Study designs and outcomes of randomized trials that compared a DOAC with a LMWH for the treatment of cancer-associated VTE
| Name of trial . | Hokusai VTE Cancer31 2018 . | SELECT-D34 2018 . | ADAM-VTE33 2019 . | Caravaggio32 2020 . |
|---|---|---|---|---|
| DOAC evaluated | Edoxaban | Rivaroxaban | Apixaban | Apixaban |
| No. of patients | 1050 | 406 | 287 | 1155 |
| Hematologic malignancy, n (%) | 111 (10.6) | 33 (8.1) | 28 (9.3) | 85 (7.4) |
| Lymphoma, n (%) | Not reported | Lymphoma 23 (5.7); CLL 3 (0.7) | 16 (5.3) | Not reported |
| Study design | Noninferiority | Pilot trial | Superiority | Noninferiority |
| Primary outcome | Composite of recurrent VTE or major bleeding | Recurrent VTE | Major bleeding | Recurrent VTE |
| Exclusion criteria* | ||||
| Cancer type | Basal-cell or squamous-cell carcinoma of the skin | Basal-cell or squamous-cell carcinoma of the skin, esophageal or gastro-esophageal cancer | Not specified | Basal-cell or squamous-cell carcinoma of the skin, primary brain tumor known brain mets; acute leukemia |
| Life expectancy | <3 mo | Not specified | <60 d | <6 mo |
| Platelets (×109/L) | <50 | <100 | <50 | <75 |
| Antiplatelet use | Aspirin >100 mg daily, other antiplatelet agents, or chronic NSAIDs | Aspirin >75 mg daily or dual antiplatelet therapy | Not specified | Aspirin >165 mg daily or other antiplatelet agents |
| Drug interaction | P-gp inhibitors | Strong CYP3A4 inhibitors or inducers | Strong CYP3A4 inducers | Strong CYP3A4 or P-gp inhibitors or inducers |
| Other | Not applicable | Weight <40 kg | Not applicable | Recent brain, spinal or ophthalmic surgery |
| Qualifying index event (symptomatic and unsuspected events unless specified) | PE: segmental or more proximal; DVT: lower-limb proximal; other sites: none | PE: type not reported; DVT: lower-limb proximal (symptomatic only); other sites: none | PE: type not reported; DVT: lower or upper-limb; other sites: splanchnic, cerebral vein | PE: segmental or more proximal; DVT: lower-limb proximal; other sites: none |
| Outcome recurrent VTE | PE: subsegmental (symptomatic), segmental or more proximal (symptomatic or unsuspected); DVT: lower-limb distal (symptomatic) or proximal (symptomatic or unsuspected) | PE: vessel greater than 2.5 mm or more proximal (symptomatic or unsuspected); DVT: lower-limb proximal (symptomatic) | Any venous or arterial thromboembolism including (PE, VTE, MI, stroke, TIA, arterial thromboembolism) (symptomatic or unsuspected) | PE: segmental or more proximal (symptomatic or unsuspected); DVT: lower-limb (symptomatic or unsuspected) or upper limb (symptomatic) |
| DOAC regimen | LMWH for ≥5 d followed by edoxaban 60 mg PO daily | Rivaroxaban 15 mg twice daily for 3 wk then 20 mg once daily | Apixaban 10 mg twice daily for 7 d followed by 5 mg twice daily | Apixaban 10 mg twice daily for 7 d followed by 5 mg twice daily |
| DOAC dose reduction | 30 mg daily if CrCl 30-50 mL/min, weight ≤60 kg, or use of P-gp inhibitors | No | 2.5 mg twice daily for the use of strong CYP3A4 and/or P-gp inhibitors | No |
| Duration of anticoagulant therapy | 12 mo | 6 mo | 6 mo | 6 mo |
| Composite rVTE or major bleeding DOAC vs LMWH, n (%) | 67 (12.8) vs 71 (13.5)† | Not reported | Not reported | 51 (8.9) vs 66 (11.4) |
| Recurrent VTE, DOAC vs LMWH, n (%) | 41 (7.9) vs 59 (11.3)† | 8 (3.9) vs 18 (8.9) | 1 (0.7) vs 9 (6.3) | 32 (5.6) vs 46 (7.9) |
| Major bleeding, DOAC vs LMWH, n (%) | 36 (6.9) vs 21 (4)† | 11 (5.4) vs 6 (3) | 0 vs 2 (1.4) | 22 (3.8) vs 23 (4) |
| Any bleeding, DOAC vs LMWH, n (%) | 97 (18.6) vs 73 (13.9)† | 36 (17.7) vs 13 (6.4) | 9 (6.2) vs 9 (6.3) | 70 (12.2) vs 56 (9.7) |
| Death, DOAC vs LMWH, n (%) | 6 mo: 140 (26.8) vs 127 (24.2) 12 mo: 206 (39.5) vs 192 (36.6) | 6 mo: 48 (23.6) vs 56 (27.6) | 6 mo: 23 (16) vs 15 (11) | 6 mo: 135 (23.4) vs 153 (26.4) |
| Name of trial . | Hokusai VTE Cancer31 2018 . | SELECT-D34 2018 . | ADAM-VTE33 2019 . | Caravaggio32 2020 . |
|---|---|---|---|---|
| DOAC evaluated | Edoxaban | Rivaroxaban | Apixaban | Apixaban |
| No. of patients | 1050 | 406 | 287 | 1155 |
| Hematologic malignancy, n (%) | 111 (10.6) | 33 (8.1) | 28 (9.3) | 85 (7.4) |
| Lymphoma, n (%) | Not reported | Lymphoma 23 (5.7); CLL 3 (0.7) | 16 (5.3) | Not reported |
