SGLT2 inhibitors vs. GLP-1 receptor agonists and clinical outcomes in patients with diabetes with/without atrial fibrillation.

CONTEXT: The coexistence of diabetes mellitus and atrial fibrillation (AF) is associated with substantial risks of adverse cardiovascular events. OBJECTIVE: The relevant outcomes associated with the use of sodium-glucose cotransporter-2 inhibitor (SGLT2i) versus glucagon-like peptide-1 receptor agonists (GLP-1RA) among patients with type 2 diabetes (T2D) with/without concomitant AF remained unknown. METHODS: In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database, there were 344,392 and 31,351 patients with T2D without AF, and 11,462 and 816 T2D patients with AF treated with SGLT2i and GLP-1RA from May 1, 2016, to December 31, 2019. Patients were followed from the drug-index date until the occurrence of study events, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. We used propensity score stabilized weight to balance covariates across two medication groups. RESULTS: The incidence rate of all study outcomes in patients with concomitant AF was much higher than in those without concomitant AF. For the AF cohort, SGLT2i vs. GLP-1RA was associated with a lower risk of hospitalization for heart failure (2.32 vs. 4.74 events per 100 person-years; hazard ratio (HR):0.48 [95% confidential interval (CI):0.36-0.66]), with no benefit seen for the non-AF cohort (P for homogeneity < 0.01). SGLT2i vs. GLP-1RA was associated with a lower risk of composite kidney outcomes both in the AF (0.38 vs. 0.79 events per 100 person-years; HR:0.47; [95%CI:0.23-0.96]) and non-AF cohorts (0.09 vs. 0.18 events per 100 person-years; HR:0.53; [95%CI:0.43-0.64]). There were no significant differences in the risk of major adverse cardiovascular events and all-cause mortality in those who received SGLT2i compared to GLP-1RA for the AF or non-AF cohorts. CONCLUSION: Considering the high risk of developing HF and/or high prevalence of concomitant HF in patients with diabetes, whether SGLT2i should be the preferred treatment to GLP-1RA for such a high-risk population requires further investigation.

Clinical significance of regional constructive and wasted work in patients receiving cardiac resynchronization therapy.

Background: Previous studies have shown that global constructive work (CW) and wasted work (WW) predict response to cardiac resynchronization therapy (CRT). This study evaluated the predictive value of regional CW and WW for reverse remodeling and clinical outcomes after CRT. Methods: We performed a prospective study involving 134 CRT candidates with left bundle branch block and left ventricular ejection fraction ≤35%. Global and regional CW and WW were calculated using pressure-strain loop analysis. CRT response was defined by reverse remodeling as a reduction of ≥15% in left ventricular end-systolic volume after six months. Results: At six-month follow-up, 92 (69%) patients responded to CRT. Of the regional CW and WW measures, lateral wall (LW) CW and septal WW were most strongly and significantly correlated with reverse remodeling. At multivariate analysis, LW CW and septal WW were both independent determinants of reverse remodeling. When LW CW and septal WW were included in the model, global CW and WW were not independently associated with reverse remodeling. LW CW and septal WW predicted reverse remodeling with an area under the curve (AUC) of 0.783 (95% CI: 0.700-0.866) and 0.737 (95% CI: 0.644-0.831), respectively. Using both variables increased the AUC to 0.832 (95% CI: 0.755-0.908). Both LW CW ≤878 mmHg% (HR 2.01; 95% CI: 1.07-3.79) and septal WW ≤181 mmHg% (HR 2.60; 95% CI: 1.38-4.90) were significant predictors of combined death and HF hospitalization at two-year follow-up. Conclusion: LW CW and septal WW before CRT are important determinants of reverse remodeling and clinical outcomes.

The Role of Artificial Intelligence in Coronary Calcium Scoring in Standard Cardiac Computed Tomography and Chest Computed Tomography With Different Reconstruction Kernels.

