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There are many anticoagulant test indexes available for direct oral anticoagulants (DOACs), but how to select the appropriate index and the index cutoff values are still controversial. This is the first study, to our knowledge, to assess the association of different coagulation indicators with clinical outcomes among DOACs using a meta-analysis of observational studies. A medical literature search was conducted using PubMed, Web of Science, EMBASE, ClinicalTrials.gov , and the Cochrane Library from inception to February 2020. Studies that reported relationships between coagulation indexes and clinical outcomes or the diagnostic value of coagulation assays were included in the analysis. A total of 17 articles (7 meta-analyses and 10 systematic reviews) from 8904 citations were included in the analysis. In the analysis of bleeding events with coagulation indexes for DOACs, for peak prothrombin time level (cutoff value of 19–25 s), the pooled results found a sensitivity of 0.61 (95% CI, 0.44–0.75) and a specificity of 0.71 (95% CI, 0.49–0.86). For rivaroxaban, the trough anti–factor Xa concentration (AXA-C) (cutoff value of 400–500 ng/mL) had a sensitivity of 0.53 (95% CI, 0.16–0.87) and a specificity of 0.87 (95% CI, 0.71–0.94), with a diagnostic odds ratio of 7 (95% CI, 2–32). For apixaban, trough AXA-C had a sensitivity of 0.85 (95% CI, 0.60–0.96) and a specificity of 0.83 (95% CI, 0.52–0.95). The AUC of the AXA-C peak was higher than that of the trough AXA-C for apixaban, with a higher sensitivity and specificity. Compared with trough concentration of anti–factor IIa for dabigatran, the peak concentration had a higher specificity (98%) at the cutoff value of 484 ng/mL. In the analysis of thromboembolic events with coagulation indexes for DOACs, peak and trough prothrombin time values were not typically correlated with subsequent symptomatic venous thromboembolism, without a sensitivity or specificity higher than 90%. Trough AXA-C had a sensitivity of 100% and but a low specificity (<50%) for rivaroxaban-apixaban. Trough AXA-C had a sensitivity of 100% and a specificity of 32% with a cutoff value of 108 ng/mL for dabigatran. Peak prothrombin time (19–25 s) and AXA-C had a better predictive value on bleeding outcomes for rivaroxaban and apixaban, whereas peak concentration of anti–factor IIa activity can be an indicator for dabigatran. Coagulation indexes might not be a good indicator of thromboembolic events of DOACs. Because the limited studies focused on association of coagulation indicators and clinical outcomes, more studies are needed to verify this in the future. • This first pooled analysis assesses association of coagulation indicators with clinical outcomes for DOACs. • PT and AXA showed a better predictive value on bleeding outcomes for rivaroxaban and apixaban • Peak concentration of anti-IIa can be an indicator for dabigatran. • Coagulation indexes could not be a good indicator for thromboembolic events of DOACs. [ABSTRACT FROM AUTHOR]

Different coagulation indices for direct oral anticoagulants (DOACs) exist in clinical practice, but limited data are available for the diagnostic power of these indices. This review and meta-analysis aims to explore the diagnostic value of coagulation indices for DOACs. PubMed, Web of Science, EMBASE, Clinical Trials.gov , and the Cochrane Library were searched from inception of each database to 15 February 2020. Studies reporting a relationship between coagulation indices and the gold standard (liquid chromatography/tandem mass spectrometry) were included in the analysis. Sixteen articles from 9169 citations evaluating the performance of coagulation indices were included in this review. A total of 236, 273, 273 rivaroxaban samples were included to assess the diagnostic power of anti-Xa activity (AXA), prothrombin time (PT), combined PT and activated partial thromboplastin time, respectively. A total of 268 dabigatran samples were included to assess the diagnostic performance of diluted thromboplastin time (dTT). AXA calibrated by rivaroxaban showed a sensitivity of 0.98 (95% confidence interval (CI): 0.91–0.99) and a specificity of 0.98 (95% CI: 0.94–0.99) at the threshold of 30 ng/mL. For dabigatran, the combined sensitivity of dTT was 0.76 (95% CI: 0.66–0.84) and combined specificity was 0.97 (95% CI: 0.92–0.99). DOAC-specific calibrated AXA was a good index to indicate concentration for rivaroxaban and apixaban. More studies on edoxaban and betrixaban are in need. Diluted TT, thrombin inhibitor assay, and ecarin-based assays were potential to measure dabigatran concentration. Due to the limited data, results should be validated in the future. • DOAC-calibrated AXA is a good index to indicate concentration for FXa inhibitors. • Diluted TT, thrombin inhibitor assay, ecarin-based assay are proper for dabigatran. • A proper cutoff is needed to interpret drug concentration in clinical practice. [ABSTRACT FROM AUTHOR]

