Clinical significance of the rivaroxaban-dronedarone interaction: insights from physiologically based pharmacokinetic modelling.

Patients with atrial fibrillation may require rhythm control therapy in addition to anticoagulation therapy for the prevention of stroke. Since 2012, the European Society of Cardiology and European Heart Rhythm Association guidelines have recommended non-vitamin K antagonist oral anticoagulants, including rivaroxaban, for the prevention of stroke in patients with atrial fibrillation. During the same period, these guidelines have also recommended dronedarone or amiodarone as second-line rhythm control agents in certain patients with atrial fibrillation and no contraindications. Amiodarone and dronedarone both strongly inhibit P-glycoprotein, while dronedarone is a moderate and amiodarone a weak inhibitor of cytochrome P450 3A4 (CYP3A4). Based on these data and evidence from physiologically based pharmacokinetic modelling, amiodarone and dronedarone are expected to have similar effects on rivaroxaban exposure resulting from P-glycoprotein and CYP3A4 inhibition. However, the rivaroxaban label recommends against the concomitant use of dronedarone, but not amiodarone, citing a lack of evidence on the concomitant use of rivaroxaban and dronedarone as the reason for the different recommendations. In this report, we discuss evidence from clinical studies and physiologically based pharmacokinetic modelling on the potential for increased rivaroxaban exposure resulting from drug-drug interaction between rivaroxaban and dronedarone or amiodarone. The current evidence supports the same clinical status and concomitant use of either amiodarone or dronedarone with rivaroxaban, which could be considered in future recommendations.

Applications of Physiologically Based Pharmacokinetic Modeling of Rivaroxaban-Renal and Hepatic Impairment and Drug-Drug Interaction Potential.

The non-vitamin K antagonist oral anticoagulant rivaroxaban is used in several thromboembolic disorders. Rivaroxaban is eliminated via both metabolic degradation and renal elimination as unchanged drug. Therefore, renal and hepatic impairment may reduce rivaroxaban clearance, and medications inhibiting these clearance pathways could lead to drug-drug interactions. This physiologically based pharmacokinetic (PBPK) study investigated the pharmacokinetic behavior of rivaroxaban in clinical situations where drug clearance is impaired. A PBPK model was developed using mass balance and bioavailability data from adults and qualified using clinically observed data. Renal and hepatic impairment were simulated by adjusting disease-specific parameters, and concomitant drug use was simulated by varying enzyme activity in virtual populations (n = 1000) and compared with pharmacokinetic predictions in virtual healthy populations and clinical observations. Rivaroxaban doses of 10 mg or 20 mg were used. Mild to moderate renal impairment had a minor effect on area under the concentration-time curve and maximum plasma concentration of rivaroxaban, whereas severe renal impairment caused a more pronounced increase in these parameters vs normal renal function. Area under the concentration-time curve and maximum plasma concentration increased with severity of hepatic impairment. These effects were smaller in the simulations compared with clinical observations. AUC and Cmax increased with the strength of cytochrome P450 3A4 and P-glycoprotein inhibitors in simulations and clinical observations. This PBPK model can be useful for estimating the effects of impaired drug clearance on rivaroxaban pharmacokinetics. Identifying other factors that affect the pharmacokinetics of rivaroxaban could facilitate the development of models that approximate real-world pharmacokinetics more accurately.

Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.

AIMS: VENTURE-AF is the first prospective randomized trial of uninterrupted rivaroxaban and vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF) undergoing catheter ablation (CA). METHODS AND RESULTS: Trial size was administratively set at 250, the protocol-specified target. Events were independently and blindly adjudicated. We randomly assigned 248 NVAF patients to uninterrupted rivaroxaban (20 mg once-daily) or to an uninterrupted VKA prior to CA and for 4 weeks afterwards. The primary endpoint was major bleeding events after CA. Secondary endpoints included thromboembolic events (composite of stroke, systemic embolism, myocardial infarction, and vascular death) and other bleeding or procedure-attributable events. Patients were 59.5 ± 10 years of age, 71% male, 74% paroxysmal AF, and had a CHA2DS2-VASc score of 1.6. The average total heparin dose used to manage activated clotting time (ACT) was slightly higher (13 871 vs. 10 964 units; P < 0.001) and the mean ACT level attained slightly lower (302 vs. 332 s; P < 0.001) in rivaroxaban and VKA arms, respectively. The incidence of major bleeding was low (0.4%; 1 major bleeding event). Similarly, thromboembolic events were low (0.8%; 1 ischemic stroke and 1 vascular death). All events occurred in the VKA arm and all after CA. The number of any adjudicated events (26 vs. 25), any bleeding events (21 vs. 18), and any other procedure-attributable events (5 vs. 5) were similar. CONCLUSION: In patients undergoing CA for AF, the use of uninterrupted oral rivaroxaban was feasible and event rates were similar to those for uninterrupted VKA therapy. NAME OF THE TRIAL REGISTRY: Clinicaltrials.gov trial registration number is NCT01729871.

