Shang-Hung Chang

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

Background and Purpose— Whether dabigatran is associated with different risks of cardiovascular, bleeding events, and mortality from warfarin in Asian patients with nonvalvular atrial fibrillation remains unclear. Methods— We used the Taiwan National Health Insurance Research Database to obtain 9940 and 9913 nonvalvular atrial fibrillation patients taking dabigatran and warfarin, respectively, from June 1, 2012, to December 31, 2013, as the dynamic cohort. Inverse probability of treatment weighting using propensity scores was used to balance covariates across 2 study groups. Patients were followed up until the first occurrence of any study outcome or end date of study. Results— During a median follow-up period of 0.67 years, there were 526 outcomes for dabigatran group. The hazard ratios (95% confidence intervals) comparing dabigatran with warfarin (reference) were as follows: ischemic stroke, 0.62 (0.52–0.73; P<0.0001); myocardial infarction, 0.67 (0.43–1.05; P=0.0803); intracranial hemorrhage, 0.44 (0.32–0.60; P<0.0001); major gastrointestinal bleeding, 0.99 (0.66–1.49; P=0.9658); all hospitalized major bleeding, 0.58 (0.46–0.74; P<0.0001); and all-cause mortality, 0.45 (0.38–0.53; P<0.0001). Dabigatran did not increase the risk of myocardial infarction or major gastrointestinal bleeding in all age groups when compared with warfarin. Total 8772 patients (88%) took a 110-mg dose in dabigatran group. The magnitude of effect for each outcome of 110-mg was comparable with that of 150-mg dose in the subgroup analysis. Conclusions— In real-world practice, dabigatran was associated with a reduced risk of ischemic stroke, intracranial hemorrhage, all hospitalized major bleeding, and all-cause mortality compared with warfarin in Asian patients with nonvalvular atrial fibrillation. Dabigatran did not increase the risk of major gastrointestinal bleeding or myocardial infarction compared with warfarin.

Augmentation of diabetic wound healing and enhancement of collagen content using nanofibrous glucophage-loaded collagen/PLGA scaffold membranes

This work developed nanofibrous drug-loaded collagen/poly-D-L-lactide-glycolide (PLGA) scaffold membranes that provided the sustained release of glucophage for the wounds associated with diabetes. PLGA, glucophage, and collagen were firstly dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol and were spun into nanofibrous membranes by electrospinning. High-performance liquid chromatography assay was used to characterize the in vivo and in vitro release rates of the pharmaceuticals from the membranes. High concentrations of glucophage were released for over three weeks from the nanofibrous membranes. The nanofibrous glucophage-loaded collagen/PLGA membranes were more hydrophilic than collagen/PLGA membranes and exhibited a greater water-containing capacity. The glucophage-loaded collagen/PLGA membranes markedly promoted the healing of diabetic wounds. Moreover, the collagen content of diabetic rats using drug-eluting membranes was higher than that of the control rats, because of the down-regulation of matrix metalloproteinase 9. The experimental results herein suggest that the nanofibrous glucophage-loaded collagen/PLGA membranes had effect for increasing collagen content in treating diabetic wounds and very effective promoters of the healing of such wounds in the early stages.

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]; P < .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.

Enhancement of Diabetic Wound Repair Using Biodegradable Nanofibrous Metformin-Eluting Membranes: in Vitro and in Vivo

This work developed biodegradable nanofibrous drug-eluting membranes that provided sustained release of metformin for repairing wounds associated with diabetes. To prepare the biodegradable membranes, poly-d-l-lactide-glycolide (PLGA) and metformin were first dissolved in 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) and were spun into nanofibrous membranes by electrospinning. An elution method and an HPLC assay were utilized to characterize the in vivo and in vitro release rates of the pharmaceuticals from the membranes. The biodegradable nanofibrous membranes released high concentrations of metformin for more than three weeks. Moreover, nanofibrous metformin-eluting PLGA membranes were more hydrophilic and had a greater water-containing capacity than virgin PLGA fibers. The membranes also improved wound healing and re-epithelialization in diabetic rats relative to the control. The experimental results in this work suggest that nanofibrous metformin-eluting membranes were functionally active in the treatment of diabetic wounds and very effective as accelerators in the early stage of healing of such wounds.

Clinical events occurrence and the changes of quality of life in chronic haemodialysis patients with dry weight determined by echocardiographic method.

