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Rationale and design of PROACT Xa: A randomized, multicenter, open-label, clinical trial to evaluate the efficacy and safety of apixaban versus warfarin in patients with a mechanical On-X Aortic Heart Valve.
Jawitz, OK, Wang, TY, Lopes, RD, Chavez, A, Boyer, B, Kim, H, Anstrom, KJ, Becker, RC, Blackstone, E, Ruel, M, et al
American heart journal. 2020;:91-99
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Abstract
Vitamin K antagonists are the only approved oral anticoagulants for long-term prophylaxis against valve thrombosis and thromboembolism in patients with a mechanical heart valve. Despite the proven efficacy and safety of anticoagulation with the oral direct factor Xa inhibitor apixaban compared with warfarin in high-risk populations including subjects with atrial fibrillation or with venous thromboembolism, it remains unknown whether patients with a mechanical heart valve can be safely managed with apixaban. The On-X Aortic Heart Valve and On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft may have lower rates of valve thrombosis and thromboembolism than conventional bileaflet and tilting disc valves due its unique pyrolytic carbon composition and flared inlet design. DESIGN PROACT Xa is a randomized, multicenter, open-label, active-controlled trial comparing apixaban with warfarin in patients with an On-X Aortic Heart Valve or On-X Ascending Aortic Prosthesis with the Vascutek Gelweave Valsalva Graft. The study will randomize approximately 1,000 patients from approximately 60 sites in North America who underwent aortic valve replacement at least 3 months prior. Patients will be randomized 1:1 to receiving apixaban 5 mg twice daily or warfarin with a target international normalized ratio of 2.0-3.0. The last randomized participant will be followed for at least 2 years. The primary efficacy outcome is the composite of valve thrombosis and valve-related thromboembolism, and the primary safety outcome is major bleeding. Assuming the primary outcome occurs in warfarin-anticoagulated patients at a rate of 1.75%/patient-year, the study has more than 90% power to assess noninferiority of apixaban treatment with an absolute noninferiority margin of 1.75%/patient-year. A second co-primary analysis is to compare the hazard rate for the apixaban arm to twice the objective performance criterion for thromboembolism and valve thrombosis, that is, 3.4%/patient-year. SUMMARY PROACT Xa will determine whether patients with an On-X Aortic Heart Valve can be anticoagulated with apixaban as an alternative to warfarin.
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Effectiveness and Safety of Off-label Dosing of Non-vitamin K Antagonist Anticoagulant for Atrial Fibrillation in Asian Patients.
Lee, KN, Choi, JI, Boo, KY, Kim, DY, Kim, YG, Oh, SK, Baek, YS, Lee, DI, Roh, SY, Shim, J, et al
Scientific reports. 2020;(1):1801
Abstract
Non-vitamin K antagonist anticoagulants (NOACs) have been used to prevent thromboembolism in patients with atrial fibrillation (AF) and shown favorable clinical outcomes compared with warfarin. However, off-label use of NOACs is frequent in practice, and its clinical results are inconsistent. Furthermore, the quality of anticoagulation available with warfarin is often suboptimal and even inaccurate in real-world data. We have therefore compared the effectiveness and safety of off-label use of NOACs with those of warfarin whose anticoagulant intensity was accurately estimated. We retrospectively analyzed data from 2,659 and 3,733 AF patients at a tertiary referral center who were prescribed warfarin and NOACs, respectively, between 2013 and 2018. NOACs were used at off-label doses in 27% of the NOAC patients. After adjusting for significant covariates, underdosed NOAC (off-label use of the reduced dose) was associated with a 2.5-times increased risk of thromboembolism compared with warfarin, and overdosed NOAC (off-label use of the standard dose) showed no significant difference in either thromboembolism or major bleeding compared with warfarin. Well-controlled warfarin (TTR ≥ 60%) reduced both thromboembolism and bleeding events. In conclusion, the effectiveness of NOACs was decreased by off-label use of the reduced dose.
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Atrial Fibrillation and Malignancy: The Clinical Performance of Non-Vitamin K Oral Anticoagulants-A Systematic Review.
