Introduction

Venous thromboembolic (VTE) disease, a spectrum of events that include acute deep venous thrombosis (DVT), asymptomatic DVT and pulmonary embolism (PE), is diagnosed in approximately 900,000 patients in the United States annually.^{1, 2} Treatment strategies for patients with VTE are based upon the use of anticoagulants. Prior to the development of direct thrombin inhibitors and Factor Xa inhibitors, the majority of patients were treated with either subcutaneous low-molecular weight heparin or a vitamin K antagonist (VKA, e.g. warfarin). Recently, novel oral anticoagulants (e.g. dabigatran, apixaban, rivaroxaban, edoxaban) have also been studied in the treatment of VTE; however, only rivaroxaban is currently approved for use in the United States for the treatment of patients with VTE.

While the role of anticoagulation in patients with VTE is well established, the optimal duration of therapy for patients with a VTE is controversial.³ Prior studies have shown clearly that a short duration of therapy (4-6 weeks) is of insufficient duration and increases the risk of recurrent VTE by approximately 50%.⁴ Current guidelines from the American College of Chest Physicians recommend three months of anticoagulation for patients with low risk of recurrent VTE (e.g. VTE which occurred in the setting of a transient risk factor such as surgery); ⁵ however, the guidelines also support extended and even indefinite anticoagulation for those patients with risk factors for VTE which are nonreversible.

For all other patients, the optimal duration of therapy for VTE has not been determined definitively and remains undefined. Recently completed trials have provided evidence supporting extending the duration of therapy with anticoagulation for patients with VTE; but, these studies have also raised further questions regarding the optimal treatment strategy for patients with VTE.

The AMPLIFY-EXT trial studied patients who had completed 6-12 months of anticoagulation for a VTE event and did not have either a contraindication to further anticoagulation or an indication for continued anticoagulation.⁶ Patients were randomized to either an extended course of anticoagulation (12 months) with one of two doses of apixaban (5 mg or 2.5 mg) or placebo. The primary efficacy endpoint (symptomatic recurrent VTE or death from any cause) was reduced with both apixaban 2.5 mg (3.8% vs. 11.6%; HR 0.33, 95% CI 0.22-0.48) and apixaban 5 mg (4.2% vs. 11.6%; HR 0.36, 95% CI 0.25-0.53). In regards to safety, patients randomized in the trial had already tolerated 6-12 months of anticoagulation and overall bleeding rates were low. However, major or clinically relevant non-major bleeding was increased in patients treated with apixaban 2.5 mg (3.2 % vs. 2.7%; HR 1.20, 95% CI 0.69-2.10) and apixaban 5 mg (4.3 % vs. 2.7%; HR 1.20, 95% CI 0.69-2.10).

Extended anticoagulation for VTE was also tested in the EINSTEIN-Extension study.⁷ In this trial, 1196 patients who had already completed and tolerated 6-12 months of therapy with either rivaroxaban or a VKA, and had no indication to either stop or continue anticoagulation, were randomized to either rivaroxaban 20 mg daily or placebo. After an additional 6-12 months of therapy, treatment with an extended course of rivaroxaban reduced the incidence of DVT or PE (1.3% vs. 7.1%, HR 0.18, 95% CI 0.09-0.39). Major or clinically relevant non-major bleeding was significantly higher in the patients treated with rivaroxaban as compared to placebo (6.0% vs. 1.2%, HR 5.19, 95% CI 2.3-11.7).

In the RE-SONATE trial, 1343 patients who had already completed and tolerated 6-18 months of therapy with an anticoagulant were randomized to either dabigatran 150 mg twice daily or placebo.⁸ After an additional 6 months of therapy (although patients were followed for an additional 12 months), treatment with an extended course of dabigatran reduced the incidence of recurrent symptomatic VTE or death associated with VTE (0.4% vs. 5.6%, HR 0.08, 95% CI 0.02-0.25). Major or clinically relevant non-major bleeding was significantly higher in the patients treated with dabigatran as compared to placebo (5.3% vs. 1.8%, HR 2.92, 95% CI 1.52-5.60). Dabigatran is currently being reviewed by the FDA for treatment of VTE.

