- Email: [email protected]
Inhibitory Interaction Potential of Linezolid on Solute Carrier Family (Slco)-1B1 and-1B3 Transporters Mediated Rifampin Uptake, In Vitro
Clinical Therapeutics Background: UI14SDF100CW is a chewable tablet of sildenafil citrate, which was developed to improve compliance through convenient administration. The purpose of this study was to evaluate the pharmacokinetic properties of sildenafil citrate chewable tablets compared with conventional sildenafil citrate film-coated tablets. Methods: A randomized, open-label, single dose, two-treatment, two-period, two-way crossover study was conducted in 60 healthy male volunteers. In each period, subjects received a single oral dose of UI14SDF100CW or sildenafil citrate film-coated tablet (both tablets contain 140.45mg of sildenafil citrate which is 100 mg as sildenafil). Serial blood samples were collected up to 24 hours post-dose for pharmacokinetic (PK) analysis. Plasma concentration of sildenafil was determined using a validated LC-MS/MS assay. PK parameters of sildenafil was calculated using non-compartmental methods. This study was approved by Institutional Review Board of Chungnam National University Hospital. (No. CNUH 2012-01-021) Results: The plasma sildenafil concentration – time profiles of two formulation is similar.. For UI14SDF100CW, the Cmax and the AUClast of sildenafil were 1068.69 ± 458.25 (mean ± standard deviation) mg/L and 3580.59 ± 1680.29 h*mg/L, and their corresponding values for sildenafil citrate film-coated tablet were 1146.84 ± 501.70 mg/L and 3406.35 ± 1452.31 h*mg/L, respectively. The geometric mean ratios (90% confidence intervals) of UI14SDF100CW to sildenafil citrate film-coated tablet for Cmax and AUClast were 0.933 (0.853 – 1.021) and 1.034 (0.969 – 1.108), respectively, which met the bioequivalence criteria of Korean regulatory agency. Conclusions: UI14SDF100CW has similar pharmacokinetic properties compared to a conventional sildenafil citrate film-coated tablet. Therefore, UI14SDF100CW can be an alternative treatment option for sildenafil citrate film-coated tablet, providing better compliance.
Safety, Tolerability, and Pharmacokinetics of Single and Multiple Dose JPI-289, A Novel Poly (ADP-Ribose) Polymerase-1 Inhibitor in First-In-Human Study of Healthy Volunteers S. Han1; Y.H. Kim1; H. Youn Choi1; D.-J. Soh2; J.-M. Kim2; J.-W. Nam2; J.-W. Kim2; K.-S. Bae1; and H.-S. Lim1 1 College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea; and 2Jeil Pharmaceutical Co, Ltd, Seoul, Republic of Korea Background: JPI-289 is a promising poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor with therapeutic potential for acute ischemic stroke by suppressing microglial activation and facilitating neuroprotection. The aim of this study was to investigate the safety, tolerability and pharmacokinetics of JPI-289 in healthy volunteers. Methods: A first-in-human, single ascending dose (SAD), and then multiple ascending dose (MAD), Phase I, randomized, double-blind, and placebo-controlled clinical trials were conducted in 64 healthy, Korean, male subjects. In SAD study, 35 to 600 mg of JPI-289 was infused intravenously over 30 minutes to 40 subjects (JPI-289 : placebo = 6 : 2 in each dose group). In MAD study, 150, 300 or 450 mg of JPI-289 was infused over 1 hour every 12 hours to each of 24 subjects (JPI-289 : placebo = 6 : 2 in each dose group) for 4.5 days (7 times). The plasma and urine concentrations of JPI-289 and its metabolites were determined using a validated liquid chromatography-mass spectrometry method. Pharmacokinetics were evaluated by non-compartmental method. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. Results: Adverse events reported in the study were all mild in intensity and resolved without any sequelae. In the SAD study, JPI-289 reached a mean Tmax at 0.47 to 0.50 hour after dosing and then declined, with a mean elimination half-life (t 1/2) of 2.18
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to 3.21 hours. AUClast (658.82 to 32,066.88 ng*h/mL) and Cmax (422.72 to 10,381.25 ng/mL) tended to increase supra-proportionally especially at higher doses in SAD study. However, C max showed dose-proportionality in the range of 75-600mg. In the MAD study, observed accumulation index ranged from 1.52 to 1.76 after 7 repeated dosing every 12 hours. The effective half-life of JPI-289 was 1.88 to 3.05 hours, indicating that JPI-289 rapidly reaches steady state. % Recovered of JPI-289 measured in urine was 2.65 to 9.05%. In both studies, concentration of metabolites was less than 10% of JPI-289. Conclusions: JPI-289 was well tolerated in healthy volunteers in dose ranges of 35 to 600 mg in SAD study, and 150 to 450 mg in MAD study where JPI-289 was administered evey 12 hour for 4.5 days. This study characterized plasma and urine pharmacokinetics of JPI289, successfully. The tolerable dose ranges and pharmacokinetic characteristics of JPI-289 evaluated in these studies will be the useful in further clinical development of JPI-289.
