We found that patients with venous thromboembolism with ongoing risk factors have an appreciable risk of recurrence because even with aspirin, the rate of recurrent venous thromboembolism in such patients was 3.6%, as compared with a rate of recurrence of 5.6% in those with unprovoked venous thromboembolism. Konstantinides SV, et al. 
The EINSTEIN Investigators. Patients were eligible for inclusion in the study if they were 18 years of age or older; had objectively confirmed, symptomatic proximal deep-vein thrombosis or pulmonary embolism; had been treated for 6 to 12 months with an anticoagulant agent, including a vitamin K antagonist or a direct oral anticoagulant agent such as dabigatran, rivaroxaban, apixaban, or edoxaban; and had not interrupted therapy for more than 7 days before randomization. N Engl J Med 2003;349:631-639, 15. michler robert einstein appointed surgery chair jumps 
Clinically relevant nonmajor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, unscheduled contact with a physician, interruption or discontinuation of the study drug, or discomfort or impairment of activities of daily living.26 (Further details regarding the criteria are provided in the Supplementary Appendix.). Lancet 2008;372:31-39, 20. With aspirin, the rate of recurrent venous thromboembolism was 3.6% among the patients in whom the index event was provoked (i.e., associated with a known event, such as surgery or hospital admission) and 5.6% among those in whom the index event was unprovoked (i.e., idiopathic) (, Major bleeding occurred in 6 patients (0.5%) in the 20-mg rivaroxaban group and in 5 patients (0.4%) in the 10-mg rivaroxaban group, as compared with 3 patients (0.3%) in the aspirin group (, Clinically relevant nonmajor bleeding occurred in 30 patients (2.7%) in the 20-mg rivaroxaban group and in 22 patients (2.0%) in the 10-mg rivaroxaban group, as compared with 20 patients (1.8%) in the aspirin group (. Alternatives to a VKA for patients who need extended anticoagulation (class IIa, level B): Dabigatran 150 mg BID (or 110 mg BID for patients 80 years of age or taking concomitant verapimil). Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2013;368:709-718, 9. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. Figure 2A shows the time course of symptomatic fatal or nonfatal recurrent venous thromboembolism. With aspirin, the rate of recurrent venous thromboembolism was 3.6% among the patients in whom the index event was provoked (i.e., associated with a known event, such as surgery or hospital admission) and 5.6% among those in whom the index event was unprovoked (i.e., idiopathic) (Table 3). Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. Dr. Weitz reports receiving consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Portola, and Pfizer; Drs. The per-protocol population excluded patients who had a rate of adherence to the study-drug regimen of less than 80% or who had other major protocol violations. both in Canada; Bayer Pharmaceuticals, Leverkusen (A.W.A.L., M.C.S.F., G.H., A.F.P., S.D.B. A full list of inclusion and exclusion criteria is provided in the Supplementary Appendix, available at NEJM.org. Study drugs were administered for up to 12 months. A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). This article was published on March 18, 2017, at NEJM.org. Arch Intern Med 2008;168:425-430, March 30, 2017N Engl J Med 2017; 376:1211-1222
From the Thrombosis and Atherosclerosis Research Institute and McMaster University, Hamilton, ON (J.I.W. A primary efficacy outcome event occurred in 17 of 1107 patients (1.5%) who were receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) who were receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) who were receiving aspirin. S1 through S4 in the Supplementary Appendix). Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. Of the 31 patients who were excluded from the analyses because they did not take any study drug, 1 patient who was assigned to receive 20 mg of rivaroxaban had a nonfatal primary efficacy outcome event. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. The protocol (available with the full text of this article at NEJM.org) was approved by the institutional review board at each participating center. However, this number was increased to 3300 when review of blinded data revealed a lower-than-expected overall incidence of the primary efficacy outcome. Valuable tools for building a rewarding career in health care. Patients were enrolled at least 24 hours after they had received the last dose of a direct oral anticoagulant agent or, if they were receiving a vitamin K antagonist, when the international normalized ratio was 2.5 or lower. