The new oral anti-coagulants and the phase 3 clinical trials - a systematic review of the literature

Abstract

BackgroundAnticoagulation with vitamin K antagonists such as warfarin has historically been used for the long term management of patients with thromboembolic disease. However, these agents have a slow onset of action which requires bridging therapy with heparin and its analogues, which are available only in parenteral route. To overcome these limitations, new oral anticoagulants such as factor Xa inhibitors and direct thrombin inhibitors have been developed. The aim of this article is to systematically review the phase 3 clinical trials of new oral anticoagulants in common medical conditions.MethodsWe searched PubMed (Medline) from January 2007 to February 2013 using “Oral anticoagulants”, “New oral anticoagulants”, “Randomized controlled trial”, “Novel anticoagulants”, “Apixaban”, “Rivaroxaban”, “Edoxaban”, “Dabigatran etexilate”, “Dabigatran” and a combination of the above terms. The available evidence from the phase 3 RCTs was summarized on the basis of individual drug and the medical conditions categorized into “atrial fibrillation”, “acute coronary syndrome”, “orthopedic surgery”, “venous thromboembolism” and “medically ill patients”.ResultsApixaban, rivaroxaban and dabigatran have been found to be either non-inferior or superior to enoxaparin in prophylaxis of venous thromboembolism in knee and hip replacement with similar bleeding risk, superior to warfarin for stroke prevention in atrial fibrillation with significant reduction in the risk of major bleeding, non-inferior to aspirin for reducing cardiovascular death and stroke in acute coronary syndrome with significant increase in the risk of major bleed. Rivaroxaban and dabigatran are also superior to the conventional agents in the management of symptomatic venous thromboembolism. However, compared to enoxaparin, apixaban and rivaroxaban use lead to significantly increased bleeding risk in medically ill patients. Additional studies evaluating the specific reversal agents of these new drugs for the management of life-threatening bleeding or other adverse effects are necessary.ConclusionConsidering their pharmacological properties, their efficacy and bleeding complications, the new oral agents offer a net favourable clinical profile in orthopedic surgery, atrial fibrillation, acute coronary syndrome and increase the risk of bleeding in critically ill patients. Further studies are necessary to determine the long term safety and to identify the specific reversal agents of these new drugs.

Rivaroxaban for the treatment of venous thromboembolism. A “real-life” perspective in 103 patients

“…After feasibility studies [5,6], EINSTEIN clinical trials were initiated to test the efficacy of rivaroxaban as a single agent for the management of symptomatic VTE. The results of the EINSTEIN-DVT [7] and EINSTEIN-PE [8] studies demonstrated non-inferiority of rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) versus standard classical treatment (heparin and VKAs) in terms of the primary outcome (recurrent VTE) (2.1% in the rivaroxaban group vs. 3% in the control group; P b 0.001) [9].…”

Determination of dabigatran in plasma, serum, and urine samples: comparison of six methods

“…Non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran were developed to overcome the major drawbacks of vitamin K antagonists (VKAs), in particular their need for continuous effect monitoring [4]. Dabigatran etexilate is rapidly hydrolyzed to its active form dabigatran after oral administration and intestinal absorption by non-specific ubiquitous esterases in gut, blood, and liver [5,6]. Peak plasma concentration are attained 2 h after ingestion [7], and the terminal half-life time was determined to be 12-17 h in patients with normal creatinine clearance [5], allowing for a fixed daily dosing regimen without the need to routinely monitor coagulation for dose adjustment [7].…”

The Health Impact Fund: How Might It Work for Novel Anticoagulants in Atrial Fibrillation?

“…In the last 3 years, following successful phase 3 clinical trials, three agents(dabigatran, apixaban and rivaroxaban) have been incorporated into guidelines worldwide and more NOACs are in the pipeline [38][39][40] . As with statins, ACEIs, ARBs and other CVD drug classes, "me-too" agents are anticipated and trials are already underway [41][42][43][44] . "Me-too" drugs are expensive and do not serve society well [41][42][43] .…”

“…Based on trials or predicted trial outcomes (for edoxaban 44 NOACs, like warfarin, and all drugs, have risks(excess bleeding) as well as benefits (prevention of stroke/thromboembolism). Trial data may be used to estimate risks as well as benefits, and to compare different agents.…”