Safety and effectiveness of edoxaban in a real-world clinical setting: Two-year follow-up of the ETNA-AF-Europe study

Abstract Funding Acknowledgements Type of funding sources: Private company. Main funding source(s): Daiichi Sankyo Europe OnBehalf ETNA-AF-Europe investigators Background Oral anticoagulation (OAC) for stroke prevention is essential in the management of patients with atrial fibrillation (AF). The assessment of OAC use in routine clinical care and the effects of this therapy on outcomes and safety are important. Purpose: We analysed two-year outcome data with adjudicated follow-up results in 13,417 patients with AF treated with edoxaban. Methods: ETNA-AF-Europe (Clinicaltrials.gov: NCT02944019) enrolled 13,417 consecutive patients with AF treated with edoxaban in 825 centres in 10 European countries and 2-year prospectively collected, real world data is presented. Results: Edoxaban was prescribed according to licence recommendations in 83.1% (n = 11,146) of patients (Table). Whilst three quarters of patients were prescribed edoxaban 60 mg (n = 10,248, 76.4%), the quarter prescribed edoxaban 30 mg were older (79.5 versus 71.8 years), had a higher stroke risk (CHA2DS2-VASc score: 3.9 versus 3.0) and a higher bleeding risk (HAS-BLED score: 2.9 versus 2.4). Thromboembolic and bleeding events were more common in patients receiving edoxaban 30 mg OD without differences in intracranial haemorrhage (ICH) (Figure). Patients prescribed a non-recommended dose of edoxaban had a numerically higher stroke risk (CHA2DS2-VASc score: 3.6 versus 3.1) with subsequent higher rates of ischemic stroke and mortality, however they also had higher bleeding rates, with the exception of ICH (table) despite a similar initial bleeding risk (HAS-BLED score: 2.7 versus 2.5). Conclusions: In this large, European data set reporting two-year outcomes on edoxaban therapy, no additional safety signals were observed and event rates were in line with those observed in ETNA-AF after 1 year and in ENGAGE AF-TIMI 48, re-affirming the safety and effectiveness of edoxaban licence recommendations in a real world setting of patients with AF. All key events of interest, other than intracranial haemorrhage, were numerically lower in patients prescribed the licenced recommended dose. Outcomes with rec. vs non-rec. dosesn (%/year [95%CI])Recommended dose (n = 11,146; 83.1%)Non-recommended dose (n = 2271; 16.9%)Any stroke/SEE138 (0.68 [0.57;0.80])31 (0.76 [0.51;1.07])Ischaemic stroke99 (0.48 [0.39;0.59])26 (0.63 [0.41; 0.93])Major bleeding189 (0.93 [0.80;1.07])49 (1.20 [0.89;1.59])Intracranial haemorrhage43 (0.21 [0.15;0.28])7 (0.17 [0.07;0.35])All-cause mortality729 (3.55 [3.30;3.82])208 (5.04 [4.38;5.78])CV mortality405 (1.97 [1.79;2.18])113 (2.74 [2.26;3.30])CI, confidence interval; CV, cardiovascular; rec., recommended; SEE, systemic embolic event.Abstract Figure. Annualised event rates at 2-year F

Analysis of additivity and synergism in the anti-plasmodial effect of purified compounds from plant extracts

In the search for antimalarials from ethnobotanical origin, plant extracts are chemically fractionated and biological tests guide the isolation of pure active compounds. To establish the responsibility of isolated active compound(s) to the whole antiplasmodial activity of a crude extract, the literature in this field was scanned and results were analysed quantitatively to find the contribution of the pure compound to the activity of the whole extract. It was found that, generally, the activity of isolated molecules could not account on their own for the activity of the crude extract. It is suggested that future research should take into account the “drugs beside the drug”, looking for those products (otherwise discarded along the fractionation process) able to boost the activity of isolated active compounds

Device complications with addition of defibrillation to cardiac resynchronisation therapy for primary prevention

Objective: In patients indicated for cardiac resynchronisation therapy (CRT), the choice between a CRT-pacemaker (CRT-P) versus defibrillator (CRT-D) remains controversial and indications in this setting have not been well delineated. Apart from inappropriate therapies, which are inherent to the presence of a defibrillator, whether adding defibrillator to CRT in the primary prevention setting impacts risk of other acute and late device-related complications has not been well studied and may bear relevance for device selection. // Methods: Observational multicentre European cohort study of 3008 consecutive patients with ischaemic or non-ischaemic dilated cardiomyopathy and no history of sustained ventricular arrhythmias, undergoing CRT implantation with (CRT-D, n=1785) or without (CRT-P, n=1223) defibrillator. Using propensity score and competing risk analyses, we assessed the risk of significant device-related complications requiring surgical reintervention. Inappropriate shocks were not considered except those due to lead malfunction requiring lead revision. // Results: Acute complications occurred in 148 patients (4.9%), without significant difference between groups, even after considering potential confounders (OR=1.20, 95% CI 0.72 to 2.00, p=0.47). During a mean follow-up of 41.4±29 months, late complications occurred in 475 patients, giving an annual incidence rate of 26 (95% CI 9 to 43) and 15 (95% CI 6 to 24) per 1000 patient-years in CRT-D and CRT-P patients, respectively. CRT-D was independently associated with increased occurrence of late complications (HR=1.68, 95% CI 1.27 to 2.23, p=0.001). In particular, when compared with CRT-P, CRT-D was associated with an increased risk of device-related infection (HR 2.10, 95% CI 1.18 to 3.45, p=0.004). Acute complications did not predict overall late complications, but predicted device-related infection (HR 2.85, 95% CI 1.71 to 4.56, p<0.001). // Conclusions: Compared with CRT-P, CRT-D is associated with a similar risk of periprocedural complications but increased risk of long-term complications, mainly infection. This needs to be considered in the decision of implanting CRT with or without a defibrillator

Impact of extending device longevity on the long-term costs of implantable cardioverter-defibrillator therapy: a modelling study with a 15-year time horizon.