Russo, V, Bottino, R, Rago, A, Micco, PD, D' Onofrio, A, Liccardo, B, Golino, P, Nigro, G
Seminars in thrombosis and hemostasis. 2019;(2):205-214
Abstract
Atrial fibrillation (AF) is commonly diagnosed in the setting of active cancer. Because of an increased risk of either thromboembolic events or bleeding, the decision to initiate therapeutic anticoagulation in patients with active cancer can be challenging. Moreover, little is still known about the optimal anticoagulation therapy in the setting of AF and cancer, and no guidelines are as yet available. Considering that nonvitamin K antagonist oral anticoagulants (NOACs) are recommended as alternatives to vitamin K antagonists for stroke prevention in AF patients with CHA2DS2-VASc score ≥2, the authors performed a systematic review of the current literature to describe the efficacy and safety of NOACs in AF patients with malignancy.
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Fixed-Dose Four-Factor Prothrombin Complex Concentrate for Vitamin K Antagonist Reversal: Does One Dose Fit All?
Schwebach, AA, Waybright, RA, Johnson, TJ
Pharmacotherapy. 2019;(5):599-608
Abstract
Four-factor prothrombin complex concentrate (4F-PCC) has emerged as the preferred option for emergent reversal of vitamin K antagonists (VKAs); however, the optimal dosing strategy is unknown. Although several studies have attempted to determine the optimal dose of 4F-PCC using a variety of dosing regimens, no dosing strategy has been found to be superior. Many of these studies have evaluated a low, fixed dose of 4F-PCC rather than individualized dosing as recommended in product labeling. The purpose of this review was to evaluate the efficacy and safety of various fixed-dose strategies of 4F-PCC for emergent VKA reversal and to assess limitations of the existing literature. A search of the PubMed database was performed from the earliest available date through 2018 for relevant articles describing fixed-dose 4F-PCC for VKA reversal. Reference lists of relevant articles were also manually reviewed. Most currently available studies are primarily observational and heterogeneous in design. A very low fixed dose of 500 IU is likely inadequate for successful VKA reversal, but increased fixed doses of 1000-1500 IU have found some degree of success and may be considered for VKA reversal. However, many of these studies consistently identified a trend toward international normalized ratio (INR) reversal failure in patients presenting with high baseline INR values or intracranial hemorrhage, suggesting that higher 4F-PCC doses are needed in these patients. Available studies are underpowered to determine whether a dose-dependent association with thrombotic risk exists. Additional large, randomized studies are needed to determine the optimal dosing strategy and ascertain the role for fixed-dose 4F-PCC.
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Anticoagulation Management in Patients with Valve Replacement.
Saksena, D, Muralidharan, S, Mishra, YK, Kanhere, V, Mohanty, BB, Srivastava, CP, Mange, J, Puranik, M, Nair, MP, Goel, P, et al
The Journal of the Association of Physicians of India. 2018;(1):59-74
Abstract
BACKGROUND Prosthetic valve implantation requires postoperative prophylactic anticoagulation to preclude thrombotic events. The aim of this review is to assess the role of anticoagulation therapy in the management of valve replacement patients. METHODOLOGY Literature from PubMed, Embase, Medline and Google Scholar were searched using the terms "valvular heart disease", "anticoagulant", "mechanical heart valve", "bioprosthesis", "bridging", "Vitamin K antagonist (VKA)", and "acenocoumarol". A committee comprising leading cardiothoracic surgeons from India was convened to review the literature and suggest key practice points. RESULTS Prosthetic valve implantation requires postoperative prophylactic anticoagulation to preclude thrombotic events. A paramount risk of thromboembolic events is observed during the first three months after surgery for both mechanical and bioprosthetic devices. The VKA therapy with individualized target international normalized ratio (INR) is recommended in patients after prosthetic valve replacement. Therapies for the management of prosthetic valve complications should be based on the type of complications. Special care is mandated in distinguished individuals and those with various co-morbidities. CONCLUSION In patients with prosthetic valve replacement, anticoagulant therapy with VKA seems to be an effective option. The role for non-VKA oral anticoagulants in the setting of prosthetic valve replacement has yet to be established. Furthermore, whether the novel oral anticoagulants are safe and efficacious in patients after placement of a bioprosthetic valve remains unanswered.
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The impact of antipsychotics as a risk factor for thromboembolism.
