A meta-analysis of intracranial haemorrhage in patients with Brain tumour receiving therapeutic anticoagulation : J.I ZWICKER , R.KARP LEAF , and M. CARRIER Division of hematology-oncology # Journal club presentation I should this paper to review how safe of using the anticoagulant in Brain tumour patients.

2. Introduction
• Intracranial haemorrhage is commonly observed in both primary or
metastasis brain tumour in the absence of anticoagulation.
• Venous thromboembolism ( VTE ) พบได้ประมาณ15-30% โดยมีรายงานใน
Glioma
• Limited data to Guide appropriate treatment of Patients with Brain
tumour in setting of Anticoagulant.
• Recently research of matched cohort study in patients with Brain
metastasis that indicated anticoagulation could safely be administered
to Brain metastasis

3. AIMs
• Result of Meta-analysis in order to systematically assess the
consistency of theses finding Across studies and to evaluate whether a
similar tread regarding the safely of anticoagulation applies in the
setting of Primary brain tumour

4. Methods
• Systematic literature search strategy
• PubMed, EMBASE, GoogleScholar, Bibliographies of relevant review
and conference abstracts ( American Society of Hematology,
International Society of Thrombosis and Hemostatsis and American
Society of Clinical oncology )
• The Protocol and Systematic search strategy of the review are
documented online
• No language or publication year restrictions

5. Inclusion criteria
• Case-Control, Cohort or RCT of Any type of Malignancy with CNS
involvement
• Treatment group receiving Therapeutic Anticoagulation เช่นพวก
Wafarin, Enoxaparin or UFH
• Cohort that did not receive therapeutic anticoagulation ( with event rate
of ICH reported for both groups )

6. Primary and Secondary analysis
• Planned primary analysis was the summary statistic of the odds ratio
( OR ) of ICH in patient with brain tumours receiving anticoagulation
compare with those not receiving anticoagulation
• Planned secondary analysis included the OD of ICH for
• Patients on anticoagulation with Brian metastasis or Primary brain
tumor
• A renal cell carcinoma/ melanoma subgroup and LMWH Vs
Wafarin

7. Primary and Secondary analysis
• Articles identified in the initial search strategy were uploaded to
www.covidence.org and Two reviewers ( J.I.Z and M.C ) independently
assessed them for inclusion in the review
• Discussed potentially eligible studies
• Independently extracted data
• Mutual consensus was required for study inclusion
• The quality and Bias of Observational studies were assessed
by the Criteria recommended by the Meta-analysis of
Observational studies in EPidermiology ( MOOSE ) Group.

8. Statistical analysis
• Analyses were performed using Comprehensive Meta-Analysis ( CMA )
Version 2.2 software
• The summary statistic for ICH were obtained by calculated the odds
ratio using a Random effects model
• Heterogeneity across studies was estimated by means of the I2
statistics
• Summary analysis across studies was planned only if the I2 was not
considered high ( เช่น มีค่าน้อยกว่า 50% )

9. • Excluded on initial review based
on review article , Care report,
no relevant or anticoagulation
was not therapeutics
101
unique
Reference
19
Included
82
Excluded
7
Included
11
Excluded
• Absence of a control arm
and ICH rate not specifically
described in the control arm
• Additional two articles
( Olin et al. and Khoury et
al ) through other searches

10. Characteristics of Studies included in the meta-analysis
• 9 studies ( 3 = only metastasis , 5 = only glioma , 1 = only glioma )
• All study were retrospective cohort with no randomised trials identified
• Indication for anticoagulation were treatment of VTE in all studies, 4 of studies
included control cohort not diagnosed with VTE
• 4 studies included patients who received either LMWH or warfarin
• However, anticoagulant-specific event rates were only described in 3.

