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High-dose steroid therapy for CNS inflammatory diseases increases INR in patients taking oral vitamin K antagonist.
Gelibter, S, Orrico, M, Croese, T, Bosco, L, Martinelli, V, Sangalli, F, Filippi, M
Journal of neurology. 2019;(12):3160-3161
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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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Apixaban versus warfarin in evaluation of progression of atherosclerotic and calcified plaques (prospective randomized trial).
Win, TT, Nakanishi, R, Osawa, K, Li, D, Susaria, SS, Jayawardena, E, Hamal, S, Kim, M, Broersen, A, Kitslaar, PH, et al
American heart journal. 2019;:129-133
Abstract
Warfarin has been showed to increase vascular calcification. Apixaban, a direct factor Xa inhibitor, has no interaction with vitamin K and its effect on coronary plaques is unknown. We randomized and compared warfarin and apixaban on progression of coronary atherosclerotic plaques measured by coronary computed tomographic angiography in 66 subjects with non-valvular atrial fibrillation over the period of one-year follow up. There was significant higher total, calcified and low attenuation plaque volume in the group randomized to warfarin as compared to apixaban (all P < .05). Greater volume of total (β2 = 28.54; P = .03), low attenuation plaque (β2 = 3.58; P = .02) and calcified (β2 = 14.10; P = .005) plaque progression was observed in the VKA_group.
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Regional differences in patient characteristics and outcomes during uninterrupted anticoagulation with dabigatran versus warfarin in catheter ablation of atrial fibrillation: the RE-CIRCUIT study.
Hohnloser, SH, Calkins, H, Willems, S, Verma, A, Schilling, R, Okumura, K, Nordaby, M, Kleine, E, Biss, B, Gerstenfeld, EP, et al
Journal of interventional cardiac electrophysiology : an international journal of arrhythmias and pacing. 2019;(2):145-152
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Abstract
PURPOSE To describe regional differences in patient characteristics, ablation procedures, and bleeding events in the RE-CIRCUIT study. RE-CIRCUIT was a prospective, multicenter study that captured data from different regions, providing an opportunity to understand the practices followed in various regions. The incidence of major bleeding events (MBEs) was significantly lower with uninterrupted dabigatran versus uninterrupted warfarin. METHODS Patients were randomized to receive dabigatran 150 mg twice daily or warfarin. Ablation was performed with uninterrupted anticoagulation for 8 weeks after the procedure. Regions were Western Europe, Eastern Europe, North America, and Asia. RESULTS Of 704 patients screened across 104 sites, 635 underwent catheter ablation (dabigatran, 317; warfarin, 318). Patient characteristics were different across various regions. Patients from North America had the highest prevalence of atrial flutter (33%), coronary artery disease (29%), diabetes mellitus (18%), and previous myocardial infarction (9%). Hypertension was most prevalent in Eastern Europe (75%), as was congestive heart failure (40% vs 2% in Western Europe). Pulmonary vein isolation alone was the preferred technique used in most patients (86% in North America and 75-83% elsewhere) and radio frequency was the preferred energy source. The major outcome measure, incidence of MBEs during and up to 2 months after the procedure, was consistently lower with uninterrupted dabigatran versus warfarin, irrespective of regions and their procedural differences, and different ablation techniques utilized. CONCLUSIONS This analysis shows that the benefits of dabigatran over a vitamin K antagonist in patients undergoing atrial fibrillation ablation are consistent across all geographic regions studied. TRIAL REGISTRATION NCT02348723 (https://clinicaltrials.gov/ct2/show/NCT02348723).
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Rivaroxaban Versus Vitamin K Antagonist in Antiphospholipid Syndrome: A Randomized Noninferiority Trial.
