Extended Non-Vitamin K Antagonist Oral Anticoagulation Therapy for Prevention of Recurrent Venous Thromboembolism. a Review of Phase III and Phase IV Studies

Duration of anticoagulation can be categorised into initial treatment, lasting 3, 6 or 12 months, and long-term treatment beyond 12 months. There is a strong rationale for anticoagulation treatment beyond the acute phase in many patients with venous thromboembolism (VTE), being the risk of recurrent VTE after stopping anticoagulation high, particularly for unprovoked deep vein thrombosis (DVT). Several non-vitamin K antagonist oral anticoagulants (NOACs) have been approved in the acute setting; accumulating evidence suggests continuing treatment with these agents beyond 12 months offers additional benefits to patients with VTE.

Apixaban, dabigatran and rivaroxaban have been studied in this setting in a series of phase III extension studies (AMPLIFY-EXT, RE-MEDY and RE-SONATE, and EINSTEIN EXT, respectively).

AMPLIFY-EXT evaluated patients who had completed 6-12 months of anticoagulation treatment with apixaban. Patients received either a further 12 months of apixaban at a dose of 2.5 mg or 5 mg twice daily, or placebo. Recurrent VTE or mortality from any cause were 3.8%, 4.2% and 11.6%, respectively (relative risk [95% confidence interval (CI)] vs placebo: 0.33 [0.22-0.48] and 0.66 [0.25-0.53], respectively); for major bleeding, rates were 0.2%, 0.1% and 0.5%, respectively (relative risk [95% CI] vs placebo: 0.49 [0.09-2.64] and 0.25 [0.03-2.24], respectively).

In RE-MEDY, patients received either dabigatran (150 mg twice daily) or warfarin for 6-36 months after at least 3 months of prior anticoagulation treatment. Recurrent or fatal VTE occurred in 1.8% of patients treated with dabigatran versus 1.3% of warfarin-treated patients (P=0.01 for non-inferiority); major bleeding rates were lower with dabigatran (0.9% vs 1.8%) but this difference was not statistically significant.

In the RE-SONATE study, dabigatran (150 mg twice daily) or placebo was administered for up to 12 months. Recurrent or fatal VTE was significantly lower with dabigatran (0.4% vs 5.6%; P<0.001). Rates of major bleeding were low in both groups (0.3% with dabigatran; no major bleeding episodes occurred in the placebo group); however, for the composite of major or non-major clinically relevant bleeding, the rate was significantly greater with dabigatran (5.3% vs 1.8%; P=0.001).

In EINSTEIN EXT, patients who had completed 6-12 months of rivaroxaban or VKA anticoagulation treatment were randomised to receive either rivaroxaban or placebo for 6 or 12 months. Extended rivaroxaban treatment was associated with a significantly lower rate of recurrent VTE (1.3% vs 7.1%, respectively; P<0.001), and there was a moderate, non-significant, increase in the rate of major bleeding complications (0.7% of patients in the rivaroxaban group vs none in the placebo group; P=0.11).

The phase III extension studies demonstrate the benefits of extended NOAC use versus treatment cessation, with reduced recurrence rates versus placebo, although associated with a potential moderate increase in bleeding risk; in addition, based on outcomes in patients given placebo, it is clear that not prescribing anticoagulation treatment is not a viable approach.

VTE is associated with substantial costs, and recurrent episodes increase costs further. The costs are attributable to hospitalisation, treatment facility and staff and outpatient management. The lack of routine coagulation monitoring needed with use of NOACs may simplify patient management, thereby further reducing the burden on healthcare providers and patients.

US and European guidelines advise long-term therapy in certain instances. They support NOAC use where they have been selected as the initial therapy choice and therapy needs to be extended beyond 3 months.

In addition to clinical trials of extended anticoagulation, assessment of this therapy in routine clinical practice is essential, in order to confirm whether the results of clinical trials apply to a broad range of patients beyond the highly controlled setting of a clinical study. Phase IV data are now emerging (Dresden Noacs Registry, Xalia Study, Einstein Choice Study, Start Register) and are supportive of the findings from phase III studies. Future studies involving all NOACs will be valuable in determining the safety and effectiveness of long-term NOAC use in a wider patient population.