Long-term benefit of implantable cardioverter/defibrillator therapy after elective device replacement: results of the INcidence free SUrvival after ICD REplacement (INSURE) trial--a prospective multicentre study.

AIMS: Prevention of sudden cardiac death by means of the implantable cardioverter/defibrillator (ICD) is considered to be a lifelong therapy. However, it is still unresolved if patients who never experienced an appropriate ICD intervention during generator longevity really need to undergo device replacement. METHODS AND RESULTS: The INSURE trial was a multicentre prospective observational cohort study that enrolled patients at the time of their first ICD replacement. Patients with and without previous appropriate ICD therapy were enrolled prospectively and were evaluated every 3-6 months after ICD replacement. Primary endpoint of the study was the first occurrence of appropriate ICD therapy after device replacement. Five hundred and ten patients (83% males, mean age 65 ± 10 years, mean ejection fraction 39 ± 16%) were enrolled between 2002 and 2007 in the study after an average lifespan of their first ICD generator of 62 ± 18 months. Three years after elective ICD replacement, the rates of appropriate ICD therapies in patients with (n = 245) and without (n = 265) former appropriate ICD intervention were 48.1 and 21.4% (adjusted hazard ratio 3.08, CI: 2.15-4.39, P < 0.001). Notably, no predictive factors for lower need of ICD therapy could be identified in patients without prior appropriate ICD intervention. CONCLUSIONS: In this study, a significant number of ICD-indicated patients without the need for therapy by their first device received appropriate ICD intervention after generator replacement. There were no predictors for lower need of ICD therapy. Hence, ICD replacement appears still necessary in patients without prior ICD interventions.

Reduction of atrial fibrillation burden by atrial overdrive pacing: experience with an improved algorithm to reduce early recurrences of atrial fibrillation.

AIMS: Two independent studies have revealed a potential limitation of post-mode switch overdrive pacing (PMOP), which is its delayed start. METHODS AND RESULTS: We conducted a prospective, randomized, single blind, crossover design study (the post-long pause overdrive pacing study) to test the efficacy of an improved version of PMOP (PMOP(enhanced)). A total of 45 patients were enrolled, of whom 41 were analysed. The median number of atrial tachycardia/atrial fibrillation (AT/AF) episodes per day (1.38 vs. 1.19), the median number of early recurrences of atrial fibrillation (ERAF) per day (0.56 vs. 0.51), and the median AT/AF burden (time per day spent in AT/AF) (2.47 vs. 2.51 h) were not significantly different during the control and active study periods. Based on the median number of episodes per week recorded 90 days prior to enrollment, the patients were stratified by the median and then split into two groups, Group A (lower 2-Quartiles) and Group B (upper 2-Quartiles). The median AT/AF burden was significantly lower in Group B during the active study period (3.71 vs. 1.71 h, P = 0.02).The median number of AT/AF episodes per day and the median number of ERAF per day in Group B showed a trend towards reduction when the algorithm was turned on (3.79 vs. 2.44 and 2.77 vs. 1.86, respectively). In contrast, in Group A we did not demonstrate any difference in AT/AF frequency, ERAF frequency, or burden. CONCLUSION: The main finding of this study is that temporary overdrive pacing at 90 bpm for 10 min starting just prior to device-classified AT/AF termination does not show a positive effect on the overall study population. However, when enabled in patients who suffer from a high percentage of ERAF, a significant reduction in the AT/AF burden could be demonstrated. Based on these findings, further prospective studies on a more targeted patient population are needed to confirm our results.

Atrial fibrillation burden during the post-implant period after crt using device-based diagnostics.

UNLABELLED: AF Burden After CRT Implantation. AIMS: Cardiac resynchronization therapy (CRT) is increasingly used in congestive heart failure (CHF) patients (with cardiac dyssynchrony). In addition to delivering therapy, CRT devices offer a variety of diagnostic tools for continuous long-term monitoring of clinically relevant information (i.e., occurrence and duration of arrhythmia episodes). METHODS AND RESULTS: Eighty-four patients with drug-refractory CHF in NYHA-class II-IV received a CRT device. The response to CRT was assessed by determining NYHA class at baseline and at 3 months follow-up. Atrial fibrillation (AF) burden (defined as time of AF per day) was continuously measured by the device. A significant gradual reduction of AF burden (from 9.88 +/- 12.61 to 4.20 +/- 9.24 [hours/day]) and number of patients experiencing AF episodes (from 26 to 13) were observed during CRT. CONCLUSIONS: (1) Diagnostic features for long-term monitoring of physiological variables provide useful information on the state and course of AF and may improve disease management. (2) AF burden reduces over time during the first 3 months after CRT implantation.