Secondary prevention strategies have also evaluated therapies other than anticoagulants. In the WARFASA trial, extended therapy with aspirin was compared to placebo in 403 patients with a prior unprovoked VTE who had already completed 6-18 months of therapy with a VKA.⁹ Treatment with aspirin reduced the primary efficacy endpoint of symptomatic recurrent VTE or non-fatal/fatal PE (6.6% vs. 11.2% per year, HR 0.58, 95% CI 0.36-0.93, p=0.02). Major or clinically relevant non-major bleeding occurred infrequently and was similar in patients treated with aspirin and placebo (n=4 vs. n=4, HR 0.98, 95% CI 0.24-3.96, p=0.97).

Taken as a whole, these data support personalizing the treatment strategies for patients with VTE. In those patients in whom the risk of recurrent VTE is low (e.g. VTE occurred in the setting of indwelling vascular access) or patients in whom the risk of bleeding is significant, shorter duration of anticoagulation (three months) is appropriate. Patients with significant, non-reversible risk factors for VTE (e.g. multiple prior VTE) should be treated with prolonged, possibly even lifelong, anticoagulation. For patients in whom the risk of a recurrent event is between these two extremes, the duration of therapy should be tailored to maximize the potential benefit while minimizing the risk of bleeding events.

Moving forward, comparative effectiveness studies that compare two active therapies and studies that refine the patient populations in whom extended therapies is appropriate are needed. While an extended duration of therapy in patients who have tolerated an initial course of anticoagulation reduces the recurrence of VTE, this benefit must be weighed against the concomitant risk of bleeding. For patients in whom the risk of bleeding is significant, the use of aspirin can be considered as an alternative therapy to reduce the risk of recurrent VTE. Improved risk scores and other methods to risk stratify patients at risk for recurrent VTE are needed to better guide clinicians as they treat patients with VTE.

Table 1: Extended Therapy for VTE reduces Recurrent VTE
		Duration of Initial Therapy	Duration of Extended Therapy	Primary Endpoint	Event Rate (%)	Event Rate (%/yr)	Hazard Ratio
AMPLIFY-EXT	Apixaban 2.5 mg Daily	6-12 months	12 months	Symptomatic, Recurrent VTE or Death from Any Cause	14/840 (1.7%)	73/829 (8.8)	0.19 (0.11-0.33)
	Apixaban 5 mg Daily	6-12 months	12 months	Symptomatic, Recurrent VTE or Death from Any Cause	14/813 (1.7%)	73/829 (8.8)	0.20 (0.11-0.34)
EINSTEIN-EXT	Rivaroxaban 20 mg Daily	6-12 months	6-12 months	Recurrent VTE	8/602 (1.3%)	42/594 (7.1%)	0.18 (0.09-0.39)
RE-SONATE	Dabigatran 150 mg Twice Daily	6-18 months	6 months	Symptomatic VTE or Death associated with VTE	3/681 (0.4%)	37/662 (5.6%)	0.08 (0.02-0.25)
WARFASA	Aspirin 100mg Daily	6-18 months	24 months	Recurrent VTE	28/205 (6.6%)	43/197 (11.2%)	0.58 (0.36-0.93)

References

1. Goldhaber SZ, Bounameaux H: Pulmonary embolism and deep vein thrombosis. Lancet 2012;379:1835-1846.
2. Roger VL, Go AS, Lloyd-Jones DM, et al.: Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation 2011;123:e18-e209.
3. Kearon C, Akl EA: Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood 2014;123:1794-801
4. Boutitie F, Pinede L, Schulman S, et al.: Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants' data from seven trials. BMJ 2011;342:d3036.
5. Guyatt GH, Akl EA, Crowther M, et al.: Executive summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141(2 Suppl):7S-47S.
6. Agnelli G, Buller HR, Cohen A, et al.: Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699-708.
7. Buller HR, Prins MH, Lensin AW, et al.: Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:1287-1297.
8. Schulman S, Kearon C, Kakkar AK, et al.: Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013;368:709-718.
9. Becattini C, Agnelli G, Schenone A, et al.: Aspirin for preventing the recurrence of venous thromboembolism. N Engl J Med 2012;366:1959-1967.

Keywords: Anticoagulants, Antithrombins, Benzimidazoles, Factor Xa Inhibitors, Heparin, Low-Molecular-Weight, Molecular Weight, Morpholines, Pulmonary Embolism, Pyrazoles, Pyridines, Pyridones, Thiazoles, Thiophenes, Venous Thrombosis, Vitamin K, Warfarin, beta-Alanine

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