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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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[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.
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Multi-dose drug dispensing as a tool to improve medication adherence: A study in patients using vitamin K antagonists.
van Rein, N, de Geus, KS, Cannegieter, SC, Reitsma, PH, van der Meer, FJM, Lijfering, WM
Pharmacoepidemiology and drug safety. 2018;(1):46-51
Abstract
PURPOSE Multi-dose drug dispensing (MDD) is a dosing aid that provides patients with disposable bags containing all drugs intended for 1 dosing moment. MDD is believed to increase medication adherence, but studies are based on self-reported data, and results may depend on socially desirable answers. Therefore, our purpose was to determine the effect of MDD on medication adherence in non-adherent patients taking vitamin K antagonists (VKAs), and to compare with instructing patients on medication use. METHODS We conducted a before-after study in non-adherent patients where MDD was the exposure and change in adherence after MDD initiation was the outcome (within patient comparison). Time in therapeutic range (TTR) was selected as a measure for adherence, as this reflects stability of VKA treatment. To analyze whether MDD improved adherence as compared with standard care (ie, letters or calls from nurses of the anticoagulation clinic), non-adherent patients without MDD were also followed to estimate their TTR change over time (between patient comparison). RESULTS Eighty-three non-adherent VKA patients started using MDD. The median TTR was 63% before MDD and 73% 6 months after MDD. The within patient TTR increased on average by 13% (95%CI 6% to 21%) within 1 month after starting MDD and remained stable during the next 5 months. The TTR of MDD-patients increased 10% (95%CI 2% to 19%) higher as compared with non-MDD patients within 1 month but was similar after 4 months (TTR difference 3%, 95%CI -2% to 9%). CONCLUSIONS Adherence improved after initiation of MDD. Compared with instructing patients, MDD was associated with better adherence within 1 month but was associated with similar improvement after 4 months.
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Meta-analysis of risk of stroke and thrombo-embolism with rivaroxaban versus vitamin K antagonists in ablation and cardioversion of atrial fibrillation.
Nairooz, R, Sardar, P, Pino, M, Aronow, WS, Sewani, A, Mukherjee, D, Paydak, H, Maskoun, W
International journal of cardiology. 2015;:345-53
Abstract
BACKGROUND Anticoagulation in cardioversion and ablation of atrial fibrillation is imperative for reducing thrombo-embolic events. Ample information is available about the use of warfarin and vitamin K antagonists (VKA) but few trials examine safety and efficacy of rivaroxaban in these procedures. We aim to explore the hypothesis that rivaroxaban causes equal thrombo-embolic and bleeding events when used in atrial fibrillation patients undergoing ablation or cardioversion compared to VKA. METHODS We searched the online databases as well as conference abstracts till December 2014 for studies comparing rivaroxaban with VKA in atrial fibrillation patients undergoing catheter ablation or cardioversion. We report events as Odds ratio using random effects model except when event rates were less than 1% we used Peto Odds Ratio. RESULTS A total of 8872 atrial fibrillation patients in 15 studies undergoing either catheter ablation or cardioversion were included in this analysis. There were significantly lower stroke events with rivaroxaban compared with VKA (Peto Odds Ratio (POR) 0.33, 95% confidence interval (CI) [0.11, 0.95]; P=0.04), and significantly less thrombo-embolic events with rivaroxaban compared with VKA (POR 0.46, 95% CI [0.21, 0.97]; P=0.04). Major and minor bleeding were equal with rivaroxaban versus VKA (Odds Ratio (OR) 0.92, 95% CI [0.62, 1.36]; P=0.68) and (OR 0.81,95% CI [0.58, 1.11]; P=0.19) respectively. CONCLUSION The use of rivaroxaban in ablation and cardioversion of atrial fibrillation may be associated with decreased risk of stroke and thromboembolism with equal bleeding risk compared to VKA.
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[Perioperative management of new oral anticoagulants].
Samama, CM, Pernod, G, Albaladejo, P, Sie, P, ,
Presse medicale (Paris, France : 1983). 2014;(6 Pt 1):637-44
Abstract
New oral anticoagulants do represent a major step forward as compared to low molecular weight heparins and vitamin K antagonists. Several issues deserve attention regarding their perioperative management. Three (and very soon four or five) active molecules are available on the market, adding to the major intra- and inter-individual variability, to the high number of drug-drug interactions, and to the interferences of renal function and many other parameters. New tests are available including the diluted thrombin time for dabigatran and a specific anti-Xa test for rivaroxaban and apixaban. No antidote is approved yet. Scheduled surgery: the safest suggestion is to mimic the perioperative management of vitamin K antagonist, with a 5-day interruption and low molecular weight heparin bridging whenever necessary. Emergency procedures: several suggestions issued from the Groupe d'Intérêt en Hémostase Péri-opératoire are proposed.
