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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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Rivaroxaban for Preventing Venous Thromboembolism in High-Risk Ambulatory Patients with Cancer: Rationale and Design of the CASSINI Trial. Rationale and Design of the CASSINI Trial.
Khorana, AA, Vadhan-Raj, S, Kuderer, NM, Wun, T, Liebman, H, Soff, G, Belani, C, O'Reilly, EM, McBane, R, Eikelboom, J, et al
Thrombosis and haemostasis. 2017;(11):2135-2145
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Abstract
Venous thromboembolism (VTE) is a frequent complication of cancer associated with morbidity, mortality, increased hospitalizations and higher health care costs. Cancer patients at increased risk for VTE can be identified using a validated risk assessment score, and the incidence of VTE can be reduced in high-risk settings using anticoagulation. Rivaroxaban is a potent, oral, direct, factor Xa inhibitor approved for the prevention and treatment of thromboembolic events, including VTE. CASSINI is a double-blind, randomized, parallel-group, multicentre study comparing rivaroxaban with placebo in adult ambulatory patients with various cancers who are initiating systemic cancer therapy and are at high risk of VTE (Khorana score ≥ 2). Patients with primary brain tumours or those at risk for bleeding are excluded. Approximately 700 patients will be randomized 1:1 to rivaroxaban 10 mg daily or placebo for up to 6 months if there is no evidence of VTE from compression ultrasonography (CU) during screening or from routine care imaging within 30 days prior to randomization. Mandatory CU will also be performed at weeks 8 and 16 (±7 days), and at study end (±3 days). The primary efficacy hypothesis is that anticoagulation with rivaroxaban reduces the composite of objectively confirmed symptomatic or asymptomatic, lower-extremity, proximal deep-vein thrombosis (DVT); symptomatic, upper-extremity DVT; symptomatic or incidental pulmonary embolism; and VTE-related death compared with placebo. The primary safety objective is to assess major bleeding events (Clinical trial information: NCT02555878).
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Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study.
Glund, S, Stangier, J, van Ryn, J, Schmohl, M, Moschetti, V, Haazen, W, De Smet, M, Gansser, D, Norris, S, Lang, B, et al
Clinical pharmacokinetics. 2017;(1):41-54
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Abstract
BACKGROUND AND OBJECTIVES Idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy. METHODS In this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45-64 years; 16 elderly, 65-80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days. Idarucizumab doses of 1, 2.5 and 5 g or 2 × 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion ~2 h after DE at steady state. RESULTS Dabigatran-prolonged diluted thrombin time, ecarin clotting time and activated partial thromboplastin time were reversed to baseline immediately after idarucizumab infusion in all groups. Reversal was sustained with doses ≥2.5 g. Idarucizumab was well tolerated under all conditions. No impact of age on idarucizumab pharmacokinetics was observed; however, subjects with mild or moderate renal impairment demonstrated increased exposure (up to 84 %), decreased clearance and prolonged (by up to 49 %) initial half-life of idarucizumab compared with healthy middle-aged subjects. CONCLUSIONS Impaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity, and was safe and well tolerated in middle-aged, elderly and renally impaired volunteers. The results support the clinical use of a 5 g dose of idarucizumab. CLINICAL TRIAL REGISTRATION http://www.clinicaltrials.gov . Unique identifier: NCT01955720.
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[Role of local citrate anticoagulation in continuous blood purification to patients at high risk of bleeding in ICU].
Zhao, S, Ou, H, Peng, Y, Liu, Z, Yang, M, Xiao, X
Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences. 2016;(12):1334-1339
Abstract
To evaluate the safety and efficiency of citrate anticoagulant-based continuous blood purification in patients at high risk of bleeding.
Methods: One hundred and fifty-two patients at high risk of bleeding were divided into local citrate group (group A, n=68) and heparin group (group B, n=84). Clotting function, change of pH, ionized sodium, bicarbonate ion, ionized calcium, activated clotting time (ACT) and complications were monitored before and during treatment.
Results: Compared to the group A, the incidence of clotting in filter and chamber, the degree of bleeding or fresh bleeding were significantly reduced in the group B (P<0.05). ACT of post-filter at 4, 8 and 12 h during the treatment in the group A was significantly extended compared with that without treatment (P<0.05), while there was no significant change in group B (P>0.05). The pH value, the levels of ionized sodium, bicarbonate ion and ionized calcium during the treatment were maintained in normal range in both group A and group B.
Conclusion: Local citrate-based continuous blood purification can achieve effective anticoagulation and decrease the incidence of bleeding. It is an ideal choice for patients at high risk of bleeding.
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An in vitro analysis of the effect of acidosis on coagulation in chronic disease states - a thromboelastograph study.
