The optimal antithrombotic strategy for post-stroke patients with atrial fibrillation and extracranial artery stenosis-a nationwide cohort study.

BACKGROUND: In post-stroke atrial fibrillation (AF) patients who have indications for both oral anticoagulant (OAC) and antiplatelet agent (AP), e.g., those with carotid artery stenosis, there is debate over the best antithrombotic strategy. We aimed to compare the risks of ischemic stroke, composite of ischemic stroke/major bleeding and composite of ischemic stroke/intracranial hemorrhage (ICH) between different antithrombotic strategies. METHODS: This study included post-stroke AF patients with and without extracranial artery stenosis (ECAS) (n = 6390 and 28,093, respectively) identified from the Taiwan National Health Insurance Research Database. Risks of clinical outcomes and net clinical benefit (NCB) with different antithrombotic strategies were compared to AP alone. RESULTS: The risk of recurrent ischemic stroke was higher for patients with ECAS than those without (12.72%/yr versus 10.60/yr; adjusted hazard ratio [aHR] 1.104, 95% confidence interval [CI] 1.052-1.158, p < 0.001). For patients with ECAS, when compared to AP only, non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy was associated with lower risks for ischaemic stroke (aHR 0.551, 95% CI 0.454-0.669), the composite of ischaemic stroke/major bleeding (aHR 0.626, 95% CI 0.529-0.741) and the composite of ischaemic stroke/ICH (aHR 0.577, 95% CI 0.478-0.697), with non-significant difference for major bleeding and ICH. When compared to AP only, warfarin monotherapy was associated with higher risks of major bleeding (aHR 1.521, 95% CI 1.231-1.880), ICH (aHR 2.045, 95% CI 1.329-3.148), and the composite of ischaemic stroke and major bleeding. With combination of AP plus warfarin, there was an increase in ischaemic stroke, major bleeding, and the composite outcomes, when compared to AP only. NOAC monotherapy was the only approach associated with a positive NCB, while all other options (warfarin, combination of AP-OAC) were associated with negative NCB. CONCLUSIONS: For post-stroke AF patients with ECAS, NOAC monotherapy was associated with lower risks of adverse outcomes and a positive NCB. Combination of AP with NOAC or warfarin did not offer any benefit, but more bleeding especially with AP-warfarin combination therapy.

Association of initial serum sodium change and clinical outcome in patients with diabetes receiving sodium-glucose cotransporter-2 inhibitor therapy: A multicentre database analysis in Taiwan.

AIM: The study aimed to assess the impact of varying degrees of initial serum sodium change among patients with type 2 diabetes (T2D) starting sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy and their subsequent clinical outcome. METHODS: We used medical data from a multicentre health care provider in Taiwan and recruited 4400 patients with T2D with baseline normal serum sodium (135-145 mmol/L) and follow-up serum sodium measures available after 3 months of SGLT2i treatment from 1 June 2016 to 31 December 2021. RESULTS: After a median of 2.9 (2.4, 3.4) months of SGLT2i treatment, overall, there was a minimal change in serum sodium levels (from 139.6 ± 2.4 to 139.5 ± 3.7 mmol/L). Most patients (87.8%) maintained normal sodium levels, while 8.6% (n = 378) experienced hyponatraemia (<135 mmol/L) and 3.6% (n = 158) hypernatraemia (>145 mmol/L). Factors independently associated with hyponatraemia included cancer history, chronic lung disease, insulin use, higher glycated haemoglobin, impaired liver function, lower baseline sodium and greater initial decline in kidney function. Conversely, factors linked to hypernatraemia included older age, absence of cancer history, loop diuretic and non-steroidal anti-inflammatory drug use, higher baseline sodium and a lesser initial decline in kidney function. Over a median of 26.0 months of follow-up, hyponatraemia shortly after starting SGLT2i therapy was associated with significantly increased risks of major adverse cardiovascular events [hazard ratio (HR): 2.52; 95% confidence interval (CI): 1.83-3.48], heart failure for hospitalization (HR: 1.66; 95% CI: 1.16-2.37), major adverse renal events (HR: 2.27; 95% CI: 1.73-2.96) and all-cause death (HR: 2.98; 95% CI: 2.17-4.11) after adjusting for clinically relevant factors. Non-linear analysis indicated that a more pronounced initial decline in serum sodium levels correlated steeply with higher risks of these adverse events. CONCLUSION: While most patients with T2D maintain stable serum sodium homeostasis on SGLT2i therapy, a subset may experience dysnatraemic events with potential worse clinical consequences. Physicians should be vigilant about monitoring sodium levels and considering the associated risks when initiating SGLT2i therapy in patients with risk.

Early reduction in albuminuria is associated with a steeper 'dip' in initial estimated glomerular filtration rate but favourable long-term kidney outcomes in people with diabetes receiving sodium-glucose cotransporter-2 inhibitors.

