Phase III Trials of New Oral Anticoagulants in the Acute Treatment and Secondary Prevention of VTE: Comparison and Critique of Study Methodology and Results

Abstract

The traditional treatment of venous thromboembolism (VTE) has been use of heparin and vitamin K antagonists (VKA), and although shown to be effective, they have numerous limitations. New oral anticoagulants (NOACs) including direct thrombin (factor IIa) inhibitors (dabigatran) and selective factor Xa inhibitors (rivaroxaban, apixaban and edoxaban) have emerged as promising alternatives with the potential to overcome the limitations of traditional treatments. Clinical trials have been performed with a view to making significant changes to the acute, long-term and extended treatment of VTE. Data are now available on the efficacy and safety, including bleeding rates, of the NOACs in comparison with VKA in the acute treatment and secondary prevention of VTE as well as in comparison with placebo extended VTE treatment. This review compares and contrasts the design and results of the Phase III trials of NOACs in VTE and discusses the implications of the NOACs in terms of treatment strategies in VTE patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-014-0119-7) contains supplementary material, which is available to authorized users.

Safety and efficacy of direct oral anticoagulants compared to warfarin for extended treatment of venous thromboembolism -a systematic review and meta-analysis

“…There are several aspects to the generalizability of the results that arise from the selection of patients into the studies, which in general is a limitation to RCTs [22,23]. Firstly, the studies that investigated the safety and efficacy of DOACs included a small proportion of patients of older age > 75, patients with extreme bodyweight and excluded patients with severe renal impairment and severe liver failure [8,[14][15][16][17]23].…”

“…Firstly, the studies that investigated the safety and efficacy of DOACs included a small proportion of patients of older age > 75, patients with extreme bodyweight and excluded patients with severe renal impairment and severe liver failure [8,[14][15][16][17]23]. There have been raised concerns about the use of DOACs in patients with renal impairment due to their pharmacokinetic profile and a possible accumulation, which could lead to an increased risk of bleeding in patients with renal impairment [23][24][25][26]. It is known that the use of VKAs in patients with renal impairment increases the risk of bleeding and thus it is not only a concern regarding DOACs [27].…”

“…In our meta-analysis, it was only possible to compare the safety and efficacy of dabigatran to VKAs, and thus, it is not possible to comment on the safety and efficacy of rivaroxaban and apixaban compared to VKAs for extended treatment. The question remains whether the results of our analysis can be translated into the patients seen in clinical practice, which might have more comorbid conditions and therefore a higher risk of recurrent events and bleeding and whether the risk-benefit profile will remain if extended treatment is studied in a real world population [23,31].…”

New insights into treatment of venous thromboembolism

“…10,36,37 Rivaroxaban and apixaban were used in the phase 3 clinical trials without the need for initial LMWH bridging. Dabigatran and edoxaban, however, were used only after initial 5-10 days of LMWH therapy, so should not be used immediately from day 1 onward in acute VTE treatment.…”

“…A comparison of NOAC with warfarin (REMEDY for dabigatran) has recently been discussed in detail elsewhere. 10,36,37 Because no head-to-head comparison between the NOACs exists, it is a matter of personal choice between physician and patient which drug to choose. A patient's renal function, preference of once daily (rivaroxaban) over twice daily (dabigatran, apixaban) dosing, FDA approval status of the drug, familiarity/comfort of a health care professional with the If at least one of the questions is answered with "yes," then the patient should be admitted to hospital.…”