Effectiveness and safety of betrixaban extended prophylaxis for venous thromboembolism compared with standard-duration prophylaxis intervention in acute medically ill patients: a systematic literature review and network meta-analysis

Figures & data

Figure 1. PRISMA diagram.

Table 1. Summary of studies included in the network meta-analysis.

Study	Key eligibility criteria	Interventions	Baseline characteristics	Outcomes analyzed	Setting	Reference
APEX	Aged ≥40 years; cause of hospitalization either acute heart failure, acute respiratory failure, acute infection, acute rheumatic disorders or acute ischemic stroke; at least one additional VTE risk factor of either ≥75 years, or 60–74 years with D-dimer ≥2 ULN, or 40–59 with D-dimer ≥2 ULN and history of VTE or cancer; expected to be immobilized for ≥3 days.	Betrixaban 80 mg once daily (loading dose of 160 mg for first dose) for 35–42 days (n = 3,759) Enoxaparin 40 mg once daily for 10 ± 4 days (n = 3,754)	Age 76 years; Male 45%; Weight 80 kg	VTE, VTE related death, major bleeding, PE, asymptomatic, symptomatic DVT and all DVT	Patients were enrolled from 35 countries in North America, Europe, South America, South Africa, Asia and Australia	^20
ARTEMIS	Aged ≥60 years; acutely ill with congestive heart failure, or acute respiratory illness with chronic lung disease, or clinically diagnosed acute infection or inflammatory disorder; expected be immobilized for ≥4 days.	Fondaparinux sodium 2.5 mg once daily for 6–14 days (n = 429) Placebo once daily for 6–14 days (n = 420)	Age 75 years; Male 42%; Weight 70 kg	VTE, VTE related death, PE, symptomatic DVT and all DVT	35 centers in eight countries	^45
Belch 1981	Aged ≥40 and ≤80 years; admitted to hospital with heart failure or chest infection.	UFH 5000 units/8 h until mobile (n = 50) No prophylaxis (n = 50)	Age 66 years; Male 69%; Weight 22% obese	PE^a	1 center in Scotland	^34
CERTIFY	Hospitalized medical patients; ≥70 years; acute medical illness; significant decrease in mobility expected for ≥4 days.	Certoparin 3000 units once daily (n = 1,624) for 8–20 days UFH 5000 units/8 h (n = 1,615) for 8–20 days	Age 79 years; Male 41%; Weight 72 kg	VTE, VTE-related death, major bleeding, PE, symptomatic, asymptomatic DVT and all DVT	Recruited from 172 centers between January 2007 and June 2009	^46
Forette 1995	Aged ≥70 years; admitted to hospital for an estimated minimum duration of 4 weeks for a recent and presumed transient decrease in their locomotor autonomy; absence of existing DVT.	Nadroparin 3075 units per day for 28 days (n = 146) UFH 5000 units twice daily for 28 days (n = 149)	Age 83 years; Male 75%; Weight 59 kg	Major bleeding, PE, all DVT^b	Hospital setting (35 centers in France)	^47
LIFENOX	Aged ≥40 years; hospitalized for acute decompensation of heart failure, active cancer (unless for planned chemotherapy), or severe systemic infection; additional risk factor of chronic pulmonary disease, or obesity, or history of VTE or aged ≥60 years; expected hospitalization of at least 6 days.	Enoxaparin 40 mg once daily for 6–14 days (n = 4,174) Placebo once daily for 6–14 days (n = 4,145)	Age 65 years; Male 63%; BMI 23	VTE-related	Hospital setting. 193 sites in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia. Recruitment began in January 2008 and was completed in September 2010	^48
PREVENT	Aged ≥40 years; acute medical condition with projected hospitalization of 4 days and 3 days of prior immobilization; hospitalization for acute congestive heart failure; acute respiratory failure; infection without septic shock; acute rheumatologic disorders; inflammatory bowel disease.	Dalteparin 5000 units once daily for 14 days (n = 1,856) Placebo once daily for 14 days (n = 1,850)	Age 69 years; Male 48%; BMI 27	VTE, VTE related death, major bleeding, PE, symptomatic, asymptomatic DVT and all DVT	Between July 2001 and April 2002, 3,706 patients were enrolled at 219 study centers in 26 countries	^35

^a Only included as a sensitivity analysis in this network meta-analysis.

^b The type of DVT reported in Forette and Wolmark⁴⁷ was not specified so it could only be considered for the all DVT analysis.

Abbreviations. VTE, venous thromboembolism; ULN, upper limit of normal; DVT, deep vein thrombosis; PE, pulmonary embolism; UFH, unfractionated heparin; BMI, body mass index.

Figure 2. Results of the bias assessment. Abbreviation. ITT, intention-to-treat.

Figure 3. Risk of bias graph. Abbreviation. ITT, intention-to-treat.

Figure 4. Base case results of the network meta-analysis.

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Data availability statement

Raw data were generated at Portola Pharmaceuticals. Derived data supporting the findings of this study are available from the corresponding author (VL) on request.