Concomitant Use Of Amiodarone Research Articles

Construction of warfarin population pharmacokinetics and pharmacodynamics model in Han population based on Bayesian method

The purpose of this paper is to study the genetic polymorphisms of related gene loci (CYP2C9*3, VKORC1-1639G > A) based on demographic and clinical factors, and use the maximum a posterior Bayesian method to construct a warfarin individualized dose prediction model in line with the Chinese Han population. Finally, the built model is compared and analyzed with the widely used models at home and abroad. In this study, a total of 5467 INR measurements are collected from 646 eligible subjects in our hospital, and the maximum a posterior Bayesian method is used to construct a warfarin dose prediction that conforms to the Chinese Han population on the basis of the Hamberg model. The model is verified and compared with foreign models. This study finds that body weight and concomitant use of amiodarone have a significant effect on the anticoagulant effect of warfarin. The model can provide an effective basis for individualized and rational dosing of warfarin in Han population more accurately. In the performance of comparison with different warfarin dose prediction models, the new model has the highest prediction accuracy, and the prediction percentage is as high as 72.56%. The dose predicted by the Huang model is the closest to the actual dose of warfarin. The population pharmacokinetics and pharmacodynamics model established in this study can better reflect the distribution characteristics of INR values after warfarin administration in the Han population, and performs better than the models reported in the literature.

Major bleeding in patients with atrial fibrillation treated with apixaban versus warfarin in combination with amiodarone: nationwide cohort study

BackgroundAmiodarone is an established treatment for atrial fibrillation (AF) but might interfere with the metabolism of apixaban or warfarin. Therefore, the aim was to investigate the occurrence of major bleeding...

Associations among Plasma Concentrations of Edoxaban and M-4, Prothrombin Time, and the SLCO1B1*15 Haplotype in Patients With Nonvalvular Atrial Fibrillation.

The authors aimed to examine the impact of single nucleotide polymorphisms in P-glycoprotein, the hepatic uptake transporter organic anion transporter protein 1B1, cytochrome P450 ( CYP ) 3A5, and carboxylesterase-1 ( CES1 ) on the steady-state dose-adjusted trough concentrations of edoxaban (C Edo /D) and M-4 (C M-4 /D). They also investigated whether C M-4 and C Edo affect prothrombin time (PT). The analyses included 152 patients with nonvalvular atrial fibrillation (NVAF) undergoing AF catheter ablation. The CYP3A5*3 ; CES1 c.1168-33A>C, c.257+885T>C; SLCO1B1 c.388A>G, c.521T>C; and ABCB1 c.3435C>T, c.2677G>A/T, c.1236C>T genotypes were determined. Stepwise selection multiple linear regression analyses demonstrated that creatinine clearance (Ccr), concomitant use of amiodarone, and SLCO1B1*15 haplotype status were independent factors influencing C M-4 /D (partial R2 = 0.189, 0.098, 0.067, respectively, all P values < 0.005). Ccr and concomitant use of amiodarone were independent factors influencing C Edo /D (partial R2 = 0.260, 0.117, respectively, both P value < 0.001). C Edo and C M-4 showed a weak correlation with PT (ρ = 0.369 and 0.315, both P values < 0.001). Although information concerning Ccr, concomitant use of amiodarone, and SLCO1B1*15 haplotype may be useful in assessing the pharmacokinetics of edoxaban, further studies are needed to clarify the requirement of PT monitoring at the trough level for dose adjustment of edoxaban in patients with NVAF.

Abstract 10926: Warfarin Dosing Algorithms With the Information on Genotype and Amiodarone for Patients Without Extracorporeal Circulation Devices Could Be Beneficial for Those With Left Ventricular Assist Devices