Effect of Organic Cation Transporter Genetic Polymorphism on Ethambutol Pharmacokinetics Using Physiologically Based Pharmacokinetic (PBPK) Model M.M. Parvez1; N. Kaisar1; Y.J. Lee1; H.J. Shin1; J.A. Jung2; and J.-G. Shin1,2 1 Inje University College of Medicine, Busan, South Korea; and 2 Inje University Busan Paik Hospital, Busan, South Korea Background: Ethambutol is a potent antimycobacterial agent used in tuberculosis (TB) treatment. Renal elimination is the major route and recently reported as a substrate of organic cation transporters. We previously reported that genetic polymorphism in OCT transporters has decreased metformin clearance. Therefore, we aimed to evaluate effect of OCT2 variants on ethambutol transport in vitro and prediction of pharmacokinetics using physiologically based pharmacokinetic modeling. Methods: The transport experiments were conducted using human embryonic kidney cells stably transfected with human OCT2 transporter wild type and variants (T199I, T201M and A270S) in vitro. A full PBPK model for ethambutol was developed following permeability limited mechanistic kidney model (MechKim) in the SIMCYP simulator (Ver 15.1) using in vitro data. A 25mg/kg single dose for the healthy subjects in the simulator was used to build the model. It was then optimized and verified using clinical pharmacokinetic data. The verified PBPK model was then used to predict the effect of OCT2 genetic variants on ethambutol pharmacokinetics in healthy subjects in the SIMCYP population database. Results: The ethambutol uptake was saturable and active for OCT2. The genetic variants of OCT2-T199I (1% in KOR), -T201M (2% in KOR) and -A270S (14% in OR) were reduced 3.2-fold, 7-fold, and 1.7-fold ethambutol transport compared with wild-type, respectively. The predicted pharmacokinetics showed the unchanged amount of ethambutol excretion in urine and the total amount in kidney cells were 2-5 fold difference between the wild and mutant groups. The AUC ratio were 1.42, 1.40 and 1.36 fold higher and CL were 30.2, 29.3 and 28.7 % lower for having T199I, T201M and A270S subjects compared to wild type. Conclusions: This in vitro to in vivo extrapolation study showed genetic polymorphism in OCT2 transporter affected on ethambutol pharmacokinetics which may explain interindividual response.
