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Purpose: Major disadvantages of the percutaneous coronary intervention (PCI) are the high occurrence of repeat revascularization due to restenosis and disease progression. The current study aimed to identify indicators that can predict the risk of repeat revascularization. Methods: A total of 143 patients who underwent PCI and had genetic test results were enrolled. We retrospectively reviewed their medical records after the first PCI. P2Y12 reaction unit (PRU) test results were obtained by VerifyNow; 4 candidate genes (NOS3, MMP3, AGT, and AGT1R) and 380 genes related to platelet activation-related processes and clopidogrel activity were selected for analysis. Repeat revascularization and in-stent restenosis (ISR) were used as clinical outcomes, and PRU and ADP aggregation rates were used as platelet function outcomes in analysis. Results: After the first PCI, the incidence of repeat revascularization at 18, 30, and 42 months was 14.1% (20/142), 17.5% (24/137), and 39.7% (31/78), respectively. In the candidate gene analysis, rs7830 (NOS3) was associated with both ADP aggregation rate and 18- and 30-month ISR, and rs 62,275,847 (AGTR1) was associated with both ADP aggregation rate and 30-month ISR. In the pathway, gene-set analysis, the linkage rs471683 and rs7785386 of GNAI1|GNAT3 were associated with PRU and ADP aggregation rate, 18-month and 30-month ISR, and repeat revascularization within 30 months. Rs1715389 of GNAI1|GNAT3 was associated with both PRU and ADP aggregation rate, 18-month and 30-month ISR, and repeat revascularization within 30 months. Rs7313458 of ITPR2 was associated with PRU and ADP aggregation rate, 18-month and 30-month ISR, and repeat revascularization within 18 months. Conclusions: The genetic polymorphisms of rs7830 (NOS3), rs62275874 (AGTR1), linkage rs471683 and rs7785386 (GNAI1|GNAT3), rs1715389 (GNAI1|GNAT3), and rs7313458 (ITPR2) may lead to an increased risk of in-stent restenosis and revascularization after the first PCI in Chinese patients by affecting the efficacy of clopidogrel. The above six SNP may be used as potential genetic biomarkers for high risk of in-stent restenosis and revascularization after the first PCI in Chinese patients. [ABSTRACT FROM AUTHOR]

Introduction: Individual variability of rivaroxaban was observed in clinical application. This study aimed to identify genetic variants associated with the variability of pharmacodynamics and bleeding risk of rivaroxbaban in patients with nonvalvular atrial fibrillation (NVAF). Materials and Methods: From June 2017, and July 2019, this study enrolled 257 patients with NVAF receiving rivaroxaban. Pharmacodynamics was assessed by determining anti‐Factor Xa (anti‐FXa) level 3 h after rivaroxaban administration as peak concentration. Whole‐exome sequencing was performed to detected single nucleotide polymorphisms (SNPs). This study was registered (NCT03161496). Results: The bleeding events within 12 months were significantly related to the peak anti‐FXa level (p =.027). SUSD3 rs76292544 was associated with 12‐month bleeding events (odds ratio [OR]: 4.20, 95% confidence interval [CI]: 2.17–8.14, p = 6.43×10−5). Five SNPs including NCMAP rs4553122 (p = 2.29×10−5), PRF1 rs885821 (p = 7.02×10−5), PRKAG2 rs12703159 (p = 7.97×10−5), PRKAG2 rs13224758 (p = 8.70×10−5), and POU2F3 rs2298579 (p = 8.24×10−5) were associated with peak anti‐FXa level. Genetic variants of 52 SNPs from 36 genes including GOT2 rs14221 and MMP13 rs640198 were potentially related to 12‐month bleeding events caused by rivaroxaban's efficacy. Conclusions: Peak anti‐FXa level was associated with risk of bleeding events in patients with NVAF receiving rivaroxaban. SUSD3 rs76292544 was suggestively associated with 12‐month bleeding events and five SNPs (NCMAP rs4553122, PRF1 rs885821, PRKAG2 rs12703159, rs13224758 and POU2F3 rs2298579) were suggestively associated with peak anti‐FXa level. [ABSTRACT FROM AUTHOR]

Background: Data available for pharmacokinetics (PK)/pharmacodynamics (PD) of ticagrelor and significant endogenous/exogenous factors or biomarkers related to bleeding events in both healthy and clinical patients are limited. Objective: Based on PK and PD data from multicenter healthy subjects and patients, we aimed to establish an integrated approach towards population PK (pop PK) and the PD model of ticagrelor. Methods: This study was conducted as a multicenter, prospective clinical registration study involving both healthy subjects and clinical patients. The integrated Pharmacokinetic/pharmacodynamic (PK/PD) models were characterized based on PK/PD [ticagrelor concentration, aggregation baseline (BASE), P2Y12 response unit (PRU) and inhibition rate (INHIBIT)] data from 175 healthy volunteers. The model was corrected by sparse PD (BASE, PRU and INHIBIT) data from 208 patients with acute coronary syndrome (ACS). The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored. Results: A one-compartment, linear model with first-order absorption was adopted as PK model. Food status (FOOD) and body weight (WT) significantly influenced clearance and improved the fitting degree of the PK model, while SEX was selected as the covariates of the PD model. For patients taking ticagrelor 90 mg, the peak value [mean (95% CI)] of PRU was 355.15 (344.24–366.06) and the trough value was 3.64 (3.14–4.15). The PRU mean parameters were basically within the expected range (80–200) of the literature suggestions. Conclusion: A fixed dose of ticagrelor, without adjusting the dosing regimen other than covariates of FOOD/WT/SEX, could be used in patients with acute coronary syndromes, and the standard regimen could be used in Chinese patients from the perspective of exposure. [ABSTRACT FROM AUTHOR]