AIM: To assess if early change in albuminuria was linked to an initial change in estimated glomerular filtration rate (eGFR) and long-term kidney outcomes in people with type 2 diabetes (T2D) receiving sodium-glucose cotransporter-2 (SGLT2) inhibitors. METHODS: Using a medical database from a multicentre healthcare institute in Taiwan, we retrospectively enrolled 8310 people receiving SGLT2 inhibitors from 1 June 2016 to 31 December 2021. We compared the risks of initial eGFR decline, major adverse renal events (MARE; >50% eGFR reduction or development of end-stage kidney disease), major adverse cardiovascular events (MACE), or hospitalization for heart failure (HHF) using a Cox proportional hazards model. RESULTS: In all, 36.8% (n = 3062) experienced a >30% decrease, 21.0% (n = 1743) experienced a 0%-30% decrease, 14.4% (n = 1199) experienced a 0%-30% increase, and 27.7% (n = 2306) experienced a >30% increase in urine albumin-to-creatine ratio (UACR) after 3 months of SGLT2 inhibitor treatment. Greater acute eGFR decline at 3 months correlated with greater UACR reduction: -3.6 ± 10.9, -2.0 ± 9.5, -1.1 ± 8.6, and -0.3 ± 9.7 mL/min/1.73 m2 for the respective UACR change groups (p < 0.001). Over a median of 29.0 months, >30% UACR decline was associated with a higher risk of >30% initial eGFR decline (hazard ratio [HR] 2.68, 95% confidence interval [CI] 1.61-4.47]), a lower risk of MARE (HR 0.66, 95% CI 0.48-0.89), and a comparable risk of MACE or HHF after multivariate adjustment (p < 0.05). The nonlinear analysis showed early UACR decline was linked to a lower risk of MARE but a higher risk of initial steep eGFR decline of >30%. CONCLUSION: Physicians should be vigilant for the potential adverse effects of abrupt eGFR dipping associated with a profound reduction in UACR, despite the favourable long-term kidney outcomes in the population with T2D receiving SGLT2 inhibitor treatment.

Comparing clinical outcomes in patients with type 2 diabetes mellitus after ischaemic stroke: Sodium-glucose cotransporter 2 inhibitors users versus non-users. A propensity score matching National Cohort Study.

AIM: This nationwide cohort study evaluated the impact of sodium-glucose co-transporter-2 inhibitors (SGLT2i) on patients with type 2 diabetes mellitus (T2DM) after ischaemic stroke (IS), aiming to compare clinical outcomes between SGLT2i-treated patients and those not receiving SGLT2i. MATERIALS AND METHODS: Utilizing Taiwan's National Health Insurance Research Database, we identified 707 patients with T2DM treated with SGLT2i and 27 514 patients not treated with SGLT2i after an IS, respectively, from 1 May 2016 to 31 December 2019. Propensity score matching was applied to balance baseline characteristics. The follow-up period extended from the index date (3 months after the index acute IS) until the independent occurrence of the study outcomes, 6 months after discontinuation of the index drug, or the end of the study period (31 December 2020), whichever came first. RESULTS: After propensity score matching, compared with the non-SGLT2i group (n = 2813), the SGLT2i group (n = 707) exhibited significantly lower recurrent IS rates (3.605% per year vs. 5.897% per year; hazard ratio: 0.55; 95% confidence interval: 0.34-0.88; p = 0.0131) and a significant reduction in all-cause mortality (5.396% per year vs. 7.489% per year; hazard ratio: 0.58; 95% confidence interval: 0.39-0.85; p = 0.0058). No significant differences were observed in the rates of acute myocardial infarction, cardiovascular death, heart failure hospitalization, or lower limb amputation. CONCLUSIONS: Our findings indicate significantly lower risks of recurrent IS and all-cause mortality among patients with T2DM receiving SGLT2i treatment. Further studies are required to validate these results and investigate the underlying mechanisms behind the observed effects.

Association of Valve Size and Hemodynamic Performance With Clinical Outcomes in Aortic Valve Replacement　- A Long-Term Follow-up in an Asian Population.

BACKGROUND: Studies of the influence of smaller body type on the severity of prosthesis-patient mismatch (PPM) after small-sized surgical aortic valve replacement (SAVR) are few, but the issue is particularly relevant for Asian patients.Methods and Results: 695 patients who underwent SAVR with bioprosthetic valves had their hemodynamic valve performance analyzed at 3 months, 1 year, 3 years, and 5 years after operation, and clinical outcomes were assessed. The patients were stratified into 3 valve size groups: 19/21, 23, and 25/27 mm. A smaller valve was associated with higher mean pressure gradients at the 4 time points after operation (P trend <0.05). However, the 3 valve size groups demonstrated no significant differences in the risk of clinical events. At none of the time points did patients with projected PPM show increased mean pressure gradients (P>0.05), whereas patients with measured PPM did (P<0.05). Compared with patients with projected PPM, those with measured PPM demonstrated higher rates of infective endocarditis readmission (adjusted hazard ratio [aHR] 3.31, 95% confidence interval [CI] 1.06-10.39) and a higher risk of composite outcomes (aHR 1.45, 95% CI 0.95-2.22, P=0.087). CONCLUSIONS: Relative to those receiving larger valves, patients receiving small bioprosthetic valves had poorer hemodynamic performance but did not demonstrate differences in clinical events in long-term follow-up.