Inhibitory Interaction Potential of Linezolid on Solute Carrier Family (Slco)-1B1 and-1B3 Transporters Mediated Rifampin Uptake, In Vitro N. Kaisar1; M.M. Parvez1; Y.J. Lee1; H.J. Shin1; J.A. Jung2; and J.-G. Shin1,2
Volume 39 Number 8S
Posters 1
Inje University College of Medicine, Busan, South Korea; and Inje University Busan Paik Hospital, Busan, South Korea Background: Rifampin is the most commonly used 1st line drug for the treatment of tuberculosis (active and latent infection) and linezolid in 2nd line treatment especially in MDR-TB. It is known that rifampin acts as a potent substrate and inhibitor of organic anion transporter polypeptide (OATP)-1B1 and -1B3. Recently reported, linezolid has inhibition potential on OATPs mediated drug uptake. Therefore, we aimed to investigate potential transporter mediated drug interactions (DDIs) between rifampin and linezolid in vitro. Methods: Cellular uptake of rifampin and linezolid was measured using HEK cells which were stably transfected with OATPs, OATs (organic anionic transporter) and OCTs (organic cationic transporter). Uptake/inhibition kinetics parameters were estimated using non-linear kinetic model using Phoenix software package (WinNonlin 5.1, Pharsight, USA) and DDI index (R-value) was calculated using the static modeling following FDA draft guidance for DDIs study. Results: Both OATP1B1- and OATP1B3-mediated rifampin uptakes were strongly inhibited by linezolid in a noncompetitive manner. The Ki values of linezolid were 15.5 and 10.0 µM for OATP1B1 and OATP1B3, respectively. Furthermore, the estimated drug-drug interaction (DDI) indexes (R= 1+ [I]u,inlet,max/ Ki) of linezolid were 2.65 and 3.56 (cut off ≥ 1.25) for OATP1B1 and OATP1B3, respectively, suggesting DDI interactions possibilities in vivo. The net transport activity of linezolid through SLC transporters (OATPs, OATs and OCTs) was negligible, suggesting involvement of active transport and mutual DDIs unlikely. Conclusions: The present in vitro data showed OATP1B1- and OATP1B3- mediated rifampin uptake was significantly inhibited by the linezolid with higher DDI index suggested possible drug-interaction may take place between rifampin and linezolid. 2
The Effects of Candidate SNPS in PKPD Pathway on Antipsychotics-Induced Amenorrhea in Female Schizophrenia Patients H.S. Kim1,2; J.J. Moon2; D.J. Kim1; E.Y. Kim1,2; J.C. Shim3; and J.-G. Shin1,2 1 Inje University College of Medicine, Busan, South Korea; 2 Inje University Busan Paik Hospital, Busan, South Korea; and 3 Shim JooCheol Psychiatry Clinic, Busan, South Korea Background: Amenorrhea frequently occurs in female patients taking under antipsychotic drugs (APs).It may affect drug compliance resulting treatment failure. The aim of this study was to explore the genetic effects of candidate single nucleotide polymorphisms (SNPs) in pharmacokinetics and pharmacodynamics (PKPD) pathway of APon AP-induced amenorrhea in female schizophrenia patients. Methods: Eighty-nine female schizophrenic patients (age range from 18 to 40) taking the same AP for more than 3 months were enrolled. Amenorrhea was defined as the absence of menses for three months or three periods in a row. The serum levelsof prolactin, estradiol (E2), Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) were measured. Cytochrome P450 2D6 (CYP2D6), dopamine receptor D2 (DRD2) and estrogen receptor 1 (ESR1) were genotyped. Results: Compared to the patients without amenorrhea (n= 67), prolactin level was higher (71.5 vs. 94.1 ng/mL; p= 0.044) and E2 was lower (46.7 vs. 27.0ng/mL; p= 0.007) inthe patients with amenorrhea (n= 22). There was no difference in other hormonesand baseline characteristics between the patients with and without amenorrhea. Amisulpiride, chlorpromazine, haloperidol, paliperidone, and risperidone were observed to highly increase prolactin level and categorized to drugs increasing prolactin level.
August 2017
DRD2 -141insC (OR= 0.59, 95% CI= 0.34-0.99; p= 0.049) and drugs increasing prolactin level (OR= 6.17, 95% CI= 1.28-29.64; p= 0.023) were identified as predictors for AP-induced amenorrhea using multiple logistic regression analysis identified. Conclusions: This finding is the first evidence suggesting that DRD2 -141insC might be a possible protective biomarker for AP-induced amenorrhea. Further studies to confirm the DRD2 -141insC as a biomarker for AP-induced amenorrhea are needed in larger female antipsychotic patients.
