Effectiveness and Safety of Four Direct Oral Anticoagulants in Asian Patients With Nonvalvular Atrial Fibrillation.

BACKGROUND: Whether four direct oral anticoagulants (DOACs) are superior to warfarin in Asian patients with nonvalvular atrial fibrillation (NVAF) remains unclear. METHODS: This nationwide retrospective cohort study was based on data from Taiwan's National Health Insurance Research Database from June 1, 2012, to December 31, 2017, covering patients with NVAF taking edoxaban (n = 4,577), apixaban (n = 9,952), rivaroxaban (n = 33,022), dabigatran (n = 22,371), and warfarin (n = 19,761). Propensity score weighting was used to balance covariates across study groups. Patients were followed up until occurrence of study outcomes or end date of study. RESULTS: Edoxaban, apixaban, and rivaroxaban were associated with a lower risk of ischemic stroke/systemic embolism than warfarin. All DOACs had a lower risk of major bleeding than warfarin. Apixaban was associated with a lower risk of major bleeding than rivaroxaban and dabigatran, whereas the risk of major bleeding was comparable between edoxaban and apixaban. The reduced risks of thromboembolism/major bleeding for the four DOACs persisted in high-risk subgroups, including those with chronic kidney disease, elderly patients (age ≥ 75 years), secondary stroke prevention, or CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, age 65-74 years, and female sex) ≥ 4. A total of 2,924 (64%), 6,359 (64%), 31,108 (94%), and 19,821 (89%) patients received low-dose edoxaban (15-30 mg/d), apixaban (2.5 mg bid), rivaroxaban (10-15 mg/d), and dabigatran (110 mg bid), respectively. The effectiveness/safety outcomes with the four low-dose DOACs compared with warfarin were consistent with the main analysis. CONCLUSIONS: In the largest real-world practice study among Asian patients with NVAF, four DOACs were associated with a comparable or lower risk of thromboembolism, and a lower risk of bleeding than warfarin. There was consistency even among high-risk subgroups and whether standard-or low-dose regimens were compared.

Thromboembolic, Bleeding, and Mortality Risks of Rivaroxaban and Dabigatran in Asians With Nonvalvular Atrial Fibrillation.

BACKGROUND: It is unclear whether the non-vitamin K antagonist oral anticoagulant agents rivaroxaban and dabigatran are superior to warfarin for efficacy and safety outcomes in Asians with nonvalvular atrial fibrillation (NVAF). OBJECTIVES: The aim of this study was to compare the risk for thromboembolic events, bleeding, and mortality associated with rivaroxaban and dabigatran versus warfarin in Asians with NVAF. METHODS: A nationwide retrospective cohort study was conducted of consecutive patients with NVAF taking rivaroxaban (n = 3,916), dabigatran (n = 5,921), or warfarin (n = 5,251) using data collected from the Taiwan National Health Insurance Research Database between February 1, 2013 and December 31, 2013. The propensity score weighting method was used to balance covariates across study groups. Patients were followed until the first occurrence of any study outcome or the study end date (December 31, 2013). RESULTS: A total of 3,425 (87%) and 5,301 (90%) patients were taking low-dose rivaroxaban (10 to 15 mg once daily) and dabigatran (110 mg twice daily), respectively. Compared with warfarin, both rivaroxaban and dabigatran significantly decreased the risk for ischemic stroke or systemic embolism (p = 0.0004 and p = 0.0006, respectively), intracranial hemorrhage (p = 0.0007 and p = 0.0005, respectively), and all-cause mortality (p < 0.0001 and p < 0.0001, respectively) during the short follow-up period. In comparing the 2 non-vitamin K antagonist oral anticoagulant agents with each other, no differences were found regarding risk for ischemic stroke or systemic embolism, intracranial hemorrhage, myocardial infarction, or mortality. Rivaroxaban carried a significantly higher risk for hospitalization for gastrointestinal bleeding than dabigatran (p = 0.0416), but on-treatment analysis showed that the risk for hospitalized gastrointestinal bleeding was similar between the 2 drugs (p = 0.5783). CONCLUSIONS: In real-world practice among Asians with NVAF, both rivaroxaban and dabigatran were associated with reduced risk for ischemic stroke or systemic embolism, intracranial hemorrhage, and all-cause mortality without significantly increased risk for acute myocardial infarction or hospitalization for gastrointestinal bleeding compared with warfarin.

Heart failure enhances arrhythmogenesis in pulmonary veins.

1. Heart failure (HF) predisposes to atrial fibrillation (AF) as a result of substrate remodelling. The present study aimed to investigate the impact of HF on the electrical remodelling of the pulmonary veins (PV) and left atrium (LA). 2. The electrical activity was recorded in LA and PV from control rabbits and rabbits with rapid ventricular pacing-induced HF, using a multi-electrode array system and conventional microelectrodes. 3. Compared with the control-PV (n = 21), the HF-PV (n = 13) had a higher incidence and frequency of rapid pacing-induced spontaneous activity (85 vs 29%, P = 0.005; 3.5 ± 0.2 vs 1.7 ± 0.1 Hz, P < 0.001) and high-frequency irregular electrical activity (92 vs 38%, P = 0.01; 23 ± 1 vs 19 ± 1 Hz, P = 0.003), greater depolarized resting membrane potential (-59 ± 1 vs -70 ± 2 mV, P < 0.001), higher incidence of early afterdepolarizations (EAD; 69 vs 6%, P = 0.001) and delayed afterdepolarizations (DAD; 92 vs 25%, P = 0.001), and slower conduction velocity (38 ± 2 vs 63 ± 2 cm/s, P < 0.05). In comparison to the HF-LA, the HF-PV had a higher incidence of spontaneous activity and high-frequency irregular electrical activity (85 vs 39%, P = 0.04; 92 vs 46%, P = 0.03), and higher incidence of EAD and DAD, and those differences were not found between the control-LA and control-PV. The control-PV with high-frequency irregular electrical activity had a higher incidence of DAD and spontaneous activity as compared with those without it. 4. HF contributed to an increased automaticity, triggered activity and conduction disturbance in the PV. The PV possessed more arrhythmogenic properties, which might play an important role in the genesis of AF in HF.

