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Cohen AT, et al. "Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients". The New England Journal of Medicine. 2016. 375(6):534-44.
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Clinical Question

Among acutely medically ill patients, does extended thromboprophylaxis with betrixaban reduce the rate of VTE when compared with enoxaparin?

Bottom Line

Among acutely ill medical patients, extended-duration betrixaban for 35-42 days did not reduce the primary endpoint of asymptomatic proximal DVT or symptomatic VTE compared to a standard regimen of enoxaparin for 6-14 days.

Major Points

Hospitalized medically ill patients are at an increased risk of VTE during the hospitalization and following discharge. Randomized placebo-controlled trials including MEDENOX, PREVENT, and ARTEMIS demonstrated promise of in-hospital thromboprophylaxis with LMWH, with a relative risk reduction of 45 to 63%.[1][2][3] However, medically ill patients may remain at risk for VTE during the post-discharge period, with as many as 56.6% of all VTE events occurring after hospital discharge.[4] Studies such as MAGELLAN indicate that extended VTE prophylaxis with rivaroxaban may reduce rates of recurrent VTE at the expense of excess bleeding when compared to standard-course enoxaparin VTE prophylaxis. It is unclear whether extended anticoagulation with another DOAC may be efficacious without increasing the risk of clinically significant bleeding.

The Acute Medically Ill VTE Prevention With Extended Duration Betrixaban (APEX) trial randomized 7,513 acutely ill hospitalized patients at risk for VTE in a 1:1 ratio to betrixaban (an oral factor Xa inhibitor) for 35–42 days or enoxaparin for 6-14 days. A sequential, gate-keeping procedure was performed to compare the efficacy of betrixaban with enoxaparin in three progressively inclusive cohorts: patients with an elevated D-dimer level (cohort 1), patients with an elevated D-dimer level or age ≥75 years (cohort 2), and all the enrolled patients (overall population). The study's unusual statistical plan required that if any analysis of the between-group differences did not reach statistical significance, then the other analyses would be considered exploratory. In cohort 1, there was no significant difference in the primary endpoint between extended duration betrixaban and standard duration enoxaparin (6.9% vs. 8.5%; P=0.054). Consequently, analyses of the other two cohorts became exploratory. In these cohorts, results favored betrixaban with a modest improvement in cohort 2 (5.6% vs. 7.1%; P=0.03) and in the overall population (5.3% vs. 7.0%; P=0.006). But again, as a result of the prespecified statistical plan, these must be interpreted as exploratory analyses. Major bleeding rates were similar (0.7% vs. 0.6%; P=0.55). The authors conclude that extended duration betrixaban does not improve rates of the primary efficacy endpoint among medically ill patients with an elevated D-dimer, but that exploratory suggest betrixaban may benefit certain subgroups.

Limitations of this trial include its atypical statistical analysis plan, missing ultrasonographic data in 15% of patients, and the use of a primary composite endpoint which included asymptomatic VTE events which are of uncertain clinical significance. Nevertheless betrixaban was approved by the FDA in June 2017[5] for extended VTE prophylaxis in hospitalized medically ill patients on the basis of this study. As expected, this generated controversy given that betrixaban is one of the only drugs approved by the FDA on the basis of a trial which failed to meet its primary endpoint. In contrast to the FDA, UK NICE denied marketing authorization for betrixaban based on the failure of this study to meet its primary endpoint.[6]


As of October 2018, no guidelines have been published that reflect the results of this trial.


  • Multicenter, prospective, randomized, double-blind, double-dummy, active-controlled, phase 3 trial
  • N=7513 randomized in a 1:1 ratio (N=7441 included in the modified intention-to-treat [mITT] population)
    • Betrixaban (n=3721)
      • Cohort 1 (n=1914)
      • Cohort 2 (n=2842)
      • Overall population (n=3112)
    • Enoxaparin (n=3720)
      • Cohort 1 (n=1956)
      • Cohort 2 (n=2893)
      • Overall population (n=3174)
  • Setting: 460 sites in 35 countries
  • Enrollment: 2012-2015
  • Follow-up: 30±5 days after the assessment on day 42
  • Analysis: A sequential, gate-keeping procedure was performed to test the primary efficacy outcome in the following cohorts:
    • Cohort 1: patients with an elevated D-dimer level (≥ 2x upper limit of the normal range)
    • Cohort 2: patients with an elevated D-dimer level or age ≥ 75 years
    • Overall population: patients in the mITT population with all evaluable endpoints
  • Primary outcome:
    • Efficacy: A composite of
      • Asymptomatic proximal deep-vein thrombosis between day 32 and day 47
      • Symptomatic proximal or distal deep-vein thrombosis between day 1 and day 42
      • Symptomatic nonfatal pulmonary embolism between day 1 and day 42
      • Death from venous thromboembolism between day 1 and day 42
    • Safety: Major bleeding at any point until 7 days after the discontinuation of all study medications


