Population pharmacokinetic analysis for dabigatran etexilate in Chinese patients with non-valvular atrial fibrillation.

We aimed to develop a pharmacokinetic (PK) and pharmacodynamic (PD) model from healthy Chinese subjects and real-world non-valvular atrial fibrillation (NVAF) patients. We also investigated meaningful intrinsic and extrinsic factors and related biomarkers for bleeding events. We characterized the integrated PK/PD models based on rich PK/PD data [dabigatran concentration, activated partial thromboplastin time (APTT), prothrombin time (PT), and anti-factor IIa (anti-FIIa) activity] from 118 healthy volunteers and sparse PD data [APTT, PT, and anti-FIIa] from 167 patients with NVAF after verifying the model extrapolation performance. We also documented the correlations between PD biomarkers and clinically relevant bleeding events over one year. Next, we used the final integrated PK/PD model (a two-compartment, linear model with first-order absorption) to evaluate the influence of dosage and individual covariates on PD parameters. The age, high-density liptein cholesterol (HDL-C), and creatinine clearance (CrCL) improved the PK model fit. The linear direct-effects PD model described the correlation between APTT, PT, and anti-FIIa and plasma concentration. CrCL improved the PD model fit. Anti-FIIa was more sensitive to the increase in dabigatran exposure than APTT and PT in the PD model. Therefore, fixed dabigatran doses could be prescribed for patients with NVAF without adjusting for age and HDL-C. We observed an elevated bleeding tendency with higher peak and trough values of APTT, PT, and anti-FIIa. Randomized studies should be performed to evaluate the efficacy and safety of low-dose dabigatran in Chinese patients with NVAF.

Effect of indobufen vs. aspirin on platelet accumulation in patients with stable coronary heart disease after percutaneous coronary intervention: An open-label crossover study.

Purpose: This study compared the effect of indobufen with that of aspirin on platelet function in patients with stable coronary heart disease after percutaneous coronary intervention (PCI). Methods: Patients with stable coronary heart disease who had undergone PCI and received dual antiplatelet therapy (aspirin 100 mg + clopidogrel 75 mg once daily) for at least 12 months were allocated to receive indobufen 100 mg twice daily + clopidogrel 75 mg once daily, clopidogrel 75 mg once daily alone, indobufen 100 mg twice daily alone, and aspirin 100 mg once daily alone for 1 month each in an open-label crossover manner. Platelet function was assessed by using the rates of arachidonic acid (AA)-induced platelet aggregation (AA-PAR) and adenosine diphosphate (ADP)-induced platelet aggregation (ADP-PAR) measured by light transmission aggregometry, the platelet reactivity index measured by vasodilator-stimulated phosphoprotein (PRI-VASP), and the plasma and urinary thromboxane B2 (TXB2) concentrations recorded at baseline and during each treatment phase. Results: Of 56 patients enrolled, 52 completed the study. The AA-PAR was lower in the indobufen alone group than in the aspirin alone group [5.21% (3.39, 7.98) vs. 5.27% (4.06, 6.60), p = 0.038], while biologically, a difference of 0.06% may represent no significant difference; there was no significant between-group difference in the plasma [531.16 pg/ml (203.89, 1035.06) vs. 373.93 pg/ml (194.04, 681.71), p = 0.251] or urinary [3951.97 pg/ml (2006.95, 6077.01) vs. 3610.48 pg/ml (1664.60, 6247.61), p = 0.717] TXB2 concentration. When the aspirin + clopidogrel group and indobufen + clopidogrel group were compared, similar results were found for AA-PAR [3.97% (3.05, 5.12) vs. 3.83% (3.10, 5.59), p = 0.947] and both plasma [849.47 pg/ml (335.96, 1634.54) vs. 455.41 pg/ml (212.47, 1489.60), p = 0.629], and urinary [4122.97 pg/ml (2044.96, 7459.86) vs. 3812.81 pg/ml (1358.95, 6021.07), p = 0.165] TXB2 concentrations. ADP-PAR was lower in the clopidogrel alone group than in the indobufen alone group (47.04% ± 16.89 vs. 61.7% ± 10.50, p < 0.001), as was PRI-VASP (66.53% ± 18.06 vs. 77.72% ± 19.87, p = 0.002). Conclusion: These findings suggest that indobufen has antiplatelet effects similar to those of aspirin in patients with stable coronary heart disease after PCI, and may be an alternative for patients with aspirin intolerance after coronary stenting.