The maintenance of circulating blood volume within an optimal range is necessary for haemodialysis patients to avoid circulating complications, including over‐hydration and dehydration. Inferior vena cava diameter (IVCD) estimation is a non‐invasive method to obtain a well correlation with the intravascular fluid status, and it may get a reliable ideal dry weight (DW) for chronic haemodialysis patients. We try to analysis the life quality changes and circulating complication in chronic haemodialysis patients who adjust DW with this tool in comparing with the traditional method. A total of 100 chronic haemodialysis patients, ranging from 26 to 77 years old, were involved in this study. They are randomly divided into study (n = 50) and control group (n = 50). All of them received the IVCD estimation by echocardiography every month for 3 months. The patients in the study group adjusted the DW with the IVCD estimated by echocardiographic method, however, patients in the control group with the traditional method. The quality of life (QOL) was evaluated with the short form 36 questionnaire (SF‐36) in the beginning and the end of the study. The scores of physical functioning (PF), role limitation‐physical (RP), general health (GH) and role limitation‐emotional (RE) have much improvement in the patients of the study group than those in the control group. Besides, the occurrence of clinical events due to circulating complications during the study period showed significant reduction in the extents of hypotension, gastrointestinal upset, discontinuation of haemodialysis, muscular cramps, tinnitus, headache and chest discomforts with electrocardiographic changes; and these effects, especially, are significant in the patients with over‐dehydrated status, which with the IVCD < 8 mm/m2 detected by echocardiographic method. The study demonstrated that ideal DW estimated by echocardiographic method not only improved the QOL but also reduced the circulating complications during haemodialysis for chronic haemodialysis patients.

SYNTAX score: an independent predictor of long-term cardiac mortality in patients with acute ST-elevation myocardial infarction.

IntroductionThis observational study aimed to determine whether the SYNergy between percutaneous coronary intervention (PCI) with TAXUS drug-eluting stent and the cardiac surgery (SYNTAX) score can act as an independent predictor for cardiac death on long-term follow-up in patients with acute ST-elevation myocardial infarction (STEMI). MethodsOne hundred and fifty-three patients admitted to the Chang Gung Memorial Hospital in Linkou because of acute STEMI from 1 January 2008 to 31 December 2009, who subsequently underwent a primary PCI, were included in this study. SYNTAX scores were calculated immediately after the primary PCI; and the prognostic value of the SYNTAX score in relation to cardiovascular events, which were defined as low-risk (SYNTAX score 0–22) and intermediate-risk to high-risk (SYNTAX score>22), was determined. Long-term follow-up was available in 141 patients (92%, mean follow-up duration of 30±11 months). ResultsBy Kaplan–Meier estimates, cardiac death-free survival was 99.1% in the low-risk group vs. 78.6% in the intermediate-risk to high-risk group at 42 months of follow-up (P<0.001). For all-cause death, the survival rate was 93.1% in the low-risk group vs. 78.6% in the intermediate-risk to high-risk group at 42 months of follow-up (P=0.002). Multivariate Cox-regression analysis showed that independent predictors of cardiac death were the SYNTAX score (odds ratio 15.90; 95% confidence interval 1.04–244.21) and symptom to onset-to-therapy interval (odds ratio 25.57; 95% confidence interval 1.00–655.96). ConclusionThe SYNTAX score is a strong independent predictor of cardiac death in intermediate-risk to high-risk patients with acute STEMI.

Combination of Duplex Ultrasound-Guided Manual Declotting and Percutaneous Transluminal Angioplasty in Thrombosed Native Dialysis Fistulas

Background. To investigate the safety, feasibility, efficacy, and long-term patency rate of manual declotting under duplex ultrasound (US) guidance followed by percutaneous transluminal angioplasty (PTA) in thrombosed native arteriovenous fistulas (AVFs). Methods. Of 87 consecutive thrombosed AVFs evaluated by duplex US, 22 patients with 25 recently thrombotic events in 22 AVFs were suitable for manual declotting. PTA was performed following successful declotting, and long-term patency was assessed. Results. The procedure success rate of manual declotting was 80% (20 of 25), and a residual stenosis of 74 ± 9% was identified by duplex US after declotting. PTA reduced the diameter stenosis to 25 ± 6% and increased the lumen diameter from 1.33 ± 0.85 mm to 4.62 ± 0.98 mm. Neither embolic nor bleeding complications were noted during the procedure. The average procedure time and the fluoroscopy time were 28.4 ± 9.9 and 7.2 ± 4.1 minutes, respectively. Primary patency rates at 1, 2, and 3 years were 47%, 35%, and 28%; assisted primary patency rates at 1, 2, and 3 years were 71%, 63%, and 63%; and secondary patency rates at 1, 2, and 3 years were 76%, 71%, and 63%, respectively, during a maximum follow-up period of 42 months. Conclusion. The combination of duplex US-guided manual declotting and angioplasty of underlying stenosis is a safe and feasible method to treat recently thrombosed native AVFs in selected patients. It simplifies the interventional procedure, reduces cost and radiation exposure time, and extends life span of dialysis fistula with acceptable long-term patency rate.

Simvastatin-ezetimibe combination therapy is associated with a lower rate of major adverse cardiac events in type 2 diabetics than high potency statins alone: A population-based dynamic cohort study.