PURPOSE: To assess the correlation of coronary calcium score (CS) obtained by artificial intelligence (AI) with those obtained by electrocardiography gated standard cardiac computed tomography (CCT) and nongated chest computed tomography (ChCT) with different reconstruction kernels. PATIENTS AND METHODS: Seventy-six patients received standard CCT and ChCT simultaneously. We compared CS obtained in 4 groups: CS CCT , by the traditional method from standard CCT, 25 cm field of view, 3 mm slice thickness, and kernel filter convolution 12 (FC12); CS AICCT , by AI from the standard CCT; CS ChCTsoft , by AI from the non-gated CCT, 40 cm field of view, 3 mm slice thickness, and a soft kernel FC02; and CS ChCTsharp , by AI from CCT image with same parameters for CS ChCTsoft except for using a sharp kernel FC56. Statistical analyses included Spearman rank correlation coefficient (ρ), intraclass correlation (ICC), Bland-Altman plots, and weighted kappa analysis (κ). RESULTS: The CS AICCT was consistent with CS CCT (ρ = 0.994 and ICC of 1.00, P < 0.001) with excellent agreement with respect to cardiovascular (CV) risk categories of the Agatston score (κ = 1.000). The correlation between CS ChCTsoft and CS ChCTsharp was good (ρ = 0.912, 0.963 and ICC = 0.929, 0.948, respectively, P < 0.001) with a tendency of underestimation (Bland-Altman mean difference and 95% upper and lower limits of agreements were 329.1 [-798.9 to 1457] and 335.3 [-651.9 to 1322], respectively). The CV risk category agreement between CS ChCTsoft and CS ChCTsharp was moderate (κ = 0.556 and 0.537, respectively). CONCLUSIONS: There was an excellent correlation between CS CCT and CS AICCT , with excellent agreement between CV risk categories. There was also a good correlation between CS CCT and CS obtained by ChCT albeit with a tendency for underestimation and moderate accuracy in terms of CV risk assessment.

Clinical outcomes in elderly atrial fibrillation patients at increased bleeding risk treated with very low dose vs. regular-dose non-vitamin K antagonist oral anticoagulants: a nationwide cohort study.

AIMS: The Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial showed that edoxaban at a very low dosage (VLD) of 15 mg/day was more effective than a placebo at preventing stroke/systemic embolism without significantly increasing the risk of serious bleeding. We aimed to compare the effectiveness and safety for VLD non-vitamin K antagonist oral anticoagulants (NOACs) [edoxaban 15 mg o.d., dabigatran 110 or 150 o.d., apixaban 2.5 mg o.d., or rivaroxaban 10 mg (without the diagnosis of chronic kidney disease) or <10 mg o.d.] vs. regular-dosage (RD) NOACs (edoxaban 60/30 mg o.d. or other labeling-dosage NOACs) among a real-world cohort of elderly atrial fibrillation (AF) population similar to the ELDERCARE-AF cohort. METHODS AND RESULTS: In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database (NHIRD), we identified a total of 7294 and 4151 consecutive AF patients aged 80 years or older with a CHADS2 (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke/transient ischemic attack (2 points) score ≥2 who met the enrollment criteria (generally similar to ELDERCARE-AF) taking VLD and RD NOACs from 1 June 2012 to 31 December 2019, respectively. Propensity-score stabilized weighting (PSSW) was used to balance covariates across study groups. Patients were followed up from the first date of prescription for NOACs until the first occurrence of any study outcome, death, or until the end date of the study period (31 December 2020). After PSSW, VLD NOAC was associated with a comparable risk of ischemic stroke/systemic embolism and major bleeding but a higher risk of major adverse limb events (MALEs) requiring lower limb revascularization or amputation [hazard ratio (HR): 1.54, 95% confidential interval (CI): 1.09-2.18; P = 0.014), venous thrombosis (HR: 3.75, 95% CI: 1.56-8.97; P = 0.003), and all-cause mortality (HR: 1.21, 95% CI: 1.15-1.29; P <0.001) compared with RD NOACs. VLD NOACs showed worse outcomes in most net clinical outcome (NCO) benefits. The main result was consistent based on on-treatment analysis or accounting for death as a competing risk. In general, the advantage of NCOs for the RD NOACs over VLD NOACs persisted in most high-risk subgroups, consistent with the main analysis (P for interaction > 0.05). CONCLUSION: Use of VLD NOACs was associated with a greater risk of arterial and venous thrombosis, death as well as the composite outcomes, when compared with that of RD NOAC in high-risk elderly AF patients at increased bleeding risk. Thromboprophylaxis with RD NOAC is still preferable over VLD NOAC for the majority of elderly AF patients at increased bleeding risk.

