Table 1.
Main clinical features of the studies included according to PICO criteria
| Source and author | Study design | No. of pts | Participants | Intervention | Comparator | Median follow-up | Primary outcome | Definition of major ICH |
|---|---|---|---|---|---|---|---|---|
| Lee et al14 (2021) | R | 111 | Pts with primary or secondary brain tumors who received either a DOAC or LMWH for the treatment of VTE | DOAC (55 pts): Rivaroxaban (38) Apixaban (13) Edoxaban (3) Dabigatran (1) | LMWH (56 pts): Enoxaparin | 6 mo | Incidence of any ICH within 6 mo | NR |
| Jo et al15 (2021) | R | 220 | Pts with high-grade glioma and VTE on LMWH | LMWH (88 pts) | No anticoagulation (22 pts) | 12 mo | Incidence of 1-y ICH | NR |
| Dubinski et al9(2021) | R | 46 | Pts who underwent craniotomy for primary tumor resection and PE | DOACs (14 pts): Rivaroxaban (6) Edoxaban (8) | LMWH (32 pts) | 15 mo (DOACs) and 9 mo (LMWH) | Clinical course, 6- and 12-mo follow-up and survival | Any hemorrhage that was ≥10 mL in volume, required surgical intervention, or was associated with clinical symptoms, such as nausea and vomiting, or focal neurologic deficit |
| Burth et al16 (2021) | R | 172 | Pts with glioblastoma and pts with brain metastases with (cases)/without (controls) AF | Full anticoagulation (enoxaparin 40 mg, phenprocoumon, DOAC, or heparin) vs prophylactic anticoagulation/heparin | No anticoagulation | 8.6 and 7.2 mo | Incidence of ICH in pts with glioblastoma and brain metastases with/without AF | NR |
| De Melo Junior et al17 (2020) | R | 53 | VTE pts on therapeutic anticoagulation started within the first 30 d after intracranial neurosurgical procedure (mostly primary neoplastic lesions) | Total 29 pts: warfarin | Total 21 pts: DOAC (19 rivaroxaban and 2 apixaban) or 4 pts enoxaparin 1 mg/kg twice daily | 161 d. | Risk of ICH | NR |
| Leader et al10 (2020) | R | 96 | Pts with brain metastases and anticoagulation therapy prescribed at therapeutic doses for either VTE or AF | DOAC (41 pts) Apixaban (11) Dabigatran (5) Edoxaban (8) Rivaroxaban (17) | LMWH (55 pts): Enoxaparin (34) Nadroparin (15) Tinzaparin (6) | 136 d with DOAC and 175 d with LMWH | Major ICH during 12 mo of follow-up | ICH that measured ≥10 mL in volume, required surgical intervention, or was associated with clinical symptoms, focal neurologic deficits, or changes in cognitive function |
| Horstman et al18 (2018) | R | 125 | Pts with brain metastasis with or without history of long-term (>1 mo) anticoagulation therapy | 67 pts on anticoagulant therapy: once-daily enoxaparin (1.5 mg/kg) or twice-daily enoxaparin (1 mg/kg q12h) | 58 pts: Not on anticoagulant therapy | NR | Incidence of ICH associated with anticoagulant use | NR |
| Carney et al8 (2019) | R | 172 | Pts with primary and secondary brain tumors on anticoagulation with a DOAC or LMWH for the treatment of VTE | Primary brain tumors: total 67 pts 20 with DOACs 47 with enoxaparin Brain metastases: total 105 21 with DOAC 84 with enoxaparin | Enoxaparin ≥1.5 mg/kg, once daily | NR | Major ICH within 12 mo from start of anticoagulation | ICH that measured ≥10 mL in volume, required surgical intervention, or was associated with clinical symptoms, focal neurologic deficits, or changes in cognitive function |
| Gessler et al19 (2018) | R | 35 | Pts with primary and secondary tumors who underwent craniotomy on anticoagulant treatment for cerebral vein thrombosis | Full therapeutic anticoagulation (25 pts) | Intermediate dosing of LMWH (10 pts) | 181 d | Investigate the occurrence, risk factors, and outcomes associated with the development of cerebral vein thrombosis after craniotomy | NR |