Ordi-Ros, J, Sáez-Comet, L, Pérez-Conesa, M, Vidal, X, Riera-Mestre, A, Castro-Salomó, A, Cuquet-Pedragosa, J, Ortiz-Santamaria, V, Mauri-Plana, M, Solé, C, et al
Annals of internal medicine. 2019;(10):685-694
Abstract
BACKGROUND The potential role of new oral anticoagulants in antiphospholipid antibody syndrome (APS) remains uncertain. OBJECTIVE To determine whether rivaroxaban is noninferior to dose-adjusted vitamin K antagonists (VKAs) for thrombotic APS. DESIGN 3-year, open-label, randomized noninferiority trial. (EU Clinical Trials Register: EUDRA [European Union Drug Regulatory Authorities] code 2010-019764-36). SETTING 6 university hospitals in Spain. PARTICIPANTS 190 adults (aged 18 to 75 years) with thrombotic APS. INTERVENTION Rivaroxaban (20 mg/d or 15 mg/d, according to renal function) versus dose-adjusted VKAs (target international normalized ratio, 2.0 to 3.0, or 3.1 to 4.0 in patients with a history of recurrent thrombosis). MEASUREMENTS The primary efficacy outcome was the proportion of patients with new thrombotic events; the primary safety outcome was major bleeding. The prespecified noninferiority margin for risk ratio (RR) was 1.40. Secondary outcomes included time to thrombosis, type of thrombosis, changes in biomarker levels, cardiovascular death, and nonmajor bleeding. RESULTS After 3 years of follow-up, recurrent thrombosis occurred in 11 patients (11.6%) in the rivaroxaban group and 6 (6.3%) in the VKA group (RR in the rivaroxaban group, 1.83 [95% CI, 0.71 to 4.76]). Stroke occurred more commonly in patients receiving rivaroxaban (9 events) than in those receiving VKAs (0 events) (corrected RR, 19.00 [CI, 1.12 to 321.9]). Major bleeding occurred in 6 patients (6.3%) in the rivaroxaban group and 7 (7.4%) in the VKA group (RR, 0.86 [CI, 0.30 to 2.46]). Post hoc analysis suggested an increased risk for recurrent thrombosis in rivaroxaban-treated patients with previous arterial thrombosis, livedo racemosa, or APS-related cardiac valvular disease. LIMITATION Anticoagulation intensity was not measured in the rivaroxaban group. CONCLUSION Rivaroxaban did not show noninferiority to dose-adjusted VKAs for thrombotic APS and, in fact, showed a non-statistically significant near doubling of the risk for recurrent thrombosis. PRIMARY FUNDING SOURCE Bayer Hispania.
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Effects of fasting on warfarin sensitivity index in patients undergoing cardiovascular surgery.
Katada, Y, Nakagawa, S, Nishimura, A, Sato, YK, Taue, H, Matsumura, K, Yamazaki, K, Minakata, K, Yano, I, Omura, T, et al
European journal of clinical pharmacology. 2019;(4):561-568
Abstract
PURPOSE Warfarin shows large inter- and intra-individual variabilities in its pharmacokinetics and pharmacodynamics. Sufficient understanding of factors affecting the response to warfarin is necessary to achieve improved outcomes for warfarin therapy. In this study, we evaluated effects of fasting on the anticoagulant properties of warfarin. METHODS We conducted a retrospective observational study involving a total of 58 patients, who received cardiovascular surgeries and subsequent warfarin therapy. The effect of dietary intake on the anticoagulant properties with warfarin was assessed by measurement of the international normalized ratio of prothrombin time (PT-INR): the anticoagulant activities of warfarin were expressed as the warfarin sensitivity index (WSI). Additionally, fluctuations in WSI during the study period were obtained as differences between the maximum and minimum WSI. RESULTS The maximum PT-INR and WSI values were significantly higher for patients who were fasting for different reasons during the postoperative period than those in the group without reduced dietary intake. The differences between maximum and minimum WSI in the fasting group significantly increased compared with those in the groups with moderate or no reduced dietary intake. Meanwhile, effects of other markers of clinical conditions including the baseline Child-Pugh score and Charlson Comorbidity Index on WSI were not significant. CONCLUSIONS Our results indicate that postoperative fasting was significantly associated with the anticoagulation activity of warfarin. In patients fasting for different reasons during the postoperative period, closer control of PT-INR values and warfarin adjustments may be required to avoid adverse effects such as bleeding in warfarin treatment.
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Viscoelastic properties of plasma fibrin clots are similar in patients on rivaroxaban and vitamin K antagonists.
Kopytek, M, Zabczyk, M, Natorska, J, Siudut, J, Malinowski, KP, Ptaszek, P, Glajcar, A, Goralczyk, T, Undas, A
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2019;(1)
Abstract
Unfavorable fibrin clot features have been observed in patients with venous thromboembolism (VTE). We investigated whether rivaroxaban, a direct factor Xa inhibitor, and vitamin K antagonists (VKAs) can improve plasma clot viscoelastic properties. We studied four age- and sex-matched groups: 25 healthy controls, 15 VTE patients taking rivaroxaban 20 mg/day (blood concentration, 145 (67 - 217) ng/ml), 15 VTE patients taking VKA (INR: 2 - 3), and 15 VTE patients who stopped oral anticoagulant therapy (OAT). Using a hybrid rheometier the storage (G') and loss (G") moduli were evaluated in citrated plasma after addition of 5 pmol/l tissue factor. Fiber thickness within clots was assessed using scanning electron microscopy. Higher G' but not G" was observed for VTE patients taking rivaroxaban (+34%; post hoc, P = 0.029) compared to controls. As reflected by lower G' and G", patients taking rivaroxaban (-19% and -30%; post hoc, P = 0.0013 and P < 0.0001, respectively) formed less stiff and viscous clots compared to VTE patients after OAT withdrawal, also after adjustment for fibrinogen. VTE patients treated with rivaroxaban and VKA had similar clot viscoelastic properties (post hoc, P = 0.85 for G' and P = 0.29 for G"). G' and G" correlated with plasma rivaroxaban concentrations (r = -0.67, P = 0.005 and r = -0.59, P = 0.021, respectively), and the time from the last dose of rivaroxaban intake (r = 0.59, P = 0.02 and r = 0.58, P = 0.022, respectively). G' and G" showed no association with INR in patients on VKAs. G' or G" were not associated with fibrin diameter on scanning electron microscopy images in either group. Our preliminary study shows that both rivaroxaban and VKA improve clot viscoelastic properties in VTE patients, which might contribute to their antithrombotic effects. G' and G" may reflect specific clot physical features, beyond key plasma clot characteristics, which highlights benefits from comprehensive plasma clot analysis in patients with thrombotic diseases.
