The Pharmacogenetic Variability Associated with the Pharmacokinetics and Pharmacodynamics of Rivaroxaban in Healthy Chinese Subjects: A National Multicenter Exploratory Study.

PURPOSE: This study aimed to explore the pharmacogenetic variability associated with the pharmacokinetics (PK) and pharmacodynamics (PD) of rivaroxaban in healthy Chinese subjects. METHODS: This was a multicenter study that included 304 healthy adults aged 18 to 45 years with unknown genotypes. All participants were administered a single dose of rivaroxaban at 10 mg, 15 mg, or 20 mg. PK and PD parameters were measured, and exome-wide association analysis was conducted. FINDINGS: Sixteen SNPs located on 11 genes influenced the AUC0-t. Among these, the 3 most influential genes were MiR516A2, PARP14, and MIR618. Thirty-six SNPs from 28 genes were associated with the PD of rivaroxaban. The 3 most influential genes were PKNOX2, BRD3, and APOL4 for anti-Xa activity, and GRIP2, PLCE1, and MLX for diluted prothrombin time (dPT). Among them, BRD3 played an important role in both the PK and PD of rivaroxaban. Anti-Xa activity (ng/mL) differed significantly among subjects with BRD3 rs467387: 145.1 ± 55.5 versus 139.9 ± 65.1 versus 164.0 ± 68.6 for GG, GA, and AA carriers, respectively (P = 0.0002). IMPLICATIONS: This study found that that the regulation of the BRD3 gene might affect the PK and PD of rivaroxaban, suggesting that it should be studied as a new pharmacologic target. The correlation between this gene locus and clinical outcomes has yet to be verified in patients undergoing clinical treatment.

De-escalation of Antiplatelet Therapy After Percutaneous Coronary Intervention in East Asian Patients With Acute Coronary Syndrome.

PURPOSE: East Asian individuals have a lower risk of thromboembolic events while potentially carrying a higher risk of bleeding events compared with non-Asian individuals. The aim of the present analysis was to investigate the effectiveness and safety of the de-escalation of antiplatelet therapy compared with standard dual antiplatelet therapy (DAPT) in East Asian patients undergoing percutaneous coronary intervention (PCI). METHODS: Randomized controlled trials comparing de-escalation with DAPT in patients with acute coronary syndrome (ACS) were retrieved from electronic databases from their inception until March 2022. Outcomes included major adverse cardiovascular events (MACE), ischemic events, major bleeding, minor bleeding, and any bleeding. Subgroup analyses based on treatment strategy were conducted. Statistical analysis was performed by using Review Manager version 5.4. FINDINGS: Eight randomized controlled trials from 539 potentially relevant publications with a total of 15,744 East Asian patients were included. Pooled data from these studies found a significantly lower MACE (0.82; 95% CI, 0.69-0.98) and major bleeding event (0.62; 95% CI, 0.46-0.82) in de-escalation than standard-DAPT without heterogeneity. Subgroup analysis was divided into DAPT followed by P2Y12 inhibitor monotherapy and a reducing dose of P2Y12 inhibitors. DAPT followed by P2Y12 inhibitor monotherapy had a 48% lower incidence of major bleeding events than standard DAPT (0.52; 95% CI, 0.27-1.00); there was no significant difference in major bleeding (0.99; 95% CI, 0.55-1.76) between the reducing dose of P2Y12 inhibitors and standard DAPT. IMPLICATIONS: De-escalation is a promising and potentially optimal antiplatelet therapy for patients from East Asia with PCI. DAPT followed by P2Y12 inhibitor monotherapy might be a safer and equally effective approach compared with standard DAPT in East Asian patients with PCI. PROSPERO identifier: CRD42022319983.

Genetic variants influenced the risk of bleeding and pharmacodynamics of rivaroxaban in patients with nonvalvular atrial fibrillation: A multicentre prospective cohort study.

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.

Identification of genetic biomarkers associated with pharmacokinetics and pharmacodynamics of apixaban in Chinese healthy volunteers.