Inclusion Criteria

  • Hospitalized with one of the following conditions:
    • Acutely decompensated heart failure with prior symptomatic chronic heart failure
    • Acute respiratory failure with chronic symptomatic lung disease
    • Acute infection without septic shock
    • Acute rheumatic disorder
    • Acute ischemic stroke with lower limb hemiparesis/paralysis
  • Eligibility risk factors:
    • Age ≥ 75 years
    • Age 60–74 years with elevated D-dimer
    • Age 40–59 years with elevated D-dimer and history of VTE or cancer
  • Immobility:
    • ≥ 24 hours observed or anticipated severe immobility
    • Observed or anticipated severe or moderate immobility for ≥ 3 additional days
  • Anticipated ≥ 3 days of hospitalization

Exclusion Criteria

  • A condition requiring prolonged anticoagulation or anti-platelets
  • Active bleeding or at high risk of bleeding
  • Contraindication to anticoagulant therapy
  • General conditions in which subjects are not suitable to participate in the study

Baseline Characteristics

Comparisons are betrixaban vs. enoxaparin

  • Demographics:
    • Age: 76.6 vs. 76.2 years
    • Male: 45.4% vs. 45.8%
  • Body-mass index: 29.21 vs. 29.54
  • Duration of hospitalization: 10 (7–14) vs. 10 (8–14) days
  • Concomitant P-glycoprotein inhibitor: 18.0% vs. 17.3%
  • Previous thromboprophylaxis ≤ 96 h: 51.3% vs. 50.1%
  • Acute medical condition:
    • Heart failure: 44.6% vs. 44.5%
    • Infection: 29.6% vs. 28.2%
    • Respiratory failure: 11.9% vs. 12.6%
    • Ischemic stroke: 10.9% vs. 11.5%
    • Rheumatic disorder: 2.9% vs. 3.1%
  • Risk factor for VTE:
    • Level of D-dimer ≥ 2× ULN: 62.3% vs. 62.1%
    • Age ≥ 75 years: 68.5% vs. 67.0%
    • History of cancer: 12.4% vs. 11.8%
    • History of VTE: 8.3% vs. 7.9%
    • History of NYHA class III–IV heart failure: 22.7% vs. 23.0%
    • Concurrent acute infectious disease: 16.0% vs. 16.5%
    • Severe varicosities: 18.7% vs. 18.4%
    • Hormone-replacement therapy: 1.1% vs. 0.8%
    • Hereditary or acquired thrombophilia: <0.1% vs. 0.1%


  • For patients without severe renal insufficiency (CrCl ≥ 15 to < 30 mL/min) or concomitant use of a strong P-gp inhibitor:
    • After an initial dose of two 80 mg capsules of betrixaban or placebo, participants were randomized to:
      • Betrixaban: 80 mg PO once daily for 35-42 days plus enoxaparin placebo once daily for 10±4 days
      • Enoxaparin: 40 mg SC once daily for 10±4 days and betrixaban placebo once daily for 35-42 days
  • For patients with severe renal insufficiency (CrCl ≥ 15 to < 30 mL/min):
    • After an initial dose of two 40 mg capsules of betrixaban or placebo, participants were randomized to:
      • Betrixaban: 40 mg PO once daily for 35-42 days plus enoxaparin placebo once daily for 10±4 days
      • Enoxaparin: 20 mg SC once daily for 10±4 days and betrixaban placebo once daily for 35-42 days
  • For patients who are receiving a strong P-gp inhibitor:
    • After an initial dose of two 40 mg capsules of betrixaban or placebo, participants were randomized to:
      • Betrixaban: 40 mg PO once daily for 35-42 days plus enoxaparin placebo once daily for 10±4 days
      • Enoxaparin: 40 mg SC once daily for 10±4 days and betrixaban placebo once daily for 35-42 days