| Chai-Adisaksopha et al20 (2017) | R | 364 | Pts with primary or metastatic brain tumors with VTE (182) treated with anticoagulation and 182 control subjects (pts without brain tumors with VTE on anticoagulant treatment) | Therapeutic dose of LMWH; 5.9% pts received reduced-dose LMWH | 162 of 182 pts in the control group received therapeutic dose LMWH; 3.6% pts received-reduced dose LMWH | 6.7 mo | Incidence of the first major bleeding after starting anticoagulant therapy | |
| Mantia et al11 (2017) | R | 133 | Pts with primary brain tumors on therapeutic anticoagulation for VTE | Enoxaparin (50 pts) 1 mg/kg, twice daily (76%) or enoxaparin at 1.5 mg/kg (2 pts) or enoxaparin less than standard therapeutic dosing (8 pts) | No anticoagulation (83 pts) | NR | Major ICH from time of diagnosis of primary brain tumor | Any hemorrhage that was ≥10 mL in volume, required surgical intervention, or was associated with clinical symptoms such as nausea and vomiting, focal neurologic deficit, or change in cognitive function |
| Al Megren et al21 (2017) | R | 152 | Glioma pts with VTE or cerebral vein thrombosis | Full anticoagulation with/without IVC filter with LMWH or unfractionated heparin or fondaparinux (76 pts) | No anticoagulation: glioma pts without VTE (76 pts) | 11 mo | ICH defined as any bleeding into the cranial vault over the follow-up period | NR |
| Khoury et al22 (2016) | R | 173 | Pts with glioblastoma and VTE with/without anticoagulation | Total 97 pts: LMWH (69), warfarin (26), heparin (2) | No treatment: 76 pts | 6.1 mo | Incidence of ICH | NR |
| Donato et al3 (2015) | R | 293 | Pts with brain metastasis on therapeutic enoxaparin for the treatment of VTE | Enoxaparin 1 mg/kg twice daily (76 pts), 1.5 mg/kg once daily (17 pts), and modified dose-reduced therapeutic dosing (11 pts) | 189 controls: no anticoagulation | NR | Measurable (>1 mL in volume) ICH from initial diagnosis of brain metastases | Larger volume bleeds (>10 mL), the presence of new symptoms, or the need for surgical intervention |
| Smith et al23 (2015) | R | 69 | Pts who underwent surgical resection of primary or metastatic brain tumor | Full anticoagulation with warfarin, enoxaparin, heparin, dalteparin | Prophylactic doses of heparin or enoxaparin | NR | Determine the risk factors for VTE in pts who underwent neurosurgical resection of brain tumors | NR |
| Yust-Katz et al24 (2015) | R | 64 | Pts with glioblastoma who developed a VTE during the course of their disease | Anticoagulation alone in 36 pts (8 with Coumadin and 28 with LMWH) | 2 pts had IVC filter alone and 21 pts received both an IVC filter and anticoagulation | NR | Estimate the frequency of VTE in glioblastoma pts and identify potential risk factors for the development of VTE during adjuvant chemotherapy | NR |
| Chaichana et al25 (2013) | R | 126 | Pts who underwent surgery for primary or metastatic brain tumors | Total: 109 81 treated with heparin, 28 with enoxaparin | Total: 17 pts who had vena cava filters placed | NR | The incidence of perioperative VTE and of treatment-related complication | NR |
| Aishima and Yoshimoto26 (2013) | R | 23 | Pts who underwent surgery for primary or metastatic brain tumors | Screening cohort with serum D-dimer level | Nonscreening cohort | NR | The effectiveness and safety of screening strategy for the detection and prevention of VTE | NR |
| Alvarado et al27 (2012) | R | 74 | Pts with melanoma with brain metastasis and VTE | Total: 57 pts Anticoagulation alone in 26 pts, 31 also IVC filter placement | No coagulation in 17 pts: 13 had IVC filter, 4 only supportive measures | 3.4 mo | Risk and benefits of systemic anticoagulation in these pts | NR |
