Reaching a New APEX; Betrixaban vs. Enoxaparin for Thromboprophylaxis

Achal Patel, Mercer University College of Pharmacy

Venous thromboembolism (VTE) is the third leading cause of vascular diagnosis following heart attack and stroke. [1] It is categorized into two types: deep vein thrombosis (DVT) and pulmonary embolism (PE). Venous thromboembolism affects men and women of all ages, and patients that are immobilized are at a higher risk. [1]

The Chest Guidelines recommend anticoagulants for up to two weeks after hospital discharge. [2] However, the risk of a VTE remains increased for at least a month. Therefore, Bevyxxa® (betrixaban), which is a direct and selective factor Xa inhibitor, was tested for extended-duration therapy for thromboprophylaxis in acutely ill medical patients. [3]

Extended thromboprophylaxis with betrixaban in acutely ill medical patients
Design Randomized, double-blind, double-dummy, active-controlled, multinational clinical trial; N= 7,513
Objective To assess the safety and efficacy of betrixaban compared to enoxaparin
Study Groups Betrixaban (n= 3,759), Enoxaparin (n= 3,754)
Methods Inclusion criteria:

– Male or female patients aged ≥ 40 years.

– At least one of the following as the cause of the acute hospitalization:

o   Acutely decompensated heart failure with prior symptomatic chronic heart failure

o   Acute respiratory failure in patients with chronic symptomatic lung disease

o   Acute infection without septic shock (e.g., with systolic blood pressure < 90 mmHg after fluid challenge that requires pressor therapy) at screening and randomization.

o   Acute rheumatic disorders including acute lumbar pain, sciatica, vertebral compression, rheumatoid arthritis, systemic lupus erythematosus, etc.

o   Acute ischemic stroke with lower extremity hemiparesis or hemiparalysis, or with immobility of other origin that satisfies protocol immobility requirements.

– Eligibility Risk Factors. Any one of the following:

o   ≥ 75 years of age, or

o   60 through 74 years of age with D-dimer ≥ 2ULN, or

o   40 through 59 years of age with D-dimer ≥ 2ULN and a history of either VTE (DVT or PE) or cancer (excluding non-melanoma carcinoma of the skin)

– Immobilization

o   Patients have been Severely Immobilized for 24 hours or are anticipated to be Severely Immobilized for 24 hours. Severely Immobilized means patients are confined to a bed or chair for the majority of the day and can only be independently mobile to the in-room toilet. In-bed/chair physical therapy is permitted.

o   After 24 hours of Severe Immobilization, patients are anticipated to be Severely Immobilized or Moderately Immobilized for 3 or more days. Moderately Immobilized means patients can be independently mobile to the in-room or ward toilet; can be mobilized by physical therapy or nursing staff; and can be off-ward with assistance.

– Hemoglobin

o   Hgb ≥ 10.0 g/dL during current presentation prior to randomization. A single value of Hgb < 10.0 g/dL does not disqualify a patient. Hgb may be repeated after initial stabilization, e.g., after diuresis in patients with acute decompensated heart failure, or

o   Hgb ≥ 9.5 g/dL from two (2) consecutive blood samples taken on consecutive days with stable or rising (i.e., not falling) values.

– Length of Hospitalization

o   Expected total length of current hospitalization ≥ 3 days.

o   Enrollment occurs < 96 hours after hospitalization/presentation (e.g., in Emergency Department) for acute medical illness.

Exclusion criteria:

– A condition requiring prolonged anticoagulation or anti-platelets

– Life expectancy < 8 weeks

– 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

Patients in the study were randomly assigned using an interactive voice-response system. They were either given subcutaneous enoxaparin 40 mg daily for 10±4 days plus placebo for 35 to 42 days. In the other group, patients were given placebo daily for 10±4 days plus oral betrixaban (loading dose of 160 mg for first dose) followed by 80 mg for 35 to 42 days

Patients with renal insufficiency or concomitant P-glycoprotein inhibitor received 50% of the medication (20 mg of enoxaparin, 80 mg loading dose of betrixaban followed by 40 mg daily)

During follow-up, clinicians were instructed to confirm suspected cases of DVT by ultrasonography, and to confirm suspected PE by computed tomography, a ventilation–perfusion lung scan, pulmonary angiography, or autopsy. In patients without clinically confirmed venous thromboembolism, mandatory ultrasonography was performed for the detection of asymptomatic deep-vein thrombosis after the administration of the last dose.