High-phosphate diet causes atrial remodeling and increases atrial fibrillation vulnerability via STAT3/NF-κB signaling and oxidative stress.

AIM: Hyperphosphatemia is associated with adverse cardiovascular outcomes in both the general population and patients with end-stage renal disease. We evaluated whether high inorganic phosphate (Pi) intake causes atrial remodeling and increased atrial fibrillation (AF) risk. METHODS: The 5/6 nephrectomized chronic kidney disease (CKD) mice were fed a high-Pi (2%) diet for 10 weeks. AF vulnerability was evaluated through transesophageal burst atrial pacing. Phosphoproteomic, Western blotting, and immunohistochemistry were used to evaluate the effects of high Pi in atrial fibroblasts, atrial myocytes, and HL-1 myocytes. RESULTS: CKD and sham mice fed a high-Pi diet exhibited increased AF vulnerability, atrial fibrosis, and oxidative stress compared with mice fed a normal diet. Compared with normal (1 mM) Pi, high (2 mM) Pi significantly increased the activity of atrial fibroblasts and mitochondrial oxidative stress. Phosphoproteomic analysis revealed that compared with normal Pi, high Pi considerably increased the phosphorylation of intracellular proteins in atrial fibroblasts, including proteins related to NF-κB signaling and STAT3. Inhibition of NF-κB, STAT3, and Nox4 by small interfering RNA reduced the high-Pi-induced expression of collagen. In HL-1 myocytes, the high Pi induced the degradation of myofibril proteins and hyperphosphorylation of RyR2, which was abolished by Nox4 and CaMKII inhibition. Switching back to a normal-Pi diet improved the atrial abnormalities induced by high-Pi diet. CONCLUSIONS: High-Pi intake causes atrial structural and electrical remodeling and increases AF vulnerability, which is mediated through STAT3/NF-κB signaling and oxidative stress. High dietary Pi intake can exert detrimental effects on atria and may increase AF risk.

Prothrombin Time-International Normalized Ratio Predicts the Outcome of Atrial Fibrillation Patients Taking Rivaroxaban.

Background: Although direct oral anticoagulants (DOACs) for patients with atrial fibrillation (AF) are considered to be safe, over or under anticoagulation and increased bleeding or thromboembolic risk are still considered individually. We aimed to investigate whether there is an association between prothrombin time and international normalized ratio (PT-INR) or activated partial thromboplastin time (aPTT) ratio, and the risks of ischemic stroke/systemic embolism (IS/SE) and major bleeding among AF patients taking rivaroxaban or dabigatran. Methods: This multi-center cohort study in Taiwan included 3192 AF patients taking rivaroxaban and 958 patients taking dabigatran for stroke prevention where data about PT-INR and aPTT were available. Results: For patients treated with rivaroxaban, a higher INR level was not associated with a higher risk of major bleeding compared to an INR level < 1.1. The risk of IS/SE was lower for patients having an INR ≥ 1.5 compared to those with an INR < 1.1 (aHR:0.57; [95%CI: 0.37−0.87]; p = 0.01). On-label dosing of rivaroxaban and use of digoxin were independent factors associated with an INR ≥ 1.5 after taking rivaroxaban. For patients taking dabigatran, a higher aPTT ratio was not associated with a higher risk of major bleeding. The risk of IS/SE was lower for patients having an aPTT ratio of 1.1−1.2 and 1.3−1.4 than those with an aPTT ratio < 1.1. Conclusions: In AF patients, rivaroxaban with an INR ≥ 1.5 was associated with a lower risk of IS/SE. PT-INR or aPTT ratios were not associated with bleeding events for rivaroxaban or dabigatran. INR may help predict the outcome of AF patients who take rivaroxaban.

Development of Interstitial Lung Disease Among Patients With Atrial Fibrillation Receiving Oral Anticoagulants in Taiwan.

