Role of apixaban in VTE management: Who, when, and how

Venous thromboembolism (VTE) is associated with an increased risk of morbidity and mortality. Given the challenges posed by conventional therapies used for the treatment of VTE, Dr Lim Xiu Qi Cheryl, Associate Consultant from the Department of Haematology-Oncology at National University Cancer Institute, Singapore (NCIS), shares her insights on the role of apixaban (Eliquis, Pfizer), an oral factor Xa inhibitor, in the treatment of acute VTE and prevention of recurrent VTE.

VTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE), can be a serious condition. It is the 3^rd most common cause of cardiovascular death, after stroke and myocardial infarction [Lancet 2012;379:1835-1846].

Conventional treatment of VTE involves bridging anticoagulation from a parenteral anticoagulation, such as heparin, to an oral vitamin K antagonist (VKA), such as warfarin. While warfarin is effective in preventing recurrent VTE, patients on warfarin require regular international normalized ratio (INR) monitoring for dose adjustment to ensure that warfarin remains within the therapeutic range.

The need for frequent INR monitoring with warfarin treatment, together with that of multiple drug and dietary interactions, call for newer anticoagulants. Direct oral anticoagulants (DOACs) have been introduced since 2010. As their name suggests, these agents act directly on clotting factors to exert their anticoagulant effect. These agents include apixaban, dabigatran, edoxaban and rivaroxaban. Unlike warfarin, these agents do not require frequent blood test monitoring and have fewer drug and dietary interactions. Most importantly, these agents have been proven to be as effective as warfarin. 

Role of apixaban in VTE

This article aims to discuss the role of apixaban in managing VTE. Apixaban has a rapid onset of action. Its predictable pharmacokinetics allows a fixed dosing regimen. Along with rivaroxaban, apixaban is recommended by the NICE guidelines (NG518) for the treatment of confirmed proximal DVT or PE. [https://www.nice.org.uk/guidance/ng158/chapter/Recommendations#anticoagulation-treatment-for-suspected-or-confirmed-dvt-or-pe]

For patients who are not suitable to be on either apixaban or rivaroxaban, NICE recommends that low molecular weight heparin (LMWH) be given for at least 5 days, followed by either dabigatran or edoxaban. An alternative option is to offer LMWH  together with a VKA for at least 5 days or until the INR reached ≥2.0 in two consecutive readings, followed by treatment with VKA alone.

Who and when

According to the NICE recommendations, physicians should perform baseline blood tests (including full blood count, prothrombin time [PT] and activated partial thromboplastin time [APTT], renal and hepatic function) when initiating anticoagulation therapy. Patient’s comorbidities, contraindications, and personal preferences should be considered when deciding on choice of treatment.

“For patients with no renal impairment, active cancer, antiphospholipid syndrome or haemodynamic instability, patients can be offered either apixaban or rivaroxaban as first-line anticoagulation therapy,” explained Dr Lim Xiu Qi Cheryl from the Department of Haematology-Oncology at NCIS, Singapore.

Anticoagulation therapy should be offered for at least 3 months to patients with proximal DVT or PE. “After 3 months, it is recommended that the benefits and risks of continuing, stopping, or changing anticoagulation should be assessed and discussed with the patients,” Lim advised.

“There has not been any direct head-to-head comparison of apixaban and rivaroxaban. Hence, either agent can be offered to patients as first-line anticoagulation therapy. [As] apixaban is given twice daily, some patients may prefer rivaroxaban, as the latter is only given once daily,” said Lim.

For patients who initiated apixaban for the treatment of DVT and PE, an initial oral dose of 10 mg twice daily is recommended for 7 days, followed by 5 mg twice daily for at least 3 months, as per prescribing information. After the initial anticoagulation treatment period, a prophylactic dose of 2.5 mg twice daily may be considered to prevent recurrent VTE if anticoagulation therapy is to be extended.

“For patients with renal impairment and a creatinine clearance [CrCl] of <25mL/min, I would advise that apixaban to be avoided,” she said, noting that these patients have been excluded from the AMPLIFY trial.

AMPLIFY trial

One of the important evidence contributing to the placement of apixaban in the management of VTE comes from the AMPLIFY trial. 

The AMPLIFY study randomized 5,395 patients with confirmed symptomatic proximal DVT or PE to receive either apixaban or conventional therapy comprising subcutaneous enoxaparin followed by warfarin. Apixaban was given at a dose of 10 mg twice daily for 7 days, after which the dosing was 5 mg twice daily for 6 months. [N Engl J Med 2013;369:799-808]

The primary efficacy outcome — a composite of recurrent symptomatic VTE or VTE-related death —occurred in similar proportion of patients treated with apixaban vs conventional therapy (2.3 percent vs 2.7 percent; relative risk [RR], 0.84; 95 percent confidence interval [CI], 0.60–1.18) [Figure 1A]. The difference in risk between the two groups was −0.4 percentage points, thus meeting the noninferiority criteria between the two treatments (p<0.001 for noninferiority). 

Moreover, apixaban was associated with significantly fewer major bleeding than conventional therapy (0.6 percent vs 1.8 percent; RR, 0.31; p<0.001 for superiority) [Figure 1B].

The rate of the composite outcome of major bleeding and clinically relevant non-major (CRNM) bleeding was also lower in the apixaban group vs the conventional therapy group (4.3 percent vs 9.7 percent; RR, 0.44; p<0.001).

For other adverse events (AEs), the rates were similar in both the apixaban and the conventional therapy groups, including those for elevations in liver-function tests.

How long to treat?

While the NICE guidelines recommend treatment duration of at least 3 months, the duration may be extended for prevention of recurrent VTE — keeping in mind that the duration of overall treatment should be individualized after careful assessment of the treatment benefit vs the risk of bleeding.

“For patients with unprovoked VTE, for which the risk of recurrence is as high as 40 percent at 5 years, it may be appropriate to consider a longer course of therapy,” wrote Dr Jean Connors from Brigham and Women’s Hospital, Boston, Massachusetts, US, in a linked editorial. [N Engl J Med 2013;368:767-769]

The AMPLIFY-EXT study sought to shed light into this matter by comparing the efficacy and safety of apixaban vs placebo in 2,482 patients with VTE who had completed 6–12 months of anticoagulation treatment and for whom their physicians were uncertain about continuing therapy. They were given the study drugs for another 12 months. [N Engl J Med 2013;368:699-708]

In this study population, extended anticoagulation with apixaban significantly lowered the risk of recurrent VTE or VTE-related death compared with placebo (p<0.001), without an increase in the rate of major bleeding.

These findings, therefore, “provide a rationale for continuing anticoagulation therapy for an additional 12 months … for patients with VTE for whom there is uncertainty about the benefits and risks of continued therapy,” according to the investigators.