Duration March 2012 – November 2015
Primary Outcome Measure A composite of asymptomatic proximal deep-vein thrombosis between day 32 and day 47, symptomatic proximal or distal deep-vein thrombosis, symptomatic nonfatal pulmonary embolism, or death from venous thromboembolism between day 1 and day 42
Baseline Characteristics
Characteristic Betrixaban (n= 3,759) Enoxaparin (n= 3,754)
Age 76.6 ± 8.46 76.2 ± 8.31
Sex (male) 1,705 (45.4%) 1,720 (45.8%)
Mean weight (kg) 79.84 80.74
Median number of days of hospitalization 10 (7-4) 10 (8-14)
Creatinine clearance
< 15 mL/min 1 (< 0.1%) 0
15 to < 30 mL/min 174 (4.6%) 150 (4.0%)
30 to <60 mL/min 1,602 (42.6%) 1,531 (40.8%)
60 to < 90 mL/min 1,299 (34.6%) 1.346 (35.9%)
≥ 90 mL/min 672 (17.9%) 716 (19.1%)
Missing data 11 (0.3%) 11 (0.3%)
Race
White 3,503 (93.2%) 3,518 (93.7%)
Asian 9 (0.2%) 7 (0.2%)
Black 74 (2%) 73 (1.9%)
Other 173 (4.6%) 156 (4.2%)
Concomitant strong P-gp inhibitor 677 (18.0%) 649 (17.3%)
Previous thromboprophylaxis ≤96 h 1,928 (51.3%) 1,879 (50.1%)
Acute medical condition
Heart failure 1,677 (44.6%) 1,672 (44.5%)
Infection 1,112 (29.6%) 1,058 (28.2%)
Respiratory failure 448 (11.9%) 474 (12.6%)
Ischemic stroke 411 (10.9) 432 (11.5%)
Rheumatic disorder 109 (2.9%) 117 (3.1%)
Risk factors for VTE
Level of d-dimer ≥2 ×ULN 2,341 (62.3%) 2,332 (62.1%)
Age ≥75 y 2,575 (68.5%) 2,517 (67%)
History of cancer 466 (12.4%) 443 (11.8%)
History of deep vein thrombosis or pulmonary embolism 312 (8.3%) 296 (7.9%)
 History of deep vein thrombosis or pulmonary embolism 853 (22.7%) 865 (23.0%)
History of New York Heart Association class III or IV heart failure 602 (16.0%) 620 (16.5%)
Results  

Cohort 1 (elevated D-dimer) Betrixaban (n= 1,914) Enoxaparin (n= 1,956)
Primary endpoints
Primary efficacy outcome 132/1,914 (6.9%) 166/1956 (8.5%)
Asymptomatic proximal DVT 105 129
Symptomatic proximal or distal DVT 14 19
Symptomatic nonfatal PE 5 17
Death from VTE 12 11
Secondary endpoints
Symptomatic VTE 30/2,313 (1.3%) 44/2,313 (1.9%)
Primary efficacy outcome plus death from any cause 232/2,014 (11.5%) 264/2,054 (12.9%)

 

Cohort 2 (elevated D-diner and ≥ 75 years of age) Betrixaban (n= 2,842) Enoxaparin (n= 2,893)
Primary endpoints
Primary efficacy outcome 160/2,842 (5.3%) 204/2,893 (7.0%)
Asymptomatic proximal DVT 128 162
Symptomatic proximal or distal DVT 14 21
Symptomatic nonfatal PE 9 18
Death from VTE 13 13
Secondary endpoints
Symptomatic VTE 35/3,407 (1.0%) 49/3,407 (1.4%)
Primary efficacy outcome plus death from any cause 291/2,973 (9.8%) 329/3,018 (10.9%)

 

Overall population Betrixaban (n= 3,112) Enoxaparin (n= 3,174)
Primary endpoints
Primary efficacy outcome 165/3,112 (5.3%) 223/3,174 (7.0%)
Asymptomatic proximal DVT 133 176
Symptomatic proximal or distal DVT 14 22
Symptomatic nonfatal PE 9 18
Death from VTE 13 17
Secondary endpoints
Symptomatic VTE 35/3,721 (0.9%) 54/3,720 (1.5%)
Primary efficacy outcome plus death from any cause 298/3,245 (9.2%) 359/3,310 (10.8%)

