The proof for new oral anticoagulants: clinical trial evidence

Abstract

INTRODUCTION: Patients undergoing elective total hip or total knee replacement surgery are at increased risk of venous thromboembolism in the post-operative period and are recommended to receive thromboprophylaxis for 10-35 days. Although several thromboprophylactic agents are available, these are associated with well-recognized limitations. For the low molecular weight heparins (LMWHs) such as enoxaparin, these limitations include parenteral administration, indirect mode of action, inability to inhibit clot-bound thrombin and association with complications such as heparin-induced thrombocytopenia. These limitations make post-operative thromboprophylaxis challenging. Several new oral anticoagulants are in the advanced stages of clinical development. These agents have been designed to target either thrombin (dabigatran etexilate) or factor Xa (rivaroxaban and apixaban), which are key coagulation cascade enzymes. METHODS AND RESULTS: This review will present the published phase III clinical trial evidence of the efficacy and safety of dabigatran etexilate, rivaroxaban and apixaban, compared with the LMWH enoxaparin for the prevention of venous thromboembolism in patients who have undergone elective total hip or total knee replacement surgery. All three agents have shown comparable or superior efficacy compared with the European dose regimen of enoxaparin (40 mg once daily), and comparable rates of major bleeding events. Dabigatran etexilate and rivaroxaban are currently licensed for use following elective hip and knee replacement surgery in many countries, but no direct comparative data exist upon which to base the choice of agent. CONCLUSION: A thorough assessment of each individual patient's thromboembolic and bleeding risks should be the basis of selecting the agent in order to balance efficacy and safety.

Fig. 1

Composite of total venous thromboembolic events (asymptomatic deep vein thrombosis and non-fatal pulmonary embolism) and all-cause mortality during treatment with either dabigatran etexilate, 150 mg or 220 mg once daily, or enoxaparin, 40 mg once daily: 28–35 days in RE-NOVATE® I (n = 3,494) (a) and 6–10 days in RE-MODEL™ (n = 2,076) (b) trials [5, 6]

Fig. 2

Major bleeding events during treatment with either dabigatran etexilate, 150 mg or 220 mg once daily, or enoxaparin, 40 mg once daily: 28–35 days in RE-NOVATE® I (n = 3,494) (a) and 6–10 days in RE-MODEL™ (n = 2,076) (b) trials [5, 6]. Major bleeding during the treatment period was defined as: clinically overt bleeding associated with ≥20 g/l fall in haemoglobin; clinically overt leading to transfusion of ≥2 units packed cells or whole blood; fatal, retroperitoneal, intracranial, intraocular or intraspinal bleeding and bleeding warranting treatment cessation or leading to reoperation

Fig. 3

Major bleeding events during treatment with either rivaroxaban, 10 mg once daily, or enoxaparin, 40 mg once daily, for 35 days in RECORD1 during total hip arthroplasty (n = 4,541); with either rivaroxaban, 10 mg once daily for 31–39 days, or enoxaparin, 40 mg once daily for 10–14 days, in RECORD2 during total hip arthroplasty (n = 2,509); with either rivaroxaban, 10 mg once daily, or enoxaparin, 40 mg once daily, for 10–14 days in RECORD3 during total knee arthroplasty (n = 2,531) and with either rivaroxaban, 10 mg once daily, or enoxaparin, 30 mg twice daily, for 10–14 days in RECORD4 during total knee arthroplasty (n = 3,148). Major bleeding during the treatment period was defined as bleeding that was fatal, occurred in a critical organ (e.g. retroperitoneal, intracranial, intraocular or intraspinal bleeding), required reoperation or extra-surgical site bleeding that was clinically overt and was associated with a fall in haemoglobin level of at least 2 g/dl, or that required transfusion of ≥2 units packed cells or whole blood [–13]

Fig. 4

Composite of any deep vein thrombosis, non-fatal pulmonary embolism and all-cause mortality during treatment with either apixaban, 2.5 mg twice daily, or enoxaparin, 30 mg twice daily, for 10–14 days in the ADVANCE-1 study (n = 3,195) during total knee arthroplasty (a); and with either apixaban, 2.5 mg twice daily, or enoxaparin, 40 mg once daily, for 10–14 days in the ADVANCE-2 study (n = 3,057) during total knee arthroplasty (b) [15, 16]

Fig. 5

Major bleeding events during treatment with either apixaban, 2.5 mg twice daily, or enoxaparin, 30 mg twice daily, for 10–14 days in the ADVANCE-1 study (n = 3,195) during total knee arthroplasty (a); and with either apixaban, 2.5 mg twice daily, or enoxaparin, 40 mg once daily, for 10–14 days in the ADVANCE-2 study (n = 3,057) during total knee arthroplasty (b). Major bleeding was defined as acute, clinically overt bleeding accompanied by one or more of the following events: a decrease in the haemoglobin level of 2 g/dl or more within a 24-h period; a transfusion of ≥2 or more units of packed red cells; bleeding at a critical site (i.e. intracranial, intraspinal, intraocular, pericardial or retroperitoneal bleeding); bleeding into the operated joint, requiring an additional operation or intervention; intramuscular bleeding with the compartment syndrome or fatal bleeding [15, 16]