Yung-Hsin Yeh

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

BACKGROUNDnIt 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).nnnOBJECTIVESnThe 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.nnnMETHODSnA nationwide retrospective cohort study was conducted of consecutive patients with NVAF taking rivaroxaban (nxa0= 3,916), dabigatran (nxa0= 5,921), or warfarin (nxa0= 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).nnnRESULTSnA 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 (pxa0= 0.0004 and pxa0= 0.0006, respectively), intracranial hemorrhage (pxa0= 0.0007 and pxa0= 0.0005, respectively), and all-cause mortality (pxa0< 0.0001 and pxa0<xa00.0001, 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 (pxa0= 0.0416), but on-treatment analysis showed that the risk for hospitalized gastrointestinal bleeding was similar between the 2 drugs (pxa0= 0.5783).nnnCONCLUSIONSnIn 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.

Association Between Use of Non–Vitamin K Oral Anticoagulants With and Without Concurrent Medications and Risk of Major Bleeding in Nonvalvular Atrial Fibrillation

Importance Non–vitamin K oral anticoagulants (NOACs) are commonly prescribed with other medications that share metabolic pathways that may increase major bleeding risk. Objective To assess the association between use of NOACs with and without concurrent medications and risk of major bleeding in patients with nonvalvular atrial fibrillation. Design, Setting, and Participants Retrospective cohort study using data from the Taiwan National Health Insurance database and including 91 330 patients with nonvalvular atrial fibrillation who received at least 1 NOAC prescription of dabigatran, rivaroxaban, or apixaban from January 1, 2012, through December 31, 2016, with final follow-up on December 31, 2016. Exposures NOAC with or without concurrent use of atorvastatin; digoxin; verapamil; diltiazem; amiodarone; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; cyclosporine; erythromycin or clarithromycin; dronedarone; rifampin; or phenytoin. Main Outcomes and Measures Major bleeding, defined as hospitalization or emergency department visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding. Adjusted incidence rate differences between person-quarters (exposure time for each person during each quarter of the calendar year) of NOAC with or without concurrent medications were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score. Results Among 91 330 patients with nonvalvular atrial fibrillation (mean age, 74.7 years [SD, 10.8]; men, 55.8%; NOAC exposure: dabigatran, 45 347 patients; rivaroxaban, 54 006 patients; and apixaban, 12 886 patients), 4770 major bleeding events occurred during 447 037 person-quarters with NOAC prescriptions. The most common medications co-prescribed with NOACs over all person-quarters were atorvastatin (27.6%), diltiazem (22.7%), digoxin (22.5%), and amiodarone (21.1%). Concurrent use of amiodarone, fluconazole, rifampin, and phenytoin with NOACs had a significant increase in adjusted incidence rates per 1000 person-years of major bleeding than NOACs alone: 38.09 for NOAC use alone vs 52.04 for amiodarone (difference, 13.94 [99% CI, 9.76-18.13]); 102.77 for NOAC use alone vs 241.92 for fluconazole (difference, 138.46 [99% CI, 80.96-195.97]); 65.66 for NOAC use alone vs 103.14 for rifampin (difference, 36.90 [99% CI, 1.59-72.22); and 56.07 for NOAC use alone vs 108.52 for phenytoin (difference, 52.31 [99% CI, 32.18-72.44]; Pu2009<u2009.01 for all comparisons). Compared with NOAC use alone, the adjusted incidence rate for major bleeding was significantly lower for concurrent use of atorvastatin, digoxin, and erythromycin or clarithromycin and was not significantly different for concurrent use of verapamil; diltiazem; cyclosporine; ketoconazole, itraconazole, voriconazole, or posaconazole; and dronedarone. Conclusions and Relevance Among patients taking NOACs for nonvalvular atrial fibrillation, concurrent use of amiodarone, fluconazole, rifampin, and phenytoin compared with the use of NOACs alone, was associated with increased risk of major bleeding. Physicians prescribing NOAC medications should consider the potential risks associated with concomitant use of other drugs.

Acute Kidney Injury in Asians With Atrial Fibrillation Treated With Dabigatran or Warfarin.