Sex Differences in Epidemiological Distribution and Outcomes of Surgical Mitral Valve Disease.

BACKGROUND: Mitral valve (MV) disease is the most common form of valvular heart disease. Findings that indicate women have a higher risk for unfavorable outcomes than men remain controversial. This study aimed to determine the sex-based differences in epidemiological distributions and outcomes of surgery for MV disease. METHODS AND RESULTS: Overall, 18,572 patients (45.3% women) who underwent MV surgery between 2001 and 2018 were included. Outcomes included in-hospital death and all-cause mortality during follow up. Subgroup analysis was conducted across different etiologies, including infective endocarditis (IE), degenerative, ischemic, and rheumatic mitral pathology. The overall MV repair rate was lower in women than in men (20.5% vs. 30.6%). After matching, 6,362 pairs (woman : man=1 : 1) of patients were analyzed. Women had a slightly higher risk for in-hospital death than men (10.8% vs. 9.8%; odds ratio [OR]: 1.11, 95% confidence interval [CI]: 0.99-1.24; P=0.075). Women tended to have a higher incidence of de novo dialysis (9.8% vs. 8.6%; P=0.022) and longer intensive care unit stay (8 days vs. 7.1 days; P<0.001). Women with IE had poorer in-hospital outcomes than men; however, there were no sex differences in terms of all-cause mortality. CONCLUSIONS: Sex-based differences of MV intervention still persist. Although long-term outcomes were comparable between sexes, women, especially those with IE, had worse perioperative outcomes than men.

Outcomes of Endovascular Treatment for Infective Aortic Aneurysms　- A Multicenter Retrospective Study.

BACKGROUND: In Taiwan, infective native aortic aneurysms (INAAs) are relatively common, so the aim of present study was to demonstrate the comparative outcomes of endovascular repair for thoracic and abdominal INAAs.Methods and Results: Patients with naïve thoracic or abdominal INAAs managed with endovascular repair between 2001 and 2018 were included in this multicenter retrospective cohort. The confounding factors were adjusted with propensity score (PS). Of the 39 thoracic and 43 abdominal INAA cases, 41 (50%) presented with aneurysmal rupture, most of which were at the infrarenal abdominal (n=35, 42.7%) or descending thoracic aorta (n=25, 30.5%). Salmonella spp. was the most frequently isolated pathogen. The overall in-hospital mortality rate was 18.3%. The risks of in-hospital death and death due to rupture were significantly lower with thoracic INAAs (12.8% vs. 23.3%; PS-adjusted odds ratio (OR) 0.24, 95% confidence interval (CI) 0.06-0.96; 0.1% vs. 9.3%; PS-adjusted OR 0.11, 95% CI 0.01-0.90). During a mean follow-up of 2.5 years, the risk of all-cause death was significantly higher with thoracic INAAs (35.3% vs. 15.2%; PS-adjusted HR 6.90, 95% CI 1.69-28.19). Chronic kidney disease (CKD) was associated with death. CONCLUSIONS: Compared with thoracic INAAs, endovascular repair of abdominal INAAs was associated with a significantly higher in-hospital mortality rate. However, long-term outcomes were worse for thoracic INAAs, with CKD and infections being the most important predictor and cause of death, respectively.

Early Surgery for Infective Endocarditis Complicated With Neurologic Injury.

OBJECTIVES: To estimate the association between early surgery and the risk of mortality in patients with left-sided infective endocarditis in the context of stroke. DESIGN: Retrospective cohort study. SETTING: This study was a multiinstitution study based on the Chang Gung Research Database, which contains electronic medical records from 7 hospitals in northern and southern Taiwan; these include 2 medical centers, 2 regional hospitals, and 3 district hospitals. PARTICIPANTS: Patients with active left-sided infective endocarditis who underwent valve surgery between September 2002 and December 2018. INTERVENTIONS: The authors divided patients into 2 groups, with versus without preoperative neurologic complications, had undergone early (within 7 d) or later surgery, and with brain ischemia or hemorrhage. MEASUREMENTS AND MAIN RESULTS: Three hundred ninety-two patients with a median time from diagnosis to surgery of 6 days were included. No significant differences in postoperative stroke, in-hospital mortality, or follow-up outcomes were observed between the patients with and without neurologic complications. Among the patients with preoperative neurologic complications, patients who underwent early surgery had a lower 30-day postoperative mortality rate (13.1% v 25.8%; hazard ratio, 0.21; 95% CI 0.07-0.67). In the subgroup analysis of the comparison between brain ischemia and hemorrhage groups, there was no significant between-group difference in the in-hospital outcomes or outcomes after discharge. CONCLUSIONS: Early cardiac surgery may be associated with more favorable clinical outcomes in patients with preoperative neurologic complications. Thus, preoperative neurologic complications should not delay surgical interventions.

