Association Between Treatment With Apixaban, Dabigatran, Rivaroxaban, or Warfarin and Risk for Osteoporotic Fractures Among Patients With Atrial Fibrillation: A Population-Based Cohort Study.

BACKGROUND: It is unclear whether anticoagulant type is associated with the risk for osteoporotic fracture, a deleterious complication of anticoagulants among patients with atrial fibrillation (AF). OBJECTIVE: To compare the risk for osteoporotic fracture between anticoagulants. DESIGN: Population-based cohort study. SETTING: Territory-wide electronic health record database of the Hong Kong Hospital Authority. PARTICIPANTS: Patients newly diagnosed with AF between 2010 and 2017 who received a new prescription for warfarin or a direct oral anticoagulant (DOAC) (apixaban, dabigatran, or rivaroxaban). Follow-up ended on 31 December 2018. MEASUREMENTS: Osteoporotic hip and vertebral fractures in anticoagulant users were compared using propensity score-weighted cumulative incidence differences (CIDs). RESULTS: There were 23 515 patients identified (3241 apixaban users, 6867 dabigatran users, 3866 rivaroxaban users, and 9541 warfarin users). Overall mean age was 74.4 years (SD, 10.8), ranging from 73.1 years (warfarin) to 77.9 years (apixaban). Over a median follow-up of 423 days, 401 fractures were identified (crude event number [weighted rate per 100 patient-years]: apixaban, 53 [0.82]; dabigatran, 95 [0.76]; rivaroxaban, 57 [0.67]; and warfarin, 196 [1.11]). After 24-month follow-up, DOAC use was associated with a lower risk for fracture than warfarin use (apixaban CID, -0.88% [95% CI, -1.66% to -0.21%]; dabigatran CID, -0.81% [CI, -1.34% to -0.23%]; and rivaroxaban CID, -1.13% [CI, -1.67% to -0.53%]). No differences were seen in all head-to-head comparisons between DOACs at 24 months (apixaban vs. dabigatran CID, -0.06% [CI, -0.69% to 0.49%]; rivaroxaban vs. dabigatran CID, -0.32% [CI, -0.84% to 0.18%]; and rivaroxaban vs. apixaban CID, -0.25% [CI, -0.86% to 0.40%]). LIMITATION: Residual confounding is possible. CONCLUSION: Among patients with AF, DOAC use may result in a lower risk for osteoporotic fracture compared with warfarin use. Fracture risk does not seem to be altered by the choice of DOAC. These findings may help inform the benefit-risk assessment when choosing between anticoagulants. PRIMARY FUNDING SOURCE: The University of Hong Kong and University College London Strategic Partnership Fund.

Carbamylated Lipoproteins and Progression of Diabetic Kidney Disease.

BACKGROUND AND OBJECTIVES: Protein carbamylation is a consequence of uremia and carbamylated lipoproteins contribute to atherogenesis in CKD. Proteins can also be carbamylated by a urea-independent mechanism, and whether carbamylated lipoproteins contribute to the progression of CKD has not been investigated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A case-control study was performed to determine whether there were changes in plasma levels of carbamylated lipoproteins in individuals with type 2 diabetes with eGFR >60 ml/min per 1.73 m2 compared with a group of age- and sex-matched healthy controls. A cohort of 1320 patients with type 2 diabetes with baseline eGFR ≥30 ml/min per 1.73 m2 was longitudinally followed up to evaluate the association between carbamylated lipoproteins and progression of CKD. The primary kidney outcome was defined as doubling of serum creatinine and/or initiation of KRT during follow-up. Plasma carbamylated LDLs and HDLs was measured by ELISA. RESULTS: In individuals with diabetes with eGFR >60 ml/min per 1.73 m2, both plasma carbamylated LDL and HDL levels were higher compared with healthy controls (P<0.001). After a mean follow-up of 9 years of the diabetic cohort, individuals in the top quartile of carbamylated LDL (hazard ratio, 2.21; 95% confidence interval, 1.42 to 3.46; P<0.001) and carbamylated HDL (hazard ratio, 4.53; 95% confidence interval, 2.87 to 7.13; P<0.001) had higher risk of deterioration of kidney function compared with those in the lowest quartile. On multivariable Cox regression analysis, plasma carbamylated LDL was no longer associated with kidney outcome after adjusting for baseline eGFR and potential confounding factors. However, the association between plasma carbamylated HDL and kidney outcome remained significant and was independent of HDL cholesterol. CONCLUSIONS: Plasma carbamylated HDL but not carbamylated LDL was independently associated with progression of CKD in patients with type 2 diabetes.