BACKGROUNDnWhether dabigatran is associated with a lower risk of acute kidney injury (AKI) in patients with nonvalvular atrial fibrillation (NVAF) remains unknown.nnnOBJECTIVESnThe authors compared the risk of AKI in Asians with NVAF who were prescribed dabigatran versusxa0warfarin.nnnMETHODSnThe authors analyzed patients enrolled in the Taiwan nationwide retrospective cohort study from June 1, 2012, to December 31, 2013. Dabigatran and warfarin were taken by 7,702 and 7,885 NVAF patients without a history of chronic kidney disease (CKD) and 2,256 and 2,089 NVAF patients with a history of CKD, respectively. A propensity-score weighted method was used to balance covariates across study groups.nnnRESULTSnA total of 6,762 (88%) and 940 (12%) CKD-free patients and 2,025 (90%) and 231 (10%) CKD patients took dabigatran 110 mg and 150 mg twice daily, respectively. Dabigatran was associated with a lower risk of AKI than warfarin for either the CKD-free (hazard ratio [HR]: 0.62; 95% confidence interval [CI]: 0.49 to 0.77; pxa0< 0.001) or CKD (HR:xa00.56; 95% CI: 0.46 to 0.69; pxa0< 0.001) cohort. As the increment in CHA2DS2-VASc score (a risk score based on congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke/transient ischemic attack, vascular disease, aged 65 to 74 years, and female sex) increased from 0/1 to 6+ points, the incidence of AKI for the dabigatran group was relatively stable (1.87% to 2.91% per year for the CKD-free cohort; 7.31% to 13.15% per year for the CKD cohort) but increased obviously for patients taking warfarin for either CKD-free (2.00% to 6.16% per year) or CKD cohorts (6.82 to 26.03% per year). The warfarin group had a significantly higher annual risk of AKI than the dabigatran group for those with a high CHA2DS2-VASc score (≥4 for the CKD-free cohort andxa0≥3 for the CKD cohort). Subgroup analysis revealed that among dabigatran users, those taking either low-dose or standard-dose dabigatran, those with a warfarin-naïve or warfarin-experienced history, those with or without diabetes, and those with CHA2DS2-VAScxa0≥4 or HAS-BLEDxa0≥3 (risk score based on hypertension, abnormal renal and liver function, stroke, prior major bleeding, labile international normalized ratios, age 65 years or older, drugs or alcohol usage history) all had a lower risk of AKI than those taking warfarin.nnnCONCLUSIONSnAmong Asians with NVAF, dabigatran is associated with a lower risk of AKI than warfarin.

Electrophysiological and mechanical effects of caffeic acid phenethyl ester, a novel cardioprotective agent with antiarrhythmic activity, in guinea-pig heart.

Caffeic acid phenethyl ester (CAPE) is an active component of propolis that exhibits cardioprotective and antiarrhythmic effects. The detailed mechanisms underlying these effects, however, are not entirely understood. The aim of this study was to elucidate the electromechanical effects of CAPE in guinea-pig cardiac preparations. Intracardiac electrograms, left ventricular (LV) pressure, and the anti-arrhythmic efficacy were determined using isolated hearts. Action potentials of papillary muscles were assessed with microelectrodes, Ca(2+) transients were measured by fluorescence, and ion fluxes were measured by patch-clamp techniques. In a perfused heart model, CAPE prolonged the atrio-ventricular conduction interval, the Wenckebach cycle length, and the refractory periods of the AV node and His-Purkinje system, while shortening the QT interval. CAPE reduced the occurrence of reperfusion-induced ventricular fibrillation and decreased LV pressure in isolated hearts. In papillary muscles, CAPE shortened the action potential duration and reduced both the maximum upstroke velocity and contractile force. In fura-2-loaded single ventricular myocytes, CAPE decreased cell shortening and the Ca(2+) transient amplitude. Patch-clamp experiments revealed that CAPE produced a use-dependent decrease in L-type Ca(2+) current (ICa,L) (IC50=1.1 μM) and Na(+) current (INa) (IC50=0.43 μM), caused a negative-shift of the voltage-dependent inactivation and a delay of recovery from inactivation. CAPE decreased the delayed outward K(+) current (IK) slightly, without affecting the inward rectifier K(+) current (IK1). These results suggest that the preferential inhibition of Ca(2+) inward and Na(+) inward currents by CAPE may induce major electromechanical alterations in guinea-pig cardiac preparations, which may underlie its antiarrhythmic action.

Young Male Patients with Atrial Fibrillation and CHA2DS2-VASc Score of 1 May Not Need Anticoagulants: A Nationwide Population-Based Study