Importance: There are emerging concerns from case reports and pharmacovigilance analyses of a possible risk of interstitial lung disease (ILD) associated with the use of factor Xa (FXa) inhibitors. Objective: To evaluate the risk of incident ILD associated with the use of oral anticoagulants (OACs) in patients with nonvalvular atrial fibrillation (NVAF). Design, Setting, and Participants: This nationwide retrospective cohort study used data from the Taiwan National Health Insurance Research Database. Patients with NVAF without preexisting lung disease who received OACs from June 1, 2012, to December 31, 2017, were included. Propensity score stabilized weighting (PSSW) was used to balance covariates across the medication groups (FXa inhibitors, dabigatran, and warfarin, with warfarin as the reference). Patients were followed up from the drug index date until the onset of ILD, death, or end of the study (December 31, 2019), whichever occurred first. Data were analyzed from September 11, 2021, to August 3, 2022. Exposures: Patients with NVAF were treated with FXa inhibitors, dabigatran, or warfarin. Main Outcomes and Measures: New-onset idiopathic ILD. Results: Among the 106 044 patients (mean [SD] age, 73.4 [11.9] years; 59 995 men [56.6%]) included in the study, 64 555 (60.9%) received FXa inhibitors (apixban [n = 15 386], edoxaban [n = 12 413], and rivaroxaban [n = 36 756]), 22 501 (21.2%) received dabigatran, and 18 988 (17.9%) received warfarin at baseline. The FXa inhibitors were associated with a higher risk of incident ILD (0.29 vs 0.17 per 100 patient-years; hazard ratio, 1.54 [95% CI, 1.22-1.94]; P < .001), whereas dabigatran was associated with a nonsignificant difference in risk of incident ILD compared with warfarin (reference) after PSSW. The higher risk of incident ILD for FXa inhibitors vs warfarin was consistent with several high-risk subgroups. Conclusions and Relevance: Results of this study suggest that FXa inhibitors were associated with lung injury among patients with NVAF who were treated with OACs. Physicians should be vigilant in monitoring for any potential adverse lung outcomes associated with the use of these drugs.

Different Renal Function Equations and Dosing of Direct Oral Anticoagulants in Atrial Fibrillation.

Background: Randomized trials of direct oral anticoagulants (DOACs) adopted the Cockcroft-Gault (CG) formula to calculate estimated glomerular filtration rate (eGFR) to determine the dosages of DOACs. Objectives: The authors aimed to investigate the agreements/disagreements of eGFRs calculated using different equations (CG, Modified Diet in Renal Disease [MDRD], and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] formulas), and their impacts on the dosages of DOACs and clinical outcomes. Methods: Medical data from a multicenter health care provider in Taiwan including 39,239 patients with atrial fibrillation were used. Among these patients, there were 11,185 and 2,323 patients treated with DOACs and warfarin, respectively. Results: At the cutoff values of eGFR of <15, 15-50, and >50 mL/min, the agreements were 78% between MDRD and CG and 81% between CKD-EPI and CG. The disagreements among the different equations were largely due to overestimations, especially for patients aged >75 years and with a body weight of <50 kg (58.8% for MDRD and 50.9% for CKD-EPI). Among patients receiving DOACs whose dosages were defined as "on label" based on MDRD or CKD-EPI, only those whose dosages were "truly on label" based on CG were associated with a lower risk of major bleeding (adjusted HR: 0.34; 95% CI: 0.26-0.45) compared to warfarin. Conclusions: The adoptions of MDRD or CKD-EPI rather than CG would result in inappropriate dosing of DOACs (mainly overdosing), which would attenuate the advantages of DOACs compared to warfarin. The CG equation should be used as the gold standard to calculate eGFRs and guide the DOAC dosages.

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.

Oral Anticoagulant Use for Patients with Atrial Fibrillation with Concomitant Anemia and/or Thrombocytopenia.