Galectin-3 and risk of cardiovascular events and all-cause mortality in type 2 diabetes.

AIMS: Recent clinical studies have shown that galectin-3 is a prognostic indicator in patients with coronary heart disease and in patients with heart failure. Experimental data suggest that galectin-3 may play a role in atherogenesis. We have evaluated whether serum galectin-3 level is associated with cardiovascular outcome in type 2 diabetes. MATERIALS AND METHODS: Galectin-3 was measured in baseline samples in 1495 persons with type 2 diabetes. The primary cardiovascular outcome, incident cardiovascular events, was defined as first non-fatal myocardial infarction, non-fatal stroke, coronary revascularization, or death from cardiovascular cause. The secondary outcome was all-cause mortality. RESULTS: At baseline, 12% of the subjects had prevalent cardiovascular disease. Serum galectin-3 was increased in the group with incident cardiovascular events compared with those who remained free of events during follow up (9.03 ± 2.98 ng/mL vs 8.15 ± 2.76, P < 0.01). Serum galectin-3 was also significantly increased in those subjects with a fatal outcome. The hazard ratios (HR) for cardiovascular events and all-cause mortality for individuals in the top quartile were 2.50 (95% CI 1.87, 3.36, P < 0.001) and 3.92 (95%CI 2.55, 6.01, P < 0.001), respectively. In a multivariate Cox regression analysis including traditional risk factors, log (eGFR), baseline albuminuria, and cardiovascular disease status, the HR per standard deviation change in galectin-3 was 1.13 (95% CI 1.02, 1.26, P = 0.02) for cardiovascular events and 1.17 (95% CI 1.01, 1.35, P = 0.04) for all-cause mortality. CONCLUSIONS: Serum galectin-3 is associated with adverse cardiovascular outcomes in persons with type 2 diabetes independent of traditional risk factors.

Galectin-3 is independently associated with progression of nephropathy in type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Galectin-3 has been implicated in cardiac and renal fibrosis and serves as a prognostic clinical indicator in heart failure. The aim of the present study was to evaluate whether serum galectin-3 level is associated with progressive kidney disease in type 2 diabetes. METHODS: Galectin-3 was measured in baseline samples by ELISA in 1320 participants with type 2 diabetes with eGFR ≥30 ml min-1 1.73 m-2. The primary outcome was defined as doubling of serum creatinine and/or initiation of renal replacement therapy during follow-up. The secondary outcome was progression to macroalbuminuria in individuals with normo- or microalbuminuria at baseline. RESULTS: Serum galectin-3 levels were significantly increased in a random subgroup of 270 type 2 diabetic individuals with eGFR >60 ml min-1 1.73 m-2 compared with an age- and sex-matched non-diabetic control group (7.58 ± 2.29 ng/ml vs 6.10 ± 1.91 ng/ml, respectively, p < 0.01). In the whole diabetic cohort, after a mean follow-up of 9 years, galectin-3 was independently associated with doubling of serum creatinine (HR 1.19; 95% CI 1.14, 1.24, p < 0.001) and incident macroalbuminuria (HR 1.20; 95% CI 1.12, 1.30, p < 0.001), even after adjusting for traditional risk factors, baseline eGFR and albuminuria status. Individuals with galectin-3 levels in the highest quartile had a fourfold risk of renal function loss and threefold risk of incident macroalbuminuria. CONCLUSIONS/INTERPRETATION: Serum galectin-3 was independently associated with progressive renal disease in type 2 diabetes. Further mechanistic studies are warranted to determine whether galectin-3 is simply a disease biomarker or is also a mediator of the development and progression of diabetic nephropathy.