Background: Novel biomarkers for personalizing anticoagulation remain undetermined. We aimed to investigate the association of plasma miRNAs with pharmacokinetic–pharmacodynamic (PK-PD) profiles of rivaroxaban. Methods: This is a multicenter, exploratory study of miRNAs in a Chinese population. Healthy volunteers and patients receiving rivaroxaban were enrolled in the study. The area under the plasma concentration–time curve from time 0-t h (AUC0-t) and anti-Xa activity at 3 h (AXA3h) were measured in healthy volunteers, and AXA3h was measured in patients. MiRNAs were detected by miRNA microarray in 26 healthy volunteers with 20 mg rivaroxaban, and quantitative reverse transcription polymerase chain reaction was used to exclude undetectable ones. MiR-320a-3p and miR-483-5p were then quantified in 65 healthy volunteers and 71 patients. MiRNA levels at 3 h were compared between high and low AXA3h or AUC0-t subjects and in matched patients with or without bleeding during follow-up. The miRNA targets were predicted by TargetScan, miRTarBase, and miRDB. Validated genes were included in GO enrichment and KEGG analyses. The protein–protein interaction network was established by STRING and visualized by Cytoscape. Results: A total of 136 Chinese subjects completed the study. In healthy volunteers taking 15 mg rivaroxaban, the miR-320a level at 3 h was significantly positively correlated with AXA3h and AUC0-t (r = 0.359, p = 0.025; r = 0.370, p = 0.02, respectively). A positive correlation was also observed between miR-483 and AXA3h or AUC0-t (r = 0.372, p = 0.02; r = 0.523, p = 0.001, respectively). MiR-320a and miR-483 levels at 3 h in the higher AUC0-t group were significantly higher than those at 0 h. MiR-483 levels at 3 h may distinguish healthy volunteers with high or low AXA3h or AUC0-t. In the 10 mg fed subgroup, higher 3 h mir-483 levels were also observed compared with the control group. No significant differences were found in the comparisons among patients. Bioinformatic analysis showed that these miRNAs may play a regulatory role by targeting ABCG2, ITGB3, PTEN, MAPK1/3, etc. Conclusions: MiR-320a and miR-483 levels were found to be associated with PK and PD profiles of rivaroxaban in healthy Chinese subjects. Further studies are required to verify these findings and explore the mechanisms. [ABSTRACT FROM AUTHOR]

Study Objective: East Asians have a higher risk of bleeding than Europeans when treated with ticagrelor. This study aimed to explore genetic indicators related to the high bleeding propensity in East Asian patients with acute coronary syndrome (ACS) using ticagrelor. Design: A multicenter prospective cohort study. Setting: Four sub center hospitals participating the study. Patients: Between March 2018 and July 2021, 208 patients with ACS were administered ticagrelor and underwent genetic testing. Invertention: Patients were enrolled and followed up for bleeding events for 12 months. Single‐nucleotide polymorphisms (SNPs) were detected using whole‐exome sequencing. SNPs significantly associated with cumulative bleeding events within 1‐, 6‐, and 12‐month follow‐ups were selected (p < 0.01). Among these, SNPs showing a difference of ≥2 fold in their distribution frequency among East Asians and Europeans were selected. Measurements and Main Results: Among all patients, 96.60% received ticagrelor plus aspirin or cilostazol, and 42.3% suffered from bleeding events during 12‐month follow‐up. Furthermore, 22 SNPs of 15 genes were found to have a significant association with cumulative bleeding events within 1‐, 6‐, and 12‐month follow‐ups. Among these SNPs, FIG4 rs2295837 (A>T) variant had the strongest association with bleeding events within 1 month (p = 1.28 × 10−4), with an increased risk of bleeding in T allele carriers (odds ratio [OR]: 3.07, 95% confidence interval [CI]: 1.68–5.63). PROK2 rs3796224 (C>T) variant was most strongly associated with cumulative bleeding events within 6 months (p = 4.57 × 10−4) with an increased risk of bleeding in T allele carriers (OR: 2.16, 95% CI: 1.20–3.89). Moreover, HRNR rs6662450 (C>T) variant showed the strongest relation with cumulative bleeding events within 12 months (p = 4.86 × 10−4) with a reduced risk of bleeding in T allele carriers (OR: 0.48, 95% CI: 0.24–0.95). Conclusion: Fifteen genes, including PROK2, HRNR, and FIG4, were potential biomarkers of high bleeding propensity in East Asian patients with ACS using ticagrelor. [ABSTRACT FROM AUTHOR]

