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Examining therapeutic equivalence between branded and generic warfarin in Brazil: The WARFA crossover randomized controlled trial.
Gomes Freitas, C, Walsh, M, Coutinho, EL, Vincenzo de Paola, AA, Atallah, ÁN
PloS one. 2021;(4):e0248567
Abstract
OBJECTIVES To determine whether the generic and branded warfarins used as anticoagulants in Brazil are therapeutic equivalents based on their international normalized ratio (INR) results. METHODS This crossover randomized controlled trial had four periods. We used the branded Marevan and two generic versions of warfarin sodium tablets, manufactured by União Química and Teuto laboratories, all purchased from retail drugstores. Eligible participants were outpatients from an anticoagulation clinic at a university hospital in São Paulo, Brazil. They had atrial fibrillation or flutter and had been using warfarin for at least 2 months with an INR therapeutic range of 2.0-3.0. Randomization was by numbered, opaque, sealed envelopes. Healthcare personnel and outcome assessors were blinded to treatments, but patients were not. The primary outcome was the variability in the INR (ΔINR) and secondary outcomes included mean INR. We accepted formulations as equivalent if the 95% confidence interval (CI) of the comparison of ΔINR between branded and generic formulations was within the limit of ±0.49. RESULTS One hundred patients were recruited and randomized to six sequences of treatment (four sequences with n = 17 and two sequences with n = 16). União Química generic warfarin had equivalent variability in the INR to Marevan (ΔINR +0.09 [95% CI -0.29 to +0.46], n = 84). Comparison between Teuto generic warfarin and Marevan was inconclusive (ΔINR +0.29 [95% CI -0.09 to +0.68], n = 84). CONCLUSIONS Marevan and União Química warfarin had equivalent therapeutic effectiveness and both could be confidently used for anticoagulation. The comparison between Marevan and TW was inconclusive and does not warrant a statement of equivalence. Our methods are especially important for comparing generic and branded drugs that raise concerns and may be subject of future investigations by regulatory agents. TRIAL REGISTRATION ClinicalTrials.gov NCT02017197.
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Lack of Effect of 12-Week Treatment with Risankizumab on the Pharmacokinetics of Cytochrome P450 Probe Substrates in Patients with Moderate to Severe Chronic Plaque Psoriasis.
Khatri, A, Cheng, L, Camez, A, Ignatenko, S, Pang, Y, Othman, AA
Clinical pharmacokinetics. 2019;(6):805-814
Abstract
OBJECTIVE The objective of this study was to characterize the effects of risankizumab on the in vivo activity of cytochrome P450 (CYP) 1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A in psoriasis patients using a cocktail approach. METHODS Patients with moderate to severe chronic plaque psoriasis (n = 21) received single oral doses of sensitive probe substrates for CYP1A2 (caffeine 100 mg), CYP2C9 (warfarin 10 mg), CYP2C19 (omeprazole 20 mg), CYP2D6 (metoprolol 50 mg), and CYP3A (midazolam 2 mg) on day 1, followed by 12 weeks of subcutaneous risankizumab treatment of 150 mg once every 4 weeks from day 8 to day 92, and again the same cocktail of substrates on day 98. Serial blood samples were collected for determination of the CYP probe drugs and metabolites with and without risankizumab. Trough samples were collected for risankizumab. RESULTS The 90% confidence intervals (CIs) for the area under the plasma concentration-time curve (AUC) from time zero to infinity (AUC∞) ratios for the CYP probe substrates administered with risankizumab versus without risankizumab were within the default 0.8-1.25 equivalence bounds. Similar results were observed for maximum plasma concentration (Cmax), except for omeprazole, for which the lower bound of the 90% CI for Cmax (0.73) extended slightly below the default equivalence limit. No differences were observed in metabolite-to-parent drug Cmax or AUC ratios with risankizumab versus without risankizumab. Risankizumab trough plasma concentrations significantly exceeded those of the phase III regimen of risankizumab in psoriasis (150 mg subcutaneously at weeks 0 and 4 and every 12 weeks thereafter). CONCLUSIONS Risankizumab did not affect the in vivo activity of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A enzymes in patients with moderate or severe plaque psoriasis and therefore has no potential for drug interactions through these enzymes. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02772601.
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Determinants of the Quality of Warfarin Control after Venous Thromboembolism and Validation of the SAMe-TT2-R2 Score: An Analysis of Hokusai-VTE.