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Apixaban versus warfarin in patients with atrial fibrillation.
Granger, CB, Alexander, JH, McMurray, JJ, Lopes, RD, Hylek, EM, Hanna, M, Al-Khalidi, HR, Ansell, J, Atar, D, Avezum, A, et al
The New England journal of medicine. 2011;(11):981-92
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Abstract
BACKGROUND Vitamin K antagonists are highly effective in preventing stroke in patients with atrial fibrillation but have several limitations. Apixaban is a novel oral direct factor Xa inhibitor that has been shown to reduce the risk of stroke in a similar population in comparison with aspirin. METHODS In this randomized, double-blind trial, we compared apixaban (at a dose of 5 mg twice daily) with warfarin (target international normalized ratio, 2.0 to 3.0) in 18,201 patients with atrial fibrillation and at least one additional risk factor for stroke. The primary outcome was ischemic or hemorrhagic stroke or systemic embolism. The trial was designed to test for noninferiority, with key secondary objectives of testing for superiority with respect to the primary outcome and to the rates of major bleeding and death from any cause. RESULTS The median duration of follow-up was 1.8 years. The rate of the primary outcome was 1.27% per year in the apixaban group, as compared with 1.60% per year in the warfarin group (hazard ratio with apixaban, 0.79; 95% confidence interval [CI], 0.66 to 0.95; P<0.001 for noninferiority; P=0.01 for superiority). The rate of major bleeding was 2.13% per year in the apixaban group, as compared with 3.09% per year in the warfarin group (hazard ratio, 0.69; 95% CI, 0.60 to 0.80; P<0.001), and the rates of death from any cause were 3.52% and 3.94%, respectively (hazard ratio, 0.89; 95% CI, 0.80 to 0.99; P=0.047). The rate of hemorrhagic stroke was 0.24% per year in the apixaban group, as compared with 0.47% per year in the warfarin group (hazard ratio, 0.51; 95% CI, 0.35 to 0.75; P<0.001), and the rate of ischemic or uncertain type of stroke was 0.97% per year in the apixaban group and 1.05% per year in the warfarin group (hazard ratio, 0.92; 95% CI, 0.74 to 1.13; P=0.42). CONCLUSIONS In patients with atrial fibrillation, apixaban was superior to warfarin in preventing stroke or systemic embolism, caused less bleeding, and resulted in lower mortality. (Funded by Bristol-Myers Squibb and Pfizer; ARISTOTLE ClinicalTrials.gov number, NCT00412984.).
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Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter.
Cairns, JA, Connolly, S, McMurtry, S, Stephenson, M, Talajic, M, ,
The Canadian journal of cardiology. 2011;(1):74-90
Abstract
The stroke rate in atrial fibrillation is 4.5% per year, with death or permanent disability in over half. The risk of stroke varies from under 1% to over 20% per year, related to the risk factors of congestive heart failure, hypertension, age, diabetes, and prior stroke or transient ischemic attack (TIA). Major bleeding with vitamin K antagonists varies from about 1% to over 12% per year and is related to a number of risk factors. The CHADS(2) index and the HAS-BLED score are useful schemata for the prediction of stroke and bleeding risks. Vitamin K antagonists reduce the risk of stroke by 64%, aspirin reduces it by 19%, and vitamin K antagonists reduce the risk of stroke by 39% when directly compared with aspirin. Dabigatran is superior to warfarin for stroke prevention and causes no increase in major bleeding. We recommend that all patients with atrial fibrillation or atrial flutter, whether paroxysmal, persistent, or permanent, should be stratified for the risk of stroke and for the risk of bleeding and that most should receive antithrombotic therapy. We make detailed recommendations as to the preferred agents in various types of patients and for the management of antithrombotic therapies in the common clinical settings of cardioversion, concomitant coronary artery disease, surgical or diagnostic procedures with a risk of major bleeding, and the occurrence of stroke or major bleeding. Alternatives to antithrombotic therapies are briefly discussed.
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[Peculiarities of antithrombotic treatment in exacerbation of coronary heart disease and transcutaneous coronary interventions in patients suffering from atrial fibrillation and taking vitamin K antagonists (literature review)].