| Study design | Noninferiority | Pilot trial | Superiority | Noninferiority |
| Primary outcome | Composite of recurrent VTE or major bleeding | Recurrent VTE | Major bleeding | Recurrent VTE |
| Exclusion criteria* | ||||
| Cancer type | Basal-cell or squamous-cell carcinoma of the skin | Basal-cell or squamous-cell carcinoma of the skin, esophageal or gastro-esophageal cancer | Not specified | Basal-cell or squamous-cell carcinoma of the skin, primary brain tumor known brain mets; acute leukemia |
| Life expectancy | <3 mo | Not specified | <60 d | <6 mo |
| Platelets (×109/L) | <50 | <100 | <50 | <75 |
| Antiplatelet use | Aspirin >100 mg daily, other antiplatelet agents, or chronic NSAIDs | Aspirin >75 mg daily or dual antiplatelet therapy | Not specified | Aspirin >165 mg daily or other antiplatelet agents |
| Drug interaction | P-gp inhibitors | Strong CYP3A4 inhibitors or inducers | Strong CYP3A4 inducers | Strong CYP3A4 or P-gp inhibitors or inducers |
| Other | Not applicable | Weight <40 kg | Not applicable | Recent brain, spinal or ophthalmic surgery |
| Qualifying index event (symptomatic and unsuspected events unless specified) | PE: segmental or more proximal; DVT: lower-limb proximal; other sites: none | PE: type not reported; DVT: lower-limb proximal (symptomatic only); other sites: none | PE: type not reported; DVT: lower or upper-limb; other sites: splanchnic, cerebral vein | PE: segmental or more proximal; DVT: lower-limb proximal; other sites: none |
| Outcome recurrent VTE | PE: subsegmental (symptomatic), segmental or more proximal (symptomatic or unsuspected); DVT: lower-limb distal (symptomatic) or proximal (symptomatic or unsuspected) | PE: vessel greater than 2.5 mm or more proximal (symptomatic or unsuspected); DVT: lower-limb proximal (symptomatic) | Any venous or arterial thromboembolism including (PE, VTE, MI, stroke, TIA, arterial thromboembolism) (symptomatic or unsuspected) | PE: segmental or more proximal (symptomatic or unsuspected); DVT: lower-limb (symptomatic or unsuspected) or upper limb (symptomatic) |
| DOAC regimen | LMWH for ≥5 d followed by edoxaban 60 mg PO daily | Rivaroxaban 15 mg twice daily for 3 wk then 20 mg once daily | Apixaban 10 mg twice daily for 7 d followed by 5 mg twice daily | Apixaban 10 mg twice daily for 7 d followed by 5 mg twice daily |
| DOAC dose reduction | 30 mg daily if CrCl 30-50 mL/min, weight ≤60 kg, or use of P-gp inhibitors | No | 2.5 mg twice daily for the use of strong CYP3A4 and/or P-gp inhibitors | No |
| Duration of anticoagulant therapy | 12 mo | 6 mo | 6 mo | 6 mo |
| Composite rVTE or major bleeding DOAC vs LMWH, n (%) | 67 (12.8) vs 71 (13.5)† | Not reported | Not reported | 51 (8.9) vs 66 (11.4) |
| Recurrent VTE, DOAC vs LMWH, n (%) | 41 (7.9) vs 59 (11.3)† | 8 (3.9) vs 18 (8.9) | 1 (0.7) vs 9 (6.3) | 32 (5.6) vs 46 (7.9) |
| Major bleeding, DOAC vs LMWH, n (%) | 36 (6.9) vs 21 (4)† | 11 (5.4) vs 6 (3) | 0 vs 2 (1.4) | 22 (3.8) vs 23 (4) |
| Any bleeding, DOAC vs LMWH, n (%) | 97 (18.6) vs 73 (13.9)† | 36 (17.7) vs 13 (6.4) | 9 (6.2) vs 9 (6.3) | 70 (12.2) vs 56 (9.7) |
| Death, DOAC vs LMWH, n (%) | 6 mo: 140 (26.8) vs 127 (24.2) 12 mo: 206 (39.5) vs 192 (36.6) | 6 mo: 48 (23.6) vs 56 (27.6) | 6 mo: 23 (16) vs 15 (11) | 6 mo: 135 (23.4) vs 153 (26.4) |
Primary end points in bold. All trials compared the DOAC to dalteparin 200 IU/kg daily for a month then dose reduced to 150 IU/kg daily.
ADAM-VTE, apixaban and dalteparin in active malignancy-associated venous thromboembolism; CrCl, creatinine clearance as per Crockoff Gault equation; CYP3A4, cytochrome P450 3A4; Hgb, hemoglobin g/L; mets, metastases; MI, myocardial infarction; NSAID, nonsteroidal anti-inflammatory; P-gp, permeability-glycoprotein; Plt, platelet count (× 109/L); rVTE, recurrent VTE; SELECT-D, selected cancer patients at risk of recurrence of venous thromboembolism; TIA, transient ischemic attack.
All trials excluded patients with Eastern Cooperative Oncology Group 3 or 4, impaired liver function, pregnancy, creatinine clearance <30 mL/min, or history of heparin-induced thrombocytopenia. Most trials excluded bacterial endocarditis, uncontrolled hypertension, thrombectomy, vena cava filter insertion, or thrombolysis.
Reported at 12 mo in Hokusai VTE Cancer, whereas other studies reported at 6 mo.