Optimal Duration of Dual Antiplatelet Therapy after Drug-Eluting Stent Implantation: A Pairwise and Network Meta-Analysis of Randomised Controlled Trials Y. Fei; M.F. Tsoi; T.T. Cheung; and B.M.Y. Cheung The University of Hong Kong, Hong Kong, China Background: The optimal duration of dual antiplatelet therapy (DAPT) after coronary drug-eluting stent (DES) implantation remains uncertain. Despite recent studies, direct comparison between shortterm (< 12 months) and extended (> 12 months) DAPT is limited. We performed a network meta-analysis to assess the risk of mortality and other cardiovascular outcomes with different DAPT durations in order to guide clinical practice. Methods: We searched for randomised controlled trials comparing different durations of DAPT after DES implantation. Those reporting frequencies of cardiovascular and bleeding events were eligible to be included. Statistic analysis was performed using frequentist approach and Bayesian framework in R. Results: We included 12 randomised controlled trials with altogether 34920 patients for analysis. Extended DAPT (> 12 months) significantly lowered the risk of myocardial infarction (OR 0.56, 95%CI 0.46-0.68 and 0.58, 0.44-0.77), and stent thrombosis (0.44, 0.30-0.65 and 0.49, 0.29-0.82) when compared to 12-month and short-term DAPT (< 12 months), respectively. However, it was associated with increased major bleeding (1.53, 1.21-1.93 and 2.58, 1.62-4.10). Compared to 12-month DAPT, extended DAPT had more all-cause death (1.27, 1.03-1.57); short-term DAPT had less major bleeds (0.59, 0.39-0.91). Conclusions: Although extending DAPT beyond 12 months after DES implantation reduced myocardial infarction and stent thrombosis, the risk of major bleeding and all-cause mortality was substantially increased. No clear superiority of extended or short-term DAPT over 12-month DAPT was identified. DAPT duration should always be tailored for different patients after considering their benefit-risk profiles.
Network Meta-Analysis of Cardiovascular Outcomes in Randomised Controlled Trials of New Antidiabetic Drugs Y. Fei; M.F. Tsoi; C.R. Kumana; T.T. Cheung; and B.M.Y. Cheung The University of Hong Kong, Hong Kong, China Background: The prevalence of cardiovascular disease is high in patients with type 2 diabetes mellitus (T2DM). However, evidence from randomised controlled trials (RCTs) that directly compared the effect of new antidiabetic drugs on cardiovascular outcomes in these patients was limited. We performed a network meta-analysis to assess the cardiovascular safety of different classes of these drugs. Methods: We searched for RCTs involving glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose co-transporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors in T2DM patients with established cardiovascular risks. RCTs that reported rates of major adverse cardiovascular events and mortality
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Safety, Tolerability, and Pharmacokinetics of Single and Multiple Dose JPI-289, A Novel Poly (ADP-Ribose) Polymerase-1 Inhibitor in First-In-Human Study of Healthy Volunteers S. Han1; Y.H. Kim1; H. Youn Choi1; D.-J. Soh2; J.-M. Kim2; J.-W. Nam2; J.-W. Kim2; K.-S. Bae1; and H.-S. Lim1 1 College of Medicine, University of Ulsan, Asan Medical Center, Seoul, Republic of Korea; and 2Jeil Pharmaceutical Co, Ltd, Seoul, Republic of Korea Background: JPI-289 is a promising poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor with therapeutic potential for acute ischemic stroke by suppressing microglial activation and facilitating neuroprotection. The aim of this study was to investigate the safety, tolerability and pharmacokinetics of JPI-289 in healthy volunteers. Methods: A first-in-human, single ascending dose (SAD), and then multiple ascending dose (MAD), Phase I, randomized, double-blind, and placebo-controlled clinical trials were conducted in 64 healthy, Korean, male subjects. In SAD study, 35 to 600 mg of JPI-289 was infused intravenously over 30 minutes to 40 subjects (JPI-289 : placebo = 6 : 2 in each dose group). In MAD study, 150, 