Ogłodek, EA, Just, MJ, Grzesińska, AD, Araszkiewicz, A, Szromek, AR
Pharmacological reports : PR. 2018;(3):533-539
Abstract
Patients with schizophrenia are predisposed toward developing cardiovascular disease. Although neuroleptics affect the cardiovascular system, it is also important to consider the consequences of the disease itself such as lower physical activity due to living on disability pension, inadequate nutrition, and/or nicotine addiction, being more common among patients with schizophrenia versus the general population. All these factors combined lead to an increased risk of death caused by cardiovascular conditions in schizophrenic patients. Individuals receiving typical antipsychotic drugs have been reported to have elevated concentrations of antiphospholipid antibodies, including anticoagulants and anticardiolipin antibodies. The presence of both antibodies is associated with an increased risk for thromboembolism. It is also likely that mental illness is accompanied by increased procoagulant activity. Patients with acute psychosis have been shown to have a statistically significant increase in the concentrations of D-dimer, P-selectin, and in the expression of platelet glycoprotein IIb/IIIa receptors. Learning about causes and mechanisms of venous thromboembolism could help to reduce or neutralize the adverse effects of antipsychotic treatment and facilitate the identification of appropriate markers necessary to monitor changes and provide preventive care against hazardous and potentially fatal complications such as deep venous thrombosis and pulmonary embolism. Before atypical neuroleptic treatment is administered to hospitalized patients, all possible risk factors for thromboembolism should be considered to allow the application of lower risk drugs. Also, other preventive measures should be taken into account, including hydration, compression stockings, regular exercise of lower extremities, and low-molecular-weight heparin injections.
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Anticoagulation in atrial fibrillation : Current evidence and guideline recommendations.
Erath, JW, Hohnloser, SH
Herz. 2018;(1):2-10
Abstract
Atrial fibrillation (AF) is the most frequently encountered sustained arrhythmia with a prevalence of 0.5-10%, depending predominantly on age. The arrhythmia is associated with significant morbidity and mortality, mainly due to thromboembolic events including stroke and systemic embolisms. These complications can be effectively prevented with anticoagulation therapy either with vitamin K antagonists (VKA) or with non-vitamin K antagonists (NOAC). VKA therapy is effective in preventing strokes but these medications are difficult to use, are associated with significant bleeding risk, and have pharmacokinetic/dynamic properties that make their use cumbersome. NOACs-either factor II or factor Xa inhibitors-have been developed over the past two decades and have been tested against VKA in large randomized controlled trials. This trial evidence was complemented more recently by increasing real-world data comprising several 100,000 patients. Finally, NOACs have been examined for their use in specific clinical situations, for example, in patients undergoing cardioversion, catheter ablation, or coronary interventions. In all of these clinical scenarios, NOACs have been similarly effective or-in many instances-even superior to treatment with VKA. Recent guidelines, therefore, recommend NOAC therapy for stroke prevention in AF as first-line therapy.
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Sodium pentosan polysulfate efficacy as thromboprophylaxis agent in high-risk women following gynecological surgery.
Indirayani, I, Kalok, A, Nik Ismail, NA, Shah, SA, Lim, PS, Mohamed Ismail, NA, Nur Azurah, AG, Omar, MH, Shafiee, MN
The journal of obstetrics and gynaecology research. 2018;(8):1458-1465
Abstract
AIM: Sodium pentosan polysulfate (Na-PPS) is a plant-based agent that has similar action with low-molecular-weight heparin. It inhibits factor Xa, preventing blood clot formation. To date, its use in clinical practice as thromboprophylaxis agent is still limited. In addition, the efficacy and safety profile of this agent was not robustly reported globally, especially for countries with major Muslim population. We hypothesized that Na-PPS was equally effective as the standard thromboprophylaxis. We aim to compare the efficacy and safety of Na-PPS against standard agent (fondaparinux or enoxaparin). METHODS This was a randomized control, open-label trial. Women underwent major gynecological surgery were randomized to receive either subcutaneous 50 mg of Na-PPS twice daily or subcutaneous enoxaparin 40 mg once daily. Fondaparinux 2.5 mg once daily was given to Muslim women as an alternative to enoxaparin. The treatment was started 6 h postoperatively, for at least 3 days. All the patients received thromboembolic deterrent stockings. The primary efficacy outcome was venous thromboembolism up to 3 days postsurgery. The main safety outcomes were minor and major bleeding. RESULTS Among 109 participants, there was no incidence of venous thromboembolism. None of the women developed major bleeding. Minor bleeding was observed in 28.3% (15/53) and 5.4% (3/56) of Na-PPS and standard thromboprophylaxis group, respectively (P = 0.001). CONCLUSION Na-PPS was associated with increased risk of minor bleeding. There was insufficient data to conclude its efficacy as thromboprophylaxis. Further research is needed to evaluate Na-PPS safety as a standard thromboprophylactic agent.