OBJECTIVE: Hemoglobin levels and platelet counts have been associated with adverse clinical outcomes in patients with cardiovascular conditions. We aimed to assess the impact of oral anticoagulant use for patients with atrial fibrillation and concomitant anemia or thrombocytopenia. METHODS: We used medical data from a multicenter health care system in Taiwan including 37,074 patients with atrial fibrillation. Patients were categorized into 3 groups based on hemoglobin and platelet levels: Group 1 (hemoglobin >10g/dL and platelet>100 K/µL; n = 29,147), Group 2 (hemoglobin<10 g/dL or platelet<100 K/µL; n = 7078), and Group 3 (hemoglobin <10 g/dL and platelet <100 K/µL; n = 849). Patients in each category were further stratified as 3 groups according to their stroke prevention strategies: no oral anticoagulant use (non-OAC), warfarin, or nonvitamin K antagonist oral anticoagulants (NOACs). RESULTS: A higher hemoglobin or platelet level was associated with a higher risk of ischemic stroke/systemic embolism but lower risks of intracranial hemorrhage and major bleeding. The composite risks of ischemic stroke/systemic embolism, intracranial hemorrhage and major bleeding were higher in Group 3 or Group 2, compared with Group 1 (6.79% a year vs 6.41% year vs 4.13% year). Compared to non-OACs, warfarin was not associated with a lower composite risk in the 3 groups. NOACs were associated with a lower composite risk in Group 1 (adjusted hazard ratio:0.68, [95% confidence interval:0.60-0.76]) and Group 2 (adjusted hazard ratio:0.73, [95% confidence interval:0.53-0.99]) but was nonsignificant in Group 3. CONCLUSIONS: Patients with atrial fibrillation with anemia or thrombocytopenia were a high-risk population. Compared with no OAC use, NOACs were associated with better clinical outcomes for patients with atrial fibrillation and advanced anemia (hemoglobin <10g/dL) or thrombocytopenia (platelet <100 K/µL) but not for those with both conditions.

Outcomes after ticagrelor versus clopidogrel treatment in end-stage renal disease patients with acute myocardial infarction: a nationwide cohort study.

Clinical outcomes are unknown after ticagrelor treatment in patients with end-stage renal disease (ESRD) who are diagnosed with acute myocardial infarction (AMI). ESRD patients who were on hemodialysis and received dual antiplatelet therapy (DAPT) for AMI between July 2013 and December 2016 were identified in Taiwan's National Health Insurance Research Database. Using stabilized inverse probability of treatment weighting, patients receiving aspirin plus ticagrelor (n = 530) were compared with those receiving aspirin plus clopidogrel (n = 2462) for the primary efficacy endpoint, a composite of all-cause death, nonfatal myocardial infarction, or nonfatal stroke, and bleeding, defined according to the Bleeding Academic Research Consortium. Study outcomes were compared between the two groups using Cox proportional hazards model or competing risk model for the hazard ratio or subdistribution hazard ratio (SHR). During 9 months of follow-up, ticagrelor was comparable to clopidogrel with respect to the risks of primary efficacy endpoint [11.69 vs. 9.28/100 patient-months; SHR, 1.16; 95% confidence interval (CI) 0.97-1.4] and bleeding (5.55 vs. 4.36/100 patient-months; SHR 1.14; 95% CI 0.88-1.47). In conclusion, among hemodialysis patients receiving DAPT for AMI, ticagrelor was comparable to clopidogrel with regard to the composite efficacy endpoint and bleeding.

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.

Non-vitamin K antagonist oral anticoagulants and warfarin in atrial fibrillation patients with concomitant peripheral artery disease.