Introduction: To identify the potential factors responsible for the individual variability of dabigatran, we investigated the genetic variations associated with clinical outcomes and pharmacodynamics (PD) in Chinese patients with nonvalvular atrial fibrillation (NVAF). Materials and methods: Chinese patients with NVAF taking dabigatran etexilate with therapeutic doses were enrolled. The primary (bleeding events) and secondary (thromboembolic and major adverse cardiac events) outcomes for a 2‐year follow‐up were evaluated. Peak and trough PD parameters (anti‐FIIa activity, activated partial thromboplastin time and prothrombin time) were detected. Whole‐exome sequencing, genome‐wide sequencing and candidate gene association analyses were performed. Results: There were 170 patients with NVAF treated with dabigatran (110 mg twice daily) who were finally included. Two single‐nucleotide polymorphisms (SNPs) were significantly related with bleeding, which include UBASH3B rs2276408 (odds ratio [OR] = 8.79, 95% confidence interval [CI]: 2.99–25.83, p = 7.77 × 10−5 at sixth month visit) and FBN2 rs3805625 (OR = 8.29, 95% CI: 2.87–23.89, p = 9.08 × 10−5 at 12th month visit), as well as with increased trends at other visits (p <.05). Furthermore, minor allele carriers of 16 new SNPs increased PD levels, and those of one new SNP decreased PD values (p < 1.0 × 10−5). Lastly, 33 new SNPs were found to be associated with bleeding and PD among 14 candidate genes. Unfortunately, the low number of secondary outcomes precluded further association analyses. Conclusions: Genetic variations indeed affected bleeding and PD in Chinese patients with NVAF treated with dabigatran. The functions of these suggestive genes and SNPs might further be explored and verified in more in vivo and in vitro investigations. [ABSTRACT FROM AUTHOR]

(1) Background: The purpose of this study was to evaluate the effect of gene polymorphisms on prothrombin time (PT) and activated partial thromboplastin time (APTT) in a healthy Chinese population. (2) Methods: A total of 403 healthy volunteers from a series of novel oral anticoagulants (NOACs) bioequivalence trials in China were included. Coagulation tests for PT and APTT were performed in the central lab at Peking University First Hospital. Whole-exome sequencing (WES) and genome-wide association analysis were performed. (3) Results: In the correlation analysis of PT, 105 SNPs from 84 genes reached the genome-wide significance threshold (p < 1 × 10−5). Zinc Finger Protein 594 (ZNF594) rs184838268 (p = 4.50 × 10−19) was most significantly related to PT, and Actinin Alpha 1 (ACTN1) was found to interact most with other candidate genes. Significant associations with previously reported candidate genes Aurora Kinase B (AURKB), Complement C5(C5), Clock Circadian Regulator (CLOCK), and Histone Deacetylase 9(HDAC9) were detected in our dataset (p < 1 × 10−5). PiggyBac Transposable Element Derived 2(PGBD2) rs75935520 (p = 4.49 × 10−6), Bromodomain Adjacent To Zinc Finger Domain 2A(BAZ2A) rs199970765 (p = 5.69 × 10−6) and Protogenin (PRTG) rs80064850 (p = 8.69 × 10−6) were significantly correlated with APTT (p < 1 × 10−5). The heritability values of PT and APTT were 0.83 and 0.64, respectively; (4) Conclusion: The PT and APTT of healthy populations are affected by genetic polymorphisms. ZNF594 and ACTN1 variants could be novel genetic markers of PT, while PRTG polymorphisms might be associated with APTT levels. The findings could be attributed to ethnic differences, and need further investigation. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to identify genetic variations associated with the metabolism of dabigatran in healthy Chinese subjects, with particular focus given to pharmacokinetics (PK) and pharmacodynamics (PD). Methods: Healthy Chinese adults aged 18–65 years with unknown genotypes from a bioequivalence trial were included according to the protocol registered at ClinicalTrial.org (NCT03161496). All subjects received a single dose (150 mg) of dabigatran etexilate. PK (main outcomes: area under the concentration-time, AUC0-t, of total and free dabigatran) and PD (main outcomes: anti-FIIa activity, APTT, and PT) parameters were evaluated. Whole-exome sequencing and genome-wide association analyses were performed. Additionally, candidate gene association analyses related to dabigatran were conducted. Results: A total of 118 healthy Chinese subjects were enrolled in this study. According to the p -value suggestive threshold (1.0 × 10−4), the following three SNPs were found to be associated with the AUC0–t of total dabigatran: SLC4A4 SNP rs138389345 (p = 5.99 × 10−5), FRAS1 SNP rs6835769 (p = 6.88 × 10−5), and SULT1A1 SNP rs9282862 (p = 7.44 × 10−5). Furthermore, these SNPs were also found to have significant influences on the AUC0–t of free dabigatran, maximum plasma concentration, and anti-FIIa activity (p < 0.05). Moreover, we identified 30 new potential SNPs of 13 reported candidate genes (ABCB1 , ABCC2 , ABCG2 , CYP2B6 , CYP1A2 , CYP2C19 , CYP3A5 , CES1 , SLCO1B1 , SLC22A1 , UGT1A1 , UGT1A9 , and UGT2B7) that were associated with drug metabolism. Conclusion: Genetic variations were indeed found to impact dabigatran metabolism in a population of healthy Chinese subjects. Further research is needed to explore the more detailed functions of these SNPs. Additionally, our results should be verified in studies that use larger sample sizes and investigate other ethnicities. [ABSTRACT FROM AUTHOR]

