The new oral anticoagulants in the 2012 guidelines

Reviewed by Andrew NICOLAIDES, Nicosia, Cyprus

Two classes of oral anticoagulants are now available: (i) inhibitors of factor lla (thrombin) such as dabigatran and AZD 0837, and (ii) inhibitors of factor Xa such as rivaroxaban and apixaban. The aim of this review is to present the phase 3 studies and the recommendations for use of these drugs in the 2012 guidelines on the prevention and management of venous thromboembolism (VTE).

Prevention of VTE

Dabigatran: Two randomized control trials (RCTs) in hip replacement and two RCTs in knee replacement have demonstrated equivalence to enoxaparin in both efficacy and bleeding.

Rivaroxaban: Two RCTs in hip replacement and two RCTs in knee replacement have demonstrated superiority to enoxaparin without increased bleeding.

Apixaban: One RCT in knee replacement did not meet the noninferiority criteria with enoxaparin and one RCT in hip replacement demonstrated superiority to enoxaparin without increased bleeding.

Recommendations for the approved drugs will be grade A.

Treatment of Venous Thromboembolism

Dabigatran: The RE-COVER¹ trial compared dabigatran with vitamin K antagonists (VKA) for 6 months in patients with symptomatic VTE following an initial 6 to 10 days of low-molecular-weight heparins. There was no difference in efficacy in terms of recurrent VTE and death, but there was decreased bleeding in the dabigatran group.

The RE-MEDY² trial compared dabigatran with a VKA for 6 to 36 months in patients with symptomatic VTE following an initial period of VKA therapy for 3 to 12 months. There was noninferiority in terms of VTE recurrence with a decrease in major and minor bleeding in the dabigatran group. However, dabigatran was associated with an increased risk of acute coronary syndromes.

Rivaroxaban: The EINSTEIN DVT³ trial compared rivaroxaban with standard VKA therapy in patients with symptomatic deep venous thrombosis (without pulmonary embolism) for 3, 6, or 12 months. There was nonsuperiority in terms of first symptomatic recurrent VTE and safety was equivalent. Subgroup analysis showed a reduction in recurrent deep venous thrombosis if rivaroxaban was given for 12 months.

The EINSTEIN EXTENSION trial compared rivaroxaban with placebo for 6 or 12 months in patients with symptomatic deep venous thrombosis or pulmonary embolism who completed treatment with K antivitamins. Rivaroxaban was superior to placebo. The number needed to treat (NNT) to prevent one primary efficacy outcome was 15 and the number needed to harm (NNH) (bleeding) was 139.

The EINSTEIN trial is still ongoing.

These drugs provide clinicians and patients with a simple and effective option for continued anticoagulant treatment with reduction in recurrent VTE without the need for monitoring. Further studies are required to determine whether there will be a reduction in the postthrombotic syndrome.

Recommendations for the approved drugs will be grade A.

References:
1. Schulman S, Keavon C, Ajay K, et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. NEJM. 2009;2342-2352.
2. Ma TK, Yan BP, Lam YY. Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of clinical data. Pharmcol & Ther. 2011;129:185-194.
3. Buller HR, Lensign AW, Prins MH, et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis: the Einstein–DVT Dose-Ranging Study. Blood J. 2008;112:2242-2247.