AIMS: To investigate the effectiveness, safety, and outcomes of lower limb events for non-vitamin K antagonist oral anticoagulants (NOACs) vs. warfarin among atrial fibrillation (AF) patients with concomitant peripheral artery disease (PAD). METHODS AND RESULTS: In this nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, a total of 5768 and 2034 consecutive AF patients with PAD patients taking NOACs or warfarin were identified from 1 June 2012 to 31 December 2017, respectively. We used propensity score stabilized weighting to balance covariates across study groups. In the cohort, there were 89% patients were taking low-dose NOAC (dabigatran 110 mg twice daily, rivaroxaban 10-15 mg daily, apixaban 2.5 mg twice daily, or edoxaban 30 mg daily). Non-vitamin K antagonist oral anticoagulant was associated with a comparable risk of ischaemic stroke, and a lower risk of acute myocardial infarction [hazard ratio (HR): 0.61, 95% confidence interval (CI): 0.42-0.87; P = 0.007], lower extremity thromboembolism (HR: 0.56, 95% CI: 0.44-0.72; P < 0.0001), revascularization procedure (HR: 0.58, 95% CI: 0.47-0.72; P < 0.0001), lower limb amputation (HR: 0.32, 95% CI: 0.23-0.46; P < 0.0001), and all major bleeding (HR: 0.64, 95% CI: 0.50-0.80; P = 0.0001) than warfarin after weighting. The advantage of NOACs over warfarin persisted in high-risk subgroups including patients of ≥75 years of age, diabetes, renal impairment, or use of concomitant antiplatelet agent. CONCLUSION: This population-based study indicated that NOACs were associated with a comparable risk of ischaemic stroke, and a significantly lower risk of major adverse limb events and major bleeding than warfarin among AF patients with concomitant PAD. Therefore, thromboprophylaxis with NOACs may be considered for such patients.

Efficacy and Safety of Ticagrelor vs. Clopidogrel in East Asian Patients with Acute Myocardial Infarction: A Nationwide Cohort Study.

Ticagrelor improves clinical outcomes in patients with acute myocardial infarction (AMI). This study aimed to compare the efficacy and safety of ticagrelor vs. clopidogrel in East Asian patients with AMI. Between July 2013 and December 2015, patients with AMI prescribed dual antiplatelet therapy were identified from the National Health Insurance Research Database of Taiwan. Using propensity score weighting, ticagrelor was compared with clopidogrel for the primary efficacy end point (a composite of all-cause death, myocardial infarction (MI), and stroke) and bleeding. A total of 32,442 patients with AMI (ticagrelor: 10,057; clopidogrel: 22,385) were eligible for analysis. After propensity score weighting, ticagrelor was comparable to clopidogrel in the incidence rate of the primary efficacy end point (23.6 vs. 22.76/100 patient-years; hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.89-1.06; P = 0.513). Ticagrelor was associated with a lower risk of stroke (1.78 vs. 2.66/100 patient-years; HR 0.64; 95% CI 0.49-0.85; P = 0.002) and higher risks of overall (21.59 vs. 18.35/100 patient-years; HR 1.16; 95% CI 1.06-1.27; P = 0.002) and Bleeding Academic Research Consortium (BARC) type 2 bleeding (18.67 vs. 15.08/100 patient-years; HR 1.22; 95% CI 1.11-1.36; P < 0.001). The risks of death, MI, and BARC 3 or 5 bleeding were comparable between ticagrelor and clopidogrel. In the present study, ticagrelor was comparable to clopidogrel in the composite of death, MI, and stroke, but had an increased risk of BARC type 2 bleeding. Ticagrelor may be beneficial in preventing post-MI stroke in East Asian patients.

Oral Anticoagulants and Antiplatelet Agents in Patients With Atrial Fibrillation and Concomitant Critical Limb Ischemia: A Nationwide Cohort Study.

BACKGROUND: Evidence of clinical outcomes for oral anticoagulants and antiplatelet treatment (APT) in patients with atrial fibrillation (AF) and critical limb ischemia (CLI) is very limited. METHODS: In this nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, 1223 patients with AF and CLI taking direct-acting oral coagulants (DOACs), warfarin, or APT were identified from June 1, 2012, to December 31, 2017. We used propensity score stabilized weighting (PSSW) to balance covariates across study groups. RESULTS: After PSSW, DOAC (n = 446) was associated with lower risks of ischemic stroke/systemic embolism (IS/SE), all major adverse limb events, and all major bleeding events compared with warfarin (n = 237). DOAC was associated with lower risks of IS/SE, acute myocardial infarction (AMI), and all major adverse limb events and a comparable risk of major bleeding events compared with APT (n = 540). DOAC has a lower risk of composite net-clinical-benefit outcome (IS/SE, AMI, all major adverse limb events, plus all major bleeding events) compared with warfarin (hazard ratio [HR]: 0.48; 95% confidence interval [CI]: 0.35-0.65; P < 0.0001) or APT (HR: 0.44; 95% CI: 0.34-0.56; P < 0.0001). The composite net-clinical-benefit outcome was comparable for warfarin vs APT. The reduced risk of net-clinical-benefit outcome for DOAC vs warfarin or APT persisted in high subgroups including age > 75 years, presence of diabetes mellitus, or chronic kidney disease. CONCLUSIONS: DOAC was associated with a significantly lower risk of composite net-clinical-benefit outcome than either warfarin or APT in patients with AF and concomitant CLI. Further prospective study is necessary to validate the findings in the future.