White, H, Bird, R, Sosnowski, K, Jones, M
Clinical medicine (London, England). 2016;(3):230-4
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Abstract
Thrombosis is a complication of many chronic illnesses. Chronic obstructive pulmonary disease (COPD) and diabetes mellitus are common medical conditions frequently associated with a hypercoagulable state. Acidaemia has been shown to reduce coagulation. COPD and diabetes mellitus during acute deterioration can present with a severe acidaemia. The impact of this acidaemia on coagulation is poorly studied. Patients presenting with a diagnosis of diabetic ketoacidosis or type II respiratory failure from COPD and a pH of less than 7.2 were included in our study. A coagulation screen and a thromboelastograph (TEG) were performed on admission and 24 hours later. The mean pH on admission was 7.07 and mean base excess was -16.3. The activated partial thromboplastin time was associated with pH change but remained within the normal range (26-41 s). All other coagulation and TEG parameters failed to show evidence of association (p>0.05). In the two models of non-haemorrhagic acidosis investigated, coagulation was not altered by the changes in pH. More work is needed to understand the complex relationship between factors affecting coagulation in individual disease processes.
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Effects of non-vitamin K antagonist oral anticoagulants on fibrin clot and whole blood clot formation, integrity and thrombolysis in patients with atrial fibrillation.
Lau, YC, Xiong, Q, Shantsila, E, Lip, GY, Blann, AD
Journal of thrombosis and thrombolysis. 2016;(4):535-44
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Non-vitamin K antagonist oral anticoagulants (NOACs) are replacing warfarin and heparins in several clinical situations. With varying modes of action, the effects of NOACs on thrombus formation, integrity, and lysis is unknown. To determine whether two techniques of thrombelastography (TEG) and a micro-plate assay (MPA) provide novel data on thrombus formation, integrity and lysis in those taking a NOACs compared to warfarin and a control group taking aspirin. We assessed thrombogenesis, clot integrity and fibrinolysis in blood (TEG) and plasma (MPA) from 182 atrial fibrillation patients-50 on aspirin, 50 on warfarin, and 82 on a NOAC (17 apixaban, 19 dabigatran and 46 rivaroxaban). Eleven of 16 TEG indices and 4 of 5 MPA indices differed (p ≤ 0.01) between those on aspirin, warfarin or a NOAC. Three TEG indices and 4 MPA indices differed (p < 0.01) between the NOACs. Time to initiation of clot formation was most rapid on apixaban, then rivaroxaban and slowest on dabigatran. The rate of clot formation was most rapid on dabigatran, then apixaban, and slowest on rivaroxaban. Clot density was greatest on rivaroxaban, then apixaban, but weakest on dabigatran. The rate of clot dissolution was most rapid in apixaban, then dabigatran, and slowest on rivaroxaban. The TEG and MPA identify major differences in thrombogenesis and fibrinolysis in different NOACs. These techniques may have value in investigating the effects of these drugs on haemostasis in a clinical setting, and in identifying those in need of targeted therapy.
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Impact of Switching From a Vitamin K Antagonist to Rivaroxaban on Satisfaction With Anticoagulation Therapy: The XANTUS-ACTS Substudy.
Coleman, CI, Haas, S, Turpie, AG, Kuhls, S, Hess, S, Evers, T, Amarenco, P, Kirchhof, P, Camm, AJ, ,
Clinical cardiology. 2016;(10):565-569
Abstract
BACKGROUND The efficacy, safety, and ease of use of rivaroxaban may reduce anticoagulation-treatment burden and improve nonvalvular atrial fibrillation (NVAF) patient satisfaction compared with vitamin K antagonists (VKAs). HYPOTHESIS Transitioning from a VKA to rivaroxaban improves treatment satisfaction in routine practice. METHODS Xarelto for Prevention of Stroke in Patients With Atrial Fibrillation (XANTUS) is a prospective, noninterventional study in patients with NVAF prescribed rivaroxaban for prevention of stroke in routine practice. Patients receiving a VKA 4 weeks prior to the initial XANTUS study visit and switched to rivaroxaban were asked to complete the Anti-Clot Treatment Scale (ACTS). Changes from the initial visit to the first follow-up visit at ∼ 3 months (corresponding to a comparison of rivaroxaban vs prior VKA) for ACTS burden and benefit scores were calculated using and reported as least squared mean differences (LSMDs) with 95% confidence intervals (CIs). RESULTS The study included 1291 NVAF patients with prior VKA treatment. The mean baseline ACTS burden and benefit scores were 50.51 ± 8.42 and 10.30 ± 2.70, respectively. After ∼ 3 months of rivaroxaban treatment, LSMDs were 4.38 points (95% CI: 2.53-6.22, P < 0.0001) for the burden and 1.01 points (95% CI: 0.27-1.75, P = 0.0075) for the benefit score. Fifty-four percent and 48% of patients reported experiencing at least a minimally important clinical difference in burden and benefit scores, respectively. CONCLUSIONS Within this XANTUS cohort, switching from a VKA to rivaroxaban yielded statistically and clinically significant improvements in ACT burden and benefit scores.
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Laropiprant attenuates EP3 and TP prostanoid receptor-mediated thrombus formation.