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. In patients with DVT of the leg or PE and active cancer (cancer-associated thrombosis) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), and (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B). Secondary aims of the study were to determine whether the lower dose of rivaroxaban was as effective as the higher dose and whether it was associated with less bleeding. MMWR Morb Mortal Wkly Rep 2012;61:401-404, 4. Clinically relevant nonmajor bleeding occurred in 30 patients (2.7%) in the 20-mg rivaroxaban group and in 22 patients (2.0%) in the 10-mg rivaroxaban group, as compared with 20 patients (1.8%) in the aspirin group (Table 4). Nonmajor bleeding that was associated with a study-drug interruption for more than 14 days occurred in 17 patients (1.5%) in the 20-mg rivaroxaban group and in 12 patients (1.1%) in the 10-mg rivaroxaban group, as compared with 12 patients (1.1%) in the aspirin group. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. Major bleeding occurred in 6 patients (0.5%) in the 20-mg rivaroxaban group and in 5 patients (0.4%) in the 10-mg rivaroxaban group, as compared with 3 patients (0.3%) in the aspirin group (Table 4). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. Randomized, double-blinded, phase 3 study, Completed 6-12 months of primary anticoagulant therapy with either vitamin K antagonist or novel anticoagulant (without interruption of anticoagulant therapy for more than 7 days), Indication for therapeutic anticoagulation, Indication for antiplatelet therapy or NSAIDs, Contraindication to anticoagulation (e.g., active bleeding), Concomitant use of strong inhibitors of CYP3A4 and P-gp, Median duration of study drug administration: 349 days, Enrolled >24 h after last dose of therapeutic anticoagulant. The sponsor collected, maintained, and analyzed the data; the academic authors had access to the data at all times through the sponsor. In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B). The main conclusion of this study is that up to 1 year of rivaroxaban at a dose of either 20 mg/d or 10 mg/d is efficacious in preventing recurrent VTE in patients who have completed 6-12 months of primary anticoagulant therapy, and this approach is not associated with increased bleeding compared to aspirin 100 mg/d. Consequently, the number of patients who would need to be treated for up to 12 months with rivaroxaban instead of aspirin to prevent one episode of fatal or nonfatal recurrent venous thromboembolism without increasing the risk of bleeding was 33 with the 20-mg dose and 30 with the 10-mg dose. 
The per-protocol population included all those in the intention-to-treat population with the exception of those who had a rate of adherence to the study-drug regimen of less than 80% or who had other major protocol violations. Efficacy and safety outcomes were analyzed with the use of a Cox proportional-hazards model, stratified according to the index diagnosis (deep-vein thrombosis or pulmonary embolism). 
Chest 2016;149:315-352, 5. ), and the Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa (P.S.W.) The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer, time-limited period (eg, 6, 12, or 24 months) (Grade 1B). In prespecified subgroup analyses of the primary efficacy outcome and the composite outcome of major and clinically relevant nonmajor bleeding, results were consistent with the overall treatment effects (Figs. 
Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. astronomers This includes the ASPIRE and WARFASA trials of aspirin and the AMPLIFY-EXT trial of apixaban. Consequently, additional studies are needed to determine the utility of continuing treatment for longer periods. Eriksson BI, Borris LC, Friedman RJ, et al. 
In patients with VTE who have completed 6-12 months of anticoagulation, does long-term rivaroxaban treatment reduce the rate of recurrent VTE compared to aspirin? Ann Intern Med 2009;150:604-612, 25. einstein told cook audiobook audible science This page was last edited on 3 December 2017, at 22:35. 
); Janssen Research and Development, Raritan, NJ (L.H. Thromb Haemost 2015;114:645-650, 23. Therefore, we found that rivaroxaban was more effective than aspirin for the prevention of recurrent venous thromboembolism and was associated with a similar risk of bleeding. trials In conclusion, we found that rivaroxaban, at both a treatment dose (20 mg) and a thromboprophylactic dose (10 mg), was more effective than aspirin for the prevention of recurrent venous thromboembolism among patients who were in equipoise for continued anticoagulation. Our study has several potential limitations. The main reasons for premature discontinuation of a study medication were adverse events, nonadherence to the study-drug regimen, protocol violations, and efficacy or safety outcomes. Demographic and Clinical Characteristics of the Patients at Baseline. Patients were instructed to report to the study center if they had symptoms suggestive of recurrent venous thromboembolism or bleeding. 