AIMS: To determine the long-term costs of extending device longevity in four patient populations requiring a single-chamber implantable cardioverter-defibrillator (ICD) or requiring cardiac resynchronization therapy with defibrillation (CRT-D) device over a 15-year time window.METHODS AND RESULTS: We considered patient populations with an accepted indication for a single-chamber ICD for prevention of sudden cardiac death in the context of preserved (Population A) or impaired (Population B) left ventricular function; or with indication for a CRT-D device in the context of heart failure in New York Heart Association class II (Population C) or III (Population D). Expected patient survival and a cost analysis, including the cost of complications, was undertaken from a hospital perspective. Extended device longevity of 5 vs. 9 years for ICDs (Populations A and B); 4 vs. 7 years for CRT-Ds (Populations C and D) were considered. Over a 15-year time horizon, total, yearly, and per diem savings, per patient, from extending ICD longevity to 9 years were €10 926.91, €728.46, and €1.99 for Population A, and €7661.32, €510.75, and €1.40 for Population B. Total, yearly, and per diem savings from extending CRT-D longevity to 7 years were €13 630.38, €908.69, and €2.49 for Population C, and €10 968.29, €731.22, and €2.00 for Population D. Avoidance of a generator replacement amounted up to 46.6-62.5% of the saving.CONCLUSION: Extending device longevity has an important effect on the long-term cost of device therapy, both for ICD and CRT-D. This has important implications for device choice

Impact of extending device longevity on the long-term costs of implantable cardioverter-defibrillator therapy: a modelling study with a 15-year time horizon.

AIMS: To determine the long-term costs of extending device longevity in four patient populations requiring a single-chamber implantable cardioverter-defibrillator (ICD) or requiring cardiac resynchronization therapy with defibrillation (CRT-D) device over a 15-year time window.METHODS AND RESULTS: We considered patient populations with an accepted indication for a single-chamber ICD for prevention of sudden cardiac death in the context of preserved (Population A) or impaired (Population B) left ventricular function; or with indication for a CRT-D device in the context of heart failure in New York Heart Association class II (Population C) or III (Population D). Expected patient survival and a cost analysis, including the cost of complications, was undertaken from a hospital perspective. Extended device longevity of 5 vs. 9 years for ICDs (Populations A and B); 4 vs. 7 years for CRT-Ds (Populations C and D) were considered. Over a 15-year time horizon, total, yearly, and per diem savings, per patient, from extending ICD longevity to 9 years were \u20ac10 926.91, \u20ac728.46, and \u20ac1.99 for Population A, and \u20ac7661.32, \u20ac510.75, and \u20ac1.40 for Population B. Total, yearly, and per diem savings from extending CRT-D longevity to 7 years were \u20ac13 630.38, \u20ac908.69, and \u20ac2.49 for Population C, and \u20ac10 968.29, \u20ac731.22, and \u20ac2.00 for Population D. Avoidance of a generator replacement amounted up to 46.6-62.5% of the saving.CONCLUSION: Extending device longevity has an important effect on the long-term cost of device therapy, both for ICD and CRT-D. This has important implications for device choice

The benefit of pacemaker therapy in patients with neurally mediated syncope and documented asystole: a meta-analysis of implantable loop recorder studies

Aim: Although the efficacy of cardiac pacing in patients with neurally mediated syncope (NMS) and documented asystole is established, a more robust point estimate of the benefit, which is not possible with any individual study, is lacking. Methods and results: We undertook a meta-analysis of individual participant data from four studies that reported follow-up data on syncope recurrence with cardiac pacing in patients with NMS who had had an electrocardiographic (ECG) documentation of an asystolic event by means of implantable loop recorder (ILR). Of a total of 1046 patients, who had ILR implanted, 383 (36.6%) patients had an ECG documentation of a diagnostic event during mean follow-up of 13 ± 10 months. Of these, 201 (52%) patients, corresponding to 19.2% of the total ILRs, had an asystolic event of 12.8 ± 11.0 s duration documented and met the criteria for pacemaker therapy. Follow-up was available in 121 (60%) of those patients with asystolic events. Syncope recurred after pacing in 18 (14.9%) patients with an actuarial rate of 13% [95% confidence interval (CI) ±6] at 1 year, 21% (95%CI ±10) at 2 years, and 24% (95%CI ±11) at 3 years. On multivariable Cox regression analysis, positive tilt test response was the only significant predictor of syncope recurrence with a hazard ratio (95% CI) of 4.3 (1.4-13). On the contrary, type of asystolic event (sinus arrest or atrioventricular block), prodrome, cardiac abnormalities, number and duration of history of syncope, age, and gender were not predictors of recurrence of syncope. Conclusion: A long asystolic pause, suitable for pacemaker therapy, was found in one of five patients with ILR. After pacemaker implantation, most of these patients remained free of syncope recurrence for up to 3 years. The benefit of pacemaker was greater in patients with negative tilt test