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DVT Prophylaxis in Neurosurgery “Seek simplicity and distrust it” Alfred North Whitehead

DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

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Page 1: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

DVT Prophylaxis in

Neurosurgery

“Seek simplicity and distrust it”

Alfred North Whitehead

Page 2: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates
Page 3: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates
Page 4: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates
Page 5: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates
Page 6: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

54

Page 7: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates
Page 8: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

VTE Prophylaxis in Critically Ill Patients with:

Intracranial Hemorrhage

Aneurysmal Subarachnoid Hemorrhage

Traumatic Brain Injury (TBI)

Brain Tumors

Spinal Cord Injury

Page 9: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Recommendations for Prevention of VTE

in Patients Undergoing Neurosurgical and

Neurovascular Interventions in:

Elective Spine Surgery

Complicated Spinal Surgery

Elective Craniotomy

Elective Intracranial/Intra-arterial

Procedures

Intracranial Endovascular Procedures

Page 10: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

DVT, PE or VTE?

DVT is the most common, but is not

always serious

PE is the most serious, but is much less

common

If PE were always preceded by DVT, the

DVT would be a reasonable surrogate

measure, but it is not

Therefore most researchers use VTE as

the measure of choice for analysis

Page 11: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Is VTE a Reasonable Choice ?

It lumps minor superficial DVT with death

due to massive pulmonary embolism

DVT may be independent of PE, precede

PE, not be identified in patients with PE,

be disabling without leading to PE

DVT and PE may be undetected

In some studies as many as 50% of PE

have no associated DVT

Therefore, VTE probably

overestimates the risk of DVT and/or

PE with serious consequences

Page 12: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Soooo Much Data

By my count, there at least 20

randomized trials involving more than

8,000 patients assessing some

component of VTE prophylaxis

predominantly in intracranial surgery

There are also at least 4 systematic

reviews with meta analysis of the

subject(s)

Page 13: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

REF 18

RCT

refs refer to "Beyond…" paper

Ns

Pooled N

4UFH vs LMWH

23, 24 247 2Craniotomy23UFH + ICD 75LMWH + ICD 75 24UFH + ICD 48LMWH + ICD 49

25, 26 379 2Spinal surgery25200UFH + ICD LMWH + ICD 26UFH + CS 92LMWH + CS 87

19, 20 792 2CS to LMWH Mostly craniotomy19LMWH + CS 153placebo + CS 154 20LMWH + CS 241placebo + CS 244

5, 27 188 2ICD to LMWH Mostly craniotomy27ICD 60LMWH 60 5ICD 22LMWH 23ICD+LMWH 23

21, 28 203 3UFH to placebo 2Craniotomy21UFH 50placebo 50 28UFH 55placebo 48

29 50 1Spinal surgery29N=50 UFH placebo

30-32 309 4CS to ICD 3Craniotomy Can’t confirm 3rd ref Wautrecht

30N=70 ICD CS 31CS + ICD 78CS 80placebo 81

33 117 1Spinal surgery33ICD 57CS 60

34 95 1ICD to placebo Mixed craniotomy and spine

34N=95 ICD placebo

35

104 1ICD to electrical stim Mixed craniotomy and spine 35UFH 58

Calf stim +

dextran 46

Used as cohort

36 134 1Thigh ICD to foot ICD Spinal surgery Used as cohort36

ICD foot75ICD thigh 59

12Cohort

37, 38 247 7Pharmacologic 2LMWH alone Craniotomy37

LMWH150 38

LMWH97

39 2823 1LMWH and CS Craniotomy39LMWH + CS 2823

40 150 1UFH alone Craniotomy40

UFH150

41-43

1116 3UFH and ICD

Craniotomy43UFH + ICD 872 42UFH + ICD 106

Frim is used in both RCT and

cohort

41

UFH + ICD

138ICD 473

44-46 370 5Mechanical 3ICD alone Spinal surgery 44ICD 31 45ICD 200 46 139

47, 48 392 2CS and ICD Spinal Surgery 47ICD + CS 75 48ICD + CS 317

7716

Page 14: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Meta AnalysisShould simplify by pooling data

Cannot make all the included trials have

the same:

Eligibility and exclusion criteria

Choice of prophylactic method

Choice of outcome measure

and yet, pooling the data assumes that all

of these things are so similar that the

differences among the studies don’t matter

Page 15: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Khan, et al. J Neurosurg 129:906–915, 2018

Page 16: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Assumptions Underlying Meta Analyses

The risk of VTE and Intracranial

Hemorrhage is the same in cranial and

spinal patients

Page 17: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Comparing Meta Analyses

Author Number of studies RCT Cohort Spine Included DVT PE VTE

Iorio 4 no yes no yes

Collen 12 RCT, 18 cohort yes yes yes no

Hamilton 6 no no no yes

Khan 9 yes yes no no

Outcomes

Separately

Analyzed

Author Number of studies RCT Cohort Spine Included DVT PE VTE

Iorio 4 no yes no yes

Collen 12 RCT, 18 cohort yes yes yes no

Hamilton 6 no no no yes

Khan 9 yes yes no no

Outcomes

Separately

Analyzed

Page 18: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Assumptions Underlying Meta Analyses

Is the risk of VTE and Intracranial

Hemorrhage is the same in cranial and

spinal patients ?

