Idraparinux versus Standard Therapy for Venous Thromboembolic Disease

Büller, Harry R.; Cohen, Aloni; Davidson, Bruce L.; Gallus, Alexander; Pillion, G; Prins, Martin H.; Raskob, Gary E.

doi:10.1056/nejmoa064247

Cited by 304 publications

(51 citation statements)

References 11 publications

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“…It is customarily accepted in non-inferiority trials to preserve at least 50–70% of the therapeutic effect of the active control. [35–37] Based on the management study, it was hypothesized that individually tailored ECS therapy would have an equal success proportion as two years ECS therapy. [33] At a one sided significance level of 5% and a power of 80%, a sample size of 788 needed to test the hypothesis was calculated.…”

Section: Resultsmentioning

confidence: 99%

Sample Size Estimation for Non-Inferiority Trials: Frequentist Approach versus Decision Theory Approach

et al. 2015

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BackgroundNon-inferiority trials are performed when the main therapeutic effect of the new therapy is expected to be not unacceptably worse than that of the standard therapy, and the new therapy is expected to have advantages over the standard therapy in costs or other (health) consequences. These advantages however are not included in the classic frequentist approach of sample size calculation for non-inferiority trials. In contrast, the decision theory approach of sample size calculation does include these factors. The objective of this study is to compare the conceptual and practical aspects of the frequentist approach and decision theory approach of sample size calculation for non-inferiority trials, thereby demonstrating that the decision theory approach is more appropriate for sample size calculation of non-inferiority trials.MethodsThe frequentist approach and decision theory approach of sample size calculation for non-inferiority trials are compared and applied to a case of a non-inferiority trial on individually tailored duration of elastic compression stocking therapy compared to two years elastic compression stocking therapy for the prevention of post thrombotic syndrome after deep vein thrombosis.ResultsThe two approaches differ substantially in conceptual background, analytical approach, and input requirements. The sample size calculated according to the frequentist approach yielded 788 patients, using a power of 80% and a one-sided significance level of 5%. The decision theory approach indicated that the optimal sample size was 500 patients, with a net value of €92 million.ConclusionsThis study demonstrates and explains the differences between the classic frequentist approach and the decision theory approach of sample size calculation for non-inferiority trials. We argue that the decision theory approach of sample size estimation is most suitable for sample size calculation of non-inferiority trials.

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Section: Resultsmentioning

confidence: 99%

Sample Size Estimation for Non-Inferiority Trials: Frequentist Approach versus Decision Theory Approach

et al. 2015

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“…Bleeding at the surgical site was defined as major only if it required an intervention or caused hemarthrosis that delayed wound healing or mobilization, prolonged hospitalization, or was associated with deep wound infection. 9 Clinically relevant nonmajor bleeding was defined as overt bleeding that did not meet the criteria for major bleeding but required intervention or consultation with a physician or had clinical consequences 10 (details are provided in the Supplementary Appendix). All other clinically overt bleeding events were classified as minor.…”

Section: Methodsmentioning

confidence: 99%

Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis

et al. 2015

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BACKGROUND Experimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a second-generation antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty. METHODS In this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding. RESULTS Around the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively. CONCLUSIONS This study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.)

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“…The RE-COVER I and II, AMPLIFY, and Hokusai-VTE trials used the International Society of Thrombosis and Hemostasis (ISTH) definition of bleeding, while the EINSTEIN trials used a definition from the van Gogh trial that is nearly identical [26, 27]. Clinically relevant non-major (CRNM) bleeding was defined as those episodes that did not meet the criteria for major bleeding but still required medical attention (Table 3).…”

Section: Methodsmentioning

confidence: 99%

New Oral Anticoagulants for the Treatment of Venous Thromboembolism: Understanding Differences and Similarities

Dobesh

Fanikos

2014

Drugs

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Venous thromboembolism (VTE) is a major cause of morbidity, mortality, and healthcare expenditure. In the United States, approximately 0.1 % of the population experiences an initial VTE event each year. Anticoagulation therapy is the cornerstone of acute VTE treatment and for prevention of recurrent VTE events. Conventional anticoagulants, including heparin, low-molecular-weight heparins, fondaparinux, and vitamin K antagonists are widely used but have limitations. Newer oral anticoagulant agents, including direct thrombin inhibitors (e.g., dabigatran etexilate) and direct factor Xa inhibitors (e.g., rivaroxaban, apixaban, and edoxaban) have been developed to attempt to overcome some of the limitations of conventional anticoagulant therapy. These new oral agents have been evaluated for safety and efficacy in large, randomized clinical trials in the treatment and secondary prevention of VTE with results that are comparable to conventional therapy. Dabigatran, rivaroxaban, apixaban, and edoxaban are important new treatment options for patients with VTE. In this review, we compare these new agents and their associated clinical trials in VTE treatment.

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Idraparinux versus Standard Therapy for Venous Thromboembolic Disease

Cited by 304 publications

References 11 publications

Sample Size Estimation for Non-Inferiority Trials: Frequentist Approach versus Decision Theory Approach

Sample Size Estimation for Non-Inferiority Trials: Frequentist Approach versus Decision Theory Approach

Factor XI Antisense Oligonucleotide for Prevention of Venous Thrombosis

New Oral Anticoagulants for the Treatment of Venous Thromboembolism: Understanding Differences and Similarities

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