Introduction: Many prediction algorithms for warfarin maintenance dose (WD) were constructed based on the clinical and genetic information of the patients without extracorporeal circulation devices (ECDs). However, it is unclear whether might be useful for the patients with ECD, such as left ventricular assist devices (LVAD), who still require warfarin. Hypothesis: The WD algorithms constructed using non-ECD patients could be useful for LVAD patients. Methods: An observational study, the Human Genome Research Ethics Committee of OU approved (#756), was conducted at the Osaka University (OU) Hospital on 108 LVAD patients receiving warfarin therapy. Genetic polymorphisms of CYP2C9*1, *3, and VKORC1-1639G&gt;A were tested using TaqMan genotyping assay kits. WD was defined as the administered dose during the periods when the PT-INR value was within its target range. We investigated the difference between the actual warfarin dose (AWD) and the calculated warfarin dose (CWD) using an algorithm proposed by the International Warfarin Pharmacogenetics Consortium (IWPC), which we verified with 125 Japanese non-ECD patients previously (Eur J Clin Pharmacol, 75:901). Results: The percentage of patients whose difference between CWD and AWD was within 20% of AWD showed no significant difference between the LVAD and the non-ECD (%; I, LVAD, 41.7, non-ECD, 49.6, p=0.23). The root mean squared percentage error (RMSPE) to the AWD was similar between the groups (%; LVAD, 42, non-ECD, 37). As the algorithm requires if amiodarone is concomitant with warfarin, we probed the effect of the amiodarone dose on the CWD. Interestingly, RMSPE of the LVAD with ≥ 200 mg/day of amiodarone (≥ 200A) was higher compared to those with &lt; 200 mg/day (&lt;200A) and without amiodarone (%; 85.5, 25.9, 36.8). The difference between AWD and CWD of ≥ 200A was significantly higher than &lt;200A (mg/day; 0.87, -0.07; p=0.012). We verified similar tendencies using other algorithms published before. Conclusions: The WD algorithm with the information on genotype and concomitant use of amiodarone for the non-ECD could be beneficial for the LVAD. Besides them, extra careful attention should be required for patients with ≥ 200 mg/day of amiodarone not to have warfarin overdosed.

Stereoselective interaction of tolvaptan with amiodarone under racemic metabolic impact by CYP3A5 genotypes in heart failure patients.

The diuretic effect of tolvaptan is largely blood level-dependent although it does exhibit interindividual differences according to cytochrome P450 (CYP) 3A5 genotype. This study aimed to investigate the pharmacokinetic relationship between plasma tolvaptan and its monohydroxylate enantiomers and the factors affecting their metabolism in heart failure patients. Japanese heart failure patients (n = 88) receiving oral tolvaptan (median dosage 7.5mg/day) were enrolled. Blood samples were collected prior to the dosing on day 6 or later after first administration to determine the plasma concentrations of tolvaptan and its monohydroxylate enantiomers. Gene polymorphisms of CYP3A5, carbonyl reductase (CBR) 1/3, and ATP-binding cassette subfamily B member (ABCB) 1 were analyzed for their impact on tolvaptan pharmacokinetics. Serum laboratory test values and concomitant use of amiodarone were evaluated as factors related to tolvaptan metabolism. The median of the sum of the 5S- and 5R-tolvaptan plasma concentrations was 48.9 (range, 15.3-100) ng/mL. CYP3A5 genotypes significantly affected the concentration ratio of all enantiomeric metabolites to tolvaptan, while the other metabolic-related gene polymorphisms had no influence. A negative correlation was found between serum albumin and the enantiomeric ratio of tolvaptan and monohydroxylate DM-4111. Concomitant use of amiodarone increased the plasma levels of whole tolvaptan but significantly decreased the metabolic ratios of 5R-tolvaptan. 5S-tolvaptan was selectively synthesized from ketone MOP-21826 by CBR1 with a substantially smaller reaction velocity compared to tolvaptan monohydroxylation by CYP3A4/5. This study clarified the racemic impact of CYP3A5 genotypes on tolvaptan metabolism. Amiodarone may stereoselectively interact with R-forms rather than S-forms of tolvaptan.

