1. EBS presentation:
Pharmacological VTE prophylaxis in
neurosurgical patients and risk of
intracranial haemorrhage
15 December 2011
Scholar: Jonathan Li
Senior scholar: Behzad Eftekhar

2. VTE and neurosurgery
• Study by Hamilton et al. (1994): • Contributing factors for increased
risk of VTE in neurosurgery patients:
- showed rate of VTE in patients
undergoing cranitomy was 25% - intracranial surgery
- risk of PE in general neurosurgical - malignancy
population was ~5% with a
mortality rate of 9 to 50%. - duration of surgery
- decreased mobility postoperatively
- postoperative paralysis

3. pharmacological VTE prophylaxis intracranial surgery
benefit of VTE prevention risk of intracranial hemorrhage

4. EBS question
• Does the use of perioperative pharmacological VTE
prophylaxis (ie heparin) provide an overall benefit for
patients undergoing elective intracranial surgery ?
P elective intracranial surgery
I pharmacological VTE prophylaxis
C placebo or non-pharmacological VTE prophylaxis
O favourable outcome
ie. reduction of VTE risk with minimal risk of
intracranial hemorrhage

6. Search Strategy
• Medline, combined search terms:
• Brain surgery (MeSH)
• Perioperative anticoagulation (MeSH)
• Perioperative hemorrhage (MeSH)
• Cochrane database
• Scopus

9. Search results
Search strategy yielded 64 articles in Medline
• 2 x systematic reviews :
(Hamilton et al, 2011) - meta-analysis of 6 RCTs
(Lorio and Agnelli, 2000)
• 2 x Randomised control trials :
(Agnelli et al, 1998)
(Nurmohamed et al, 1996)
• 3 x prospective studies :
(Chibbaro et al, 2008)
(Gerlach et al, 2003)
(Barnett et al, 1977)
• 2 x retrospective studies :
(Bauman et al, 2009) - DBS patients only
(Cage et al, 2009)

10. Non-RCT studies
Author and year Study type Study population VTE prophylaxis protocol Outcome
Cage et al 2009 Retrospective 86 patients who had 86 patient treated between 2003 and 2005 3 patients in treatment group (12.5%) and
case control craniotomy for meningioma were given clexane within 48 hrs after surgery 8 patients (12.9%) suffered postoperative
between 2000 and 2005 for 1 to 7 days. intracranial hemorrhage.
62 control patients from 2000 to 2003 did not Incidence of VTE was 0% in clexane
receive clexane group and 4.8% in non-clexane group
Chibbaro et al Prospective 746 consecutive patients Stockings and compressors. 8 (1.07%) had significant postoperative
2008 cohort undergoing intracranial Daily Tinzaparin started on 1st postoperative hemorrhage, 1 (0.13%) had fatal PE and 3
surgery day patients (0.4%) had clinically evident VTE.
Gerlach et al 2003 Prospective 2823 intracranial procedures All patients had early postoperative imaging to 43 (1.5%) had major postoperative
cohort from 1999 to 2002. rule out postoperative haemorrhage. hemorrhage,
All patients received early (within 24hrs 42 (3.2%) in the major intracranial group
46.7% were major intracranial postoperative 0.3ml Nadroparin SC daily. All and 1 (0.07%) in non-major intracranial
procedures patients received intra and postoperative group
compression stockings
Barnett et al 1977 Prospective 150 neurosurgical patient 5000 SC heparin given preoperatively and Post op complications in 7 patients (4.6%)
cohort procedures. 12hourly postoperatively for minimum of 3 4 patients developed wound seroma,
40 specific for intracranial days 2 patients developed wound hematoma
procedure and 1 patient had non-fatal PE

11. Systematic review

12. Methodology (Hamilton et al, 2011)
Data extraction:
Inclusion criteria:
• original data • type of DVT prophylaxis
• RCTs • occurrence of VTE
• DVT prophylaxis involved • occurrence of ICH
unfractionated or LMW
heparin
• Extra-cranial bleeding
(major and minor)
Exclusion criteria:
• Assessed each RCT’s
methodology
• studies that reported only
on elective spinal
neurosurgical procedures
• Stratified analysis on whether
mechanical methods of DVT
or reported on patients prophylaxis was also used
with stroke or trauma