CD44 regulates Epac1-mediated ß-adrenergic-receptor-induced Ca2+-handling abnormalities: implication in cardiac arrhythmias.

BACKGROUND: Sustained, chronic activation of ß-adrenergic receptor (ß-AR) signaling leads to cardiac arrhythmias, with exchange proteins directly activated by cAMP (Epac1 and Epac2) as key mediators. This study aimed to evaluate whether CD44, a transmembrane receptor mediating various cellular responses, participates in Epac-dependent arrhythmias. METHODS: The heart tissue from CD44 knockout (CD44-/-) mice, cultured HL-1 myocytes and the tissue of human ventricle were used for western blot, co-immunoprecipitaiton and confocal studies. Line-scanning confocal imaging was used for the study of cellular Ca2+ sparks on myocytes. Optical mapping and intra-cardiac pacing were applied for arrhythmia studies on mice's hearts. RESULTS: In mice, isoproterenol, a ß-AR agonist, upregulated CD44 and Epac1 and increased the association between CD44 and Epac1. Isoproterenol upregulated the expression of phospho-CaMKII (p-CaMKII), phospho-ryanodine receptor (p-RyR), and phospho-phospholamban (p-PLN) in mice and cultured myocytes; these effects were attenuated in CD44-/- mice compared with wild-type controls. In vitro, isoproterenol, 8-CPT-cAMP (an Epac agonist), and osteopontin (a ligand of CD44) significantly upregulated the expression of p-CaMKII, p-RyR, and p-PLN; this effect was attenuated by CD44 small interfering RNA (siRNA). In myocytes, resting Ca2+ sparks were induced by isoproterenol and overexpressed CD44, which were prevented by inhibiting CD44. Ex vivo optical mapping and in vivo intra-cardiac pacing studies showed isoproterenol-induced triggered events and arrhythmias in ventricles were prevented in CD44-/- mice. The inducibility of ventricular arrhythmias (VAs) was attenuated in CD44-/- HF mice compared with wild-type HF controls. In patients, CD44 were upregulated, and the association between CD44 and Epac1 were increased in ventricles with reduced contractility. CONCLUSION: CD44 regulates ß-AR- and Epac1-mediated Ca2+-handling abnormalities and VAs. Inhibition of CD44 is effective in reducing VAs in HF, which is potentially a novel therapeutic target for preventing the arrhythmias and sudden cardiac death in patients with diseased hearts.

Comparisons of effectiveness and safety between on-label dosing, off-label underdosing, and off-label overdosing in Asian and non-Asian atrial fibrillation patients treated with rivaroxaban: a systematic review and meta-analysis of observational studies.

AIMS: Limited real-world data show that rivaroxaban following dosage criteria from either ROCKET AF [20 mg/day or 15 mg/day if creatinine clearance (CrCl) < 50 mL/min] or J-ROCKET AF (15 mg/day or 10 mg/day if CrCl < 50 mL/min) is associated with comparable risks of thromboembolism and bleeding with each other in patients with non-valvular atrial fibrillation (NVAF). We are aimed to study whether these observations differ between Asian and non-Asian subjects. METHODS AND RESULTS: A systematic review and meta-analysis with random effects was conducted to estimate the aggregate hazard ratio (HR) and 95% confidence interval (CI) using PubMed and MEDLINE databases from 8 September 2011 to 31 December 2022 searched for adjusted observational studies that reported relevant clinical outcomes of NVAF patients receiving rivaroxaban 10 mg/day if CrCl > 50 mL/min, on-label dose rivaroxaban eligible for ROCKET AF or J-ROCKET AF, and rivaroxaban 20 mg/day if CrCl < 50 mL/min. Effectiveness and safety endpoints were compared between ROCKET AF and J-ROCKET AF dosing regimen in Asian and non-Asian subjects, separately. Also, risks of events of rivaroxaban 10 mg/day despite of CrCl > 50 mL/min and rivaroxaban 20 mg/day despite of CrCl < 50 mL/min were compared to that of 'ROCKET AF/J-ROCKET AF dosing'. Sensitivity analyses were performed by sequential elimination of each study from the pool. The meta-regression analysis was performed to explore the influence of potential factors on the effectiveness and safety outcomes. Eighteen studies involving 67 571 Asian and 54 882 non-Asian patients were included. Rivaroxaban following J-ROCKET AF criteria was associated with comparable risks of thromboembolism in the Asian subgroup, whereas rivaroxaban following J-ROCKET AF criteria was associated with higher risks of all-cause mortality (HR:1.30; 95% CI:1.05-1.60) compared with that of ROCKET AF criteria in the non-Asian population. There were no differences in risks of major bleeding between rivaroxaban following J-ROCKET AF vs. ROCKET AF criteria either in the Asian or non-Asian population. The use of rivaroxaban 10 mg despite of CrCl > 50 mL/min was associated with a higher risk of thromboembolism (HR:1.64; 95% CI:1.28-2.11) but lower risk of major bleeding (HR:0.72; 95% CI:0.57-0.90) compared with eligible dosage criteria. The use of rivaroxaban 20 mg despite of CrCl < 50 mL/min was associated with worse clinical outcomes in the risks of thromboembolism (HR:1.32; 95% CI:1.09-1.59), mortality (HR:1.33; 95% CI:1.10-1.59), and major bleeding (HR:1.26; 95% CI:1.03-1.53) compared with eligible dosage criteria. The pooled results were generally in line with the primary effectiveness and safety outcomes by removing a single study at one time. Meta-regression analyses failed to detect the bias in most potential patient characteristics associated with the clinical outcomes. CONCLUSION: Rivaroxaban dosing regimen following J-ROCKET criteria may serve as an alternative to ROCKET AF criteria for the Asian population with NVAF, whereas the dosing regimen following ROCKET AF criteria was more favourable for the non-Asian population. The use of rivaroxaban 10 mg despite of CrCl > 50 mL/min was associated with a higher risk of thromboembolism but a lower risk of major bleeding, while use of rivaroxaban 20 mg despite of CrCl < 50 mL/min was associated with worse outcome in most clinical events.