Effectiveness and Safety of Direct Oral Anticoagulants in an Asian Population with Atrial Fibrillation Undergoing Dialysis: A Population-Based Cohort Study and Meta-Analysis.

PURPOSE: Whether direct oral anticoagulants (DOACs) are more effective and safer than warfarin among Asian patients with non-valvular atrial fibrillation (NVAF) undergoing dialysis remains unclear. METHODS: We first compared the risks of ischemic stroke/systemic embolism (IS/SE) and major bleeding associated with DOACs compared with warfarin, in NVAF Asians undergoing dialysis using the Taiwan National Health Insurance Research Database (NHIRD) (Aim 1). Next, we searched PubMed and Medline from January 1, 2010 until January 31, 2020, to perform a systematic review and meta-analysis of all observational real-world studies comparing DOACs with warfarin specifically focused on NVAF patients with stage 4 or 5 chronic kidney disease undergoing dialysis (Aim 2). Finally, we tested the hypothesis whether AF patients undergoing dialysis treated with OACs (warfarin and DOACs) would be associated with lower risk of adverse clinical outcomes as compared to those without OACs using the Taiwan NHIRD (Aim 3). RESULTS: From June 1, 2012, to December 31, 2017, a total of 3237 and 9263 NVAF patients comorbid with ESRD receiving oral anticoagulant (OACs) (490 on DOAC, 2747 on warfarin) or no OACs, respectively, were enrolled. Propensity score matching was used to balance covariates across the study groups. For the comparison of DOAC vs. warfarin (Aim 1), DOACs had comparable risks of IS/SE and major bleeding to warfarin in our present cohort. From the original 85 results retrieved, nine studies (including our study) with a total of 6490 and 22,494 patients treated with DOACs and warfarin were included in the meta-analysis, respectively. There were 5343 (82%) and 20,337 (90%) patients treated with DOACs and warfarin undergoing dialysis, respectively. The pooled meta-analysis also indicated no difference of the effectiveness (HR:0.90; [95%CI:0.74-1.10]; P = 0.32) and safety outcomes (HR:0.75; [95%CI:0.54-1.05]; P = 0.09) between DOACs and warfarin (Aim 2). For the comparison of OAC (+) vs. OAC (-) (Aim 3), OAC-treatment was associated with a higher risk of IS/SE (hazard ratio (HR):1.54; [95% confidential interval (CI):1.29-1.84];P < 0.0001) and comparable risk of major bleeding compared to those without OAC treatment. CONCLUSIONS: DOACs did not provide benefit over warfarin regarding effectiveness and safety in AF patients undergoing dialysis. The use of OAC was not associated with a lower risk of IS/SE in ESRD AF patients when compared to those without OAC use.

Impact of bleeding during dual antiplatelet therapy in patients with coronary artery disease.

This nationwide retrospective cohort study used the National Health Insurance Research Database of Taiwan to compare the impact of bleeding on clinical outcomes in patients with acute myocardial infarction (AMI) versus chronic coronary syndrome (CCS). Between July 2007 and December 2010, patients with AMI (n = 15,391) and CCS (n = 19,724) who received dual antiplatelet therapy after coronary stenting were identified from the database. AMI was associated with increased risks of MI (AMI vs. CCS: 0.38 vs. 0.16 per 100 patient-months; p < 0.01), all-cause death (0.49 vs. 0.32 per 100 patient-months; p < 0.01), and BARC type 3 bleeding (0.22 vs. 0.13 per 100 patient-months; p < 0.01) at 1 year compared with CCS, while the risk of BARC type 2 bleeding was marginally higher in the CCS patients than in the AMI patients (1.32 vs. 1.4 per 100 person-months; p = 0.06). Bleeding was an independent predictor of MI, stroke, and all-cause death in this East Asian population, regardless of the initial presentation. Among the patients with bleeding, AMI was associated with a higher risk of ischemic events at 1 year after bleeding compared with CCS (MI: 0.34 vs. 0.25 per 100 patient-months; p = 0.06; ischemic stroke: 0.22 vs. 0.13 per 100 patient-months; p = 0.02). The 1-year mortality after bleeding was comparable between the two groups after propensity score weighting. In conclusion, bleeding conferred an increased risk of adverse outcomes in East Asian patients with AMI and CCS.