Barco, S, Granziera, S, Coppens, M, Douxfils, J, Nijkeuter, M, Riva, N, Vanassche, T, Zhang, G, Lin, M, Kamphuisen, PW, et al
Thrombosis and haemostasis. 2019;(4):675-684
Abstract
BACKGROUND Time in therapeutic range (TTR) measures the quality of vitamin K antagonist (VKA) anticoagulation. In patients with atrial fibrillation, the dichotomized SAMe-TT2-R2 score (≥2 vs. < 2 points) can predict if adequate TTR is unlikely to be achieved. AIMS We validated the SAMe-TT2-R2 score in patients with venous thromboembolism (VTE) randomized to the warfarin arm of the Hokusai-VTE trial. PATIENTS AND METHODS A total of 3,874 patients were included in the primary analysis (day 31-180 from randomization). The efficacy and safety outcomes were symptomatic recurrent VTE and major or clinically relevant non-major bleeding. RESULTS The rates of recurrent VTE and bleeding events were higher in patients with a TTR below the median (< 66% vs. ≥66%) resulting in an absolute risk difference (ARD) of +0.5% (95% confidence interval: 0%, +1.1%) and +2.2% (0.9%, +3.5%), respectively. Patients with high SAMe-TT2-R2 score were 76% of total and had lower median TTR (64.7% vs. 70.7%). The SAMe-TT2-R2 score exhibited low negative (0.59) and positive (0.52) predictive value (TTR threshold 66%), and poor discrimination (c-statistic, 0.58). ARD between patients with high and low score was 0% (-0.6%, +0.7%) for recurrence and +1.3% (-0.1%, +2.7%) for bleeding. Results were confirmed in sensitivity analyses focusing on the whole study period (day 1-365). CONCLUSION In VTE patients, the SAMe-TT2-R2 score showed unsatisfactory discrimination and predictive value for individual TTR and did not correlate well with clinical outcomes. The choice of starting a patient on VKA cannot be based on this parameter and its routine use after VTE may not translate into clinical usefulness.
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A simple, sensitive, and high-throughput LC-APCI-MS/MS method for simultaneous determination of vitamin K1, vitamin K1 2,3-epoxide in human plasma and its application to a clinical pharmacodynamic study of warfarin.
Hu, K, Li, Y, Ding, R, Zhai, Y, Chen, L, Qian, W, Yang, J
Journal of pharmaceutical and biomedical analysis. 2018;:82-91
Abstract
Warfarin exerts its anticoagulation activity by blocking the vitamin K-epoxide cycle. A quantitative understanding of how warfarin and related genes interact with the vitamin K-epoxide cycle and the associated change of coagulation activity in the human body may help study the pharmacodynamics of warfarin. The plasma concentration of vitamin K1 (VK1) and vitamin K1 2,3-epoxide (VK1O) could reflect the status of vitamin K-epoxide cycle. However, their determination is a challenging task due to their extremely low concentrations in human plasma and the severe interferences caused by co-extracted lipids. In this study, we developed an LC-APCI-MS/MS method for the simultaneous determination of VK1 and VK1O in human plasma using stable deuterium-labeled vitamin K1 (vitamin K1-d7) as the internal standard (IS). Plasma samples were prepared through protein denaturation followed by one-step liquid extraction with cyclohexane. Chromatographic separation of analytes from isobaric interferences and endogenous ion suppressor was performed on a Synergi Hydro-RP column (150 mm × 4.6 mm, 4 μm) under the reversed-phase condition with isocratic elution. The selective reaction monitoring (SRM) transitions were chosen as m/z = 451.5→187.3 for VK1, m/z = 467.5→161.2 for VK1O, and m/z = 458.6→194.3 for IS in APCI positive mode. The assay was linear in the range of 100-10,000 pg/mL for the two analytes and achieved considerable extraction recoveries (87.8-93.3%, 91.0-96.9%, and 92.0% for VK1, VK1O, and IS, respectively), negligible matrix effects (93.6-96.0%, 96.3-100.1%, and 95.5%), and high selectivity with a small sample volume requirement (0.2 mL) and short run time (15 min). The validated method was successfully applied in a clinical pharmacodynamic study of warfarin, and the clotting activity was found to be negatively correlated with the plasma concentration ratio of VK1O to VK1.
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Edoxaban for the management of elderly Japanese patients with atrial fibrillation ineligible for standard oral anticoagulant therapies: Rationale and design of the ELDERCARE-AF study.