Background: The rivaroxaban dose regimen for patients with nonvalvular atrial fibrillation (NVAF) is complex in Asia. Given the high interindividual variability and the risk of bleeding caused by rivaroxaban in Asians, the influencing factors and the relationship between outlier biomarkers and bleeding events need exploration. Methods: The integrated pharmacokinetics (PK)/pharmacodynamics (PD) models were characterized based on rich PK/PD data from 304 healthy volunteers and sparse PD [anti-factor Xa activity (anti-Xa) and prothrombin (PT)] data from 223 patients with NVAF. The correlations between PD biomarkers and clinically relevant bleedings in 1 year were explored. The final integrated PK/PD model was used to evaluate the influence of dosage and individual covariates on PD parameters. Results: A two-compartment, linear model with sequential zero-order and first-order absorption was adopted. The dose-specific relative bioavailability (F1), diet status, creatinine clearance, and body mass index (BMI) improved the model fit. The apparent systemic clearance was 7.39 L/h, and the central and peripheral volumes were 10.9 and 50.9 L, respectively. The linear direct-effects model with shape factor plus the additive (and/or proportional) error model described the correlation between anti-Xa/PT and plasma concentration. Bodyweight, total cholesterol (TCHO), and diet status were selected as the covariates of the anti-Xa/PT model. Anti-Xa was more sensitive to the increase in rivaroxaban exposure compared with PT. An elevated bleeding tendency was seen with higher peak anti-Xa and PT. For a typical Chinese patient, the peak anti-Xa value (median (5%–95% PI)) of 20 and 15 mg were 309 ng/ml (139–597 ng/ml) and 296 ng/ml (138–604 ng/ml), both median values were within the expected range. For patients with CrCL 30–49 ml/min, the median peak anti-Xa with recommended 10 mg other than 15 mg were within the expected range. Conclusion: Fixed doses of rivaroxaban could be prescribed for patients with NVAF without adjustment for bodyweight, BMI, and TCHO. Randomized studies should be performed to evaluate the efficacy and safety of low-dose rivaroxaban in Chinese patients with NVAF. [ABSTRACT FROM AUTHOR]

Background: Studies show inconsistent results regarding the impact of CYP2C19 genotype on the pharmacodynamics (PD) and clinical outcomes of ticagrelor. With the implementation of genotype-guided individualized antiplatelet therapy, the association between CYP2C19 polymorphism and the efficacy and safety of ticagrelor for patients is still worthy of exploring and studying.Methods: This systematic review protocol has been registered in the PROSPERO network (No. CRD 42020158920). Electronic databases of PubMed, EmBase, and the Cochrane Library were systematically searched from inception to January 6th, 2022 to select studies investigating the impact of CYP2C19 genotype on PD and clinical outcomes of ticagrelor. The results were presented as odds ratio (OR) or weight mean difference with its 95% confidence interval (CI) by using the random-effects model. Trial sequential analysis (TSA) was used to control risk of random errors and detect the robustness of outcomes.Results: Eight studies recruited a total of 6405 patients treated with ticagrelor. Mostly trials reported no significant effect of any or no CYP2C19 loss-of-function (LOF) allele (*2 or *3) on all the endpoints. Compared with no LOF allele carriers, subgroup analysis suggested any LOF allele in Asian patients was associated with a significant decreased risk of bleeding events (OR: 0.41; 95% CI: 0.22-0.75; P = 0.004). Furthermore, any LOF allele carriers didn't yield any impact on the risk of MACEs (OR: 1.11; 95% CI: 0.76-1.64; P = 0.586), stroke (OR: 1.71; 95% CI: 0.99-2.96; P = 0.054), definite stent thrombosis (OR: 0.88; 95% CI: 0.17-4.60; P = 0.882), bleeding (OR: 0.63; 95% CI: 0.27-1.46; P = 0.281), myocardial infarction (OR: 0.81; 95% CI: 0.30-2.20; P = 0.682), and revascularization (OR: 0.81; 95% CI: 0.33-2.00; P = 0.649) in all patients. The results of TSA were indicated that more further trials would be required.Conclusions: This qualitative and quantitative study suggested Asian patients carrying any CYP2C19 LOF allele might have a lower risk of bleeding events comparing with no LOF allele carriers when treated with ticagrelor. However, we did not prove an important role of CYP2C19 genotype on the risk of PD and clinical endpoints in the whole cohort. In future, more large-scale prospective studies and more different ethnic populations should be included. [ABSTRACT FROM AUTHOR]

Purpose: Low-dose rivaroxaban is often given to patients with atrial fibrillation (AF) around the world, but the rationale for its use remains unclear. We aimed to compare the efficacy and safety of standard- or low-dose rivaroxaban in patients with AF through systematic review of literature with meta-analysis. Methods: We searched PubMed, Web of Science, EMBASE, Clinical Trials.gov, the Cochrane Library, and Bayer trial website from inception of each database until June 2020. Randomized controlled trials (RCTs) and cohort studies were included in the meta-analysis. A random-effects model was employed to calculate the pooled effect estimates. Results: Two RCTs and 17 cohort studies were included in the qualitative analysis. Indirect comparison of RCTs showed no significant difference between the two rivaroxaban dosages in risk of efficacy or safety outcomes (p > 0.05). Indirect comparison of cohort studies showed a lower risk of MACE among Caucasians in standard-dose group (HR 0.779; 95% CI 0.687–0.884; p < 0.001). Bleeding outcomes did not differ significantly between the two dosage regimens in Asian or Caucasian populations, except that the standard dose was associated with higher risk of major bleeding among elderly Caucasian patients (HR 1.329; 95% CI 1.141–1.547; p < 0.001). The quality of evidence was rated ranging from very low to low for all the efficacy and safety outcomes. Conclusion: In Caucasians with AF, standard-dose rivaroxaban may prevent MACE significantly better than low-dose treatment. Further studies in Asians are needed to verify the advantages of the standard dose. [ABSTRACT FROM AUTHOR]

