Bayer Pharma AG

Essence of this article

Although Factor Xa inhibitors have been investigated for the prevention of venous thromboembolism in acutely ill medical patients, the demonstration of a favourable benefit–risk profile has proved challenging. Large phase III clinical trials investigating the clinical outcomes of rivaroxaban and betrixaban in this patient population are ongoing.

Preventing venous thromboembolism in medically ill patients: ongoing phase III studies


Medically ill patients are at a high risk of venous thromboembolic events during their hospital stay, and this risk extends into the period after discharge from hospital. Guidelines, therefore, recommend thromboprophylaxis in at-risk patients for 6–21 days, until either restoration of full mobility or discharge from hospital, whichever comes first. Continued thromboprophylaxis with parenteral agents post discharge is not widely used because of the challenges in administering parenteral medication and a lack of compelling benefit–risk data with existing anticoagulants. Furthermore, studies of novel oral anticoagulants in acutely ill medical patients have suggested that the currently recommended durations of treatment may be insufficient to protect patients at risk of venous thromboembolism (VTE).472-474 For example, recent studies employing extended treatment durations with either enoxaparin (EXCLAIM), apixaban (ADOPT) or rivaroxaban (MAGELLAN) have all failed to demonstrate a positive benefit–risk profile for extended thromboprophylaxis in a diverse range of patients hospitalized with an acute medical illness. Although rivaroxaban met its primary efficacy endpoint and enoxaparin showed a benefit in older female patients with restricted mobility, these three studies reported an increased risk of bleeding events with all of the anticoagulants used.473-475 Lessons learnt from these trials have been considered in the respective study designs of the APEX (betrixaban) and MARINER (rivaroxaban) trials. In particular, there has been a renewed focus on identifying at-risk groups of medically ill patients who would benefit from extended-duration thromboprophylaxis. The APEX study places a greater focus on ‘truly at-risk’ patients, defined as patients who are at a higher risk of VTE than those included in the previous studies. This is reflected by the inclusion of patients with severe renal impairment (i.e. creatinine clearance <30 ml/min) and more stringent mobility criteria than those seen in EXCLAIM and ADOPT (i.e. severely immobilized for 24 hours and either moderately or severely immobilized for ≥4 days during hospitalization). It is hoped that this focus on medically ill patients at high risk of VTE will identify a group likely to benefit from extended-duration anticoagulation.476 Similarly, the study design of MARINER was modified to reduce the risk of major bleeding seen in MAGELLAN while maintaining improved efficacy compared with low molecular weight heparin/placebo. Therefore, implemented measures include a dose reduction for patients with moderate renal impairment (i.e. creatinine clearance 30-49 ml/min) and exclusion of patients at a high risk of bleeding or those who were seen not to benefit in the earlier MAGELLAN study. Because the documented increase in the risk of VTE persists well beyond hospital discharge (with a higher number of venous thromboembolic events diagnosed during the first 3 months post-hospitalization versus during hospitalization),477 studies of extended-duration thromboprophylaxis with oral anticoagulants in post-discharge medically ill patients at risk of VTE are warranted.

Acute medically ill VTE Prevention with EXtended duration betrixaban (APEX) study

The phase III APEX study (; NCT01583218) is expected to enrol 6850 medically ill patients and will evaluate the superiority of extended-duration anticoagulation with betrixaban.476

  • The APEX study is a prospective, randomized, double-blind, double-dummy, parallel-group, multicentre, multinational study
  • Extended thromboprophylaxis for prevention of VTE, or blood clots in the leg and lung, will be assessed in patients who have been hospitalized for medical conditions
  • Key exclusion criteria are:
    • Hospitalization for >96 hours before randomization
    • An inability to take enteral feeding
    • A concomitant diagnosis likely to require major surgery or an invasive procedure within 3 months
  • Primary efficacy endpoint
    • The composite of asymptomatic proximal deep vein thrombosis, symptomatic deep venous thrombosis, non-fatal (pulmonary embolus) pulmonary embolism or VTE-related death, through day 35
  • Principal safety outcome
    • Major bleeding (International Society on Thrombosis and Haemostasis [ISTH] definition)

Medically ill patient Assessment of Rivaroxaban versus placebo IN reducing post-discharge venous thromboEmbolism Risk (MARINER) study

The MARINER study (; NCT02111564) is expected to enrol 8000 patients and will evaluate the efficacy and safety of rivaroxaban in reducing post-discharge VTE risk in high-risk medically ill patients when administered for 45 days, compared with placebo. This will follow an initial period of prophylaxis during hospitalization for 3–14 days.

  • MARINER is a prospective, randomized, double-blind, placebo-controlled, event-driven study
  • Patients identified using VTE risk criteria, including but not limited to a total modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) VTE risk score ≥3
  • Key exclusion criteria include:
    • Any bleeding event within a period of 3 months prior to randomization or occurring during index hospitalization that would contraindicate the use of pharmacological thromboprophylaxis
    • Major surgery within 4 weeks of randomization or any planned major surgery or major invasive diagnostic procedure intended during the duration of the trial
    • Active cancer at time of index hospitalization
  • Primary efficacy endpoint
    • The composite of all symptomatic VTE and VTE-related death
  • Principal safety outcome
    • Major bleeding (ISTH definition)

These studies will offer further insight into the optimal duration of thromboprophylaxis in high-risk patients and will guide the use of these agents in specifically defined medically ill populations.

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