300 or 450 mg of JPI-289 was infused over 1 hour every 12 hours to each of 24 subjects (JPI-289 : placebo = 6 : 2 in each dose group) for 4.5 days (7 times). The plasma and urine concentrations of JPI-289 and its metabolites were determined using a validated liquid chromatography-mass spectrometry method. Pharmacokinetics were evaluated by non-compartmental method. Tolerability was assessed based on physical examinations, vital signs, clinical laboratory tests, and electrocardiograms. Results: Adverse events reported in the study were all mild in intensity and resolved without any sequelae. In the SAD study, JPI-289 reached a mean Tmax at 0.47 to 0.50 hour after dosing and then declined, with a mean elimination half-life (t 1/2) of 2.18
e48
to 3.21 hours. AUClast (658.82 to 32,066.88 ng*h/mL) and Cmax (422.72 to 10,381.25 ng/mL) tended to increase supra-proportionally especially at higher doses in SAD study. However, C max showed dose-proportionality in the range of 75-600mg. In the MAD study, observed accumulation index ranged from 1.52 to 1.76 after 7 repeated dosing every 12 hours. The effective half-life of JPI-289 was 1.88 to 3.05 hours, indicating that JPI-289 rapidly reaches steady state. % Recovered of JPI-289 measured in urine was 2.65 to 9.05%. In both studies, concentration of metabolites was less than 10% of JPI-289. Conclusions: JPI-289 was well tolerated in healthy volunteers in dose ranges of 35 to 600 mg in SAD study, and 150 to 450 mg in MAD study where JPI-289 was administered evey 12 hour for 4.5 days. This study characterized plasma and urine pharmacokinetics of JPI289, successfully. The tolerable dose ranges and pharmacokinetic characteristics of JPI-289 evaluated in these studies will be the useful in further clinical development of JPI-289.
Effect of Organic Cation Transporter Genetic Polymorphism on Ethambutol Pharmacokinetics Using Physiologically Based Pharmacokinetic (PBPK) Model M.M. Parvez1; N. Kaisar1; Y.J. Lee1; H.J. Shin1; J.A. Jung2; and J.-G. Shin1,2 1 Inje University College of Medicine, Busan, South Korea; and 2 Inje University Busan Paik Hospital, Busan, South Korea Background: Ethambutol is a potent antimycobacterial agent used in tuberculosis (TB) treatment. Renal elimination is the major route and recently reported as a substrate of organic cation transporters. We previously reported that genetic polymorphism in OCT transporters has decreased metformin clearance. Therefore, we aimed to evaluate effect of OCT2 variants on ethambutol transport in vitro and prediction of pharmacokinetics using physiologically based pharmacokinetic modeling. Methods: The transport experiments were conducted using human embryonic kidney cells stably transfected with human OCT2 transporter wild type and variants (T199I, T201M and A270S) in vitro. A full PBPK model for ethambutol was developed following permeability limited mechanistic kidney model (MechKim) in the SIMCYP simulator (Ver 15.1) using in vitro data. A 25mg/kg single dose for the healthy subjects in the simulator was used to build the model. It was then optimized and verified using clinical pharmacokinetic data. The verified PBPK model was then used to predict the effect of OCT2 genetic variants on ethambutol pharmacokinetics in healthy subjects in the SIMCYP population database. Results: The ethambutol uptake was saturable and active for OCT2. The genetic variants of OCT2-T199I (1% in KOR), -T201M (2% in KOR) and -A270S (14% in OR) were reduced 3.2-fold, 7-fold, and 1.7-fold ethambutol transport compared with wild-type, respectively. The predicted pharmacokinetics showed the unchanged amount of ethambutol excretion in urine and the total amount in kidney cells were 2-5 fold difference between the wild and mutant groups. The AUC ratio were 1.42, 1.40 and 1.36 fold higher and CL were 30.2, 29.3 and 28.7 % lower for having T199I, T201M and A270S subjects compared to wild type. Conclusions: This in vitro to in vivo extrapolation study showed genetic polymorphism in OCT2 transporter affected on ethambutol pharmacokinetics which may explain interindividual response.