The intention-to-treat population included all the patients who had undergone randomization with valid informed consent and who had received at least one dose of a study medication. 
N Engl J Med 2011;365:883-891, 16. Kearon C et al. 
Brighton TA, Eikelboom JW, Mann K, et al. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. Address reprint requests to Dr. Weitz at the Thrombosis and Atherosclerosis Research Institute, 237 Barton St. E., Hamilton, ON L8L 2X2, Canada, or at [emailprotected]. Lensing, Freitas, Holberg, Pap, and Berkowitz, being employees of Bayer; Dr. Prins, receiving consulting fees from Pfizer and Daiichi Sankyo; Dr. Bauersachs, receiving consulting and lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb, and Daiichi Sankyo; Dr. Beyer-Westendorf, receiving grant support, lecture fees, and fees for serving on advisory boards from Boehringer Ingelheim, Daiichi Sankyo, and Pfizer; Dr. Bounameaux, receiving grant support and fees for serving on the Thrombosis Research Institute Garfield Registry steering committee, fees for serving on the Bayer EINSTEIN CHOICE Study steering committee, consulting fees from Amgen, and fees for serving on advisory boards from Bayer, Pfizer, and Sanofi Aventis; Dr. Brighton, receiving lecture fees from Bayer, Novo Nordisk, and GlaxoSmithKline; Dr. Cohen, receiving fees for serving on a committee for Boehringer Ingelheim, grant support and fees for serving on committees from Bristol-Myers Squibb and Daiichi Sankyo, consulting fees and fees for serving on steering committees from Johnson & Johnson and Portola, grant support, consulting fees, and fees for serving on committees from Pfizer, and consulting fees from Sanofi, Janssen, and Ono Pharmaceuticals; Dr. Davidson, receiving consulting fees from Janssen and Portola; Dr. Decousus, receiving fees for attending symposia from Aspen, fees for serving on advisory boards from Pfizer and Bristol-Myers Squibb, and grant support and fees for board membership from Daiichi Sankyo and Bayer; Dr. Kakkar, receiving grant support, consulting fees, and lecture fees from Bayer and consulting and lecture fees from Sanofi, Janssen, Boehringer Ingelheim, and Daiichi Sankyo; Dr. Haskell, being an employee of Johnson & Johnson; Dr. van Bellen, receiving lecture fees and fees for serving on an advisory board from Bayer and Daiichi Sankyo and for serving on an advisory board from Bristol-Myers Squibb; Dr. Verhamme, receiving grant support, lecture fees, and fees for serving on an advisory board from Boehringer Ingelheim and LEO Pharma, lecture fees from Pfizer and Bristol-Myers Squibb, grant support from Sanofi, lecture fees and fees for serving on an advisory board from Daiichi Sankyo, and fees for serving on an advisory board from Portola Pharmaceuticals; Dr. Wells, receiving grant support, lecture fees, and fees for serving on an advisory board from Bayer, fees for serving on a writing committee from Itreas, consulting fees from Janssen Scientific Affairs, grant support from Bristol-Myers Squibb and Pfizer, and lecture fees from Daiichi Sankyo; and Dr. Prandoni, receiving consulting and lecture fees from Bayer, Sanofi, Daiichi Sankyo, and Pfizer. In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B). 
N Engl J Med 2012;366:1959-1967, 14. These benefits were observed with rates of major and clinically relevant nonmajor bleeding that were low and similar to those with aspirin. 
