Table 1 Main characteristics of randomized controlled trials included in the pooled analysis

Study design

Non inferiority Randomized, open label, noninferiority trial with blinded central outcome adjudication

Randomized, open-label, pilot trial with blinded central outcome adjudication

Randomized, open label, superiority trial with blinded central outcome adjudication

Randomized, open label, noninferiority trial with blinded central outcome adjudication

Randomized, open label, noninferiority trial with blinded central outcome adjudication

Randomized cohort of an unblinded hybrid comparative effectiveness non-inferiority trial

Number of randomized patients

1050

406

300

1170

158

671

Type of patients included

Patients with active cancer and symptomatic or incidental popliteal, femoral or iliac or IVC DVT, symptomatic or incidental PE

Patients with active cancer and symptomatic DVT, symptomatic PE, or incidental PE

Active cancer patients with acute DVT (including upper extremity), PE, splanchnic or cerebral vein thrombosis

Patients with active or recent cancer and acute DVT or PE

Patients with active cancer and acute DVT or PE at high risk of recurrent VTE

Patients with cancer and acute VTE

Mean Age (years)

64

67

64

67

69

Not reported

Male sex

52%

53%

48%

49%

49%

Not reported

Type of cancers included

Colorectal: 15%

Lung: 15%

Breast: 12%

Genitourinary: 13%

Gynecologic: 11%

Pancreatic or hepatobiliary: 9%

Upper gastrointestinal: 5%

Hematological malignancies: 11%

Other: 10%

Colorectal: 25%

Lung: 12%

Breast: 10%

Genitourinary: 17%

Gynecologic: 10%

Pancreatic or hepatobiliary: 8%

Upper gastrointestinal: 10%

Hematological malignancies: 8%

Other: 10%

Colorectal: 16%

Lung: 17%

Breast: 9%

Genitourinary: 9%

Gynecologic: 10%

Pancreatic or hepatobiliary: 16%

Upper gastrointestinal: 4%

Hematological malignancies: 8%

Other: 11%

Colorectal: 20%

Lung: 17%

Breast: 13%

Genitourinary: 9%

Gynecologic: 10%

Pancreatic or hepatobiliary: 8%

Upper gastrointestinal: 5%

Hematological malignancies: 7%

Other: 11%

Gastro-intestinal: 20%

Lung: 18%

Breast: 12%

Genitourinary: 13%

Gynecologic: 8%

Hematological malignancies: 8%

Other: 21%

Not reported

Metastatic disease

52.9%

58.0%

64.3%

67.9%

72.8%

Not reported

Treatment allocation

Intervention (edoxaban)

Control

(dalteparin)

Intervention (rivaroxaban)

Control

(dalteparin)

Intervention (apixaban)

Control

(dalteparin)

Intervention (apixaban)

Control

(dalteparin)

Intervention (rivaroxaban)

Control

(dalteparin)

Intervention (DOAC)

Control

(LMWH)

Therapeutic dose of LMWH for at least 5 days followed by edoxaban 60 or 30 mg once daily

Dalteparin 200 IU/kg once daily for 1 month followed by 150 IU/kg once daily

Rivaroxaban 15 mg twice daily for 21 days, followed by 20 mg once daily

Dalteparin 200 IU/kg once daily for 1 month followed by 150 IU/kg once daily

Apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily

Dalteparin 200 IU/kg once daily for 1 month followed by 150 IU/kg once daily

Apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily

Dalteparin 200 IU/kg once daily for 1 month followed by 150 IU/kg once daily

Rivaroxaban 15 mg twice daily for 21 days, followed by 20 mg once daily

Dalteparin 200 IU/kg once daily for 1 month followed by 150 IU/kg once daily

Any DOAC at the discretion of the treating investigator in accordance with the drug's FDA package insert

Any approved LMWH at the discretion of the treating investigator in accordance with the drug's FDA package insert

Duration of follow-up

12 months

6 months

6 months

6 months

3 months

6 months

Primary outcome

Composite of recurrent VTE or major bleeding

Recurrent VTE

Major bleeding including fatal bleeding

Efficacy: Recurrent VTE

Safety: Major bleeding

Efficacy: Composite of recurrent VTE and worsening of pulmonary vascular or venous obstruction on systematic examinations

Safety: Major bleeding

Efficacy: Recurrent VTE

Safety: Major bleeding

Secondary outcomes

Recurrent VTE

Major bleeding

CRNMB

Mortality

Major bleeding

CRNMB

Mortality

Recurrent VTE

CRNMB

Mortality

CRNMB

Mortality

CRNMB

Mortality

Recurrent VTE

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

7.9%

11.3%

4%

11%

0.7%

6.3%

5.6%

7.9%

6.4%

10.1%

6.1%

8.8%

HR (95% CI) for recurrent VTE

0.71 (95% CI 0.48–1.06)

0.43 (95% CI 0.19–0.99)

0.099 (95% CI 0.013–0.780)

0.63 (95% CI 0.37–1.07)

0.75 (95% CI 0.21–2.66)

Not reported

Major bleeding

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

6.9%

4%

6%

4%

0%

1.4%

3.8%

4%

1.4%

3.7%

5.2%

5.6%

HR (95% CI) for Major bleeding

1.77 (95% CI 1.03–3.04)

1.83 (95% CI 0.68–4.96)

Not estimable

0.82 (95% CI 0.40–1.69)

0.36 (95% CI 0.04–3.43)

Not reported

CRNMB

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

14.6%

11.1%

13%

4%

6.2%

4.9%

9%

6%

10.8%

6.1%

5.8%

2.6%

HR (95% CI) for CRNMB

1.38 (95% CI 0.98–1.94)

3.76 (95% CI 1.63–8.69)

–

1.42 (95% CI 0.88–2.30)

–

Not reported

Mortality

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

Intervention

Control

39.5%

36.6%

23.6%

27.6%

16%

11%

23.4%

26.4%

25.7%

23.8%

21.5%

18.4%

HR (95% CI) for mortality

1.12 (95% CI 0.92–1.37)

0.82 (95% CI 0.62–1.09)

1.05 (95% CI 0.56–1.97)

Not reported