13. Results (Hamilton et al, 2011)
Heparin 5000 units BD starting 2 hrs pre-operative vs untreated controls
Enoxaparin 20 mg daily starting 18 to 24 hrs post-operatively vs placebo
Nadroparin 7500 units daily starting 18 to 24 hrs post-operatively with stockings vs placebo and stocking s
Enoxaparin 40 mg daily starting within 24 hrs post-operatively with stockings vs placebo with stockings
Preoperative enoxaparin 30 mg at induction and then twice daily vs SCD treatment vs SCD and enoxoparin
Heparin 5000 units starting 2 hrs pre-operative and continued twice daily until patient was ambulatory vs saline placebo

14. Incidence of VTE (Hamilton et al, 2011)
• Pooled RR = 0.58
• Absolute risk reduction = 9.1%
i.e. for every 1000 patients
treated, 91 VTE events will be
prevented
NNT = 11
• heparin was protective regardless
of whether mechanical
prophylaxis was used
‣ RR=0.64 with dual prophylaxis
‣ RR=0.42 for heparin alone
• Only 2 of the studies
distinguished between proximal
symptomatic VTE and distal
screen-detected DVT

15. Incidence of VTE (Hamilton et al, 2011)
• Pooled RR = 0.58
• Absolute risk reduction = 9.1%
i.e. for every 1000 patients
treated, 91 VTE events will be
prevented
• estimated 10 to 20% of VTE are
symptomatic VTE events
➡ for every 1000 patients, 9 to 18
symptomatic VTE events will be
prevented
➡ NNT 111 to 222

16. Incidence of ICH (Hamilton et al, 2011)
• ICH was more common in
heparin group (15) vs control
group (8)
• Pooled RR = 1.48 but no
statistically significant
• Absolute risk increase = 0.7%
i.e. for every 1000 patients
treated, 7 patients could
experience ICH
• Number need to harm = 143

17. Discussion (Hamilton et al, 2011)
• Consistent finding across studies that heparin significantly reduces
rate of VTE by 42% in patient undergoing intracranial surgery
• There is an associated statistically insignificant 48% increase in risk of
ICH, a risk of that remains therapeutically plausible.
• Consideration need to be given to the clinical impact of events
caused (bleeding) and prevented (VTE).
• Study authors acknowledges the need to balance of statistical
significance with clinical significance
• Authors commented that the bleeding risk were not optimally
evaluated or reported in the studied RCTs and the studies analysed
were not well powered to study bleeding risk
• Estimate for symptomatic VTE reduction by heparin is comparable to
risk of ICH

18. Conclusion
• Does the use of perioperative pharmacological VTE
prophylaxis use provide a favourable outcome for patients
undergoing intracranial surgery?
From the available Level I evidence, the decision to use heparin prophylaxis is
not clear cut, therefore the decision should be tailored to the individual patient
and individual surgeons experience
• The ratio of likelihood of help with symptomatic VTE to the likelihood of harm
from ICH, is estimated to be between 1 to 2 suggesting symptomatic VTE
reduction is almost matched by an equal risk of ICH
• The use of heparin does significantly increase the efficacy of DVT prophylaxis
over mechanical methods
• Mechanical methods are less effective than anticoagulant prophylaxis but
should continue to play an important role in DVT prophylaxis
• The general reports in the literature is that bleeding risk is not ‘significantly’
increased in patient receiving anticoagulant prophylaxis

19. References:
Hamilton, M. G., R. D. Hull, et al. (1994). "Venous thromboembolism in neurosurgery and neurology
patients: a review." Neurosurgery 34(2): 280-296; discussion 296.
Hamilton, M. G., W. H.Yee, et al. (2011). "Venous thromboembolism prophylaxis in patients undergoing
cranial neurosurgery: a systematic review and meta-analysis." Neurosurgery 68(3): 571-581.