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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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Efficacy and safety of rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation and a history of cancer: observations from ROCKET AF.
Chen, ST, Hellkamp, AS, Becker, RC, Berkowitz, SD, Breithardt, G, Fox, KAA, Hacke, W, Halperin, JL, Hankey, GJ, Mahaffey, KW, et al
European heart journal. Quality of care & clinical outcomes. 2019;(2):145-152
Abstract
AIMS: The management of anticoagulation therapy in patients with atrial fibrillation (AF) and cancer is challenging due to increased thrombotic and bleeding risks. We sought to determine the safety and efficacy of rivaroxaban in patients with AF and a history of cancer. METHODS AND RESULTS ROCKET AF randomized 14 264 patients with AF to rivaroxaban or warfarin with a median follow-up of 1.9 years. Cox regression models were used to assess the association between cancer history and clinical outcomes, and the relative treatment effect of rivaroxaban vs. warfarin in these patients. A total of 640 patients enrolled in ROCKET AF had a history of cancer, with the most common types being prostate (28.6%), colorectal (16.1%), and breast (14.7%) cancer. Patients with a history of cancer were older, more frequently male, more likely to have prior vitamin K antagonist (VKA) use and had higher rates of overall bleeding [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.16-1.47; P < 0.0001] and non-cardiovascular death (HR 1.47, 95% CI 1.04-2.07; P = 0.031) compared with those with no cancer history. There were no significant associations between cancer history and stroke, venous thromboembolism, or myocardial infarction. The relative efficacy of rivaroxaban vs. warfarin for prevention of stroke/systemic embolism was similar in those with and without a history of cancer (interaction P-value = 0.21). CONCLUSION In ROCKET AF, a history of cancer was associated with a higher risk of bleeding and non-cardiovascular death, but not ischaemic events. The relative efficacy and safety of rivaroxaban compared with warfarin were not significantly different in patients with and without a history of cancer. The results of this study are exploratory and should be taken in context of the study population, which may not be generalizable to those with advanced malignancy. Further investigation is needed to understand optimal anticoagulation strategies in patients with AF and cancer.Clinical trial registration: ClinicalTrials.gov: NCT00403767.
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Impact of genetic and clinical factors on warfarin therapy in patients early after heart valve replacement surgery.
Li, B, Liu, R, Wang, C, Ren, C, Zhang, S, Zhang, F, Zhang, J, Liu, S, Wei, Y, Liu, W, et al
European journal of clinical pharmacology. 2019;(12):1685-1693
Abstract
PURPOSE Factors influencing responsiveness to warfarin at treatment onset time were not well identified in Chinese patients undergoing heart valve replacement. We sought to select the most relevant factors that associated with patient response to warfarin early after heart valve surgery. METHODS In this observational study, 289 patients starting warfarin therapy early after heart valve replacement surgery were enrolled. CYP2C9 *1, *2, *3, and *5; VKORC1-1639 G>A, CYP4F2 V433M, and GGCX rs11676382 genotypes; clinical characteristics, response to therapy, and bleeding and thrombosis events were collected. The primary outcomes were the time to the first INR equal to or more than lower limit of therapeutic range and the warfarin dose requirements. Stepwise multiple linear regression was performed to develop a dosing algorithm to predict the warfarin dose requirements. RESULTS The results of univariate analysis showed lone VKORC1-1639 G>A, CYP2C9 *1/*3, cefazolin, cefoperazone-sulbactam, increased BMI, Δhemoglobin, and white blood cell count could significantly affect patient responsiveness to warfarin in the initial period of anticoagulation. Multivariate analysis resulted in an equation: Accumulated warfarin doses (mg) = 17.068 VKORC1-1639 G>A - 4.261 hypertension + 0.593 BMI - 0.115 age - 4.852 CYP2C9 *1/*3 - 2.617 cefazolin - 4.902 cefoperazone-sulbactam - 4.537, which could explain 40.2% of the variability in warfarin dose needed to reach the first INR equal to or more than lower limit of therapeutic range. CONCLUSIONS Both genetic and clinical factors contributed to anticoagulation effect of warfarin in the initial period of treatment. Our findings could provide a basis for the personalized management of warfarin use in the early stage of anticoagulation in northern Chinese patients.