BACKGROUND: Apixaban is a superior direct oral anticoagulant exihibiting interindividual variability in concentration and response in the real world. The present study aimed to identify genetic biomarkers associated with pharmacokinetics (PK) and pharmacodynamics (PD) of apixaban in healthy Chinese subjects. METHODS: This multicenter study included 181 healthy Chinese adults taking a single dose of 2.5 mg or 5 mg apixaban and assessed their PK and PD parameters. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed using the Affymetrix Axiom CBC_PMRA Array. Candidate gene association analysis and genome-wide association study were conducted to identify genes with a predictive value for PK and PD parameters of apixaban. RESULTS: Several ABCG2 variants were associated with Cmax and AUC0-t of apixaban (p < 6.12 × 10-5) and also presented significant differences of anti-Xa3h activity and dPT3h according to different ABCG2 genotypes (p < 0.05). Besides, ABLIM2 variants were found to be associated with PK characteristics and F13A1 and C3 variants were associated with PD characteristics of apixaban (p < 9.46 × 10-8). CONCLUSION: ABCG2 variants were found to be ideal genetic biomarkers for both PK and PD characteristics of apixaban. ABLIM2, F13A1 and C3 were identified as potential candidate genes associated with inter-individual variability of apixaban. This study was registered on ClinicalTrials.gov NCT03259399.

Integrated Pharmacokinetics/Pharmacodynamics Model and Simulation of the Ticagrelor Effect on Patients with Acute Coronary Syndrome.

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.

Candidate Gene of NOS3, MMP3, AGT, and AGT1R and Pathway Analyses for Platelet Reactivity and Clinical Outcomes of Repeat Revascularization After First PCI in Chinese Patients.

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.

Circulating miR-320a-3p and miR-483-5p level associated with pharmacokinetic-pharmacodynamic profiles of rivaroxaban.

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.

Genetic variations in relation to bleeding and pharmacodynamics of dabigatran in Chinese patients with nonvalvular atrial fibrillation: A nationwide multicentre prospective cohort study.

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.

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.

Risk of infection in roxadustat treatment for anemia in patients with chronic kidney disease: A systematic review with meta-analysis and trial sequential analysis.

Background: Many studies demonstrated that roxadustat (FG-4592) could increase hemoglobin (Hb) levels effectively in anemia patients with chronic kidney disease (CKD). However, its safety remains controversial. This study aims to explore the risk of infection for CKD patients treated with roxadustat, especially focused on sepsis. Methods: We thoroughly searched for the randomized controlled trials (RCTs) comparing treatment with roxadustat versus erythropoiesis stimulating agents (ESAs) or placebo in PubMed, Embase, Cochrane Library, ClinicalTrials.gov, European Union Clinical Trials Register. Both on and not on dialysis anemia patients with CKD were included. Primary outcomes contained the incidence rates of sepsis. Secondary outcomes included infection-related consequences (septic shock and other infection events), general safety outcomes [all-cause mortality, treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (TESAEs)] and iron parameters. Moreover, a trial sequential analysis (TSA) was conducted to assess if the results were supposed to be a robust conclusion. Results: Eighteen RCTs (n = 11,305) were included. Overall, the incidence of sepsis (RR: 2.42, 95% CI [1.50, 3.89], p = 0.0003) and cellulitis (RR: 2.07, 95% CI [1.24, 3.44], p = 0.005) were increased in the roxadustat group compared with placebo group. In non-dialysis-dependent (NDD) CKD patients, the incidence of cellulitis (RR 2.01, 95% CI [1.23, 3.28], p = 0.005) was significantly higher in roxadustat group than that in the ESAs or placebo group. Both groups showed similar results in the incidence of septic shock (RR 1.29, 95% CI [0.86, 1.94], p = 0.22). A significant increased risk of all-cause mortality [risk ratios (RR): 1.15, 95% confidence interval (CI) [1.05, 1.26], p = 0.002] was found in roxadustat treatment, and TSA confirmed the result. Compared with ESAs or placebo, both the incident rates of TEAEs (RR:1.03, 95% CI [1.01, 1.04], p = 0.008) and TESAEs (RR: 1.06, 95% CI [1.02, 1.11], p = 0.002) were significantly increased in roxadustat group. As for iron parameters, changes from baseline (Δ) of hepcidin (MD: -26.46, 95% CI [-39.83, -13.09], p = 0.0001), Δ ferritin and Δ TSAT were remarkably lower in the roxadustat group, while Δ Hb, Δ iron and Δ TIBC increased significantly versus those in ESAs or placebo group. Conclusion: We found evidence that incidence rates of sepsis and cellulitis are higher in roxadustat group compared with placebo. This may be the result of improved iron homeostasis. The risk of all-cause mortality, TEAEs and TESAEs in CKD patients also increased in patients treated with roxadustat. We need more clinical and mechanistic studies to confirm whether roxadustat really causes infection.

PROK2, HRNR, and FIG4 as potential genetic biomarkers of high bleeding propensity in East Asian patients with acute coronary syndrome using ticagrelor.

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.

