Issues in Thrombosis Management and Anticoagulation

ORLANDO, Fla. – Novel oral anticoagulants, that do not require the laboratory monitoring associated with warfarin therapy, may alter the landscape of venous thromboembolism treatment and stroke prevention in atrial fibrillation. Additionally, the need for long-term anticoagulation for patients with a first episode of unprovoked deep vein thrombosis (DVT) continues to be debated.

At the 52^nd American Society of Hematology Meeting and Exposition, Jack Ansell, MD of Lenox Hill Hospital, New York, New York presented recent results of phase 3 trials evaluating new oral anticoagulants in the treatment of VTE and stroke prevention. These therapies included dabigatran etexilate , a direct thrombin factor IIa inhibitor approved by the FDA in October 2010, and investigational Factor Xa inhibitors rivaroxaban and apixaban.

The efficacy of dabigatran was evaluated in the RECOVER trial 2,539 patients with acute symptomatic DVT. Dabigatran demonstrated non-inferiority to warfarin for recurrent VTE or fatal pulmonary embolism (PE) (2.4% for dabigatran and 2.1% for warfarin; hazard ratio [HR] 1.1, P<0.001). Major bleeding was not significantly different between the two groups (1.6% for dabigatran vs. 1.9% for warfarin). The risk reduction with dabigatran for any bleeding event was significant (16.1% for dabigatran vs. 21.9 % for warfarin; HR 0.71, P<0.001).

Rivaroxaban or enoxaparin for 5 days, followed by treatment with a vitamin-K antagonist was evaluated in the EINSTEIN DVT study in approximately 3,400 patients with VTE. Rivaroxaban was non-inferior to enoxaparin for the recurrence of symptomatic VTE (2.1% for rivaroxaban vs. 3% for enoxaparin, P<0.001). Rate of major bleed was 0.8% for the rivaroxaban vs. 1.2% for the enoxaparin.

Dr. Ansell stated that in his opinion, “dabigatran and rivaroxaban can replace warfarin therapy for the treatment of acute VTE and eliminate the need for monitoring, frequent dose adjustments, worries about multiple drug interactions, and dietary adjustments.” However, dabigatran does not eliminate the need for initial therapy with a parenteral anticoagulant (unfractionated heparin [UFH] or low molecular weight heparin [LMWH]) for the first 5–7 days, and that hospitalization may still be needed.

Kenneth Bauer, MD of Beth Israel Deaconess Medical Center, Boston, Mass., further discusses the recurrence risk of in patients with first unprovoked DVT and the benefit-to-risk ratio of long-term warfarin therapy. Dr. Bauer states that a recurrent VTE rate of <5% per year is considered acceptable. Data was presented which showed that patients continued on anticoagulants for longer than 3–6 months resulted in a recurrent VTE rate of approximately 8% per year, with a case fatality rate of 4–12%, and a bleed risk of approximately 2% and a case fatality rate of 10%. Dr. Bauer states that based on this data, there appears to be no mortality benefit from long-term anticoagulation. However, the EINSTEIN Extension study took a look at continued anticoagulation therapy by comparing rivaroxaban to placebo in a group of “medium-risk patients.” Data showed symptomatic recurrent DVT and fatal/non-fatal PE to be 1.3% for rivaroxaban vs. 7.1% for placebo (HR 0.18, P<0.001) and major bleed was 0.7% for rivaroxaban vs. 0% for placebo (P=0.106).

In the prevention of stroke or systemic embolism, the RE-LY trial showed that dabigatran 110 mg twice daily was non-inferior (relative risk [RR] 0.91; P<0.001) to warfarin and dabigatran 150 mg twice daily was superior (RR 0.66; P<0.001) to warfarin. Rate of major bleed was 3.36% per year in the warfarin group vs. 2.71% per year in those receiving dabigatran 110mg (P=0.003) and 3.11% per year dabigatran 150mg group (P=0.31). The rates of hemorrhagic stroke were significantly reduced compared to those receiving warfarin (P<0.001) for both dabigatran groups. Dr. Ansell emphasized, however, that the differences between dabigatran and warfarin are minimized when the patient’s time in therapeutic range (TTR) with warfarin is optimized.

In the ROCKET AF study, rivaroxaban was evaluated against warfarin among patients at high risk for a recurrent stroke or systemic embolism. In the ITT population, recurrence of stroke or systemic embolism was 2.12% for rivaroxaban vs. 2.42% for warfarin (HR 0.88, P=0.117 for non-inferiority). Major bleed was 3.6% for rivaroxaban vs. 3.45% for warfarin (HR 1.04; P=0.576). The event rate of stroke or systemic embolism was not significantly different at any level of TTR for warfarin.

The AVERROES study looked at the efficacy of apixaban compared to aspirin in the recurrence of stroke or systemic embolism. The combined endpoint of occurrence of stroke or systemic embolism was 1.6% for apixaban vs. 3.6% for aspirin (P<0.001); for stroke only: 1.5% for apixaban vs. 3.3% for aspirin (P<0.001); for systemic embolism only: <0.1% for apixaban vs. 0.4% for aspirin. The rates of major bleed were not significantly different between the two treatment groups.

 

Off Label Use: Dabigatran etexilate is approved for to reduce the risk of stroke and systemic embolism in non-valvular atrial fibrillation; however the specific use and therapeutic lines may represent some off-label use.