Non-vitamin K antagonist oral anticoagulants in atrial fibrillation patients without previous oral anticoagulants or stable under warfarin: a nationwide cohort study.

AIMS: Investigations on non-VKA oral anticoagulants (NOACs) for atrial fibrillation (AF) patients without taking any oral anticoagulants (OACs) or staying well on warfarin were limited. We aimed to investigate the associations between stroke prevention strategies and clinical outcomes among AF patients who were previously well without taking any OACs or stayed well on warfarin for years. METHODS AND RESULTS: The retrospective analysis included a total of 54 803 AF patients who did not experience an ischaemic stroke or intra-cranial haemorrhage (ICH) for years after AF was diagnosed. Among these patients, 32 917 patients who did not receive OACs were defined as the 'original non-OAC cohort' (group 1), and 8007 patients who continuously received warfarin were defined as the 'original warfarin cohort' (group 2). In group 1, compared to non-OAC, warfarin showed no significant difference in ischaemic stroke (aHR 0.979, 95%CI 0.863-1.110, P = 0.137) while those initiated NOACs were associated with lower risk (aHR 0.867, 95%CI 0.786-0.956, P = 0.043). When compared to warfarin, the composite of 'ischaemic stroke or ICH' and 'ischaemic stroke or major bleeding' was significantly lower in the NOAC initiator with an aHR of 0.927 (95%CI 0.865-0.994; P = 0.042) and 0.912 (95%CI 0.837-0.994; P < 0.001), respectively. In group 2, when compared to warfarin, those shifted to NOACs were associated with a lower risk of ischaemic stroke (aHR 0.886, 95%CI 0.790-0.993, P = 0.002) and major bleeding (aHR 0.849, 95%CI 0.756-0.953, P < 0.001). CONCLUSIONS: The NOACs should be considered for AF patients who were previously well without taking OACs and those who were free of ischaemic stroke and ICH under warfarin for years.

Fluoroquinolones and Risk of Aortic Aneurysm or Dissection in Patients With Congenital Aortic Disease and Marfan Syndrome.

BACKGROUND: Fluoroquinolone use can be associated with an increased risk of aortic aneurysm (AA) or aortic dissection (AD). The US Food and Drug Administration recently warned against fluoroquinolone use for high-risk patients, such as those with Marfan syndrome. However, the association between fluoroquinolone use and AA/AD risk was unknown in these high-risk patients and therefore it was studied in this work.Methods and Results: Data were collected from a national database between 2000 and 2017 for 550 patients with AA/AD and any congenital aortic disease (mean age 41.5 years; 415 with Marfan syndrome). A case cross-over study was conducted to compare the risk of aortic events (AA/AD) associated with fluoroquinolone and amoxicillin use between the hazard period (from -60 days to -1 day) and a randomly selected reference period (-180 to -121 days; -240 to -181 days; and -300 to -241 days). Compared to the reference period without fluoroquinolone use, fluoroquinolone use during the hazard period was not associated with a greater risk of AA/AD (1.09% vs. 1.09%; odds ratio [OR] 1.000; 95% confidence interval [CI] 0.32-3.10), AA (OR 0.67; 95% CI 0.11-3.99), or AD (OR 1.33; 95% CI 0.30-5.96) in patients with congenital aortic disease or Marfan syndrome. This lack of association was maintained in subgroup analysis, including Marfan syndrome or not, age (≤50 vs. >50 years) and sex. CONCLUSIONS: Fluoroquinolone use was not associated with an increased risk of AA/AD in patients with congenital aortic disease, including Marfan syndrome. More evidence is required for a fluoroquinolone pharmacovigilance plan in these patients.

Comparative safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in patients with non-valvular atrial fibrillation: A network meta-analysis.