Changes in connexin expression and the atrial fibrillation substrate in congestive heart failure.

RATIONALE: Although connexin changes are important for the ventricular arrhythmic substrate in congestive heart failure (CHF), connexin alterations during CHF-related atrial arrhythmogenic remodeling have received limited attention. OBJECTIVE: To analyze connexin changes and their potential contribution to the atrial fibrillation (AF) substrate during the development and reversal of CHF. METHODS AND RESULTS: Three groups of dogs were studied: CHF induced by 2-week ventricular tachypacing (240 bpm, n=15); CHF dogs allowed a 4-week nonpaced recovery interval after 2-week tachypacing (n=16); and nonpaced sham controls (n=19). Left ventricular (LV) end-diastolic pressure and atrial refractory periods increased with CHF and normalized on CHF recovery. CHF caused abnormalities in atrial conduction indexes and increased the duration of burst pacing-induced AF (DAF, from 22+/-7 seconds in control to 1100+/-171 seconds, P<0.001). CHF did not significantly alter overall atrial connexin (Cx)40 and Cx43 mRNA and protein expression levels, but produced Cx43 dephosphorylation, increased Cx40/Cx43 protein expression ratio and caused Cx43 redistribution toward transverse cell-boundaries. All of the connexin-alterations reversed on CHF recovery, but CHF-induced conduction abnormalities and increased DAF (884+/-220 seconds, P<0.001 versus control) remained. The atrial fibrous tissue content increased from 3.6+/-0.7% in control to 14.7+/-1.5% and 13.3+/-2.3% in CHF and CHF recovery, respectively (both P<0.01 versus control), with transversely running zones of fibrosis physically separating longitudinally directed muscle bundles. In an ionically based action potential/tissue model, fibrosis was able to account for conduction abnormalities associated with CHF and recovery. CONCLUSIONS: CHF causes atrial connexin changes, but these are not essential for CHF-related conduction disturbances and AF promotion, which are rather related primarily to fibrotic interruption of muscle bundle continuity.

Funny current downregulation and sinus node dysfunction associated with atrial tachyarrhythmia: a molecular basis for tachycardia-bradycardia syndrome.

BACKGROUND: Sinoatrial node (SAN) dysfunction is frequently associated with atrial tachyarrhythmias (ATs). Abnormalities in SAN pacemaker function after termination of ATs can cause syncope and require pacemaker implantation, but underlying mechanisms remain poorly understood. This study examined the hypothesis that ATs impair SAN function by altering ion channel expression. METHODS AND RESULTS: SAN tissues were obtained from 28 control dogs and 31 dogs with 7-day atrial tachypacing (400 bpm). Ionic currents were measured from single SAN cells with whole-cell patch-clamp techniques. Atrial tachypacing increased SAN recovery time in vivo by approximately 70% (P<0.01), a change which reflects impaired SAN function. In dogs that underwent atrial tachypacing, SAN mRNA expression (real-time reverse-transcription polymerase chain reaction) was reduced for hyperpolarization-activated cyclic nucleotide-gated subunits (HCN2 and HCN4) by >50% (P<0.01) and for the beta-subunit minK by approximately 42% (P<0.05). SAN transcript expression for the rapid delayed-rectifier (I(Kr)) alpha-subunit ERG, the slow delayed-rectifier (I(Ks)) alpha-subunit KvLQT1, the beta-subunit MiRP1, the L-type (I(CaL)) and T-type (I(CaT)) Ca2+-current subunits Cav1.2 and Cav3.1, and the gap-junction subunit connexin 43 (were unaffected by atrial tachypacing. Atrial tachypacing reduced densities of the HCN-related funny current (I(f)) and I(Ks) by approximately 48% (P<0.001) and approximately 34% (P<0.01), respectively, with no change in voltage dependence or kinetics. I(Kr), I(CaL), and I(CaT) were unaffected. SAN cells lacked Ba2+-sensitive inward-rectifier currents, irrespective of AT. SAN action potential simulations that incorporated AT-induced alterations in I(f) accounted for slowing of periodicity, with no additional contribution from changes in I(Ks). CONCLUSIONS: AT downregulates SAN HCN2/4 and minK subunit expression, along with the corresponding currents I(f) and I(Ks). Tachycardia-induced remodeling of SAN ion channel expression, particularly for the "pacemaker" subunit I(f), may contribute to the clinically significant association between SAN dysfunction and supraventricular tachyarrhythmias.

Pleomorphic ventricular tachycardia: an uncommon presentation in idiopathic left ventricular tachycardia.

Idiopathic left ventricular tachycardia (ILVT) is a distinct entity that arises in the left ventricle, may have reentrant mechanism and is verapamil-sensitive. Pleomorphism as defined by multiple ventricular tachycardia morphologies is usually associated with either coronary artery disease or cardiomyopathy but very rare in cases of ILVT. In this case report, we describe an unusual case of ILVT with two ECG morphologies of the opposite axis that were successfully eliminated with radiofrequency ablation. The successful ablation sites were closely located to each other in the left lower ventricular septum.