Major adverse cardiovascular and limb events in patients with diabetes and concomitant peripheral artery disease treated with sodium glucose cotransporter 2 inhibitor versus dipeptidyl peptidase-4 inhibitor.

BACKGROUND: Whether sodium glucose co-transporter 2 inhibitors (SGLT2i) are associated with a lower risk of cardiovascular as well as adverse lower limb events in patients with type-2 diabetes mellitus (T2DM) and concomitant peripheral artery disease (PAD) is unclear. We aimed to evaluate the risk of cardiovascular and limb events, and death associated with the use of SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) among a longitudinal and national cohort of patients with T2DM. METHODS: In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, we identified a total of 11,431 and 93,972 consecutive T2DM patients with PAD taking SGLT2i and DPP4i, respectively, from May 1, 2016, to December 31, 2017. We used 1:1 propensity score matching (PSM) to balance covariates across study groups. Patients were followed from the drug index date until the occurrence of clinical outcomes, death, discontinuation of the index drug, or the end of the study period, whichever occurred first. RESULTS: Overall, 56% and 44% of the patients were treated with dapagliflozin and empagliflozin, respectively. The use of SGLT2i had comparable risks of ischemic stroke and acute myocardial infarction, and was associated with lower risks of congestive heart failure (CHF) [hazard ratio (HR): 0.66; 95% confidence interval (CI) 0.49-0.89; p = 0.0062], lower limb ischemia requiring revascularization (HR: 0.73; 95% CI 0.54-0.98; p = 0.0367) or amputation (HR: 0.43; 95% CI 0.30-0.62; p < 0.0001), and cardiovascular death (HR: 0.67; 95% CI 0.49-0.90; p = 0.0089) when compared with the DDP4i group after PSM. The subgroup analysis revealed consistent results for CHF and major adverse limb outcomes for SGLT2i versus DPP4i among patients aged ≥ 75 years, the presence of chronic kidney disease and established cardiovascular disease was consistent with the main analysis. CONCLUSIONS: SGLT2i were associated with lower risks of CHF and adverse lower limb events compared with DPP4i among patients with T2DM and PAD in real-world practice.

Aldehyde Dehydrogenase 2 Ameliorates Chronic Alcohol Consumption-Induced Atrial Fibrillation through Detoxification of 4-HNE.

Aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies reactive oxygen species (ROS)-generated aldehyde adducts such as 4-hydroxy-trans-2-nonenal (4-HNE). Previous meta-analyses have shown an increase in the risk of atrial fibrillation (AF) in patients with chronic alcohol consumption. ALDH2*2, a common dysfunctional polymorphism in the ALDH2 gene, has been linked to an increased risk of cancer and heart disease. We tested the effect of ALDH2 deficiency on alcohol-induced AF in a murine model of chronic-binge ethanol feeding, with ALDH2*2 knock-in (KI) mice generated by a CRISPR/CAS9 system. In addition, right atrial appendages were obtained from eight patients with AF undergoing open heart surgery. The results showed that burst atrial pacing induced a greater susceptibility to AF in ALDH2*2 KI mice exposed to chronic ethanol intoxication than in wild-type mice, resulting from a higher degree of 4-HNE accumulation and collagen deposition in their atria. Alda-1 attenuated transforming growth factor beta 1 (TGF-ß1) expression and collagen deposition in the atria and reduced AF inducibility. Patients with AF and the ALDH2*2 allele exhibited greater oxidative stress and substrate remodeling in their atria than non-carriers. In conclusion, ALDH2 deficiency may increase the risk of chronic alcohol and tachypacing-induced AF through the accumulation of 4-HNE and increased ROS production.