BACKGROUND: The introduction of non-vitamin K antagonist oral anticoagulants (NOACs), with a non-inferior or superior clinical efficacy profile compared to vitamin K antagonists (VKAs), has significantly improved the safety profile and treatment adherence of patients with non-valvular atrial fibrillation (AF). However, few studies have compared the effectiveness and safety of NOACs. Therefore, we conducted this systematic review and network meta-analysis to compare the safety and clinical effectiveness of NOACs and VKAs in patients with non-valvular AF. METHODS: An online bibliographic search was conducted to retrieve real-world evidence studies published between January 2019 and June 2022. RESULTS: Dabigatran was associated with lower risks of major bleeding, ischemic stroke, and intracranial hemorrhage than warfarin. Among the NOACs, only dabigatran had a lower risk of all-cause mortality than warfarin. Dabigatran was also associated with lower risks of major bleeding and intracranial hemorrhage than rivaroxaban. CONCLUSION: Our meta-analysis confirms that dabigatran's real-world safety and clinical effectiveness align with the results of pivotal clinical trials.

The risk of incident atrial fibrillation in patients with type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors: a nationwide cohort study.

BACKGROUND: Although a few meta-analyses were conducted to compare the risk of incident atrial fibrillation (AF) between sodium-glucose cotransporter-2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and other anti-hyperglycemic agents using indirect or direct comparison, the above analyses showed conflicting results with each other. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i, GLP-1RA, and dipeptidyl peptidase-4 inhibitor (DPP4i) among a large longitudinal cohort of diabetic patients. METHODS: In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, a total of 344,893, 44,370, and 393,100 consecutive patients with type 2 diabetes without preexisting AF receiving GLP-1RA, SGLT2i, and DPP4i, respectively, were enrolled from May 1, 2016, to December 31, 2019. We used 1:1 propensity score matching (PSM) to balance covariates across paired study groups. Patients were followed from the drug index date until the occurrence of AF, death, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. RESULTS: After PSM, there were 245,442, 43,682, and 39,190 paired cohorts of SGLT2i-DPP4i, SGLT2i-GLP-1RA, and GLP-1RA-DPP4i, respectively. SGLT2i treatment was associated with lower risk of new-onset AF in participants with type 2 diabetes compared with either DPP4i [hazard ratio (HR):0.90; 95% confidential interval (CI) 0.84-0.96; P = 0.0028] or GLP-1RA [HR 0.74; 95% CI 0.63-0.88; P = 0.0007] treatment after PSM. There was no difference in the risk of incident AF between GLP-1RA and DPP4i users [HR 1.01; 95% CI 0.86-1.19; P = 0.8980]. The above findings persisted among several important subgroups. Dapagliflozin was specifically associated with a lower risk of new-onset AF compared with DPP4i (P interaction = 0.02). CONCLUSIONS: Compared with DPP4i, SGLT2i but not GLP-1RA was associated with a lower risk of incident AF in patients with type 2 diabetes.

Clinical Outcomes in Atrial Fibrillation Patients With a History of Cancer Treated With Non-Vitamin K Antagonist Oral Anticoagulants: A Nationwide Cohort Study.

Background and Purpose: Data on clinical outcomes for nonvitamin K antagonist oral anticoagulant (NOACs) and warfarin in patients with atrial fibrillation and cancer are limited, and patients with active cancer were excluded from randomized trials. We investigated the effectiveness and safety for NOACs versus warfarin among patients with atrial fibrillation with cancer. Methods: In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database, we identified a total of 6274 and 1681 consecutive patients with atrial fibrillation with cancer taking NOACs and warfarin from June 1, 2012, to December 31, 2017, respectively. Propensity score stabilized weighting was used to balance covariates across study groups. Results: There were 1031, 1758, 411, and 3074 patients treated with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. After propensity score stabilized weighting, NOAC was associated with a lower risk of major adverse cardiovascular events (hazard ratio, 0.63 [95% CI, 0.50­0.80]; P=0.0001), major adverse limb events (hazard ratio, 0.41 [95% CI, 0.24­0.70]; P=0.0010), venous thrombosis (hazard ratio, 0.37 [95% CI, 0.23­0.61]; P<0.0001), and major bleeding (hazard ratio, 0.73 [95% CI, 0.56­0.94]; P=0.0171) compared with warfarin. The outcomes were consistent with either direct thrombin inhibitor (dabigatran) or factor Xa inhibitor (apixaban, edoxaban, and rivaroxaban) use, among patients with stroke history, and among patients with different type of cancer and local, regional, or metastatic stage of cancer (P interaction >0.05). When compared with warfarin, NOAC was associated with lower risk of major adverse cardiovascular event, and venous thrombosis in patients aged <75 but not in those aged ≥75 years (P interaction <0.05). Conclusions: Thromboprophylaxis with NOACs rather than warfarin should be considered for the majority of the atrial fibrillation population with cancer.

The risk of consequent nephropathy following initial weight loss in diabetic patients treated with sodium glucose cotransporter 2 inhibitors.