BACKGROUND Recent trials have shown a reduction in the risk of major adverse cardiac events (MACE) with simvastatin-ezetimibe therapy in patients with acute coronary syndrome. The potential benefits of simvastatin-ezetimibe for patients at a lower risk of MACE are unclear. This study aimed to investigate the differences of MACE risk between patients with type 2 diabetes mellitus (DM) using simvastatin-ezetimibe or high potency statins. METHODS This population-based dynamic cohort study used data from the Taiwan National Health Insurance Database. The study subjects were patients with type 2 DM, aged between 40 and 75 years. The simvastatin-ezetimibe group took simvastatin-ezetimibe only, and the statin group took atorvastatin or rosuvastatin but not simvastatin or ezetimibe. The two groups were matched for age, gender, medication date, DM diagnosis date, hypertension, and cardiovascular complications. The outcome variable was new-onset MACE. Univariate and multivariate survival analyses were performed. RESULTS A total of 20,485 patients (53% male; 4099 in the simvastatin-ezetimibe group and 16,396 in the statin group) were included, with a mean age of 59.1 years. In a total of 37,388 person-years, 1100 patients developed new-onset MACE. The annual incidence rate of new-onset MACE was lower in the simvastatin-ezetimibe group (2.61%) than that in the statin group (3.02%) (p=0.0476). After Cox regression analysis, simvastatin-ezetimibe use was independently associated with a lower risk of MACE (HR, 0.77; 95% confidence interval 0.66-0.90). CONCLUSIONS Compared to high potency statins alone, simvastatin-ezetimibe therapy was associated with a lower incidence of MACE in patients with type 2 DM.

Local sustained delivery of acetylsalicylic acid via hybrid stent with biodegradable nanofibers reduces adhesion of blood cells and promotes reendothelialization of the denuded artery.

Incomplete endothelialization, blood cell adhesion to vascular stents, and inflammation of arteries can result in acute stent thromboses. The systemic administration of acetylsalicylic acid decreases endothelial dysfunction, potentially reducing thrombus, enhancing vasodilatation, and inhibiting the progression of atherosclerosis; but, this is weakened by upper gastrointestinal bleeding. This study proposes a hybrid stent with biodegradable nanofibers, for the local, sustained delivery of acetylsalicylic acid to injured artery walls. Biodegradable nanofibers are prepared by first dissolving poly(D,L)-lactide-co-glycolide and acetylsalicylic acid in 1,1,1,3,3,3-hexafluoro-2-propanol. The solution is then electrospun into nanofibrous tubes, which are then mounted onto commercially available bare-metal stents. In vitro release rates of pharmaceuticals from nanofibers are characterized using an elution method, and a highperformance liquid chromatography assay. The experimental results suggest that biodegradable nanofibers release high concentrations of acetylsalicylic acid for three weeks. The in vivo efficacy of local delivery of acetylsalicylic acid in reducing platelet and monocyte adhesion, and the minimum tissue inflammatory reaction caused by the hybrid stents in treating denuded rabbit arteries, are documented. The proposed hybrid stent, with biodegradable acetylsalicylic acid-loaded nanofibers, substantially contributed to local, sustained delivery of drugs to promote re-endothelialization and reduce thrombogenicity in the injured artery. The stents may have potential applications in the local delivery of cardiovascular drugs. Furthermore, the use of hybrid stents with acetylsalicylic acid-loaded nanofibers that have high drug loadings may provide insight into the treatment of patients with high risk of acute stent thromboses.

Lesion Length Impacts Long Term Outcomes of Drug-Eluting Stents and Bare Metal Stents Differently

Background Long lesions have been associated with adverse outcomes in percutaneous coronary interventions with bare metal stents (BMS). However, the exact impact of lesion length on the short- and long-term outcomes of drug-eluting stent (DES) implantations is not as clear. Methods and Results This study compared the impact of lesion length on angiographic and clinical outcomes of BMS and DES in a single-center prospective registry. Lesion length was divided into tertiles. The primary endpoints were angiographically defined binary in-stent restenosis (ISR) rate and major adverse cardiac event (MACE). Of the 4,312 de novo lesions in 3,447 consecutive patients in the CAPTAIN registry, 2,791 lesions (of 2,246 patients) received BMS, and the remaining 1,521 lesions (of 1,201 patients) received DES. The mean follow-up duration was 4.5 years. The longer the lesion, the higher the ISR rate (14%, 18%, and 29%, p<0.001) and the lower the MACE-free survivals (p = 0.007) in the BMS group. However, lesion length showed no such correlation with ISR rates (4.7%, 3.3%, and 7.8%, p = 0.67) or MACE-free survivals (p = 0.19) in the DES group. Conclusions In our single-center prospective registry, lesion length defined in tertiles has no impact on the short-term (ISR) or long-term (MACE) outcomes of patients implanted with DES. In contrast, longer lesion correlates with higher ISR and MACE rates in BMS group.