What is known and objective: Limited data are available for the comparison between different non‐vitamin K antagonist oral anticoagulants (NOACs) on clinical outcomes. We aimed to provide evidence of different NOACs for patients with non‐valvular atrial fibrillation (NVAF). Methods: Electronic databases were searched from inception through 22 March 2020 to identify eligible studies in which clinical outcomes (stroke, systemic embolism [SE], bleeding or death events) were directly compared between different NOACs. Results: 29 real‐world studies enrolled more than 700,000 patients were included. Compared with dabigatran, apixaban had higher risk of death (OR 1.07), major bleeding (1.43), GI bleeding (1.64), ischaemic stroke and stroke/SE events (1.10); rivaroxaban had higher risk of death (1.28), major bleeding (1.24), GI bleeding (1.14) and ischaemic stroke (1.08). Compared with rivaroxaban, apixaban had lower risk of death (0.8), major bleeding (0.56) and ischaemic stroke events (0.71). Compared with edoxaban, rivaroxaban had higher risk of major bleeding (2.83), GI bleeding (5.18) and ischaemic stroke (2.28). What is new and conclusion: In view of the global burden of disease and the routine use of NOACs worldwide, the findings have immediate and important implications. Our data suggested that apixaban might be the priority choice in prevention of bleeding and stroke and dabigatran could be the priority choice in prevention of death events. Trial registration: This systematic review and meta‐analysis were conducted and reported according to the Preferred Reporting Items for Systematic Reviews (PRISMA), Meta‐analysis Of Observational Studies in Epidemiology (MOOSE) guidelines and was registered with PROSPERO (CRD42019140553). [ABSTRACT FROM AUTHOR]

Background: For patients taking factor Xa (FXa) inhibitors who have life-threatening bleeding, emergency surgery, drug interactions, etc., a rapid and precise assay is needed to monitor for potential medication failure, to assess safety during periprocedural anticoagulation management, and to manage the care of chronically anticoagulated patients. Anti-factor Xa (anti-Xa) activity assays have been recommended in guidelines, but the evaluation of different calibrations of anti-Xa activity assays and the data on the recommended range are still limited, especially in the Asian population. Methods: This is a nationwide multicenter methodology exploratory study in an Asian population, including nine hospitals from Beijing, Shanghai, Liaoning, Shandong, Jiangsu, Anhui, Henan, Chongqing, and Fujian. A total of 485 healthy volunteers and 219 patients taking rivaroxaban or apixaban (single dose) were enrolled in the study. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) was employed to detect plasma rivaroxaban and apixaban. The prothrombin time (PT), activated partial thromboplastin time (APTT), and levels of anti-Xa activity were tested as pharmacodynamic parameters in plasma samples. We evaluated the correlation of anti-Xa activity and blood concentration via HPLC-MS, and then compared the two methods of target drug-calibrated and low-molecular-weight heparin (LMWH)-antithrombin–calibrated anti-Xa activity. Correlations between variables were examined using Pearson's correlation analysis. Logistic regression was applied to evaluate significant differences in anti-Xa activity and blood concentration, using models adjusted by baseline characteristics. Results: The results suggested anti-Xa activity had better correlation with blood concentrations of apixaban and rivaroxaban than APTT and PT (p < 0.001). Target drug-calibrated anti-Xa activity had better correlation with HPLC-MS results at every dose level and blood collection time (p < 0.001). The expected concentrations (ng/mL) derived from rivaroxaban-calibrated assays of rivaroxaban 10 mg, 15 mg, and 20 mg were about 210, 330, and 270 at peak concentrations, and 28, 44, and 58, respectively, at the trough concentrations. Conclusions: In this study, we confirm that target drug calibration of anti-Xa activity is a better quantitative detection method for oral direct FXa inhibitors than LMWH-calibrated anti-Xa activity in clinical practice, and expected peak–trough levels are recommended for the Asian population. [ABSTRACT FROM AUTHOR]

Background: Due to the high risk of ischemic and arterial or venous bleeding events in atrial fibrillation (AF) or venous thromboembolism (VTE) patients with renal impairment (RI), selection of appropriate anticoagulant regimen is important. Therefore, we systematically reviewed and compared the safety and effects of oral anticoagulants in AF and VTE patients with RI. Methods: Eligible articles were identified through a literature search in PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library for studies published between January 2008 and November 2020. Network meta-analysis was conducted with STATA 14.0 to analyze the effects and safety of each drug with regard to different levels of renal function. Results: 15 studies including 82,931 patients (76,957 with AF and 5974 with VTE) were analyzed. Compared with those of warfarin, the risk ratios of effect and safety outcomes of apixaban were 0.70 (95% confidence interval [CI] 0.60–0.82) and 0.56 (95% CI 0.42–0.76) in AF patients and 0.33 (95% CI 0.19–0.59) and 0.95 (95% CI 0.68–1.34) in VTE patients. Apixaban had the first or second highest probability of being ranked first with respect to surface under the cumulative ranking curve (SUCRA) scores in the prevention of major bleeding events, while in the prevention of ischemic events, rivaroxaban showed a higher SUCRA score (0.78–0.92) in mild RI patients and dabigatran showed a higher SUCRA value (0.90–0.99) in moderate RI patients. Conclusions and Relevance: In the systematic review and meta-analysis, for AF or VTE patients with RI, direct oral anticoagulants performed comparably to or better than warfarin with regard to safety and effects. The network meta-analysis indicated that for patients with mild RI, apixaban might be safer for patients with a lower risk of ischemic events, while rivaroxaban might be suitable for patients with a lower risk of bleeding events. For patients with moderate RI, apixaban could reduce the risk of ischemic events without increasing the risk of bleeding events. For AF patients with severe RI, apixaban, rivaroxaban, and warfarin showed a similar effect. These results might provide suggestions for clinical arterial and venous thrombosis prevention. [ABSTRACT FROM AUTHOR]