11. • In a random effects model , the pooled odds ratio for ICH in patient receive therapeutic
anticoagulation VS without anticoagulation was 2.13 ( 1.00-4.57 ; p= 0.051 )
• Heterogeneity between studies was moderate with 46% p=0.07
• The risk of ICH was no influenced by administration of LMWH Vs warfarin (pooled OR,
0.75; 95% CI, 0.24–2.33; P = 0.62; I2
= 0%).
Risk of ICH in all patients with Brain Tumor receiving Anticoagulation

12. Risk of ICH with anticoagulation with Brain metastases
• Subgroup analyses according to primary or secondary brain tumor
• No statistical increase in the OD of ICH in these studies that included
patients with brain metastasis treated with anticoagulation compared
with no anticoagulant

13. Risk of ICH with anticoagulation with Brain metastases
• Considering that RCC and Melanoma are tutors commonly associated with
the development of ICH (OR, 1.07; 95% CI, 0.61–1.88; P = 0.81; I2
= 0%).
• The pooled OD for ICH for patients with melanoma or RCC receiving
Anticoagulation VS no anticoagulation was 2.30 (95% CI, 0.80–6.59; P =
0.12; I2
= 0%).

14. Risk of ICH with anticoagulation with Primary Brain Tumours
• The administration of Therapeutic anticoagulation to patients with
glioma was associated with significant increase in ICH (pooled OR,
3.75; 95% CI, 1.42–9.95; P = 0.01; I2
= 33)

15. Description of study quality
• Only retrospective cohort studies were identified for inclusion in this
meta-analysis
• Limitations common to all studies except Donato et al. include a lack
of an a pri-ori definition of intracranial haemorrhage or blinded review
of record or radiographic images
• Only 4 presented baseline characteristic of the 2 cohorts
( anticoagulation VS no anticoagulation )
• And only Donato et al. specifically matched the two cohort
( according to tumor diagnosis, year of diagnosis of brain
metastasis, age and gender.)

16. Discussion
• The overall risk of ICH with anticoagulation tended to be higher when
considering all patients with Brain tumours, The risk appear more by
Glioma.
• The overall rate of ICH varied from 1.9 to 23%
• Variation in monitoring, definition of ICH , imaging
• The incident of Fatal ICH reported was less than 1% ( 2 / 292
patients)

17. Discussion
• The Alternative to anticoagulation is placement of IVC filter, which itself
is associated with high rate of complication.
• 62% report in literature
• Pulmonary embolism or IVC filtre thrombosis 45%
• Conclusion that Although anticoagulation does appear to increase the
risk of ICH in patient with glioma, the rate of Fatal complication is quite
low and non-anticoagulant strategies are associated with high rate of
adverse events

18. Discussion
• The rate of ICH in Metastatic melanoma and RCC was known to be
higher than other malignancies
• In their matched cohort study in 1 -year cumulative incidence
of significant ICH was 35% in groups that received therapeutic
LMWH and 34% in those who did not.
• Larger studies are required in order to definitely establish the
absolute safety of routine anticoagulation in these malignancies

19. Limitations
• 1. No prospective studies included in this meta-analysis
• 2. No prospective studies are reported looking at the incidence of ICH
with therapeutic anticoagulation with protocol-scheduled imaging.

20. Their study
• 1.The Patient with brain metastasis receiving therapeutic LMWH were
matched according to age, Dx, sex and date of Dx using computer
algorithm in order to identify a similar cohort of patients with brain
metastasis
• 2. All imaging were revised blindly to evaluate to an priori definition
• 3. These approaches were not taken in the other cohort studies in this
meta-analysis , nor were VTE rate calculated using competing risk
analysis in order to account for death as a competing risk for ICH

21. Summary
• The use of Therapeutic anticoagulation in patients with Brian tumours.
• In which the case should absence of Contraindication เช่นพวก
significant intracranial hemorrhage, severe thrombocytopenia or
coagulopathy
• The administration of anticoagulation appears to be safest in patients
with brain metastases
• Increase risk of ICH in Glioma —> higher quality studies are required in
order to better evaluate the absolute increase risk associated with
therapeutic anticoagulation.