Okumura, K, Lip, GYH, Akao, M, Tanizawa, K, Fukuzawa, M, Abe, K, Akishita, M, Yamashita, T
American heart journal. 2017;:99-106
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Edoxaban-a non-vitamin K antagonist oral anticoagulant (NOAC)- 60-mg and 30-mg once-daily dose regimens are noninferior versus well-managed warfarin for the prevention of stroke or systemic embolic events (SEE) with less major bleeding in patients with nonvalvular atrial fibrillation (NVAF). There are no published data from phase 3 clinical trials specifically evaluating the use of NOACs in elderly NVAF patients, especially those considered ineligible for available oral anticoagulants. The Edoxaban Low-Dose for EldeR CARE AF patients (ELDERCARE-AF) study is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study that will compare the safety and efficacy of once-daily edoxaban 15 mg versus placebo in Japanese patients with NVAF ≥80 years of age who are considered ineligible for standard oral anticoagulant therapy. A total of 800 patients (400 in each treatment group) are planned for randomization (1:1) to either edoxaban or placebo using a stratified randomization method with CHADS2 index score (2 points, ≥3 points) as a factor. The primary efficacy end point is the time to first onset of stroke or SEE. The net clinical outcome is the composite of stroke, SEE, major bleeding, and all-cause mortality. The primary safety end point is the incidence of major bleeding. The treatment period will continue until 65 patients with the primary efficacy events (ie, stroke or SEE) have been observed (2- to 2.5-year expected mean treatment period). The results of ELDERCARE-AF may provide clarity as to the efficacy and safety of edoxaban for the prevention of stroke or SEE in this high-risk population.
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An S-warfarin and AZD1981 interaction: in vitro and clinical pilot data suggest the N-deacetylated amino acid metabolite as the primary perpetrator.
Grime, K, Pehrson, R, Nordell, P, Gillen, M, Kühn, W, Mant, T, Brännström, M, Svanberg, P, Jones, B, Brealey, C
British journal of clinical pharmacology. 2017;(2):381-392
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AIM: AZD1981 is an orally bioavailable chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) receptor antagonist progressed to phase II trials for the treatment of allergic asthma. Previously performed in vitro human hepatocyte incubations identified N-deacetylated AZD1981 as a primary metabolite. We report on metabolite exposure from a clinical excretion balance, on in vitro studies performed to determine the likelihood of a metabolite-dependent drug-drug interaction (DDI) and on a clinical warfarin DDI study. The aim was to demonstrate that N-deacetylated AZD1981 is responsible for the observed interaction. METHODS The excretion and biotransformation of [14 C]-AZD1981 were studied in healthy male volunteers, and subsequently in vitro cytochrome P450 (CYP) inhibition and hepatocyte uptake investigations were carried out with metabolites and the parent drug. A clinical DDI study using coadministered twice-daily 100 mg and 400 mg AZD1981 with 25 mg warfarin was performed. RESULTS The excretion balance study showed N-deacetylated AZD1981 to be the most abundant metabolite present in plasma. In vitro data revealed the metabolite to be a weak CYP2C9 time-dependent inhibitor, subject to more active hepatic uptake than the parent molecule. Clinically, the S-warfarin area under the plasma concentration-time curve increased, on average, 1.4-fold [95% confidence interval (CI) 1.22, 1.50] and 2.4-fold (95% CI 2.11, 2.64) after 100 mg (n = 13) and 400 mg (n = 11) AZD1981 administration, respectively. In vitro CYP inhibition and hepatocyte uptake data were used to explain the interaction. CONCLUSIONS N-deacetylated AZD1981 can be added to the small list of drug metabolites reported as sole contributors to clinical drug-drug interactions, with weak time-dependent inhibition exacerbated by efficient hepatic uptake being the cause.
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Anticoagulation Control in Warfarin-Treated Patients Undergoing Cardioversion of Atrial Fibrillation (from the Edoxaban Versus Enoxaparin-Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation Trial).