Aim: This meta‐analysis was carried out to explore if a personalized antiplatelet strategy based on genotyping is superior to conventional therapy. Methods: PubMed, Web of Science, EMBASE and the Cochrane Library were searched from the inception of each database to 5 May 2020. Studies reporting endpoints in genotype‐guided treatment group and conventional treatment group were included. The endpoint results were presented as the risk ratio (RR), with 95% confidence interval (CI). Results: A total of 10 561 patients from 16 studies (eight randomized controlled trials [RCT] and eight cohort studies) were included in the meta‐analysis. The rates of major adverse cardiovascular events (MACE), stent thrombosis and myocardial infarction (MI) were significantly lower in the genotype‐guided group than in the conventional treatment group (RR 0.56, 95% CI 0.44‐0.73, P <.0001; RR 0.40, 95% CI 0.24‐0.67, P =.0005; RR 0.45, 95% CI 0.35‐0.58, P <.00001, respectively). A significant difference was found between the two groups in major bleeding (RR 0.73, 95% CI 0.55‐0.98, P =.04), which was not robust after sensitivity analysis. Conclusion: Genotype‐guided antiplatelet treatment could decrease the risk of MACE, stent thrombosis and MI in patients with coronary artery disease or undergoing percutaneous coronary intervention, without increasing the risk of bleeding over a long follow‐up period. The decreased risk of efficacy outcomes was more obvious in cohort studies. Well‐organized RCTs and clinical trials are required to verify the benefit of genotype‐guided therapy. [ABSTRACT FROM AUTHOR]

Background: Progressive bone pain and fracture and abnormal positron emission tomography combined with a computed tomography are main reasons for the oncologists suspecting bone tumor. During the patient's medical treatment, the oncologists' unfamiliarity with adverse reactions to anti-HBV drugs were main reason for the long-term exposure to the drug and the adverse reaction (ADR) experienced by the patient. Case presentation: A 63-year-old Chinese man had a 27-month history of progressive generalized bone pain combined with spontaneous fractures. Positron emission tomography combined with a computed tomography, revealed an abnormal increase in ribose metabolism and low positron serum inorganic phosphorus concentration (0.7; 0.78–1.65 mmol/L). Serum creatinine level was 252 μmol/L (53–97) μmol/L, and glomerular filtration rate was 22.79 mL/min/1.73 m2. The patient was referred to a multidisciplinary clinic to clarify the diagnosis of myeloma or bone tumor for further treatment in 2017. His medical history revealed that he had a 30-year history of chronic hepatitis B infection. He had received lamivudine at a daily dose of 100 mg for 19 years (1990 to 2009), which had been changed to adefovir (10 mg/day) owing to lamivudine resistance in 2009. Based on the changes in the patient's laboratory markers and the results of emission computed tomography and other radiographic findings, adefovir-induced hypophosphatemic osteomalacia due to acquired renal Fanconi syndrome was suspected by the clinical pharmacist. Considerable clinical improvement was observed after adefovir discontinuation and the administration of entecavir (1.0 mg, every other day). Conclusion: Fanconi syndrome with osteomalacia can develop in patients with chronic hepatitis B infection being treated with adefovir at a conventional low dosage of 10 mg/day. This case highlights the importance of ADR as a differential diagnosis and the need of pharmacists with drug safety expertise expert in the patient management. [ABSTRACT FROM AUTHOR]

To assess bioequivalence of a generic dabigatran etexilate capsule in healthy Chinese subjects under fasting and fed conditions. This was an open‐label, single‐center, randomized four‐period crossover study with a 7‐day washout period. A single oral dose of 150 mg generic dabigatran etexilate capsule (test drug) or a commercial dabigatran etexilate capsule (Pradaxa®, reference drug) was given to healthy volunteers under the fasting and fed conditions. Plasma concentrations of total and free dabigatran were detected using a validated HPLC‐MS/MS method. A noncompartmental method was used for pharmacokinetic analysis and established coagulation assays were applied for pharmacodynamic analysis. The 90% CIs of the test/reference ratios of Cmax, AUC0‐t, and AUC0‐∞ for the total dabigatran concentration were 92.57%‐106.58%, 91.63%‐106.32%, and 92.54%‐106.17%, respectively, under fasting condition, and 99.30%‐110.74%, 98.58%‐105.37%, and 97.75%‐103.99%, respectively, under fed conditions. The 90% CIs of the ratios of the parameters for the free dabigatran were 93.18%‐106.98%, 92.13%‐107.10%, 92.89%‐106.48%, respectively, under fasting condition, and 100.05%‐110.89%, 99.37%‐106.23%, 97.59%‐103.98%, respectively, under the fed condition. Additionally, the upper limit of the 90% CIs for σWT/σWR was below 2.5. There were no significant differences in the coagulation parameters including thrombin clotting time, activated partial thromboplastin time, and anti‐IIa activity between the two preparations. The generic dabigatran etexilate capsule is bioequivalent to the brand‐named product in healthy Chinese volunteers under fasting and fed conditions. The two products have comparable pharmacodynamic parameters, with a good safety profile. In addition, food intake influences absorption of both products in a similar way. [ABSTRACT FROM AUTHOR]