Impact of P-glycoprotein and/or CYP3A4-interacting drugs on the risk-benefit profile of NOACs in patients with atrial fibrillation: a meta-analysis

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation Flanders (FWO) Background P-glycoprotein (P-gp) and CYP3A4-interacting drugs influence plasma levels of non-vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Purpose A critical appraisal of the impact of pharmacokinetically-interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF). Methods After searching Pubmed and Embase, phase III randomized controlled trials (RCTs) and longitudinal observational cohort studies on the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk-benefit profile of NOACs in AF patients during a mean/median follow-up of ≥6 months were included. A fixed effects meta-analysis was performed with the Mantel-Haenszel method. Results Fifteen studies were included (10 post hoc analyses of RCTs, 5 observational studies), investigating 21,711 and 306,421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use respectively, while only one study included P-gp/CYP3A4 inducers. In NOAC-treated AF patients, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk (RR) 1.10, 95% confidence interval (CI) (1.01-1.19)) and all-cause mortality risks (RR 1.14, 95%CI (1.05-1.23)) compared to not using P-gp/CYP3A4 inhibitors, while the risks of stroke/SE (RR 0.88, 95%CI (0.77-1.01)), intracranial bleeding (RR 0.89, 95%CI (0.68-1.15)) and gastro-intestinal bleeding (RR 1.09, 95%CI (0.91-1.30)) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI (0.61-0.92)), but higher mortality risks (RR 1.21, 95%CI (1.05-1.39)). Co-administration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI (1.31-2.06)), but no significantly different thromboembolic or mortality risks. Conclusions Given the higher bleeding and mortality risks in NOAC-treated AF patients concomitantly using P-gp/CYP3A4 inhibitors compared to NOAC users not taking interacting drugs, close monitoring of these patients is warranted, including regular medication review and addressing modifiable bleeding risk factors. Regarding P-gp/CYP3A4 inducers, a considerable research gap was identified, necessitating more research on their impact.

Impact of P-glycoprotein and/or CYP3A4-interacting drugs on effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: A meta-analysis.

P-glycoprotein (P-gp) and CYP3A4-interacting drugs influence plasma levels of non-vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Therefore, the impact of pharmacokinetically-interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF) was investigated. A meta-analysis was performed based on randomized controlled trials and observational studies retrieved from Pubmed and Embase that investigated the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk-benefit profile of NOACs in AF patients. Fifteen studies were included, investigating 21 711 and 306 421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use respectively, while only 1 study included P-gp/CYP3A4 inducers. In NOAC-treated AF patients, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk [RR] 1.10, 95% confidence interval [CI; 1.01-1.19]) and all-cause mortality risks (RR 1.14, 95%CI [1.05-1.23]) compared to not using P-gp/CYP3A4 inhibitors, while the risks of stroke/systemic embolism (RR 0.88, 95%CI [0.77-1.01]), intracranial bleeding (RR 0.89, 95%CI [0.68-1.15]) and gastrointestinal bleeding (RR 1.09, 95%CI [0.91-1.30]) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI [0.61-0.92]), similar major bleeding (RR 0.92, 95%CI [0.80-1.07]) but higher mortality risks (RR 1.21, 95%CI [1.05-1.39]). Coadministration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI [1.31-2.06]), but comparable thromboembolic (RR 1.10, 95%CI [0.75-1.61]) and mortality risks (RR 1.01, 95%CI [0.77-1.33]). Given the higher bleeding and mortality risks in NOAC-treated AF patients concomitantly using P-gp/CYP3A4 inhibitors, close monitoring is warranted.

Variables affecting the quality of anticoagulation in atrial fibrillation patients newly initiating vitamin K antagonists: insights from the national and multicentre SULTAN registry.

Vitamin K antagonists (VKAs) are effective drugs reducing the risk for stroke in atrial fibrillation (AF), but the benefits derived from such therapy depend on the international normalized ratio (INR) maintenance in a narrow therapeutic range. Here, we aimed to determine independent variables driving poor anticoagulation control [defined as a time in therapeutic range (TTR) <65%] in a 'real world' national cohort of AF patients. The SULTAN registry is a multicentre, prospective study, involving patients with non-valvular AF from 72 cardiology units expert in AF in Spain. At inclusion, all patients naïve for oral anticoagulation were started with VKAs for the first time. For the analysis, the first month of anticoagulation and those patients with <3 INR determinations were disregarded. Patients were followed up during 1 year. A total of 870 patients (53.9% male, the mean age of 73.6 ± 9.2 years, mean CHA2DS2-VASc and HAS-BLED of 3.3 ± 1.5 and 1.4 ± 0.9, respectively) were included in the full analysis set. In overall, 7889 INR determinations were available. At 1-year, the mean TTR was 63.1 ± 22.1% and 49.2% patients had a TTR < 65%. Multivariate Cox regression analysis showed that coronary artery disease [odds ratio (OR) 1.81, 95% confidence interval (CI) 1.14-2.87; P = 0.012] and amiodarone use (OR 1.54, 95% CI 1.01-2.34; P = 0.046) were independently associated with poor quality of anticoagulation (TTR <65%). This study demonstrated that the quality of anticoagulation in AF patients newly starting VKAs is sub-optimal. Previous coronary artery disease and concomitant use of amiodarone were identified as independent variables affecting the poor quality of VKA therapy during the first year.