Lip, GYH, Al-Saady, N, Jin, J, Sun, M, Melino, M, Winters, SM, Zamoryakhin, D, Goette, A
The American journal of cardiology. 2017;(5):792-796
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In the Edoxaban Versus Enoxaparin-Warfarin in Patients Undergoing Cardioversion of Atrial Fibrillation (ENSURE-AF) study (NCT 02072434), edoxaban was compared with enoxaparin-warfarin in 2,199 patients undergoing electrical cardioversion of nonvalvular atrial fibrillation (AF). In this multicenter prospective randomized open blinded end-point trial, we analyzed patients randomized to enoxaparin-warfarin. We determined time to achieve therapeutic range (TtTR); time in therapeutic range (TiTR); their clinical determinants; relation to sex, age, medical history, treatment, tobacco use, race risk (SAMe-TT2R2) score; and impact on primary end points (composite of stroke, systemic embolic event[SEE], myocardial infarction [MI], and cardiovascular death [CVD] and composite of major + clinically relevant nonmajor bleeding). Among 1,104 patients randomized to enoxaparin-warfarin, 27% were naïve to oral anticoagulants. Mean age was 64.2 ± 11 years and mean congestive heart failure, hypertension, age ≥75 (doubled), diabetes mellitus, prior stroke or transient ischemic attack (doubled), vascular disease, age 65-74, female (CHA2DS2-VASc) score was 2.6. Mean TtTR was 7.7 days (median 7 days) and mean TiTR after reaching an international normalized ratio of 2.0 to 3.0 was 71%. In 695 patients who had an INR <2.0 before the first dose and who reached an INR ≥2.0, 436 had a SAMe-TT2R2 score ≤2 and 259 had a score >2. On multivariate regression, an independent predictor of extended TtTR was creatinine clearance (p = 0.02). TtTR was marginally related to stroke/SEE/MI/CVD (p = 0.06; odds ratio 0.23, 95% confidence interval 0.02 to 1.17) but not to any bleeding. Independent predictors of TiTR were previous vitamin K antagonist experience (p<0.01) and low hypertension, abnormal renal or liver function, stroke, bleeding, labile INRs, age >65, concomitant drugs or alcohol (HAS-BLED) score (p = 0.02). TiTR was related to any bleeding (p = 0.02; odds ratio 0.39, 95% confidence interval 0.16 to 0.88), but not stroke/SEE/MI/CVD. In this cohort of warfarin users with a high TiTR no difference was seen between TtTR and TiTR in relation to SAMe-TT2R2 score. In conclusion, even in this short-term study, TiTR was significantly related to bleeding events.
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Prediction of major and clinically relevant bleeding in patients with VTE treated with edoxaban or vitamin K antagonists.
Di Nisio, M, Raskob, G, Büller, HR, Grosso, MA, Zhang, G, Winters, SM, Cohen, A
Thrombosis and haemostasis. 2017;(4):784-793
Abstract
Better understanding of risk factors for major bleeding events during anticoagulant treatment for venous thromboembolism (VTE) may help physicians when deciding on intensity and duration of treatment. The primary aim of this study was to identify risk factors for major and clinically relevant bleeding in patients receiving the oral factor Xa inhibitor edoxaban or warfarin for the treatment of acute VTE. We analysed data from 8240 patients who received ≥1 dose of study drug in the Hokusai-VTE study. Bleeding risk factors were evaluated in 4118 patients who received edoxaban and significant variables were combined in a prediction model. We used the C-statistic to estimate model discrimination and bootstrap techniques for internal validation. Major bleeding occurred in 56/4118 (1.4 %) patients given edoxaban and in 66/4122 (1.6 %) patients given warfarin. Clinically relevant bleeding occurred in 349 (8.5 %) and 423 (10.3 %), respectively. Significant risk factors for major bleeding during edoxaban treatment were female sex, concomitant antiplatelet therapy, haemoglobin ≤10 g/dl, history of arterial hypertension, and systolic blood pressure >160 mmHg. The discrimination of the model was high (C-statistic: 0.71) for major bleeding, lower for clinically relevant bleeding (C-statistic: 0.62) and when the model was applied to patients receiving warfarin (C-statistic 0.60). In conclusion, we identified five main predictors of major bleeding in patients receiving edoxaban for the treatment of acute VTE. A risk model based on these factors predicted an increased risk of bleeding with good discrimination.
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Factors associated with non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with new-onset atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II).