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies are powerful lipid-lowering drugs which have been shown to improve clinical endpoints in patients with hypercholesterolemia. However, it is not clear how effective PCSK9 monoclonal antibodies are for patients at high cardiovascular risk. Also, whether the effectiveness of PCSK9 monoclonal antibodies varies between different drug types, dosages, race, and indications for PCSK9 monoclonal antibodies remains unclear. Therefore, we used recently published studies to systematically evaluate the efficacy and safety of PCSK9 monoclonal antibodies by analyzing the lipid profiles, adverse events, and clinical endpoints in patients at high cardiovascular risk.Methods: Randomized controlled trials (RCTs) comparing PCSK9 monoclonal antibodies with placebos or active drugs in patients at high cardiovascular risk were retrieved from electronic databases from their inception until November 2019. Efficacy and safety outcomes included low-density lipoprotein cholesterol (LDL-C) and other lipid profiles, treatment-emergent adverse events (TEAEs) and adverse events of interests, and clinical endpoints. Subgroup analyses based on drug types, dosing, and race were conducted. Statistical analysis was performed using STATA 15.1 and RevMan 5.0.Results: Thirty-two RCTs were included in the systematic review, and 25 of them (57,090 individuals) were included in the meta-analysis. PCSK9 monoclonal antibodies significantly improved LDL-C and other lipid profiles (P < 0.05), and no racial differences were found. A recommended dose of 140 mg of evolocumab every 2 weeks was likely to produce a relatively stronger effect than 150 mg of alirocumab every 2 weeks in terms of the absolute change (weighted mean differences (WMD) - 0.36; 95% confidence interval (CI) - 0.71 to - 0.01; P = 0.041) and percent change (WMD - 19.53; 95% CI - 32.02 to - 7.04; P = 0.002) in LDL-C levels. Overall, PCSK9 monoclonal antibodies were safe, except for the significantly increased risk of injection site reactions (relative risks (RR) 1.54; 95% CI 1.38-1.71; P < 0.001). Both alirocumab (RR 0.89; 95% CI 0.83-0.95; P < 0.001) and evolocumab (RR 0.86; 95% CI 0.80-0.92; P < 0.001) were associated with a lower risk of major cardiovascular events (MACEs), especially in secondary preventive patients (alirocumab group: RR 0.88; 95% CI 0.82-0.95; P < 0.001; evolocumab group: RR 0.86; 95% CI 0.80-0.92; P < 0.001). The reduction in MACEs was observed in White but not in Asian subjects. No significant reduction of all-cause mortality was found (RR 0.88; 95% CI 0.72-1.07; P = 0.182).Conclusion: Both alirocumab and evolocumab are well tolerated and can greatly improve lipid profiles for patients at high cardiovascular risk. Both PCSK9 monoclonal antibodies significantly reduce the risk of nonfatal MACEs in patients with previous cardiovascular events, but the effect on all-cause mortality remains uncertain. [ABSTRACT FROM AUTHOR]

Cigarette smoking is an important cardiovascular risk factor, causing morbidity and mortality. There are many original studies on the impact of smoking, but its influence on platelet ADP-P2Y12 receptor inhibitors lack consistency. Thus, we conducted a systematic review and meta-analysis of already existing data/studies to further explore this issue. PubMed, Web of science, EMBASE, Clinical Trials, and the Cochrane Library were searched from inception to March 2018. Studies investigating the residual platelet reactivity categorized by smoking status and patients treated with platelet ADP-P2Y12 receptor inhibitors qualified the inclusion criteria. The primary outcome was P2Y12 reaction unit (PRU) value measured by VerifyNow P2Y12 assay, compared with different smoking status in ADP-P2Y12 receptor inhibitors treatment groups. Secondary outcome was post-treatment with 5 μmol/L ADP-inhibition of platelet aggregation (ADP-IPA) measured by light transmittance aggregometry (LTA). Of the 4954 citations retrieved, 12 studies involving 16 296 patients with acute coronary syndrome and/or stent deployment using platelet ADP-P2Y12 receptor inhibitors were included for meta-analysis. Pooled analysis revealed that PRU values of current smokers were 25.70 lower than nonsmokers (95% CI −38.81 to −12.60, p = 0.0001), getting better effects of antiplatelet treatment. In the smoking extent subgroup analysis, patients smoking >10 cigarettes/day shown about 46.49 lower of PRU values than patients smoking <10 cigarettes/day (p < 0.00001). Racial subgroup analyses found that smokers had increased platelet inhibition in the Caucasian population. Further, pooled analysis of ADP-IPA values for 1658 patients from five studies showed a significantly lower residual platelet reactivity in current smokers compared to that in nonsmokers (MD = −4.19; 95% CI −6.55 to −1.83; p = 0.0005). This systematic review and meta-analysis suggested that smokers have increased platelet inhibition and lower aggregation in response to clopidogrel than nonsmokers. These residual platelet reactivity observations may help to explain differential clinical outcomes in smokers vs. nonsmokers in large scale clinical trials. [ABSTRACT FROM AUTHOR]