Is specific anti-factor Xa activity measurement a way to predict relevant bleedings in non-valvular atrial fibrillation (NVAF) patients?

Direct oral anticoagulants (DOACs) are first line therapy for stroke prevention in NVAF patients. They were reported to be as effective as vitamin K antagonists (VKA) for stroke prevention in high-risk NVAF patients, with lower bleeding events. Compared to VKA, there is no need of regular anticoagulation monitoring. Yet, we still estimate 2 to 5% of major bleedings (MB) and up to 15% of clinically relevant non-major bleedings (CRNMB). The goal of this study was to investigate specific anti-Xa activity (AXA) measurement as a mean to predict bleeding complications in NVAF patients. We also determined anti-Xa overdose risk factors. We performed a prospective observational study from December 2016 to April 2020. We took blood samples on patients the day of inclusion to measure AXA. We considered as high responders, patients to whom AXA plasma levels were superior to the upper limit of the expected plasma level ranges from the European Heart Rhythm Association recommendations. MB, CRNMB from time to inclusion to April 2020 were collected. We then compared group of high responders and non-high responders. A total of 146 patients were analysed. Mean follow up was 20 months. Among them, 24 (16,4%) had MB or CRNMB during the follow up. 36 (24,6%) patients were high responders among which 10 had relevant bleedings. High responders showed a higher risk of bleeding in univariate analyses ( P = 0.034). After adjustment in multivariate analyses, only HASBLED had an increased risk of bleeding with an OR of 2.88 (1.74–5.12); probably due to a small number of patients and short time of follow up. We also showed that women and concomitant use of amiodarone were responsible for increasing AXA plasma level. AXA plasma level might be predictive of bleeding. Further studies with higher number of patients should be carried out to prove it. Female and amiodarone are both overdose risk factors.

Risk of severe hypoglycemic events from amiodarone-sulfonylureas interactions: A population-based nested case-control study.

To evaluate whether concomitant use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia. We conducted two nested case-control studies by analyzing the Taiwan National Health Insurance Research Database from 2008 to 2013 among diabetic patients continuously receiving sulfonylureas. Cases were defined as patients with severe hypoglycemia and those with a composite outcome of severe hypoglycemia, altered consciousness, and fall-related fracture in the first and second study, respectively. In both studies, each case was individually matched up to 10 randomly-selected controls. Conditional logistic regressions were employed to estimate odds ratios (ORs). We identified 1343 cases and 11 597 controls as well as 2848 cases of composite events and 24 808 controls among 46 317 sulfonylurea users. Concurrent use of amiodarone with sulfonylureas was associated with a 1.56-fold (95% CI: 0.98-2.46) increased risk of severe hypoglycemia, despite not statistically significant. Notably, an approximately 2-fold increased risk of severe hypoglycemia was observed with amiodarone therapy lasting for >180 days (adjusted OR: 2.08; 95% CI: 1.01-4.30) or at a daily dose greater than 1 defined daily dose (adjusted OR: 2.21; 95% CI: 1.25-3.91) when concurrently administrating sulfonylureas. A significantly increased risk of hypoglycemia-related composite events was also found with amiodarone concurrently used with sulfonylureas (adjusted OR: 1.59; 95% CI: 1.13-2.24). Concurrent use of amiodarone and sulfonylureas is associated with an increased risk of serious hypoglycemia among diabetic patients, with an elevated risk for amiodarone used in a long-term or at a high daily dose.

