHENA trial

Is there really an HPV genotype difference in African American versus Caucasian women? Insights from the ATHENA trial

Safety and efficacy of bevacizumab in combination with first-line chemotherapy in advanced breast cancer: data from the Italian cohort of the ATHENA trial.

The ATHENA international study investigated the safety and efficacy of bevacizumab plus first-line chemotherapy in locally recurrent/metastatic breast cancer in routine oncology practice. The present paper focuses on the outcomes of the Italian cohort of the study. A subgroup analysis was carried out to report on the safety (primary endpoint) and efficacy (secondary endpoint) outcomes of patients recruited from Italian Centers. A total of 278 patients were included. Median age was 57 years (range, 26-85), and ECOG performance status was 0 or 1 in 96% of the patients. Bevacizumab was predominantly combined with a taxane monotherapy: paclitaxel (41.4%), docetaxel (21.9%), or a taxane-based combination therapy (12.2%). The most frequent grade ≥3 adverse events previously associated with bevacizumab were hypertension (3.2%), proteinuria (2.9%), and cardiac disorders (0.7%). Median time to progression was 10.9 months. Median overall survival was 29.9 months, and 1-year survival probability was 85%. Objective responses were observed in 62.6% of the patients, and an additional 30% achieved stable disease. Results from the study support the safety and efficacy of bevacizumab in combination with chemotherapy for the treatment of locally recurrent/metastatic breast cancer in the context of routine oncology practice in Italy.