); the Division of Angiology and Hemostasis and the Faculty of Medicine, University of Geneva, Geneva (H.B. ), the Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz (R.B. From March 2014 through March 2016, a total of 3396 patients from 244 sites in 31 countries were enrolled. bair hugger lawsuits mdl Patients were followed for the primary efficacy outcome, which was the composite of symptomatic, recurrent fatal or nonfatal VTE or unexplained death for which PE could not be ruled out, and major bleeding was the primary safety outcome. Written informed consent was obtained from all the patients. In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. Third, our study was not powered to show the noninferiority of the 10-mg dose of rivaroxaban to the established treatment regimen of 20 mg, so any conclusions with respect to this issue are speculative. The EINSTEINPE Investigators. Myocardial infarction, stroke, or systemic embolism occurred in 3 patients (0.3%) in the 20-mg rivaroxaban group, in 5 patients (0.4%) in the 10-mg rivaroxaban group, and in 7 patients (0.6%) in the aspirin group (Table 2). turing alan trial homosexual centenary conduct walton athletic club working 1946 bus steps members polarimagazine 
The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. This study included patients with both provoked and unprovoked venous thromboembolism for whom there was equipoise regarding the need for continued anticoagulation. Prandoni P, Bilora F, Marchiori A, et al. Non-inferiority trial was not performed to show 10 mg/d is noninferior to the current treatment dose of 20 mg/d. All the members of the steering committee contributed to the interpretation of the results. Clinical strategies for extended anticoagulation in patients with venous thromboembolism are uncertain. The primary efficacy outcome was a composite of symptomatic, recurrent fatal or nonfatal venous thromboembolism and unexplained death for which pulmonary embolism could not be ruled out. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Kearon C, Akl EA, Ornelas J, et al. einstein albert worksheet challenge curated reviewed lessonplanet grade acc tctmd washington Both rivaroxaban doses were superior to aspirin with respect to the primary efficacy outcome (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). All the patients who stopped a study treatment earlier than scheduled were followed until the end of the intended treatment period. In patients with a second unprovoked VTE and who have a (i) low bleeding risk (see text), we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (Grade 1B); (ii) moderate bleeding risk (see text), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B); or (iii) high bleeding risk (see text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 2B). 
The incidence of adverse events was similar in all three groups. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. A new equation to estimate glomerular filtration rate. 
Rivaroxaban reduced the relative risk of recurrence by about 70% in patients with both unprovoked and provoked venous thromboembolism. Patients were randomized 1:1:1 to rivaroxaban 20 mg/d, rivaroxaban 10 mg/d, or aspirin 100 mg/d, and each group was provided with a matching placebo. Patients were assigned, in a 1:1:1 ratio, to receive 20 mg of rivaroxaban, 10 mg of rivaroxaban, or 100 mg of aspirin, all given once daily with food. The rates of death from any cause were 0.7% and 0.2% in the 20-mg and 10-mg rivaroxaban groups, respectively, as compared with 0.6% in the aspirin group. Therefore, it remains unknown whether the 10-mg dose of rivaroxaban would be sufficient to prevent recurrence in such patients. 2014 Nov 14;35(43):3033-69. http://www.wikijournalclub.org/w/index.php?title=EINSTEIN_CHOICE&oldid=27712, In patients with DVT of the leg or PE and no cancer, as long-term (first 3months) anticoagulant therapy, dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over vitamin K antagonist (VKA) therapy(all Grade 2B), In patients with DVT of the leg or PE and cancer (cancer-associated thrombosis), as long-term (first 3months) anticoagulant therapy, LMWH is recommended over other agents (Grade 2C), In patients with DVT of the leg or PE who receive extended therapy, recommend no need tochange the choice of anticoagulant after the first 3months (Grade 2C). 1. What are the clinical implications of these findings? Nephron 1976;16:31-41, 24. Low-dose aspirin for preventing recurrent venous thromboembolism. J Thromb Haemost 2005;3:692-694, 26. Kearon C, Ginsberg JS, Kovacs MJ, et al. In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), recommend switching totreatment with LMWH at least temporarily(Grade 2C). (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439. 