Is it OK to include non-randomized cohorts ?

Is it OK to assume that DVT and VTE

outcomes are similar enough to pool?

Page 19: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Comparing Meta Analyses

All methods used inconsistently across studies

Author venography echo fibrinogen angio CT V/Q

Iorio

Collen

Hamilton

Khan

Methods of Diagnosis for VTE

Page 20: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Assumptions Underlying Meta Analyses

Is the risk of VTE and Intracranial

Hemorrhage is the same in cranial and

spinal patients ?

Is it OK to include non-randomized cohorts ?

Is it OK to assume that DVT and VTE

outcomes are similar enough to pool?

Is it OK to assume that using different

diagnostic methods doesn’t affect outcome?

Page 21: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Comparing Meta Analyses

All methods used inconsistently across studies

Author placebo

compression

stockings

intermittent

compression

devices

unfractionated

heparin enoxaparin nadroparin

Iorio

Collen

Hamilton

Khan

Methods of Prophylaxis

Page 22: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Assumptions Underlying Meta Analyses

Is it OK to assume that using different

methods and combinations of prophylaxis

doesn’t affect outcome?

In addition, many studies mix populations of

patients known to have different risk of VTE

(brain tumor patients subarachnoid

hemorrhage patients and other elective

intracranial surgery patients)

Page 23: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Well, let’s just assume that all those assumptions are OK

Page 24: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0.70

0.80

0.90

Iorio Collen Hamilton Khan

Odds Ratio for DVT

lower 95% ci

Odds Ratio

upper 95% ci

Odds Ratio for DVT

Iorio Collen Hamilton Khan0.00

0.90

0.50

Page 25: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Odds Ratio for ICH or Maj. Hem.

0.00

0.50

1.00

1.50

2.00

2.50

3.00

3.50

4.00

Iorio Collen Hamilton Khan

lower 95% ci

Odds Ratio

upper 95% ci

Iorio Collen Hamilton Khan0.00

3.00

1.00

2.00

4.00

Page 26: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

NNT

Author

Number of

studiesnon-pharm

prophylaxis

chemo-

prophylaxis

absolute

risk

reduction

Number

Needed

to Treat

Agnelli 4 RCT 0.290 0.161 0.129 7.74

Collen 12 RCT, 18 cohort 0.061 0.033 0.029 34.59

Hamilton 6 RCT 0.260 0.148 0.112 8.93

Khan 9 RCT 0.215 0.126 0.089 11.24

proportion with VTE

Another View

Page 27: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

NNH

Author

Number of

studiesnon-pharm

prophylaxis

chemo-

prophylaxis

absolute

risk

increase

Number

Needed to

Harm

Agnelli 4 RCT 0.0137 0.0235 0.0098 102.20

Collen 12 RCT, 18 cohort 0.0630 0.1244 0.0888 11.26

Hamilton 6 RCT 0.0400 0.0500 0.0100 100.00

Khan 9 RCT 0.0240 0.0330 0.0090 111.11

proportion with ICH or

major hemorrhage

Another View

Page 28: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

NNT NNH

Author

absolute risk

reduction

Number

Needed to

Treat

absolute

risk increase

Number

Needed to

Harm

Collen 0.03 35 0.09 11

Iorio 0.13 8 0.01 102

Hamilton 0.11 9 0.01 100

Khan 0.09 11 0.01 111

trying to simplify the comparison

Page 29: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Agnelli

Nurmohamed

Cerrato

Collen

Hamilton

KhanIorio

Constantini

Goldhauber

MacDonald

Bostrom

Bucci

Nelson

Prestar

Skillman

Turpie

Voth

Wautrecht

Wood

Dickinson

MelonGruber

Kurtoglu

Hamidi

Page 30: DVT Prophylaxis in Neurosurgery - Medical School · DVT and PE may be undetected In some studies as many as 50% of PE have no associated DVT Therefore, VTE probably overestimates

Conclusions

Meta-analysis does not fix flaws in the

included studies

Different approaches to inclusion and

exclusion lead to wildly different results

It isn’t clear which is right

More than 3 decades of uncoordinated

underpowered randomized trials have

failed to provide clear guidance on this

issue