Philipose, S, Konya, V, Lazarevic, M, Pasterk, LM, Marsche, G, Frank, S, Peskar, BA, Heinemann, A, Schuligoi, R
PloS one. 2012;(8):e40222
Abstract
The use of the lipid lowering agent niacin is hampered by a frequent flush response which is largely mediated by prostaglandin (PG) D(2). Therefore, concomitant administration of the D-type prostanoid (DP) receptor antagonist laropiprant has been proposed to be a useful approach in preventing niacin-induced flush. However, antagonizing PGD(2), which is a potent inhibitor of platelet aggregation, might pose the risk of atherothrombotic events in cardiovascular disease. In fact, we found that in vitro treatment of platelets with laropiprant prevented the inhibitory effects of PGD(2) on platelet function, i.e. platelet aggregation, Ca(2+) flux, P-selectin expression, activation of glycoprotein IIb/IIIa and thrombus formation. In contrast, laropiprant did not prevent the inhibitory effects of acetylsalicylic acid or niacin on thrombus formation. At higher concentrations, laropiprant by itself attenuated platelet activation induced by thromboxane (TP) and E-type prostanoid (EP)-3 receptor stimulation, as demonstrated in assays of platelet aggregation, Ca(2+) flux, P-selectin expression, and activation of glycoprotein IIb/IIIa. Inhibition of platelet function exerted by EP4 or I-type prostanoid (IP) receptors was not affected by laropiprant. These in vitro data suggest that niacin/laropiprant for the treatment of dyslipidemias might have a beneficial profile with respect to platelet function and thrombotic events in vascular disease.
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Activation of coagulation system during air travel: a crossover study.
Schreijer, AJ, Cannegieter, SC, Meijers, JC, Middeldorp, S, Büller, HR, Rosendaal, FR
Lancet (London, England). 2006;(9513):832-8
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BACKGROUND There is an increased risk of venous thrombosis after air travel, but the underlying mechanism is unclear. Our aim was to ascertain whether flying leads to a hypercoagulable state. METHODS We did a crossover study in 71 healthy volunteers (15 men, 56 women), in whom we measured markers of activation of coagulation and fibrinolysis before, during, and after an 8-h flight. The same individuals participated in two control exposure situations (8-h movie marathon and daily life) to separate the effect of air travel on the coagulation system from those of immobilisation and circadian rhythm. To study the effect of risk factors for thrombosis, we included participants with the factor V Leiden mutation (n=11), those who took oral contraceptives (n=15), or both (n=15), as well as 30 individuals with no specific risk factors. FINDINGS After the flight, median concentrations of thrombin-antithrombin (TAT) complex increased by 30.1% (95% CI 11.2-63.2), but decreased by 2.1% (-11.2 to 14) after the cinema and by 7.9% (-16.2 to -1.2) after the daily life situation. We recorded a high response in TAT levels in 17% (11 of 66) of individuals after air travel (3% [2 of 68] for movie marathon; 1% [1 of 70] in daily life). These findings were most evident in the group with the factor V Leiden mutation who used oral contraceptives. We noted a high response in all variables (prothrombin fragment 1 and 2, TAT, and D-dimer) in four of 63 (6.3%) volunteers after the flight, but in no-one after either of the control situations. INTERPRETATION Activation of coagulation occurs in some individuals after an 8-h flight, indicating an additional mechanism to immobilisation underlying air travel related thrombosis.
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High-dose intravenous dalteparin can be monitored effectively using standard coagulation times.
Wilson, JM, Gilbert, J, Harlan, M, Bracey, A, Allison, P, Schooley, C, Pinto, K
Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. 2005;(2):127-38
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The objective of this study was to examine the pharmacokinetics of intravenous dalteparin (Fragmin, Pharmacia-Upjohn, Peapack, NJ) and to assess the accuracy of standard coagulation-based monitoring techniques as an estimate of drug concentration with which to guide dosing. Knowledge of the kinetic behavior of low-molecular-weight heparins (LMWHs) and the possible utility of coagulation times for monitoring may aid in the development of safe and effective dosing algorithms for percutaneous coronary interventions. Twenty normal volunteers were treated at 2-week intervals with each of three intravenous dalteparin doses. Measurement of anti-IIa, anti-Xa, activated partial thromboplastin time (aPTT), activated clotting time (ACT), and low-range ACT was performed at baseline and at seven additional time points over 8 hours. The half-life of intravenous dalteparin is 77 minutes with slight dose-related variation. The aPTT, LR-ACT, and standard ACT are prolonged after dalteparin administration with the increase closely correlated to anti-Xa activity (aPTT, r = 0.85; LR-ACT, r = 0.79). Classification of anticoagulation intensity range using aPTT or LR-ACT in comparison to anti-Xa activity (0.5-0.99, 1.0-1.49, 1.5-2, >2) displays a level of agreement (kappa: aPTT = 0.69, LR-ACT = 0.59) that is comparable to values reported for coagulation time guidance of unfractionated heparin administration. Standard coagulation times are sensitive to the anticoagulant effect of dalteparin with a degree of correlation that suggests their utility for estimating drug concentration during high dose therapy. Trials establishing a relationship between monitoring and clinical efficacy, and the risk/reward of different treatment ranges alone or in combination with GPIIb/IIIa inhibitors and clopidogrel, are necessary.