Iavelov, IS
Angiologiia i sosudistaia khirurgiia = Angiology and vascular surgery. 2010;(2):13-22
Abstract
The review analyses various approaches to management of patients presenting with atrial fibrillation and having to take vitamin K agonists in order to prevent arterial thromboembolic complications in cases they develop exacerbations of their coronary hear disease and/or require transcutaneous coronary interventions. With the problem being insufficiently studied as yet, the majority of therapeutic decisions as to the most efficient and safe methods of administering antithrombotic agents in the clinical situations involved are made based on the results of follow up of the patients, the data regarding peculiarities of the action of therapeutic agents, and common sense. Presented herein are contemporary recommendations on long-term antithrombotic therapy in patients suffering from atrial fibrillation and taking vitamin K antagonists and subjected to coronary stenting.
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Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale.
Lopes, RD, Alexander, JH, Al-Khatib, SM, Ansell, J, Diaz, R, Easton, JD, Gersh, BJ, Granger, CB, Hanna, M, Horowitz, J, et al
American heart journal. 2010;(3):331-9
Abstract
Atrial fibrillation (AF) is associated with increased risk of stroke that can be attenuated with vitamin K antagonists (VKAs). Vitamin K antagonist use is limited, in part, by the high incidence of complications when patients' international normalized ratios (INRs) deviate from the target range. The primary objective of ARISTOTLE is to determine if the factor Xa inhibitor, apixaban, is noninferior to warfarin at reducing the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism in patients with AF and at least 1 additional risk factor for stroke. We have randomized 18,206 patients from over 1,000 centers in 40 countries. Patients were randomly assigned in a 1:1 ratio to receive apixaban or warfarin using a double-blind, double-dummy design. International normalized ratios are monitored and warfarin (or placebo) is adjusted aiming for a target INR range of 2 to 3 using a blinded, encrypted point-of-care device. Minimum treatment is 12 months, and maximum expected exposure is 4 years. Time to accrual of at least 448 primary efficacy events will determine treatment duration. The key secondary objectives are to determine if apixaban is superior to warfarin for the combined endpoint of stroke (ischemic or hemorrhagic) and systemic embolism, and for all-cause death. These will be tested after the primary objective using a closed test procedure. The noninferiority boundary is 1.38; apixaban will be declared noninferior if the 95% CI excludes the possibility that the primary outcome rate with apixaban is >1.38 times higher than with warfarin. ARISTOTLE will determine whether apixaban is noninferior or superior to warfarin in preventing stroke and systemic embolism; whether apixaban has particular benefits in the warfarin-naïve population; whether it reduces the combined rate of stroke, systemic embolism, and death; and whether it impacts bleeding.
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The PROXIMAL trial: proximal protection during saphenous vein graft intervention using the Proxis Embolic Protection System: a randomized, prospective, multicenter clinical trial.
Mauri, L, Cox, D, Hermiller, J, Massaro, J, Wahr, J, Tay, SW, Jonas, M, Popma, JJ, Pavliska, J, Wahr, D, et al
Journal of the American College of Cardiology. 2007;(15):1442-9
Abstract
OBJECTIVES To determine if outcomes could be further improved, we investigated an embolic protection device placed proximal to the target lesion that could provide protection before lesion instrumentation, allow the use of conventional guidewires, and permit embolic protection in anatomy unfavorable for distal devices. BACKGROUND Embolic complications during stenting of degenerated saphenous vein coronary bypass grafts are reduced, but not eliminated, by distal protection. METHODS A total of 594 patients undergoing stenting of 639 saphenous vein grafts were prospectively randomized, using a noninferiority design, to compare 2 treatment strategies: control (distal protection whenever possible) or test (proximal protection when possible, distal when not). RESULTS The primary composite end point of death, myocardial infarction, or target vessel revascularization at 30 days by intention to treat analysis occurred in 10.0% of control and 9.2% of test patients; difference = -0.8% (95% confidence interval [CI] -5.5% to 4.0%); p for noninferiority = 0.0061. In device specific analysis, this composite end point occurred in 11.7% of distal protection patients and 7.1% of proximal protection patients (difference = -4.6% [95% CI -9.6% to 0.3%]; p for superiority = 0.10, p for noninferiority = 0.001). Finally, in the subset of patients with lesions amenable to treatment with either proximal or distal protection devices (n = 410), the primary composite end point occurred in 12.2% of distal protection patients and 7.4% of proximal protection patients; difference = -4.7% (95% CI -10.4% to 1.0%), p for superiority = 0.14, p for noninferiority = 0.001. CONCLUSIONS Using proximal embolic protection whenever possible during treatment of diseased saphenous vein grafts produced outcomes similar to those with distal embolic protection.