BACKGROUND: There is a controversy over the association between obesity and the risk of renal events in patients with type 2 diabetes mellitus (T2DM). Furthermore, whether body weight (BW) loss following sodium glucose cotransporter 2 inhibitor (SGLT2i) treatment associated with risk of adverse renal events is unknown. METHODS: We used medical data from a multi-center healthcare provider in Taiwan, enrolling 8992 T2DM patients with a baseline/following-up BW data available after around 12 weeks of SGLT2i treatment, from June 1, 2016 to December 31, 2018. Patients were followed up until the occurrence of composite renal outcome (estimated glomerular filtration rate decline > 40% or end-stage kidney disease) or the end of study period, whichever occurred first. RESULTS: Participants were divided into six baseline BMI categories: < 18.5 (n = 55); 18.5-22.9 (n = 985); 23.0-24.9 (n = 1389); 25.0-29.9 (n = 3941); 30.0-34.9 (n = 1973); and ≥ 35.0 kg/m2 (n = 649). There were 38.9%, 23.5%, 24.7%, 8.4%, 2.7%, and 1.8% of patients experienced no-BW loss, initial BW loss of 0.0-2.4%, 2.5-4.9%, 5.0-7.4%, 7.5-9.9%, and ≥ 10.0%, associated with SGLT2i treatment, respectively. Compared with patients with normal BMI (BMI: 18.5-22.9 kg/m2), underweight (BMI: < 18.5 kg/m2) was associated with a higher risk of composite renal outcome (adjusted hazard ratio (aHR) [95% confidence intervals (CI)]: 2.17; [1.16-4.04]), whereas pre-obese (BMI: 25.0-29.9 kg/m2) associated with the lowest risk of composite renal outcome (0.52; [0.40-0.68]) after multivariate adjustment. Compared with those without BW loss after SGLT2i treatment, BW loss of 0.0-2.4% (0.55; [0.43-0.70]) and 2.5-4.9% (0.78; [0.63-0.98]) were associated with a lower risk, whereas BW loss ≥ 10.0% associated with a higher risk of composite renal outcome (1.61; [1.06-2.46]) after multivariate adjustment. CONCLUSION: A modest BW loss of 0-5% associated with SGLT2i treatment was associated with a favorable renal outcome. Caution should be taken for whom are underweight at baseline or have a pronounced BW loss ≥ 10.0% associated with SGLT2i treatment, which was associated with a worse renal outcome.

The impact of weight loss related to risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium-glucose cotransporter 2 inhibitor.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) use reduces body weight (BW) in patients with type 2 diabetes mellitus (T2DM). Obesity and T2DM are strong risk factors of new-onset atrial fibrillation (AF). However, whether BW loss following SGLT2i treatment reduces AF risk in patients with T2DM remains unclear. METHODS: We used a medical database from a multicenter health care provider in Taiwan, which included 10,237 patients with T2DM, from June 1, 2016 to December 31, 2018, whose BW data at baseline and at 12 weeks of SGLT2i treatment were available. Patients were followed up from the drug index date until the occurrence of new-onset AF, discontinuation of the SGLT2i, or the end of the study period, whichever occurred first. RESULTS: The patients' baseline body mass index (BMI) was 28.08 [Formula: see text] 4.88 kg/m2. SGLT2i treatment was associated with a BW loss of 1.35 [Formula: see text] 3.28 kg (1.78%[Formula: see text] 4.47%). There were 37.4%, 47.0%, and 15.6% of patients experienced no-BW loss (n = 3832), BW loss 0.0-4.9% (n = 4814), and [Formula: see text] 5.0% (n = 1591) following SGLT2i treatment, respectively. Compared with patients with baseline BMI < 23 kg/m2, AF risk significantly increased in patients with baseline BMI [Formula: see text] 27.5 kg/m2 (P for trend = 0.015). Compared with those without BW loss after SGLT2i treatment, AF risk significantly decreased with a BW loss of [Formula: see text] 5.0% (adjusted hazard ratios [95% confidence intervals]: 0.39[0.22-0.68]). Use of diuretics, old age, high-dose SGLT2i, higher estimated glomerular filtration rate, and baseline BMI were independent factors associated with a BW loss of [Formula: see text] 5.0% following SGLT2i initiation. By contrast, neither baseline BMI nor BW loss after SGLT2i treatment predicted major cardiovascular adverse events or heart failure hospitalization risk (P for trend > 0.05). CONCLUSION: BW loss of ≥ 5.0% following SGLT2i treatment was associated with a lower risk of new-onset AF in patients with T2DM in real-world practice.

Impact of the initial decline in estimated glomerular filtration rate on the risk of new-onset atrial fibrillation and adverse cardiovascular and renal events in patients with type 2 diabetes treated with sodium-glucose co-transporter-2 inhibitors.