Genetic Polymorphisms Associated with Prothrombin Time and Activated Partial Thromboplastin Time in Chinese Healthy Population.

(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.

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.

Hemoclot Thrombin Inhibitor Assay and Expected Peak-Trough Levels of Dabigatran: A Multicenter Study.

Purpose: Dabigatran concentrations monitoring are gaining importance of special situations, but limited data are available for the expected peak and trough levels. The hemoclot thrombin inhibitor (HTI) is dabigatran-calibrated quantitative determination of dabigatran concentration. This study aims to validate HTI assay as the quantification choice of dabigatran, and providing the expected peak and trough levels. Materials and Methods: This is a multi-center methodology validate study, including seven hospitals from Beijing, Shanghai, Henan, Hunan, Chongqing, and Fujian. We retrospectively analyzed plasma samples taken from 118 healthy subjects and 183 patients receiving dabigatran. Dabigatran concentrations were measured with HTI assay and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Linear regression, Spearman correlation and Bland-Altman analysis were used in this study. Results: The mean concentration ratio of HPLC-MS/MS and HTI assays was 1.03 and 0.98 at 2 and 12 h, and the acceptance ranges for both the ratio limit as well as the limit of agreement were met, suggesting good agreement between the HTI-derived plasma concentrations and HPLC-MS/MS. The reference detection range of single dose dabigatran 150 mg in healthy subjects was 33-159 ng/ml. About 500 blood samples were taken from 183 patients suggested that the expected peak and trough levels range of dabigatran 110 mg was about 95-196 and 36-92 ng/ml. Conclusion: Hemoclot thrombin inhibitor assay can be a good quantitative detection method of dabigatran. Expected peak and trough levels provide a basis for the rational use of dabigatran, and provide important Asian population data for the update of the international clinical guidelines for hematological testing. Clinical Trial Registration: [https://clinicaltrials.gov], identifier [NCT03161496].

SLC4A4, FRAS1, and SULT1A1 Genetic Variations Associated With Dabigatran Metabolism in a Healthy Chinese Population.

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.

Effect of Genetic Polymorphism Including NUP153 and SVEP1 on the Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects.

BACKGROUND AND OBJECTIVE: The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese subjects. METHODS: This is a multi-center study in China, including three hospitals from Beijing, Nanchang, and Changsha. Healthy Chinese subjects aged 18-45 years with unknown genotypes were included. All subjects received a single oral dose of 90 mg of ticagrelor. Platelet aggregation and the area under the concentration-time curve for ticagrelor and its major active metabolite in plasma samples were assessed. Genome-wide association studies and candidate gene association analysis related to ticagrelor were performed. RESULTS: One hundred and seventy-five native Chinese subjects were enrolled and completed the study. According to the p value, the threshold of ticagrelor population was 6.57 × 10-7 (0.05/76106), one single-nucleotide polymorphism chr6:17616513 of gene NUP153 (p = 2.03 × 10-7) related to the area under the concentration-time curve for plasma concentration at time zero versus the last measurable timepoint, and one single nucleotide polymorphism rs17204533 of gene SVEP1 (p = 3.96 × 10-7) related to P2Y12 reaction unit12h of ticagrelor was identified. In addition, L1TD1, CETP, CLEC2A, CHSY1, PDZRN3, CTU2, PIEZO1, APOBEC1, SEMA6A, KAZN, and FASN polymorphisms might influence the pharmacokinetics of ticagrelor, while PARP10, TRIB1, CYP2C19, and UGT2B7 might affected its pharmacodynamics. CONCLUSIONS: Genetic variation affects the pharmacokinetics and pharmacodynamics of ticagrelor in healthy individuals. The detection of NUP153, SVEP1 gene variation will be helpful for pharmacodynamic prediction and evaluation, and the regulation of these genes may be the target of new drug development. Further studies are required to confirm the results and explore whether these single-nucleotide polymorphisms are associated only with platelet activity or also with cardiovascular events and all-cause mortality. CLINICAL TRIAL REGISTRATION: NCT03161002.

A Combined Pharmacometrics Analysis of Biomarker Distribution Under Treatment With Standard- or Low-Dose Rivaroxaban in Real-World Chinese Patients With Nonvalvular Atrial Fibrillation.

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.

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).

Effect of CYP2C19 genetic polymorphism on the pharmacodynamics and clinical outcomes for patients treated with ticagrelor: a systematic review with qualitative and quantitative meta-analysis.

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.

Standard- vs. low-dose rivaroxaban in patients with atrial fibrillation: a systematic review and meta-analysis.

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.