Target-Specific Oral Anticoagulants for Treating Venous Thromboembolism

The new target-specific oral anticoagulants (TSOACs), which include dabigatran, rivaroxaban, apixaban, and edoxaban have demonstrated safety and efficacy in the treatment of venous thromboembolism (VTE). A rapid onset of action and administration of fixed doses without monitoring are just a few advantages of these medications.

Dabigatran

RE-COVER I and II were duplicate trials comparing dabigatran 150 mg twice daily with warfarin in the treatment of VTE. A total of 5107 patients with symptomatic proximal deep vein thrombosis (DVT) of the legs or pulmonary embolism (PE) were randomized to receive either dabigatran plus warfarin placebo or warfarin plus dabigatran placebo. Both groups received initial parenteral anticoagulation for at least 5 days and until true international normalized ratio (INR) or sham INR was greater than or equal to 2 for 2 consecutive days. Patients were treated for 6 months, with additional follow-up 30 days after study completion.

The pooled analysis of RE-COVER I and II shows that at approximately 6 months, the rates of VTE or VTErelated death were similar in each arm (2.4% vs 2.2%; hazard ratio [HR] 1.09; 95% CI, 0.76-1.57). Although there was no difference in major bleeding, the risk of any bleeding favored dabigatran. Among patients with acute VTE, the oral direct thrombin inhibitor dabigatran is as effective as warfarin at reducing risk of recurrent VTE, and is associated with less bleeding. The frequency of reported acute coronary syndrome events was less than 1%, with more reported cases in the dabigatran group. Other serious adverse events were similar in both groups; however, dyspepsia was significantly more common in the dabigatran group.^1,2

Rivaroxaban

The EINSTEIN-DVT and EINSTEIN-PE trials tested rivaroxaban (15 mg twice daily for 3 weeks followed by 20 mg once daily) versus conventional therapy (enoxaparin and warfarin) in the treatment of VTE. EINSTEIN-DVT focused on patients with acute symptomatic DVT, while EINSTEIN-PE specifically looked at those with acute symptomatic PE. In the EINSTEIN trials, 3449 patients with DVT and 4832 patients with PE were followed for 3, 6, or 12 months.

In EINSTEIN-DVT, symptomatic recurrent VTE occurred in 2.1% of patients given rivaroxaban and 3.0% of those given conventional therapy (HR 0.68; 95% CI, 0.44- 1.04), demonstrating noninferiority with rivaroxaban. Major and clinically relevant nonmajor bleeding occurred in 8.1% of patients given rivaroxaban and 8.1% given conventional therapy. Net clinical benefit occurred in 2.9% of patients who received rivaroxaban and in 4.2% of patients who received conventional therapy (HR 0.67; 95% CI, 0.47-0.95). The incidence of major bleeding was also similar between the 2 groups (0.8% and 1.2%, respectively).

In EINSTEIN-PE, symptomatic recurrent VTE occurred in 2.1% of patients given rivaroxaban and 1.8% of those given conventional therapy (HR 1.12; 95% CI, 0.75- 1.68), demonstrating noninferiority with rivaroxaban. Major and clinically relevant nonmajor bleeding occurred in 10.3% of patients given rivaroxaban and 11.4% given conventional therapy. Major bleeding occurred in 1.1% and 2.2%, respectively (HR 0.49; 95% CI, 0.31- 0.79).^3,4

Apixaban

The AMPLIFY trial evaluated apixaban (10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) versus conventional treatment (enoxaparin plus warfarin) in preventing VTE recurrence or death in patients with DVT or PE (with or without DVT). A total of 5365 patients with VTE were followed.

Recurrent VTE or VTE-related death occurred in 2.3% of patients in the apixaban group and 2.7% of patients in the conventional treatment group (HR 0.84; 95% CI, 0.60-1.18; P <.001 for noninferiority). The efficacy of apixaban was similar for patients with PE and those with DVT. Major bleeding occurred significantly less in the apixaban group (0.6% vs 1.8%; HR 0.31; 95% CI, 0.17-0.55). Also, the composite outcome of major bleeding and clinically relevant nonmajor bleeding was significantly less in the apixaban group (4.3% vs 9.7%; HR 0.44; 95% CI, 0.36-0.55). The rates of other adverse events were similar in the 2 groups.⁵

Edoxaban

The HOKUSAI-VTE trial evaluated edoxaban 60 mg daily versus warfarin in the treatment of VTE. Both treatment groups received initial parenteral anticoagulation for at least 5 days and until the INR was greater than or equal to 2. Patients were treated for 3 to 12 months, although all patients were evaluated at 12 months regardless of treatment duration.

VTE recurred in 3.2% of patients in the edoxaban group and 3.5% of patients in the conventional treatment group (HR 0.89; 95% CI, 0.70-1.13; P <.001 for noninferiority. Major and clinically relevant nonmajor bleeding occurred in 8.5% of patients in the edoxaban group and 10.3% in the conventional group (HR 0.81; 95% CI, 0.71-0.94; P <.004 for superiority). The rates of other adverse events were similar between the 2 groups. In addition, for patients with PE with right ventricular dysfunction, the rate of recurrence was 3.3% and 6.2%, respectively (HR 0.52; 95% CI, 0.28-0.98).⁶

Choosing the Right TSOAC

For patients with extensive DVT or massive PE, use of a TSOAC may not be appropriate, as such patients were excluded from the above trials because they often require advanced therapy. TSOACs have not been evaluated in conjunction with thrombolytic therapy. In addition, due to the lack of an antidote if bleeding occurs, it may not be beneficial for patients at a high initial risk for bleeding, such as patients whose VTE occurs soon after major surgery or trauma, to be placed on a TSOAC.

TSOACs are all dosed differently. Rivaroxaban and apixaban can both be given as all-oral therapy and do not require bridging with parenteral anticoagulation. Dabigatran and edoxaban both require bridging. Also, Rivaroxaban and edoxaban are given once daily, while dabigatran and apixaban are dosed twice daily. For patients with renal dysfunction, warfarin is preferred to a TSOAC when the CrCl is <30 mL/min. Rivaroxaban, apixaban, and edoxaban may be the preferred agents for individuals with a CrCl between 30-50 mL/min, as dabigatran can be used; however, it is more dependent on renal metabolism/elimination than the other agents.

For patients with dyspepsia, upper gastrointestinal symptoms, or recent acute coronary syndrome, rivaroxaban, apixaban, and edoxaban are a better choice than dabigatran. For patients with recent gastrointestinal bleeding, apixaban is recommended over dabigatran, rivaroxaban, and edoxaban.

Dr. Resseguie is an advanced practice anticoagulation pharmacist for the Brigham & Women’s Hospital Anticoagulation Management Service in Boston, Massachusetts.

References

1. Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352.

2. Schulman S, Kakkar AK, Goldhaber SZ, et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129(7):764-772.

3. Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. New Engl J Med. 2010;363(26):2499-2510.

4. The EINSTEIN-PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.

5. Agnelli G, Buller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.

6. Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-1415.