The EINSTEIN Investigators. Patients were eligible for inclusion in the study if they were 18 years of age or older; had objectively confirmed, symptomatic proximal deep-vein thrombosis or pulmonary embolism; had been treated for 6 to 12 months with an anticoagulant agent, including a vitamin K antagonist or a direct oral anticoagulant agent such as dabigatran, rivaroxaban, apixaban, or edoxaban; and had not interrupted therapy for more than 7 days before randomization. N Engl J Med 2003;349:631-639, 15. michler robert einstein appointed surgery chair jumps Clinically relevant nonmajor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but was associated with the need for medical intervention, unscheduled contact with a physician, interruption or discontinuation of the study drug, or discomfort or impairment of activities of daily living.26 (Further details regarding the criteria are provided in the Supplementary Appendix.). Lancet 2008;372:31-39, 20. With aspirin, the rate of recurrent venous thromboembolism was 3.6% among the patients in whom the index event was provoked (i.e., associated with a known event, such as surgery or hospital admission) and 5.6% among those in whom the index event was unprovoked (i.e., idiopathic) (, Major bleeding occurred in 6 patients (0.5%) in the 20-mg rivaroxaban group and in 5 patients (0.4%) in the 10-mg rivaroxaban group, as compared with 3 patients (0.3%) in the aspirin group (, Clinically relevant nonmajor bleeding occurred in 30 patients (2.7%) in the 20-mg rivaroxaban group and in 22 patients (2.0%) in the 10-mg rivaroxaban group, as compared with 20 patients (1.8%) in the aspirin group (. Alternatives to a VKA for patients who need extended anticoagulation (class IIa, level B): Dabigatran 150 mg BID (or 110 mg BID for patients 80 years of age or taking concomitant verapimil). Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2013;368:709-718, 9. The primary efficacy outcome was symptomatic recurrent fatal or nonfatal venous thromboembolism, and the principal safety outcome was major bleeding. Figure 2A shows the time course of symptomatic fatal or nonfatal recurrent venous thromboembolism. With aspirin, the rate of recurrent venous thromboembolism was 3.6% among the patients in whom the index event was provoked (i.e., associated with a known event, such as surgery or hospital admission) and 5.6% among those in whom the index event was unprovoked (i.e., idiopathic) (Table 3). Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. Dr. Weitz reports receiving consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Ionis Pharmaceuticals, Janssen, Merck, Novartis, Portola, and Pfizer; Drs. The per-protocol population excluded patients who had a rate of adherence to the study-drug regimen of less than 80% or who had other major protocol violations. both in Canada; Bayer Pharmaceuticals, Leverkusen (A.W.A.L., M.C.S.F., G.H., A.F.P., S.D.B. A full list of inclusion and exclusion criteria is provided in the Supplementary Appendix, available at NEJM.org. Study drugs were administered for up to 12 months. A total of 3365 patients were included in the intention-to-treat analyses (median treatment duration, 351 days). This article was published on March 18, 2017, at NEJM.org. Arch Intern Med 2008;168:425-430, March 30, 2017N Engl J Med 2017; 376:1211-1222
From the Thrombosis and Atherosclerosis Research Institute and McMaster University, Hamilton, ON (J.I.W. A primary efficacy outcome event occurred in 17 of 1107 patients (1.5%) who were receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) who were receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) who were receiving aspirin. S1 through S4 in the Supplementary Appendix). Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. Of the 31 patients who were excluded from the analyses because they did not take any study drug, 1 patient who was assigned to receive 20 mg of rivaroxaban had a nonfatal primary efficacy outcome event. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. The protocol (available with the full text of this article at NEJM.org) was approved by the institutional review board at each participating center. However, this number was increased to 3300 when review of blinded data revealed a lower-than-expected overall incidence of the primary efficacy outcome. Valuable tools for building a rewarding career in health care. Patients were enrolled at least 24 hours after they had received the last dose of a direct oral anticoagulant agent or, if they were receiving a vitamin K antagonist, when the international normalized ratio was 2.5 or lower. Concise summaries and expert physician commentary that busy clinicians need to enhance patient care. In patients with DVT of the leg or PE and active cancer (cancer-associated thrombosis) and who (i) do not have a high bleeding risk, we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 1B), and (ii) have a high bleeding risk, we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B). Secondary aims of the study were to determine whether the lower dose of rivaroxaban was as effective as the higher dose and whether it was associated with less bleeding. MMWR Morb Mortal Wkly Rep 2012;61:401-404, 4. Clinically relevant nonmajor bleeding occurred in 30 patients (2.7%) in the 20-mg rivaroxaban group and in 22 patients (2.0%) in the 10-mg rivaroxaban group, as compared with 20 patients (1.8%) in the aspirin group (Table 4). Nonmajor bleeding that was associated with a study-drug interruption for more than 14 days occurred in 17 patients (1.5%) in the 20-mg rivaroxaban group and in 12 patients (1.1%) in the 10-mg rivaroxaban group, as compared with 12 patients (1.1%) in the aspirin group. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. Major bleeding occurred in 6 patients (0.5%) in the 20-mg rivaroxaban group and in 5 patients (0.4%) in the 10-mg rivaroxaban group, as compared with 3 patients (0.3%) in the aspirin group (Table 4). Rates of major bleeding were 0.5% in the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of rivaroxaban, and 0.3% in the aspirin group; the rates of clinically relevant nonmajor bleeding were 2.7%, 2.0%, and 1.8%, respectively. Randomized, double-blinded, phase 3 study, Completed 6-12 months of primary anticoagulant therapy with either vitamin K antagonist or novel anticoagulant (without interruption of anticoagulant therapy for more than 7 days), Indication for therapeutic anticoagulation, Indication for antiplatelet therapy or NSAIDs, Contraindication to anticoagulation (e.g., active bleeding), Concomitant use of strong inhibitors of CYP3A4 and P-gp, Median duration of study drug administration: 349 days, Enrolled >24 h after last dose of therapeutic anticoagulant. The sponsor collected, maintained, and analyzed the data; the academic authors had access to the data at all times through the sponsor. In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and a (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B). The main conclusion of this study is that up to 1 year of rivaroxaban at a dose of either 20 mg/d or 10 mg/d is efficacious in preventing recurrent VTE in patients who have completed 6-12 months of primary anticoagulant therapy, and this approach is not associated with increased bleeding compared to aspirin 100 mg/d. Consequently, the number of patients who would need to be treated for up to 12 months with rivaroxaban instead of aspirin to prevent one episode of fatal or nonfatal recurrent venous thromboembolism without increasing the risk of bleeding was 33 with the 20-mg dose and 30 with the 10-mg dose. The per-protocol population included all those in the intention-to-treat population with the exception of those who had a rate of adherence to the study-drug regimen of less than 80% or who had other major protocol violations. Efficacy and safety outcomes were analyzed with the use of a Cox proportional-hazards model, stratified according to the index diagnosis (deep-vein thrombosis or pulmonary embolism). 
Chest 2016;149:315-352, 5. ), and the Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa (P.S.W.) The primary efficacy outcome occurred in 17 of 1107 patients (1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 mg of rivaroxaban, as compared with 50 of 1131 patients (4.4%) receiving aspirin (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months over treatment of a shorter duration (Grade 1B), and we recommend treatment with anticoagulation for 3 months over treatment of a longer, time-limited period (eg, 6, 12, or 24 months) (Grade 1B). In prespecified subgroup analyses of the primary efficacy outcome and the composite outcome of major and clinically relevant nonmajor bleeding, results were consistent with the overall treatment effects (Figs. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. astronomers This includes the ASPIRE and WARFASA trials of aspirin and the AMPLIFY-EXT trial of apixaban. Consequently, additional studies are needed to determine the utility of continuing treatment for longer periods. Eriksson BI, Borris LC, Friedman RJ, et al. In patients with VTE who have completed 6-12 months of anticoagulation, does long-term rivaroxaban treatment reduce the rate of recurrent VTE compared to aspirin? Ann Intern Med 2009;150:604-612, 25. einstein told cook audiobook audible science This page was last edited on 3 December 2017, at 22:35. 
); Janssen Research and Development, Raritan, NJ (L.H. Thromb Haemost 2015;114:645-650, 23. Therefore, we found that rivaroxaban was more effective than aspirin for the prevention of recurrent venous thromboembolism and was associated with a similar risk of bleeding. trials In conclusion, we found that rivaroxaban, at both a treatment dose (20 mg) and a thromboprophylactic dose (10 mg), was more effective than aspirin for the prevention of recurrent venous thromboembolism among patients who were in equipoise for continued anticoagulation. Our study has several potential limitations. The main reasons for premature discontinuation of a study medication were adverse events, nonadherence to the study-drug regimen, protocol violations, and efficacy or safety outcomes. Demographic and Clinical Characteristics of the Patients at Baseline. Patients were instructed to report to the study center if they had symptoms suggestive of recurrent venous thromboembolism or bleeding. 
