A Literature Review of the Safety and Efficacy of New Oral Anticoagulants

Introduction

The Pharmaceutical Benefits Scheme listed three new oral anticoagulants (NOACs) – dabigatran, rivaroxaban and apixaban in 2012. These agents are non-vitamin K antagonists which have different mechanisms of action compared to warfarin. Apixaban and rivaroxaban are direct inhibitors of clotting factor Xa. By blocking factor Xa, thrombin production is inhibited and thrombus development consequently reduced. Dabigatran prevents thrombus development by the direct inhibition of thrombin. These agents are alternatives to warfarin for some indications such as the prevention of thromboembolism in non-valvular atrial fibrillation and the treatment of venous thromboembolism.

Studies demonstrate that fixed-dose NOACs are non-inferior to warfarin when used to treat atrial fibrillation and venous thromboembolism. In addition, there is mounting evidence to suggest that these agents may be superior. For example, the ARISTOTLE trial demonstrates superiority for apixaban over warfarin. The main characteristic of NOACs compared to warfarin are:

• No coagulation testing required for NOACs
• Diet does not affect the coagulation effects of NOACs
• NOACs have shorter half-lives than warfarin (apixaban 10 hours; dabigatran 14 hours; rivaroxaban 7 hours; and warfarin 40 hours). That means the anticoagulant effect of NOACs last about one day while warfarin lasts two to five days.

It is often recommended that patients who are already established on warfarin should continue on warfarin if their international normalised ratio (INR) control is adequate, which is more than 70% of INR values at target. Some sources also suggest that warfarin should be used in preference to the new oral anticoagulants for patients in the following situations:

• Patients with mechanical heart valves as there is a lack of data showing NOACs are as effective as warfarin.
• Patients with non-adherence to therapy. Due to the short half-life of NOACs, patients who regularly forget to take their medication could be at greater risk of thrombosis with these agents compared with the longer acting warfarin.
• Patients who are taking a strong inducer of enzymes or transporters should remain on warfarin. There is currently a lack of clinical data showing how the dose of NOACs should be managed when co-administered with medicines that are strong enzyme or transporter inducers or inhibitors. While warfarin is known to interact with many medications; this can be managed by dose adjustment based on INR monitoring.
• Patients with severe kidney impairment.
• Patients with severe liver impairment.
• Patients with significant bleeding risk.
• Breastfeeding patients.

Evidence on the safety of NOACs compared to warfarin continues to grow. A recent retrospective cohort study of 2,202 patients with atrial fibrillation suggests that NOACs are associated with a lower risk of major bleeds compared to warfarin. The authors of this study propose that strategies to reduce the risk of bleeding in patients with atrial fibrillation who are prescribed antithrombotic therapies include considering NOACs in preference to warfarin and avoiding multiple antithrombotic therapies.

There are a number of factors that increase the risk of bleeding with NOACs. Therefore, NOACs should be used with caution in the following situations:

• Age over 65 years;
• Uncontrolled hypertension;
• Previous stroke;
• Abnormal renal and liver function;
• Bleeding history;
• Excess alcohol intake;
• Concomitant medicines such as antiplatelet drugs, non-steroidal anti-inflammatory drugs (NSAIDs), and selective serotonin reuptake inhibitors (SSRIs); and
• In combination with strong P-glycoprotein inhibitors (e.g. erythromycin) which may increase anticoagulant effects.

In terms of managing acute bleeding, dabigatran is the only NOAC with a specific antidote currently available. For the other NOACs, the main antidote is time. The anticoagulant effects of NOACs are expected to reduce by over 90% after stopping treatment for four half-lives. In the event of bleeding, treatment should be supportive and specialist advice sought.