Background It is unclear whether oral anticoagulants are beneficial for atrial fibrillation (AF) patients with low CHA2DS2-VASc score. Age could be important in determining the risk of thromboembolism in low risk AF patients (CHA2DS2-VASc score of 1 for male or 2 for female). Methods The Taiwan National Health Insurance Research Database (NHIRD) was used and 27,521 AF patients with CHA2DS2-VASc score of 1 (male) or 2 (female) not receiving anticoagulants were acquired as the study cohort, which were classified into three age groups: 20–49, 50–64, and 65–74 years. The clinical endpoint was the occurrence of ischemic thromboembolism within one year of follow up. Results During the follow-up of 0.94 ± 0.19 years, 385 (2.19%) male patients experienced ischemic thromboembolism, with annual rate of 2.32%. The annual risk ranged from 1.29%, 2.43% to 2.77% for male patients aged 20–49, 50–64 and 65–74 years respectively. Of the female patients, 218 (2.20%) experienced clinical event with annual rate of 2.32%. The annual risk increased from 1.87%, 2.28% to 2.64% for female patients aged 20–49, 50–64 and 65–74 years respectively. There was no difference in risk between the male patients aged 20–49 years with CHA2DS2-VASc score of 1 and overall male patients with CHA2DS2-VASc score of 0. (P = 0.631) The female patients aged 20–49 years with CHA2DS2-VASc score of 2 was associated with a higher risk of thromboembolic events than overall female patients with CHA2DS2-VASc score of 1 (HR = 1.93; P = 0.008). Conclusions Age is important in determining the risk of thromboembolism in AF patients with single risk factor. In male patients <50 years old with CHA2DS2-VASc score of 1, the risk of ischemic thromboembolism was low. Considering the benefits and the risk of bleeding, oral anticoagulation therapy may not be favorable in these patients.

Combined Global Longitudinal Strain and Intraventricular Mechanical Dyssynchrony Predicts Long-Term Outcome in Patients With Systolic Heart Failure.

BACKGROUNDnLeft ventricular (LV) ejection fraction (EF) and QRS duration enable prediction of outcome in patients with systolic heart failure (SHF). We assessed the predictive value of global longitudinal strain (GLS) and mechanical dyssynchrony for prognosis in SHF patients.nnnMETHODS AND RESULTSnTwo-hundred and forty SHF patients with LVEF ≤40% were studied. Global LV function and intraventricular mechanical dyssynchrony were calculated as GLS and SD of the time to peak longitudinal strain (SDε) over 18 LV segments. The added value of GLS and SDε for outcome prediction was assessed using nested Cox models. Sixty-six patients (28%) reached the study endpoint of all-cause mortality/heart transplantation over a median follow-up period of 45 months. Baseline variables associated with adverse outcome were age, glomerular filtration rate, pulmonary artery systolic pressure, diabetes and LV end-systolic volume (model χ(2)=69.8). The predictive power of the clinical variables was greater with addition of GLS (χ(2)=81.1) or SDε (χ(2)=102.3) than with LVEF (χ(2)=73.9) or QRS duration (χ(2)=75.5; both P<0.005). GLS (HR, 1.88; P=0.03) and SDε (HR, 1.48; P=0.04) were independent predictors after adjustment for the baseline variables. Patients with impaired GLS (≥-7.8%) and mechanical dyssynchrony (SDε ≥72 ms) had poor outcome.nnnCONCLUSIONSnCombined assessment of global LV function and mechanical dyssynchrony using speckle-tracking strain enabled the prediction of long-term outcome in SHF patients.

Outcomes Associated With Paroxysmal Supraventricular Tachycardia During Pregnancy

Editorial, see p 590 nnParoxysmal supraventricular tachycardia (PSVT) is the most common symptomatic arrhythmia during pregnancy.1 Although PSVT is usually considered transient and harmless, its association with maternal and fetal outcomes during pregnancy are unknown.2–4nnIn this study, we used a national population cohort to measure the associations between PSVT events during pregnancy and maternal or fetal outcomes and to evaluate the associations between prior ablation of PSVT and those outcomes. This study was approved by the Institutional Review Board of Chang Gung Memorial Hospital, Taiwan.nnWe obtained records of all pregnancies in Taiwan between 2001 and 2012 from a national insurance database. Gestational age, birth weight, Apgar score, and fetal outcomes were obtained from Taiwan’s national birth registry to which obstetricians are required by law to report fetal and maternal information. Mothers who were 44 years of age or who had had congenital heart disease, a gap between deliveries that was 20 years, or multiparities were excluded. Informed consent was waived because of anonymous data.nnSymptomatic PSVT was defined as …

Propylthiouracil Attenuates Experimental Pulmonary Hypertension via Suppression of Pen-2, a Key Component of Gamma-Secretase