What is known and objective: Dopamine D2 receptor (DRD2) polymorphisms are inconsistently associated with elevated prolactin levels related to risperidone treatment. The aim of this systematic review and meta‐analysis was to investigate whether DRD2 polymorphisms could modulate prolactin levels in patients treated with risperidone. Methods : Three electronic databases (PubMed, EMBASE and the Cochrane Library) were searched for studies investigating the effect of DRD2 polymorphisms on prolactin levels in patients treated with risperidone until May 2018. Summary standard mean differences (SMDs) and 95% confidence intervals (CIs) were calculated with Hedges' g tests for effect estimates using random effects models. The heterogeneity, sensitivity, univariable meta‐regression, subgroup analyses and publication biases were calculated. Results and discussion : After initially identifying 886 studies, 772 patients from eight studies were included. Summary SMDs indicated that compared with A1 non‐carriers, Taq1A A1 carriers did not have different risperidone‐related prolactin levels (SMD: 0.13; 95% CI: −0.18 to 0.43; P = 0.423) among patients with schizophrenia (SCZ; SMD: 0.07; 95% CI: −0.14 to 0.29; P = 0.505) or among those without SCZ (SMD: 0.16; 95% CI: −0.39 to 0.71; P = 0.562). There was no significant difference between Del carriers and Del non‐carriers with regard to risperidone‐related prolactin levels (SMD: −0.00; 95% CI: −0.59 to 0.58; P = 0.996). In an Asian subgroup analysis, we also noted that compared with Taq1A A1A2 carriers, Taq1A A1A1 carriers had lower prolactin levels (SMD: −0.34; 95% CI: −0.66 to −0.02; P = 0.040). However, there was no significant difference in prolactin levels between A1A1 carriers and A2A2 carriers (SMD: −0.27; 95% CI: −0.60 to 0.05; P = 0.098), or between A2 carriers and A2 non‐carriers (SMD: 0.29; 95% CI: −0.01 to 0.59; P = 0.059). Based on univariable meta‐regression analyses, the effects of publication year, study design, ethnicity, comparison groups and study quality could bias the identified association of DRD2 Taq1A with risperidone‐related prolactin levels. What is new and conclusion : The findings of this study suggest that there is no significant difference between Taq1A A1 carriers and non‐A1 carriers with regard to risperidone‐related prolactin levels. As there were few A1 homozygotes, large prospective studies with robust designs are still needed to investigate whether A1A1 could affect risperidone‐related prolactin levels in the Asian population. [ABSTRACT FROM AUTHOR]

Background: The effect of risperidone treatment in patients with schizophrenia varies according to the dopamine receptor genes. This study aimed to evaluate the relationship between genes of the dopamine receptors (D1, D2, and D3) and the effect of risperidone treatment. Methods: Three electronic databases (PubMed, Embase, and Cochrane Library) were searched for relevant cohort or case‐control studies published before 9 May 2018. A systematic review and meta‐analysis was performed for qualitative and quantitative assessment of the relationship between the dopamine receptors D1, D2, and D3 (DRD1, 2, and 3) and the effect of risperidone treatment. The summary odds ratio (OR) and weighted mean difference (WMD) in a random‐effects model were used to measure these relationships. Results: Twelve studies involving 24 SNPs were included. DRD2 (Ser311Cys, rs1801028 Ser/Ser) significantly lowered the improvement rate (determined by the PANSS score) unlike Ser/Cys (WMD: −11.58, 95% CI: −17.35 to −5.18). For Asian patients, A241G (rs1799978) AA carriers showed greater improvement after risperidone therapy (P < 0.05). The polymorphisms of 141C Ins/Del (rs1799732), T939C (rs6275), rs6277, and TaqID (rs1800498) may also influence the treatment effect. TaqIA (rs1800497) and TaqIB (rs17294542) were not associated with the rate of response to risperidone. DRD3 was not associated with an improvement in the PANSS total score; however, Ser9Gly might be related to a change in negative symptoms. No significant effect of DRD1 (rs5326, rs4867798, rs4532, and rs11749676) was found. Conclusions: Our result supported the hypothesis that DRD2 affected risperidone treatment. DRD1 had no significant effect on the response to risperidone, whereas DRD3 might be associated with an improvement in negative symptoms. Larger observational studies are warranted to verify these findings and identify other genetic factors involved. [ABSTRACT FROM AUTHOR]

Purpose: The extracellular domain (ECD) of human epidermal growth factor receptor-2 (HER2) in the blood is a promising biomarker of cancer prognosis and response to therapy, whereas the clinical prognostic role of serum HER2 ECD (sHER2 ECD) level in patients with BC remains controversial. Moreover, its cut-off value significantly varies. Thus, this meta-analysis aimed to quantify the prognostic impact of this biomarker with a specific cut-off value in patients with BC.Methods: A systematic review of electronic databases was conducted to identify studies that assessed the association between baseline sHER2 ECD level with a cut-off value of 15 ng/mL and clinical outcomes in patients with BC. Overall survival (OS) was the primary endpoint, and disease-free survival (DFS), progression-free survival (PFS), and time to progression (TTP) were the secondary endpoints. An inverse variance random effects meta-analysis was conducted.Results: Twenty-three studies that included 8231 patients with BC who met the inclusion criteria were included. An elevated baseline sHER2 ECD level was associated with a hazard ratio (HR) of 2.28 (95% confidence interval [CI] 2.00-2.61; P < 0.001) for OS, and this effect was observed in all subgroups. The HRs for an elevated sHER2 ECD level for DFS, PFS, and TTP were 2.52 (95% CI 1.90-3.35; P < 0.001), 1.63 (95% CI 1.37-1.95; P < 0.001), and 1.98 (95% CI 1.66-2.36; P < 0.001), respectively.Conclusions: An elevated sHER2 ECD level with a cut-off value of 15 ng/mL was associated with poor clinical prognosis in patients with BC. Future studies should be conducted to reduce confounding and explore the mechanism. [ABSTRACT FROM AUTHOR]