Abstract Aim We aimed to investigate the genetic polymorphisms and pharmacogenetic variability associated with the pharmacodynamics (PD) and pharmacokinetics (PK) of prasugrel, in healthy Han Chinese subjects. Patients & methods Healthy, native, Han Chinese subjects (n = 36) aged 18 to 45 years with unknown genotypes were included. All subjects received a loading dose (LD) on day 1 and a maintenance dose (MD) from day 2 until day 11. Candidate gene association and gene-set analysis of biological pathways related to prasugrel and platelet activity were analyzed. Results 28 SNPs of 17 candidate genes previously associated with prasugrel or platelet activity were selected after a literature search. In the 30 mg LD groups (n = 24), ITGA2 -rs28095 was found to be significantly associated with the P2Y12 reaction unit (PRU) value at 24 h after the LD (p = 0.015). 165 study genes related to platelet activation-related processes and prasugrel activity were selected from the MSigDB database, including curated gene sets from KEGG, Bio Carta, and Gene Cards. 14 SNPs of 9 genes were found to be significantly correlated both at 24 h and 12 days after LD: ADAMTSL1, PRKCA, ITPR2, P2RY12, P2RY14, PLCB4, PRKG1, ADCY1, and LYN. Seven SNPs of 6 protein-coding genes associated with area under the concentration-time curve (AUC0-tlast) were significantly identified among the 47 selected genes, including ADAMTSL1, CD36, P2RY1, PCSK9, PON1, and SCD. Conclusion These results show that genetic variation affects the PK and PD of prasugrel in normal individuals. Further studies with larger sample sizes are required to explore whether the SNPs are associated only with prasugrel activity or also with cardiovascular events and all-cause mortality. Highlights • Prasugrel achieves a more consistent level of inhibition of platelet function. • Candidate gene and a gene-set analysis of biological pathways were used. • Genetic variation affects the PK and PD of prasugrel in normal individuals. [ABSTRACT FROM AUTHOR]

Abstract: A novel optical Rhodamine-Furan type chemosensor (RF) was easily synthesized and characterized as a revisable switch. It dispalyed high selectivity toward Al3+ among 19 metal ions and the resultant complex [RF–Al3+] as a sequential chemosensor toward F− among 16 anions in neutral aqueous media (ethanol/water, v/v=2/3, Tris–HNO3, 10mM, pH 7.0). Moreover, detecting fluoride at concentration below the maximum contaminant level in drinking water defined by the U.S. Environmental Protection Agency (4.0mgL−1, 211μM) could be achieved with a detection limit (LOD) estimated down to 1.6μM. Both sensors were very easily to construct and only required simple synthesis. The reversible ring-open mechanism of the rhodamine spirolactam induced by Al3+ binding and the 1:1 stoichiometric structure between RF and Al3+ were adequately supported by job plot evaluation, optical titration, and 1H NMR study. Finally, it could be conveniently used for the determination of fluorides in dental products such as toothpastes with “naked eye” due to the obvious color change of testing solution, showing its potentially practical application. [Copyright &y& Elsevier]