Non-vitamin K antagonist oral anticoagulants in venous thromboembolism patients: a meta-analysis of real-world studies.

BACKGROUND: The real-world studies on recurrent venous thromboembolism (VTE) and bleeding events of non-vitamin K antagonist oral anticoagulants (NOACs) in VTE patients have reported conflicting findings. Our study aimed to provide the direct comparison evidence of different NOACs for VTE patients in clinical practice settings. METHODS: Search of the medical literature was conducted using PubMed, Web of Science, EMBASE, Clinical Trials.gov, and the Cochrane Library from inception to March 22, 2021. Among the 19,996 citations retrieved, a total of 63,144 patients from 6 studies were analyzed. Clinical outcomes included recurrent VTE, death, and different bleeding events. RESULTS: Adjusted hazard ratio (HR) analysis suggested that apixaban had significant lower bleeding riskthan rivaroxaban (major, minor and any bleeding: HR = 0.61, 0.56, 0.70; p = 0.008, < 0.0001, 0.006, respectively), but no statistics difference found in recurrent VTE events (HR = 1.02, 95% confidence interval (CI) 0.71-1.47, p = 0.93). There was no significant difference of major bleeding between dabigatran and rivaroxaban (odds ratios (OR) = 0.41, 95% CI 0.09-1.90, p = 0.25), apixaban and dabigatran (OR 0.64, 95% CI 0.15-2.72, p = 0.83). No significant difference was found in the comparison of edoxaban and other NOACs in VTE recurrence, major bleeding and composite outcome. CONCLUSIONS: In the prevention of bleeding events, apixaban was associated with a lower risk than rivaroxaban, but equivalent efficacy for different NOACs in prevention of recurrent VTE. Evidence generated from the meta-analysis based on real-world data can help to guide selection between apixaban and rivaroxaban in routine clinical practice. TRIAL REGISTRATION: This systematic review and meta-analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis and Meta-analysis of Observational Studies in Epidemiology statements and was registered with PROSPERO (CRD42019140553).

Correlation between single-nucleotide polymorphisms and statin-induced myopathy: a mixed-effects model meta-analysis.

PURPOSE: A meta-analysis was performed to evaluate the correlation between single-nucleotide polymorphisms (SNPs) and risk of statin-induced myopathy (SIM). METHODS: We retrieved the studies published on SIM until April 2019 from the PubMed, Embase, and Cochrane Library databases. We collected data from 32 studies that analyzed 10 SNPs in five genes and included 21,692 individuals and nine statins. RESULTS: The analysis of the heterozygous (p = 0.017), homozygous (p = 0.002), dominant (p = 0.005), and recessive models (p = 0.009) of SLCO1B1 rs4149056 showed that this SNP increases the risk of SIM. Conversely, heterozygous (p = 0.048) and dominant models (p = 0.030) of SLCO1B1 rs4363657 demonstrated that this SNP is associated with a reduced risk of SIM. Moreover, an increased risk of SIM was predicted for carriers of the rs4149056 C allele among simvastatin-treated patients, whereas carriers of the GATM rs9806699 A allele among rosuvastatin-treated patients had a lower risk of SIM. CONCLUSION: The meta-analysis revealed that the rs4149056 and rs4363657 SNPs in SLCO1B1 and the rs9806699 SNP in GATM are correlated with the risk of SIM.

Predicting ischaemic events using platelet reactivity in patients receiving clopidogrel: Indirect meta-comparison among VerifyNow, light transmission aggregometry and thromboelastography.