Efficacy and Safety Outcomes of Direct Oral Anticoagulants and Amiodarone in Patients with Atrial Fibrillation

BackgroundDirect oral anticoagulants (DOACs) and amiodarone are widely used in the treatment of nonvalvular atrial fibrillation. The DOACs are P-glycoprotein (P-gp) and cytochrome p-450 (CYP3A4) substrates. Direct oral anticoagulant levels may be increased by the concomitant use of potent dual P-gp/CYP3A4 inhibitors, such as amiodarone, which can potentially translate into adverse clinical outcomes. We aimed to assess the efficacy and safety of drug–drug interaction by the concomitant use of DOACs and amiodarone. MethodsWe performed a systematic review of MEDLINE, the Cochrane Central Register of Clinical Trials, and Embase, limiting our search to randomized controlled trials of patients with atrial fibrillation that have compared DOACs versus warfarin for prophylaxis of stroke or systemic embolism, to analyze the impact on stroke or systemic embolism, major bleeding, and intracranial bleeding risk in patients with concomitant use of amiodarone. Risk ratio (RR) 95% confidence intervals were measured using the Mantel-Haenszel method. The fixed effects model was used owing to heterogeneity (I2) < 25%. ResultsFour trials with a total of 71,683 patients were analyzed, from which 5% of patients (n = 3212) were concomitantly taking DOAC and amiodarone. We found no statistically significant difference for any of the clinical outcomes (stroke or systemic embolism [RR 0.85; 95% CI, 0.67-1.06], major bleeding [RR 0.91; 95% CI, 0.77-1.07], or intracranial bleeding [RR 1.10; 95% CI, 0.68-1.78]) among patients taking DOAC and amiodarone versus DOAC without amiodarone. ConclusionOn the basis of the results of this meta-analysis, co-administration of DOACs and amiodarone, a dual P-gp/CYP3A4 inhibitor, does not seem to affect efficacy or safety outcomes in patients with atrial fibrillation.

CPC-106 Pharmacokinetic Drug-Drug Interactions Due to Treatment with Amiodarone – a Practical Approach

BackgroundThe drug amiodarone has a complex pharmacokinetic profile and can be a challenge to use due to the high potential for drug-drug interactions.Purpose To identify and submit proposals for handling...

The Influence of Ethnicity on Warfarin Dosage Requirement

The optimal dose of warfarin varies among individuals, and the prediction of a maintenance dose is difficult. Ethnicity has been reported to influence warfarin dosing. To quantitate the influence of ethnicity on warfarin dose requirement. We conducted a retrospective cohort study at a university anticoagulation clinic to evaluate the influence of ethnicity on warfarin dose. Inclusion criteria included age > or = 18 years, target international normalized ratio (INR) 2-3, and warfarin management within the clinic for > or = 3 months with a minimum of 5 clinic visits. We collected clinical and demographic data including age, gender, weight, ethnicity, disease states, concomitant medications, indication, weekly warfarin dosage, and INR. To assess potential confounders, multivariate, repeated-measures regression analysis was used to identify and adjust for variables that may influence the maintenance dose of warfarin. Of the 345 patients who met the inclusion criteria, 27% were Asian American, 6% Hispanic, 54% white, and 14% African American. The adjusted mean (95% CI) weekly warfarin doses for patients with an INR goal of 2 to 3 were Asian Americans 24 mg (21 to 27), Hispanics 31 mg (25 to 37), whites 36 mg (34 to 39), and African Americans 43 mg (39 to 47) (p < 0.001). Additional factors found to influence warfarin dose requirement included age, weight, concomitant use of amiodarone, and diagnosis of venous thromboembolism. Warfarin dose requirements vary across ethnic groups even when adjusted for confounding factors, suggesting that genetic variation contributes to interpatient variability.

Symptomatic Left Ventricular Aneurysm – Long-Term Survival in Medically Treated Patients

Six consecutive symptomatic patients with left ventricular aneurysm and virtual single vessel coronary diseases have been treated medically and followed for a mean period of 40.3 months (range 16–96 months). The left ventricular end-diastolic pressure was increased in all patients (21-36 mm Hg). The left ventricular ejection fraction was markedly depressed, ranging from 16 to 30%. Along with the standard antifailure medication, all patients received low doses of captopril. Symptomatic ventricular tachycardia and/or fibrillation present in 4 patients was substantially improved with concomitant use of amiodarone. It can thus provide long-term symptomatic relief in patients with ventricular aneurysm by medical treatment.