 

Adverse Events
Betrixaban (n= 3,716) Enoxaparin (n= 3,716)
Principal safety outcome in overall safety population
Major bleeding 25/3,716 (0.7%) 21/3,716 (0.6%)
Decrease in hemoglobin of ≥ 2 g/dL 12 8
Transfusion of ≥ 2 units of blood 18 9
Critical-site bleeding 3 9
Fatal bleeding 1 1
Major or clinically relevant non-major bleeding** 116/3,716 (3.1%) 59/3,716 (1.6%)
Other safety outcomes in all patients
Any adverse event 2,005/3,716 (54.0%) 1,931/3,716 (52.0%)
Any serious adverse event 657/3,716 (17.7%) 615/3,716 (16.6%)
Death
Any cause 210/3,716 (5.7%) 215/3,716 (5.8%)
Bleeding 1/3,716 (< 0.1%) 1/3,716 < 0.1%)
Venous thromboembolism 15/3,716 (0.4%) 26/3,716 (0.7%)
Other cardiovascular cause
Heart failure or cardiogenic shock 40/3,716 (1.1%) 56/3,716 (1.5%)
Arrhythmic disorder 0 1/3,716 (< 0.1%)
Myocardial infarction 11/3,716 (0.3%) 8/3,716 (0.2%)
Ischemic stroke 24/3,716 (0.6%) 28/3,716 (0.8%)
Non-cardiovascular cause 95/3,716 (2.6%) 76/3,716 (2.0%)
Undetermined or unknown cause 24/3,716 (0.5%) 19/3,716 (0.5%)
Stroke
Any 24/3,716 (0.6%) 41/3,716 (1.1%)
Ischemic 18/3,716 (0.5%) 34/3,716 (0.9%)

** p< 0.001

Percentage that Discontinued due to Adverse Events: not disclosed
Study Author Conclusions There was no significant difference between extended-duration betrixaban 80 mg daily and enoxaparin 40 mg daily.

 

The study’s design allows reducing methodological bias, which strengthens its internal validity. The external validity of the study is also strengthened with its large sample size. However, the study included predominately Caucasian, which may not be a true representation of the overall patient population seen in clinical practice, and this may be a limitation as some evidence show ethnicity may be a risk factor for VTEs. [4] In the subgroup analysis (not shown), the confidence intervals of non-white patients are wider compared to that of white patients suggesting variable results may be expected in non-white population. However, this may also be due to the small sample size. The study used a standard-duration enoxaparin as the active comparator, which is the gold standard treatment. This is a strength of the study because it reflects what is currently being done in clinical practice. . Based on the methods, mandatory ultrasonography was performed for all patients without clinically confirmed VTE; however, this is uncommon in clinical practice, and may be unnecessary expenditure of resources. Using the hierarchical design =, cohort 1 was tested for the primary outcome, which was nonsignificant. Therefore, subsequent analyses of this study are only exploratory, despite showing significant p-values. The insignificant outcome is unlikely to be a type 2 error as the study met its 90% power. Interestingly, the drug was Food and Drug Administration (FDA) approved based on this trial, despite the no differences.  It’s been reported that the data were re-analyzed by the FDA and the investigators and showed significant benefit of betrixaban. [5] The future publications of these data would be of an interest for the clinical community.

 

References

[1] What is Venous Thromboembolism (VTE)? http://www.heart.org/HEARTORG/Conditions/VascularHealth/VenousThromboembolism/What-is-Venous-Thromboembolism-VTE_UCM_479052_Article.jsp#.WmE7ohilnwe. Published July 20, 2017. Accessed January 18, 2018.

[2] Kahn SR, Lim W, Dunn AS, et al. Prevention of vte in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. chest 2012;141:2 supple195s-226s

[3] Cohen AT, Harrington RA, Goldhaber SZ, et al. Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients. N Engl J Med. 2016.

[4] White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism. Thromb Res. 2009;123 Suppl 4:S11-7

[5] US. Food and Drug Administration. FDA approved betrixaban (BECYXXA, Portola) for the prophylaxis of venous thromboembolism (VTE) in adult patients. Washington, DC: U.S Department of Hea

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