Gamma-secretase-mediated Notch3 signaling is involved in smooth muscle cell (SMC) hyper-activity and proliferation leading to pulmonary arterial hypertension (PAH). In addition, Propylthiouracil (PTU), beyond its anti-thyroid action, has suppressive effects on atherosclerosis and PAH. Here, we investigated the possible involvement of gamma-secretase-mediated Notch3 signaling in PTU-inhibited PAH. In rats with monocrotaline-induced PAH, PTU therapy improved pulmonary arterial hypertrophy and hemodynamics. In vitro, treatment of PASMCs from monocrotaline-treated rats with PTU inhibited their proliferation and migration. Immunocyto, histochemistry, and western blot showed that PTU treatment attenuated the activation of Notch3 signaling in PASMCs from monocrotaline-treated rats, which was mediated via inhibition of gamma-secretase expression especially its presenilin enhancer 2 (Pen-2) subunit. Furthermore, over-expression of Pen-2 in PASMCs from control rats increased the capacity of migration, whereas knockdown of Pen-2 with its respective siRNA in PASMCs from monocrotaline-treated rats had an opposite effect. Transfection of PASMCs from monocrotaline-treated rats with Pen-2 siRNA blocked the inhibitory effect of PTU on PASMC proliferation and migration, reflecting the crucial role of Pen-2 in PTU effect. We present a novel cell-signaling paradigm in which overexpression of Pen-2 is essential for experimental pulmonary arterial hypertension to promote motility and growth of smooth muscle cells. Propylthiouracil attenuates experimental PAH via suppression of the gamma-secretase-mediated Notch3 signaling especially its presenilin enhancer 2 (Pen-2) subunit. These findings provide a deep insight into the pathogenesis of PAH and a novel therapeutic strategy.

Association of a Family History of Atrial Fibrillation With Incidence and Outcomes of Atrial Fibrillation: A Population-Based Family Cohort Study

Importance The heritability of atrial fibrillation (AF), the contribution of genetic and environmental factors, and the association of a family history of AF with prognosis are unclear. Objectives To measure genetic and environmental factors in the familial aggregation of AF and to estimate the association of a family history of AF with major adverse cardiovascular events (MACE). Design, Setting, and Participants In this Taiwanese nationwide population-based study among more than 23 million people, a custom data set was obtained using the data of all patients having a diagnosis of AF recorded between January 1996 and December 2013 in the Taiwan National Health Insurance Research Database. The study population comprised all 23 422 955 individuals registered with the database in 2013, of whom 177 770 had a diagnosis of AF and were included in the heritability estimation. From the latter, a subgroup of patients having newly diagnosed AF with a first-degree relative affected by AF between 2000 and 2010 were selected and matched 1:4 to controls without a family history for estimating MACE-free survival. The dates of analysis were January 2010 to December 2013. Main Outcomes and Measures The prevalence and relative risk of AF in relatives of patients with AF, as well as the relative contributions of heritability and shared and nonshared environmental factors to AF susceptibility. Also measured was MACE-free survival after AF was diagnosed. Results In total, 1510 patients (204 [13.5%] female; mean [SD] age, 57.9 [9.2] years) had newly diagnosed AF with a first-degree relative affected by AF. Individuals with a first-degree relative affected by AF had a relative risk of 1.92 (95% CI, 1.84-1.99) for AF. The accountability for the phenotypic variance of AF was 19.9% for genetic factors (heritability), 3.5% for shared environmental factors, and 76.6% for nonshared environmental factors. After matching for age, sex, hypertension, type 2 diabetes, previous stroke, and anticoagulation, incident AF patients with vs without an affected first-degree relative had similar MACE-free survival. Conclusions and Relevance Genetic and environmental factors were associated with AF, with nonshared environmental factors accounting for three-fourths of the phenotypic variance in Taiwan. Patients having AF with a first-degree relative affected by AF did not have more MACE. Therefore, family history may not be particularly informative in the diagnosis or management of AF.

Ratio of transmitral early filling velocity to early diastolic strain rate predicts outcomes in patients with systolic heart failure.

Aims The ratio of transmitral early filling velocity (E) to early diastolic tissue velocity (E′) is a key diastolic function parameter. The early diastolic strain rate (E′sr) has been proposed as a substitute for E′ in the E/E′ ratio for better estimation of left ventricular (LV) filling pressure. This study aims to assess the predictive value of combined E/E′sr ratio and global longitudinal strain (GLS) for prognosis in systolic heart failure (SHF). Methods and results We retrospectively analysed 330 SHF patients with an LV ejection fraction (LVEF) ⩽ 40%. Study end points were defined as all-cause mortality or heart transplantation. The incremental value of GLS and the E/E′sr ratio over LVEF and E/E′ for outcome prediction was assessed using nested Cox models. Ninety-nine (30%) patients reached the end point over a median follow-up of 46 months. Baseline variables associated with outcomes were age, glomerular filtration rate, pulmonary artery systolic pressure, and LV end-systolic volume index. After multivariate adjustment, GLS (hazard ratio: 1.48, P = 0.025) and the E/E′sr ratio (hazard ratio: 1.41, P = 0.002) were both independent predictors. LVEF or E/E′ was not an independent predictor when GLS and E/E′sr were included in the model. Patients with impaired GLS (absolute value <7.5%) and elevated E/E′sr ratios (E/E′sr ≥ 195 cm) showed poor outcomes. Conclusion The E/E′sr ratio is stronger than E/E′ ratio in predicting prognosis of patients with systolic HF. Combined assessments of GLS and E/E′sr by speckle-tracking longitudinal strain facilitate risk stratification of these patients.