AIM: To investigate the impact of initial decline in estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes (T2D) following sodium-glucose co-transporter-2 inhibitor (SGLT2i) treatment. MATERIALS AND METHODS: We used medical data from a multicentre healthcare provider in Taiwan and recruited 11 769 patients with T2D with baseline/follow-up eGFR data available after 1 to 3 months of SGLT2i treatment from 1 June 2016 to 31 December 2018. Patients were followed up from the drug index date until the occurrence of adverse clinical events, SGLT2i discontinuation or the end of the study period, whichever took place first. RESULTS: Overall, SGLT2i treatment was associated with an initial eGFR decline of 3.5% ± 14.0% after a median treatment period of 10 weeks. A total of 37.1% (n = 4371) of patients experienced no eGFR decline, and 30.5% (n = 3593), 20.2% (n = 2376), 8.5% (n = 999) and 3.7% (n = 430) of patients experienced an eGFR decline of 0%-10%, 10%-20%, 20%-30% and more than 30%, respectively. The mean eGFR over time became stable after 6 months in all eGFR decline categories, even in the group with a pronounced eGFR decline of more than 30%. Compared with no eGFR decline, an initial eGFR decline of 0%-10%, 10%-20% or 20%-30% was not associated with a higher risk of atrial fibrillation (AF), major adverse cardiovascular events (MACE, including ischaemic stroke, systemic embolism and acute myocardial infarction)/heart failure (HF) and composite renal outcome (doubling of the serum creatinine level/end-stage kidney disease), whereas an eGFR decline of more than 30% was associated with a higher risk of new-onset AF (adjusted hazard ratio [aHR] = 2.20, 95% confidence interval [CI] = 1.40-3.47), MACE/HF (aHR = 2.09, 95% CI = 1.04-4.17) and composite renal outcome (aHR = 1.82, 95% CI = 1.18-2.83). The multivariate analysis indicated that the use of a diuretic or insulin, presence of stroke, older age, female sex, a higher HbA1c level, and a lower body mass index of less than 25 kg/m2 were independent factors associated with an eGFR decline of more than 30% following SGLT2i initiation. CONCLUSIONS: A pronounced eGFR decline of more than 30% following SGLT2i treatment was associated with adverse cardiovascular or renal events among patients with T2D.

Optimal Management of Anticoagulation Therapy in Asian Patients With Atrial Fibrillation.

Stroke prevention is the cornerstone of management of atrial fibrillation (AF), and non-vitamin K antagonist oral anticoagulants (NOACs) are commonly prescribed. Because routine monitoring of anticoagulant effects of NOACs is not necessary, appropriate dosing following the criteria of each NOACs defined in pivotal randomized trials is important. Real-world data demonstrate that underdosing NOACs is associated with a higher risk of ischemic stroke without a lower risk of major bleeding. Furthermore, renal function of AF patients should be assessed using the Cockcroft-Gault formula to prevent overestimation that could result in overdosing of NOACs. The assessment of bleeding risk is important, and the HAS-BLED score should be used to help identify patients at high risk of bleeding (HAS-BLED score ≥3). Moreover, the HAS-BLED score should be reassessed at periodic intervals to address potentially modifiable bleeding risk factors because bleeding risks of AF patients are not static. When managing NOAC-related bleeding episodes, the possibility of occult malignancies (e.g., grastrointestinal [GI] tract cancers for patients experiencing GI bleeding and bladder cancer for patients with hematuria) should be kept in mind. Addressing all of these issues is crucial to achieving better clinical outcomes for anticoagulated AF patients. More efforts are necessary to incorporate clear and easy-to-follow recommendations about optimal management of anticoagulation into the guidelines to improve AF patient care.

Effect of Permanent Pacemaker Implantation After Valve Surgery on Long-Term Outcomes.

BACKGROUND: Patients are prone to permanent pacemaker implantation (PPM) after valve surgery, yet current data on the effects of postoperative PPM are scarce and large-scale studies are lacking. The aim of this study was to determine rates and long-term outcomes of PPM after cardiac valve surgery.Methods and Results:A total of 24,014 patients who received valve surgery from 2000 to 2013 were identified from the Taiwan National Health Insurance Research Database. The number of valve surgeries and the proportion of PPM implantations after valve surgery increased (P<0.001). After 1 : 5 propensity score matching, 602 and 3,010 patients were categorized to the PPM and non-PPM groups, respectively. Late outcomes included all-cause mortality, cardiovascular death, sepsis, and readmission due to any cause. The mean follow up was 4.3 years. PPM was associated with a higher all-cause mortality rate (33.6% vs. 29.8%; hazard ratio [HR], 1.14; 95% confidence interval [CI], 0.98-1.32), though not significant at the threshold of P<0.05. PPM was also associated with higher all-cause mortality rates in subgroups that received mitral valve (MV) replacement surgery, combined aortic valve replacement (AVR) with MV surgeries, and combined AVR with tricuspid valve surgeries. CONCLUSIONS: The PPM rate after valve surgery is increasing, and is associated with short-term adverse effects. Patients with PPM may have a higher long-term mortality rate.