The intention-to-treat population included all the patients who had undergone randomization with valid informed consent and who had received at least one dose of a study medication. N Engl J Med 2011;365:883-891, 16. Kearon C et al. Brighton TA, Eikelboom JW, Mann K, et al. A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. Address reprint requests to Dr. Weitz at the Thrombosis and Atherosclerosis Research Institute, 237 Barton St. E., Hamilton, ON L8L 2X2, Canada, or at [emailprotected]. Lensing, Freitas, Holberg, Pap, and Berkowitz, being employees of Bayer; Dr. Prins, receiving consulting fees from Pfizer and Daiichi Sankyo; Dr. Bauersachs, receiving consulting and lecture fees from Boehringer Ingelheim, Bristol-Myers Squibb, and Daiichi Sankyo; Dr. Beyer-Westendorf, receiving grant support, lecture fees, and fees for serving on advisory boards from Boehringer Ingelheim, Daiichi Sankyo, and Pfizer; Dr. Bounameaux, receiving grant support and fees for serving on the Thrombosis Research Institute Garfield Registry steering committee, fees for serving on the Bayer EINSTEIN CHOICE Study steering committee, consulting fees from Amgen, and fees for serving on advisory boards from Bayer, Pfizer, and Sanofi Aventis; Dr. Brighton, receiving lecture fees from Bayer, Novo Nordisk, and GlaxoSmithKline; Dr. Cohen, receiving fees for serving on a committee for Boehringer Ingelheim, grant support and fees for serving on committees from Bristol-Myers Squibb and Daiichi Sankyo, consulting fees and fees for serving on steering committees from Johnson & Johnson and Portola, grant support, consulting fees, and fees for serving on committees from Pfizer, and consulting fees from Sanofi, Janssen, and Ono Pharmaceuticals; Dr. Davidson, receiving consulting fees from Janssen and Portola; Dr. Decousus, receiving fees for attending symposia from Aspen, fees for serving on advisory boards from Pfizer and Bristol-Myers Squibb, and grant support and fees for board membership from Daiichi Sankyo and Bayer; Dr. Kakkar, receiving grant support, consulting fees, and lecture fees from Bayer and consulting and lecture fees from Sanofi, Janssen, Boehringer Ingelheim, and Daiichi Sankyo; Dr. Haskell, being an employee of Johnson & Johnson; Dr. van Bellen, receiving lecture fees and fees for serving on an advisory board from Bayer and Daiichi Sankyo and for serving on an advisory board from Bristol-Myers Squibb; Dr. Verhamme, receiving grant support, lecture fees, and fees for serving on an advisory board from Boehringer Ingelheim and LEO Pharma, lecture fees from Pfizer and Bristol-Myers Squibb, grant support from Sanofi, lecture fees and fees for serving on an advisory board from Daiichi Sankyo, and fees for serving on an advisory board from Portola Pharmaceuticals; Dr. Wells, receiving grant support, lecture fees, and fees for serving on an advisory board from Bayer, fees for serving on a writing committee from Itreas, consulting fees from Janssen Scientific Affairs, grant support from Bristol-Myers Squibb and Pfizer, and lecture fees from Daiichi Sankyo; and Dr. Prandoni, receiving consulting and lecture fees from Bayer, Sanofi, Daiichi Sankyo, and Pfizer. In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest aspirin over no aspirin to prevent recurrent VTE (Grade 2B). 