Validity of major osteoporotic fracture diagnosis codes in the Clinical Data Analysis and Reporting System in Hong Kong.

PURPOSE: Large medical record databases facilitate epidemiology research in fracture. However, the validity of fracture in the databases is needed to ensure the reliability of data. We aimed to assess the validity of International Classification of Diseases, 9th Revision (ICD-9) code algorithms for identifying major osteoporotic fracture in the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong. METHODS: The CDARS is a database developed by the Hong Kong Hospital Authority for research purpose. We used ICD-9 code algorithm for identifying major osteoporotic fracture, including vertebral fracture, humerus fracture, forearm/wrist fracture, and hip fracture, in CDARS in 2005-2016. As high positive predictive value (PPV) is critically important in epidemiology research, we sought to determine the PPV of fracture diagnostic code in terms of ICD-9 relative to the radiography imaging and clinical notes. A total of 380 major osteoporotic fracture cases (vertebral fracture: 101 cases; humerus fracture: 81 cases; forearm/wrist fracture: 94 cases; and hip fracture: 104 cases) were randomly selected and validated. RESULTS: In 380 fracture cases, the overall PPV was 96.8%. In subgroup analysis, PPV of 100% was observed for hip, humerus, and forearm/wrist fractures, whereas PPV of 86% was observed for vertebral fracture. CONCLUSIONS: The use of ICD-9 code algorithm to identify major osteoporotic fracture in CDARS is a valid tool with a very high PPV. However, cautious interpretation is required when the study focuses on incident vertebral fracture. Copyright © 2017 John Wiley & Sons, Ltd.

Association Between Dabigatran vs Warfarin and Risk of Osteoporotic Fractures Among Patients With Nonvalvular Atrial Fibrillation.

Importance: The risk of osteoporotic fracture with dabigatran use in patients with nonvalvular atrial fibrillation (NVAF) is unknown. Objective: To investigate the risk of osteoporotic fracture with dabigatran vs warfarin in patients with NVAF. Design, Setting, and Participants: Retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly diagnosed with NVAF from 2010 through 2014 and prescribed dabigatran or warfarin were matched by propensity score at a 1:2 ratio with follow-up until July 31, 2016. Exposures: Dabigatran or warfarin use during the study period. Main Outcomes and Measures: Risk of osteoporotic hip fracture and vertebral fracture was compared between dabigatran and warfarin users using Poisson regression. The corresponding incidence rate ratio (IRR) and absolute risk difference (ARD) with 95% CIs were calculated. Results: Among 51 496 patients newly diagnosed with NVAF, 8152 new users of dabigatran (n = 3268) and warfarin (n = 4884) were matched by propensity score (50% women; mean [SD] age, 74 [11] years). Osteoporotic fracture developed in 104 (1.3%) patients during follow-up (32 dabigatran users [1.0%]; 72 warfarin users [1.5%]). Results of Poisson regression analysis showed that dabigatran use was associated with a significantly lower risk of osteoporotic fracture compared with warfarin (0.7 vs 1.1 per 100 person-years; ARD per 100 person-years, -0.68 [95% CI, -0.38 to -0.86]; IRR, 0.38 [95% CI, 0.22 to 0.66]). The association with lower risk was statistically significant in patients with a history of falls, fractures, or both (dabigatran vs warfarin, 1.6 vs 3.6 per 100 person-years; ARD per 100 person-years, -3.15 [95% CI, -2.40 to -3.45]; IRR, 0.12 [95% CI, 0.04 to 0.33]), but not in those without a history (0.6 vs 0.7 per 100 person-years; ARD per 100 person-years, -0.04 [95% CI, 0.67 to -0.39]; IRR, 0.95 [95% CI, 0.45 to 1.96]) (P value for interaction, <.001). Conclusions and Relevance: Among adults with NVAF receiving anticoagulation, the use of dabigatran compared with warfarin was associated with a lower risk of osteoporotic fracture. Additional study, perhaps including randomized clinical trials, may be warranted to further understand the relationship between use of dabigatran vs warfarin and risk of fracture.