Inhibitory Interaction Potential of Linezolid on Solute Carrier Family (Slco)-1B1 and-1B3 Transporters Mediated Rifampin Uptake, In Vitro N. Kaisar1; M.M. Parvez1; Y.J. Lee1; H.J. Shin1; J.A. Jung2; and J.-G. Shin1,2
Volume 39 Number 8S
Posters 1
Inje University College of Medicine, Busan, South Korea; and Inje University Busan Paik Hospital, Busan, South Korea Background: Rifampin is the most commonly used 1st line drug for the treatment of tuberculosis (active and latent infection) and linezolid in 2nd line treatment especially in MDR-TB. It is known that rifampin acts as a potent substrate and inhibitor of organic anion transporter polypeptide (OATP)-1B1 and -1B3. Recently reported, linezolid has inhibition potential on OATPs mediated drug uptake. Therefore, we aimed to investigate potential transporter mediated drug interactions (DDIs) between rifampin and linezolid in vitro. Methods: Cellular uptake of rifampin and linezolid was measured using HEK cells which were stably transfected with OATPs, OATs (organic anionic transporter) and OCTs (organic cationic transporter). Uptake/inhibition kinetics parameters were estimated using non-linear kinetic model using Phoenix software package (WinNonlin 5.1, Pharsight, USA) and DDI index (R-value) was calculated using the static modeling following FDA draft guidance for DDIs study. Results: Both OATP1B1- and OATP1B3-mediated rifampin uptakes were strongly inhibited by linezolid in a noncompetitive manner. The Ki values of linezolid were 15.5 and 10.0 µM for OATP1B1 and OATP1B3, respectively. Furthermore, the estimated drug-drug interaction (DDI) indexes (R= 1+ [I]u,inlet,max/ Ki) of linezolid were 2.65 and 3.56 (cut off ≥ 1.25) for OATP1B1 and OATP1B3, respectively, suggesting DDI interactions possibilities in vivo. The net transport activity of linezolid through SLC transporters (OATPs, OATs and OCTs) was negligible, suggesting involvement of active transport and mutual DDIs unlikely. Conclusions: The present in vitro data showed OATP1B1- and OATP1B3- mediated rifampin uptake was significantly inhibited by the linezolid with higher DDI index suggested possible drug-interaction may take place between rifampin and linezolid. 2
The Effects of Candidate SNPS in PKPD Pathway on Antipsychotics-Induced Amenorrhea in Female Schizophrenia Patients H.S. Kim1,2; J.J. Moon2; D.J. Kim1; E.Y. Kim1,2; J.C. Shim3; and J.-G. Shin1,2 1 Inje University College of Medicine, Busan, South Korea; 2 Inje University Busan Paik Hospital, Busan, South Korea; and 3 Shim JooCheol Psychiatry Clinic, Busan, South Korea Background: Amenorrhea frequently occurs in female patients taking under antipsychotic drugs (APs).It may affect drug compliance resulting treatment failure. The aim of this study was to explore the genetic effects of candidate single nucleotide polymorphisms (SNPs) in pharmacokinetics and pharmacodynamics (PKPD) pathway of APon AP-induced amenorrhea in female schizophrenia patients. Methods: Eighty-nine female schizophrenic patients (age range from 18 to 40) taking the same AP for more than 3 months were enrolled. Amenorrhea was defined as the absence of menses for three months or three periods in a row. The serum levelsof prolactin, estradiol (E2), Follicle-stimulating hormone (FSH), Luteinizing hormone (LH), and thyroid-stimulating hormone (TSH) were measured. Cytochrome P450 2D6 (CYP2D6), dopamine receptor D2 (DRD2) and estrogen receptor 1 (ESR1) were genotyped. Results: Compared to the patients without amenorrhea (n= 67), prolactin level was higher (71.5 vs. 94.1 ng/mL; p= 0.044) and E2 was lower (46.7 vs. 27.0ng/mL; p= 0.007) inthe patients with amenorrhea (n= 22). There was no difference in other hormonesand baseline characteristics between the patients with and without amenorrhea. Amisulpiride, chlorpromazine, haloperidol, paliperidone, and risperidone were observed to highly increase prolactin level and categorized to drugs increasing prolactin level.