Comparisons are betrixaban vs. enoxaparin

Primary Outcome

VTE (composite of asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic nonfatal PE, or VTE-related death)
Cohort 1
6.9% vs. 8.5% (RR 0.81; 95% CI 0.65-1.00; P=0.054)
Cohort 2
5.6% vs. 7.1% (RR 0.80; 95% CI 0.66-0.98; P=0.03)
Overal population
5.3% vs. 7.0% (RR 0.76; 95% CI 0.63-0.92; P=0.006)

Secondary Outcomes

Symptomatic VTE
Cohort 1
1.3% vs. 1.9% (RR 0.67; 95% CI 0.42-1.07; P=0.09)
Cohort 2
1.0% vs. 1.4% (RR 0.71; 95% CI 0.46-1.09; P=0.11)
Overal population
0.9% vs. 1.5% (RR 0.64; 95% CI 0.42-0.98; P=0.04)
Primary efficacy outcome plus death from any cause
Cohort 1
11.5% vs. 12.9% (RR 0.89; 95% CI 0.75-1.05; P=0.16)
Cohort 2
9.8% vs. 10.9% (RR 0.90; 95% CI 0.77-1.04; P=0.15)
Overal population
9.2% vs. 10.8% (RR 0.85; 95% CI 0.73-0.98; P=0.02)
Net clinical benefit (composite of VTE and major bleeding)
Cohort 1
7.4% vs. 8.9% (RR 0.82; 95% CI 0.66-1.01; P=0.07)
Cohort 2
6.1% vs. 7.4% (RR 0.82; 95% CI 0.68-1.00; P=0.05)
Overal population
5.8% vs. 7.3% (RR 0.78; 95% CI 0.65-0.95; P=0.01)

Safety Outcomes

Major bleeding
Cohort 1
0.6% vs. 0.7% (RR 0.88; 95% CI 0.44-1.76; P=0.72)
Cohort 2
0.7% vs. 0.6% (RR 1.19; 95% CI 0.66-2.11; P=0.56)
Overall safety population
0.7% vs. 0.6% (RR 1.19; 95% CI 0.67-2.12; P=0.55)
Major or clinically relevant nonmajor bleeding
Cohort 1
3.1% vs. 1.9% (RR 1.64; 95% CI 1.13-2.37; P=0.009)
Cohort 2
3.2% vs. 1.7% (RR 1.89; 95% CI 1.38-2.59; P<0.001)
Overall safety population
3.1% vs. 1.6% (RR 1.97; 95% CI 1.44-2.68; P<0.001)

Subgroup Analysis

There were no significant interactions between the trial regimen and subgroups.

Adverse Events

Any adverse event
54.0% vs. 52.0%
Serious adverse event
17.7% vs. 16.6%
Any cause: 5.7% vs. 5.8%
Bleeding: <0.1% vs. <0.1%
VTE: 0.4% vs. 0.7%
Heart failure or cardiogenic shock: 1.1% vs. 1.5%
Arrhythmic disorder: 0.0% vs. <0.1%
MI: 0.3% vs. 0.2%
Ischemic stroke: 0.6% vs. 0.8%
Noncardiovascular cause: 2.6% vs. 2.0%
Undetermined or unknown cause: 0.6% vs. 0.5%
Any stroke: 0.6% vs. 1.1%
Ischemic stroke: 0.5% vs. 0.9%


  • Approximately 15% of enrolled patients had missing or non-evaluable ultrasonography and were not included in the main efficacy analysis.
  • The study excluded individuals who required prolonged anticoagulation or dual antiplatelet therapy, were at increased risk of bleeding, had liver dysfunction, or those who had both severe renal insufficiency (CrCl 15-29 ml/min) and required the concomitant use of a P-gp inhibitor. The benefit-harm of betrixaban compared with enoxaparin in these patients remains unclear.


  • The study was funded by Portola Pharmaceuticals.
  • Data were collected by Pharmaceutical Product Development, Duke Clinical Research Institute and Percutaneous–Pharmacologic Endoluminal Revascularization for Unstable Syndromes Evaluation (PERFUSE).

Further Reading

  1. Turpie AG & Thrombosis prophylaxis in the acutely ill medical patient: insights from the prophylaxis in MEDical patients with ENOXaparin (MEDENOX) trial. Am. J. Cardiol. 2000. 86:48M-52M.
  2. Leizorovicz A et al. Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients. Circulation 2004. 110:874-9.
  3. Cohen AT et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ 2006. 332:325-9.
  4. Amin AN et al. Duration of venous thromboembolism risk across a continuum in medically ill hospitalized patients. J Hosp Med 2012. 7:231-8.
  5. [1]
  6. [2]