The present study compared performances of the three major methods used for assessing platelet reactivity (PR)-VerifyNow, light transmission aggregometry (LTA) and thromboelastography (TEG)-to predict ischaemic events in patients receiving clopidogrel. PubMed, EMBASE and the Cochrane Library were searched from their inception to April 2019 for prospective studies that examined PR using VerifyNow, LTA or TEG and the incidence of ischaemic events. The investigated diagnostic indices include sensitivity, specificity, positive (PLR) and negative likelihood ratio (NLR), diagnostic odds ratio and area under the receiver operating characteristic curves (AUC) of VerifyNow, LTA and TEG, respectively. A total of 26 prospective studies involving 22 185 patients were included in the analysis. The pooled AUC was 0.71 (95% CI: 0.67-0.75) for VerifyNow, 0.60 (95% CI: 0.55-0.64) for LTA and 0.81 (95% CI: 0.77-0.84) for TEG. Results of indirect comparisons indicated the AUC of VerifyNow was higher than that of LTA (1.18, 95% CI: 1.08-1.30) and lower than that of TEG (0.88, 95% CI: 0.82-0.94). TEG outperformed the other two methods for assessing PR in all predictive measures, including sensitivity, specificity, PLR and NLR. Despite a lack of studies that directly compared the three methods, our findings suggest that TEG should be recommended.

The predictive value of circulating microRNAs for venous thromboembolism diagnosis: A systematic review and diagnostic meta-analysis.

OBJECTIVE: Venous thromboembolism (VTE) is a common cardiovascular disease, in which pulmonary embolism (PE) is potentially life-threatening. Accurate biological markers for the early diagnosis of VTE are needed. The purpose of this study was to analyze and validate the predictive value of microRNAs for the diagnosis of VTE. METHODS: A comprehensive literature review was conducted using the PubMed, Embase, and Cochrane Library databases and is current through Sep 27, 2018. The diagnostic value of microRNAs for VTE was analyzed by creating a summary receiver operating characteristic curve (SROC) and calculating the area under the curve (AUC). RESULTS: Our analysis included 12 articles assessing a total of 1057 individuals. The most frequently researched microRNA was miR-134, and the pooled results of the predictive ability of this miRNA with 95% confidence intervals (CIs) showed an average sensitivity of 0.82 (0.69-0.91) and an average specificity of 0.83 (0.68-0.92). The average AUC for the SROC curves was 0.89 (0.86-0.92). For other microRNAs, AUC values >0.8 were considered as potential diagnostic indices. These microRNAs included miR-1233, miR-134, miR-145, miR-483-3p, miR-582, miR-532, and miR-195. CONCLUSIONS: MicroRNAs may act as novel diagnostic biomarkers for VTE, and miR-1233, miR-134, miR-145, miR-483-3p, miR-582, miR-532, and miR-195 are prime candidates. Of these, research on miR-134 is the most extensive and reliable.

Associations between human leukocyte antigen polymorphisms and hypersensitivity to antiretroviral therapy in patients with human immunodeficiency virus: a meta-analysis.