N Engl J Med 2012;366:1959-1967, 14. These benefits were observed with rates of major and clinically relevant nonmajor bleeding that were low and similar to those with aspirin. ); the Division of Angiology and Hemostasis and the Faculty of Medicine, University of Geneva, Geneva (H.B. ), the Center for Thrombosis and Hemostasis, University Medical Center Mainz, Mainz (R.B. From March 2014 through March 2016, a total of 3396 patients from 244 sites in 31 countries were enrolled. bair hugger lawsuits mdl Patients were followed for the primary efficacy outcome, which was the composite of symptomatic, recurrent fatal or nonfatal VTE or unexplained death for which PE could not be ruled out, and major bleeding was the primary safety outcome. Written informed consent was obtained from all the patients. In this randomized, double-blind, phase 3 study, we assigned 3396 patients with venous thromboembolism to receive either once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin. Third, our study was not powered to show the noninferiority of the 10-mg dose of rivaroxaban to the established treatment regimen of 20 mg, so any conclusions with respect to this issue are speculative. The EINSTEINPE Investigators. Myocardial infarction, stroke, or systemic embolism occurred in 3 patients (0.3%) in the 20-mg rivaroxaban group, in 5 patients (0.4%) in the 10-mg rivaroxaban group, and in 7 patients (0.6%) in the aspirin group (Table 2). turing alan trial homosexual centenary conduct walton athletic club working 1946 bus steps members polarimagazine 
The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. This study included patients with both provoked and unprovoked venous thromboembolism for whom there was equipoise regarding the need for continued anticoagulation. Prandoni P, Bilora F, Marchiori A, et al. Non-inferiority trial was not performed to show 10 mg/d is noninferior to the current treatment dose of 20 mg/d. All the members of the steering committee contributed to the interpretation of the results. Clinical strategies for extended anticoagulation in patients with venous thromboembolism are uncertain. The primary efficacy outcome was a composite of symptomatic, recurrent fatal or nonfatal venous thromboembolism and unexplained death for which pulmonary embolism could not be ruled out. Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. Kearon C, Akl EA, Ornelas J, et al. einstein albert worksheet challenge curated reviewed lessonplanet grade acc tctmd washington Both rivaroxaban doses were superior to aspirin with respect to the primary efficacy outcome (hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 0.47; P<0.001 for both comparisons). All the patients who stopped a study treatment earlier than scheduled were followed until the end of the intended treatment period. In patients with a second unprovoked VTE and who have a (i) low bleeding risk (see text), we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (Grade 1B); (ii) moderate bleeding risk (see text), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B); or (iii) high bleeding risk (see text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 2B). The incidence of adverse events was similar in all three groups. 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. A new equation to estimate glomerular filtration rate. Rivaroxaban reduced the relative risk of recurrence by about 70% in patients with both unprovoked and provoked venous thromboembolism. Patients were randomized 1:1:1 to rivaroxaban 20 mg/d, rivaroxaban 10 mg/d, or aspirin 100 mg/d, and each group was provided with a matching placebo. Patients were assigned, in a 1:1:1 ratio, to receive 20 mg of rivaroxaban, 10 mg of rivaroxaban, or 100 mg of aspirin, all given once daily with food. The rates of death from any cause were 0.7% and 0.2% in the 20-mg and 10-mg rivaroxaban groups, respectively, as compared with 0.6% in the aspirin group. Therefore, it remains unknown whether the 10-mg dose of rivaroxaban would be sufficient to prevent recurrence in such patients. 2014 Nov 14;35(43):3033-69. http://www.wikijournalclub.org/w/index.php?title=EINSTEIN_CHOICE&oldid=27712, In patients with DVT of the leg or PE and no cancer, as long-term (first 3months) anticoagulant therapy, dabigatran, rivaroxaban, apixaban, or edoxaban are recommended over vitamin K antagonist (VKA) therapy(all Grade 2B), In patients with DVT of the leg or PE and cancer (cancer-associated thrombosis), as long-term (first 3months) anticoagulant therapy, LMWH is recommended over other agents (Grade 2C), In patients with DVT of the leg or PE who receive extended therapy, recommend no need tochange the choice of anticoagulant after the first 3months (Grade 2C). 1. What are the clinical implications of these findings? Nephron 1976;16:31-41, 24. Low-dose aspirin for preventing recurrent venous thromboembolism. J Thromb Haemost 2005;3:692-694, 26. Kearon C, Ginsberg JS, Kovacs MJ, et al. In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are believed to be compliant), recommend switching totreatment with LMWH at least temporarily(Grade 2C). (Funded by Bayer Pharmaceuticals; EINSTEIN CHOICE ClinicalTrials.gov number, NCT02064439.