August 2017
DRD2 -141insC (OR= 0.59, 95% CI= 0.34-0.99; p= 0.049) and drugs increasing prolactin level (OR= 6.17, 95% CI= 1.28-29.64; p= 0.023) were identified as predictors for AP-induced amenorrhea using multiple logistic regression analysis identified. Conclusions: This finding is the first evidence suggesting that DRD2 -141insC might be a possible protective biomarker for AP-induced amenorrhea. Further studies to confirm the DRD2 -141insC as a biomarker for AP-induced amenorrhea are needed in larger female antipsychotic patients.
Optimal Duration of Dual Antiplatelet Therapy after Drug-Eluting Stent Implantation: A Pairwise and Network Meta-Analysis of Randomised Controlled Trials Y. Fei; M.F. Tsoi; T.T. Cheung; and B.M.Y. Cheung The University of Hong Kong, Hong Kong, China Background: The optimal duration of dual antiplatelet therapy (DAPT) after coronary drug-eluting stent (DES) implantation remains uncertain. Despite recent studies, direct comparison between shortterm (< 12 months) and extended (> 12 months) DAPT is limited. We performed a network meta-analysis to assess the risk of mortality and other cardiovascular outcomes with different DAPT durations in order to guide clinical practice. Methods: We searched for randomised controlled trials comparing different durations of DAPT after DES implantation. Those reporting frequencies of cardiovascular and bleeding events were eligible to be included. Statistic analysis was performed using frequentist approach and Bayesian framework in R. Results: We included 12 randomised controlled trials with altogether 34920 patients for analysis. Extended DAPT (> 12 months) significantly lowered the risk of myocardial infarction (OR 0.56, 95%CI 0.46-0.68 and 0.58, 0.44-0.77), and stent thrombosis (0.44, 0.30-0.65 and 0.49, 0.29-0.82) when compared to 12-month and short-term DAPT (< 12 months), respectively. However, it was associated with increased major bleeding (1.53, 1.21-1.93 and 2.58, 1.62-4.10). Compared to 12-month DAPT, extended DAPT had more all-cause death (1.27, 1.03-1.57); short-term DAPT had less major bleeds (0.59, 0.39-0.91). Conclusions: Although extending DAPT beyond 12 months after DES implantation reduced myocardial infarction and stent thrombosis, the risk of major bleeding and all-cause mortality was substantially increased. No clear superiority of extended or short-term DAPT over 12-month DAPT was identified. DAPT duration should always be tailored for different patients after considering their benefit-risk profiles.
Network Meta-Analysis of Cardiovascular Outcomes in Randomised Controlled Trials of New Antidiabetic Drugs Y. Fei; M.F. Tsoi; C.R. Kumana; T.T. Cheung; and B.M.Y. Cheung The University of Hong Kong, Hong Kong, China Background: The prevalence of cardiovascular disease is high in patients with type 2 diabetes mellitus (T2DM). However, evidence from randomised controlled trials (RCTs) that directly compared the effect of new antidiabetic drugs on cardiovascular outcomes in these patients was limited. We performed a network meta-analysis to assess the cardiovascular safety of different classes of these drugs. Methods: We searched for RCTs involving glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose co-transporter 2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors in T2DM patients with established cardiovascular risks. RCTs that reported rates of major adverse cardiovascular events and mortality
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