| Norden et al4 (2011) | R | 282 | Pts with glioma treated with bevacizumab and anticoagulants for VTE | Total 64: Enoxaparin (49) Dalteparin (1) Fondaparinux (1) Warfarin (13) | 218 pts treated without anticoagulation | NR | Hemorrhagic risk of concurrent use of bevacizumab and anticoagulants in glioma pts | Any hemorrhage of grade 3 or greater |
| Pan et al28 (2009) | R | 39 | Pts with glioblastoma with VTE or ICH | Total: 25 pts Fourteen with IVC filter and anticoagulation, 11 with anticoagulation without IVC filter | Total: 14 pts Pts with IVC filter without anticoagulation | NR | Incidence of initial and recurrent compared with the incidence of ICH in pts with glioblastoma | NR |
| Nghiemphu et al12 (2008) | R | 265 | Pts with gliomas who were treated concurrently with bevacizumab and anticoagulation for VTE | Total: 21 pts Nine on LMWH and 12 on warfarin | Total: 244 pts No anticoagulation | 184 d | Incidence of major ICH | ICH with severe neurologic deficits |
| Ghanim et al29 (2007) | R | 175 | Patients with VTE and primary or metastatic brain tumors and/or brain hemorrhage | Anticoagulants (total 39 pts): Prophylactic dose (7 pts) or therapeutic dose (32 pts) | Vena cava filter (136 pts) | 92 d | Mortality risk for VTE between pts treated with IVF and anticoagulants | NR |
| Schiff and DeAngelis5 (1994) | R | 42 | Pts with brain metastases who experienced VTE | Total: 42 29 on IV heparin followed by warfarin 2 on IV heparin 2 with warfarin alone 7 with IV heparin and subcutaneous heparin 2 with IV heparin, subcutaneous heparin, and warfarin | IVC filters | 88 d | The efficacy and complications of filters and anticoagulation | NR |
| Quevedo et al30 (1994) | R | 16 | Pts with primary brain tumors | Heparin followed by warfarin sodium | No anticoagulation | NR | The associations between VTE and factors related to the risk of occurrence of VTE. | NR |
| Altschuler et al31 (1990) | R | 23 | Pts with malignant glioma treated with anticoagulant therapy for VTE | Continuous IV heparin and an oral dose of 10 mg of warfarin | NR | NR | Safety and effectiveness of anticoagulation treatment of VTE | NR |
| Olin et al32 (1987) | R | 49 | Pts with primary and secondary brain tumors with VTE | Total 25 pts: IV heparin sodium at continuous infusion of 500 U/kg once daily or warfarin (17 pts) | Total: 24 pts treated with IVC filter | NR | The complications and mortality between pts treated with IVC filter and anticoagulants | NR |
| Choucair et al33 (1987) | R | 36 | Pts with malignant gliomas with a score of ≥60% on the Karnofsky performance scale who underwent intracranial surgery | Total: 22 pts IV heparin for 7-10 d followed by subcutaneous heparin (5000-8000 U twice daily) for at least 3 mo or oral warfarin | Total: 14 pts No anticoagulation | NR | Risk of ICH in pts with malignant gliomas, treated with anticoagulant for late postoperative thromboembolism | NR |
| Ruff and Posner34 (1983) | R | 266 | Pts with malignant astrocytoma or glioblastoma multiforme | Total: 95 pts IV heparin for 7-14 d, followed by warfarin for 6 to 14 wk | Total: 171 pts No anticoagulant | 96 wk and group 2 for 36 wk | Incidence, prevention, and treatment of VTE | NR |
| Ruff and Posner35 (1981) | R | 375 | Pts with malignant astrocytomas | Total: 103 pts Heparin followed by warfarin for 6 to 14 wk | Total: 272 pts No anticoagulation | NR | Incidence of VTE and the risk of systemic anticoagulation | NR |
AF, atrial fibrillation; IVC, inferior vena cava; NR, not reported; PE, pulmonary embolism; pts, patients; PICO, Patient/Population, Intervention, Comparison and Outcomes; R, retrospective.