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Management of therapeutic anticoagulation in patients with intracerebral haemorrhage and mechanical heart valves.
Kuramatsu, JB, Sembill, JA, Gerner, ST, Sprügel, MI, Hagen, M, Roeder, SS, Endres, M, Haeusler, KG, Sobesky, J, Schurig, J, et al
European heart journal. 2018;(19):1709-1723
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Abstract
AIMS: Evidence is lacking regarding acute anticoagulation management in patients after intracerebral haemorrhage (ICH) with implanted mechanical heart valves (MHVs). Our objective was to investigate anticoagulation reversal and resumption strategies by evaluating incidences of haemorrhagic and thromboembolic complications, thereby defining an optimal time-window when to restart therapeutic anticoagulation (TA) in patients with MHV and ICH. METHODS AND RESULTS We pooled individual patient-data (n = 2504) from a nationwide multicentre cohort-study (RETRACE, conducted at 22 German centres) and eventually identified MHV-patients (n = 137) with anticoagulation-associated ICH for outcome analyses. The primary outcome consisted of major haemorrhagic complications analysed during hospital stay according to treatment exposure (restarted TA vs. no-TA). Secondary outcomes comprised thromboembolic complications, the composite outcome (haemorrhagic and thromboembolic complications), timing of TA, and mortality. Adjusted analyses involved propensity-score matching and multivariable cox-regressions to identify optimal timing of TA. In 66/137 (48%) of patients TA was restarted, being associated with increased haemorrhagic (TA = 17/66 (26%) vs. no-TA = 4/71 (6%); P < 0.01) and a trend to decreased thromboembolic complications (TA = 1/66 (2%) vs. no-TA = 7/71 (10%); P = 0.06). Controlling treatment crossovers provided an incidence rate-ratio [hazard ratio (HR) 10.31, 95% confidence interval (CI) 3.67-35.70; P < 0.01] in disadvantage of TA for haemorrhagic complications. Analyses of TA-timing displayed significant harm until Day 13 after ICH (HR 7.06, 95% CI 2.33-21.37; P < 0.01). The hazard for the composite-balancing both complications, was increased for restarted TA until Day 6 (HR 2.51, 95% CI 1.10-5.70; P = 0.03). CONCLUSION Restarting TA within less than 2 weeks after ICH in patients with MHV was associated with increased haemorrhagic complications. Optimal weighing-between least risks for thromboembolic and haemorrhagic complications-provided an earliest starting point of TA at Day 6, reserved only for patients at high thromboembolic risk.
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[The Multimorbid Patient: Use of New Oral Anticoagulants in Patients with Chronic Kidney Disease].
Mohebbi, N
Praxis. 2018;(13):683-687
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Abstract
The Multimorbid Patient: Use of New Oral Anticoagulants in Patients with Chronic Kidney Disease Abstract. Increasing life expectancy in Western countries is associated with a high prevalence of multiple chronic diseases which is defined by the term "multimorbidity". Many of these patients suffer from chronic kidney disease (CKD) and thrombogenic comorbidities such as atrial fibrillation with the need for oral anticoagulation. For decades vitamin K antagonists have been exclusively prescribed for oral anticoagulation. However, due to altered pharmacokinetics and bioavailability of these drugs in CKD, a significant risk of bleeding exists. The introduction of direct oral anticoagulants as a new and promising alternative to vitamin K antagonists was -especially for CKD patients - highly anticipated. However, data from randomized studies are missing for older patients with advanced CKD. Consequently, a careful evaluation of the risk-benefit ratio is recommended for this sensitive patient population.