BACKGROUND: Human leukocyte antigen (HLA) alleles are implicated in drug-induced hypersensitivity, including by nevirapine and abacavir. The purpose of this meta-analysis was to evaluate the relationship between HLA polymorphisms and hypersensitivity to antiretroviral therapy in human immunodeficiency virus (HIV)-infected patients. METHODS: We conducted a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library for studies that evaluated the associations of HLA polymorphisms with antiretroviral therapy-induced hypersensitivity published in April 2019. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were considered as estimates of the effect. RESULTS: The meta-analysis included 17 studies that assessed a total of 4273 patients. First, carriers of HLA-A *24 were associated with an increased risk of hypersensitivity among patients with HIV who received antiretroviral therapy (OR: 12.12; P = 0.018). Second, five SNPs of HLA-B genotypes, including *18 (OR: 1.63; P = 0.028), *35 (OR: 2.31; P = 0.002), *39 (OR: 11.85; P = 0.040), *51 (OR: 1.66; P = 0.028), and *81 (OR: 8.11; P = 0.021), were associated with an increased risk of hypersensitivity. Conversely, carriers of HLA-B *15 were associated with a reduced risk of hypersensitivity (OR: 0.43; P < 0.001). Third, HLA-C *04 was associated with an increased risk of hypersensitivity (OR: 3.09; P < 0.001), whereas a lower risk for hypersensitivity was observed in patients who were carriers of HLA-C *02 (OR: 0.22; P = 0.030), *03 (OR: 0.53; P = 0.049), and *07 (OR: 0.61; P = 0.044). Finally, carriers of HLA-DRB1 *05 (OR: 0.18; P = 0.006) and *15 (OR: 0.23; P = 0.013) were associated with a reduced risk of hypersensitivity among patients receiving antiretroviral therapy. CONCLUSIONS: The findings of this meta-analysis indicated patients carrying HLA-A *24, HLA-B *18, *35, *39, *51, *81, HLA-C *04 were associated with a higher risk of hypersensitivity. Conversely, subjects carrying HLA-B *15, HLA-C *02, *03, *07, HLA-DRB1 *05, *15 were associated with a reduced risk of hypersensitivity.

Association between SLCO1B1 T521C polymorphism and risk of statin-induced myopathy: a meta-analysis.

Numerous studies have illustrated the relationship between SLCO1B1 T521C polymorphism and statin-induced myopathy risk; however, this association is not consistent. Three electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched from inception to October 2017 to identify potential studies. The summary odds ratios (ORs) with 95% confidence intervals (CIs) were calculated from different genetic models by using a random-effects model. Fourteen studies comprising 3265 myopathy patients and 7743 controls were included. The summary ORs suggested that 521CC (OR: 2.31; 95% CI: 1.15-4.63; P = 0.019), 521TC (OR: 1.34; 95% CI: 1.02-1.76; P = 0.034), and 521CC + TC (OR: 1.82; 95% CI: 1.32-2.51; P < 0.001) were associated with a greater risk of statin-induced myopathy than 521TT. The higher incidence of statin-induced myopathy was found to be significantly correlated with the C allele compared with the T allele (OR: 1.89; 95% CI: 1.36-2.62; P < 0.001). In addition, we observed that 521CC + TC was associated with an increased risk of myopathy in individuals who received simvastatin (OR: 2.35; 95% CI: 1.08-5.12; P = 0.032) or rosuvastatin (OR: 1.69; 95% CI: 1.07-2.67; P = 0.024) when compared with 521TT. The 521C allele was associated with a greater risk of cerivastatin-induced myopathy than the T allele (OR: 1.95; 95% CI: 1.47-2.57; P < 0.001). The findings of this study indicated that SLCO1B1 T521C was associated with a significantly higher risk of statin-induced myopathy, especially for simvastatin, rosuvastatin, and cerivastatin. Future studies should be conducted in subjects receiving specific types of drugs, and any potential adverse events need to be explored.

Determination of trace amount of Cu2+ with a multi-responsive colorimetric and reversible chemosensor.

A multi-responsive sensor 1 was constructed by combining a ferrocene unit and a rhodamine block via a carbohydrazone bond. The sensor showed high selectivity toward Cu(2+) over other common metal ions in a wide pH range with excellent reversibility and rapid response. The obvious color change from colorless to pink upon the addition of Cu(2+) could make it a suitable 'naked-eye' indicator for Cu(2+). The detection limit (LOD) obtained was down to 2.0 nM and the association constant (Ka) was evaluated as 4.65 × 10(7) M(-1). The accuracy for detecting Cu(2+) in environmental river water was compared favorably with the traditional atomic absorption spectroscopy method (AAS). Finally, we proposed a reversible ring-opening mechanism (Off-On) of the rhodamine spirolactam induced by Cu(2+) binding and a 2 : 1 stoichiometric structure between 1 and Cu(2+).