Validation of the Pooled Cohort equations in a long-term cohort study of Hong Kong Chinese.

BACKGROUND: The 2013 American College of Cardiology and the American Heart Association guidelines recommended the Pooled Cohort equations for evaluation of cardiovascular (CV) risk of individuals. OBJECTIVE: We investigated the usefulness of the Pooled Cohort equations in Chinese by validating this risk prediction model using the Hong Kong Cardiovascular Risk Factor Prevalence Study (CRISPS) cohort. METHODS: The Hong Kong CRISPS is a population-based prospective cohort study of CV risk factors among 2895 Chinese men and women (aged 25-74 years) initiated in 1995. CV events were ascertained until December 2012. The discrimination and calibration of the Pooled Cohort equations were evaluated and compared with the Framingham CV risk equation. A Hosmer-Lemeshow chi-square statistic (X(2)) of <20 indicated good calibration. RESULTS: The discrimination power of the 2 models in both men and women was moderate. The calibration score of both models were unacceptable in men (Pooled Cohort X(2), 24.1; Framingham X(2), 20.1), but was satisfactory in women (10.1 and 12.1, respectively). In men, with recalibration of the model using the CRISPS data, the accuracy of prediction improved. Recalibration, however, could not be applied to the Pooled Cohort model because the degree of miscalibration varied across the different risk categories. CONCLUSIONS: The Pooled Cohort equations provide poor calibration and moderate discrimination in Hong Kong Chinese, especially in men. In contrast, the Framingham CV risk equation can be applied to the Chinese population but requires recalibration in men.

Serum Level of Soluble Receptor for Advanced Glycation End Products Is Associated with A Disintegrin And Metalloproteinase 10 in Type 1 Diabetes.

BACKGROUND: The receptor for advanced glycation end products (RAGE) is involved in the pathogenesis of diabetic complications, and soluble forms of the receptor (sRAGE) can counteract the detrimental action of the full-length receptor by acting as decoy. Soluble RAGE is produced by alternative splicing [endogenous secretory RAGE (esRAGE)] and/or by proteolytic cleavage of the membrane-bound receptor. We have investigated the role of A Disintegrin And Metalloproteinase 10 (ADAM10) in the ectodomain shedding of RAGE. METHODS: Constitutive and insulin-induced shedding of RAGE in THP-1 macrophages by ADAM10 was evaluated using an ADAM10-specific metalloproteinase inhibitor. Serum ADAM10 level was measured in type 1 diabetes and control subjects, and the association with serum soluble RAGE was determined. Serum total sRAGE and esRAGE were assayed by ELISA and the difference between total sRAGE and esRAGE gave an estimated measure of soluble RAGE formed by cleavage (cRAGE). RESULTS: RAGE shedding (constitutive and insulin-induced) was significantly reduced after inhibition of ADAM10 in macrophages, and insulin stimulated ADAM10 expression and activity. Diabetic subjects have higher serum total sRAGE and esRAGE (p<0.01) than controls, and serum ADAM10 was also increased (p<0.01). Serum ADAM10 correlated with serum cRAGE in type 1 diabetes (r = 0.40, p<0.01) and in controls (r = 0.31. p<0.01) but no correlations were seen with esRAGE. The association remained significant after adjusting for age, gender, BMI, smoking status and HbA1c. CONCLUSION: Our data suggested that ADAM10 contributed to the shedding of RAGE. Serum ADAM10 level was increased in type 1 diabetes and was a significant determinant of circulating cRAGE.