Steinberg, BA, Shrader, P, Thomas, L, Ansell, J, Fonarow, GC, Gersh, BJ, Hylek, E, Kowey, PR, Mahaffey, KW, O'Brien, EC, et al
American heart journal. 2017;:40-47
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BACKGROUND Several non-vitamin K antagonist oral anticoagulant (NOAC) alternatives to warfarin are available for stroke prevention in atrial fibrillation (AF). We aimed to describe the factors associated with selection of NOACs versus warfarin in patients with new onset AF. METHODS The ORBIT-AF II study is a national, US, prospective, observational, cohort study of anticoagulation treatment in patients with AF receiving NOACs or warfarin in the United States from 2013 to 2016. We measured factors associated with oral anticoagulant selection in 4,670 patients recently diagnosed with AF. RESULTS At baseline, 1,169 (25%) patients were started on warfarin and 3,501 (75%) on NOACs: of these latter, 259 (6%) were started on dabigatran, 1858 (40%) on rivaroxaban, and 1384 (30%) on apixaban. Those receiving NOACs were slightly younger patients (median age 71 vs 72, P<.0001); were less likely to have prior stroke (5.3% vs 8.6%; P<.0001) or prior bleeding (2.7% vs 4.4%; P=.005); had better kidney function (mean estimated glomerular filtration rate 91 mL/min vs 80 mL/min, P<.0001); and had fewer patients at high stroke risk (CHA2DS2-VASc score [Congestive heart failure, Hypertension, Age ≥75years, Diabetes mellitus, Prior stroke, transient ischemic attack {TIA}, or thromboembolism,Vascular disease, Age 65-74years, Sex category {female}] ≥2 in 86% vs 93%; P<.0001). In multivariable analysis, factors associated with NOAC selection versus warfarin included renal function, prior stroke or valve replacement, rhythm control AF management strategy, treatment by a cardiologist, and higher patient education level. CONCLUSIONS In contemporary clinical practice, up to three-fourths of patients with new-onset AF are now initially treated with a NOAC for stroke prevention. Those selected for NOAC treatment had lower stroke and bleeding risk profiles, were more likely treated by cardiologists, and had higher socioeconomic status. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01701817.
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Rivaroxaban vs Warfarin Sodium in the Ultra-Early Period After Atrial Fibrillation-Related Mild Ischemic Stroke: A Randomized Clinical Trial.
Hong, KS, Kwon, SU, Lee, SH, Lee, JS, Kim, YJ, Song, TJ, Kim, YD, Park, MS, Kim, EG, Cha, JK, et al
JAMA neurology. 2017;(10):1206-1215
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IMPORTANCE In atrial fibrillation (AF)-related acute ischemic stroke, the optimal oral anticoagulation strategy remains unclear. OBJECTIVE To test whether rivaroxaban or warfarin sodium is safer and more effective for preventing early recurrent stroke in patients with AF-related acute ischemic stroke. DESIGN, SETTING, AND PARTICIPANTS A randomized, multicenter, open-label, blinded end point evaluation, comparative phase 2 trial was conducted from April 28, 2014, to December 7, 2015, at 14 academic medical centers in South Korea among patients with mild AF-related stroke within the previous 5 days who were deemed suitable for early anticoagulation. Analysis was performed on a modified intent-to-treat basis. INTERVENTIONS Participants were randomized 1:1 to receive rivaroxaban, 10 mg/d for 5 days followed by 15 or 20 mg/d, or warfarin with a target international normalized ratio of 2.0-3.0, for 4 weeks. MAIN OUTCOMES AND MEASURES The primary end point was the composite of new ischemic lesion or new intracranial hemorrhage seen on results of magnetic resonance imaging at 4 weeks. Primary analysis was performed in patients who received at least 1 dose of study medications and completed follow-up magnetic resonance imaging. Key secondary end points were individual components of the primary end point and hospitalization length. RESULTS Of 195 patients randomized, 183 individuals (76 women and 107 men; mean [SD] age, 70.4 [10.4] years) completed magnetic resonance imaging follow-up and were included in the primary end point analysis. The rivaroxaban group (n = 95) and warfarin group (n = 88) showed no differences in the primary end point (47 [49.5%] vs 48 [54.5%]; relative risk, 0.91; 95% CI, 0.69-1.20; P = .49) or its individual components (new ischemic lesion: 28 [29.5%] vs 31 of 87 [35.6%]; relative risk, 0.83; 95% CI, 0.54-1.26; P = .38; new intracranial hemorrhage: 30 [31.6%] vs 25 of 87 [28.7%]; relative risk, 1.10; 95% CI, 0.70-1.71; P = .68). Each group had 1 clinical ischemic stroke, and all new intracranial hemorrhages were asymptomatic hemorrhagic transformations. Hospitalization length was reduced with rivaroxaban compared with warfarin (median, 4.0 days [interquartile range, 2.0-6.0 days] vs 6.0 days [interquartile range, 4.0-8.0]; P < .001). CONCLUSIONS AND RELEVANCE In mild AF-related acute ischemic stroke, rivaroxaban and warfarin had comparable safety and efficacy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02042534.