Online Supplement - Journal of Neurology, Neurosurgery ...

Online Supplement

Title: Meta-analysis of Timing of Endovascular Aneurysm Treatment in Subarachnoid Haemorrhage: Treatment Within 1-Day May Reduce Poor

Outcome, However Results Inconsistent

Authors:

Sapna Rawal, MD. Division of Neuroradiology, Joint Department of Medical Imaging, Toronto Western Hospital, University Health Network;

Institute of Health Policy, Management and Evaluation; University of Toronto (Toronto, Canada).

Paula Alcaide-Leon, MD. Division of Neuroradiology, Department of Medical Imaging, St. Michael’s Hospital; University of Toronto (Toronto,

Canada)

R. Loch Macdonald, MD. Division of Neurosurgery, St. Michael’s Hospital, Labatt Family Centre of Excellence in Brain Injury and Trauma

Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, Department of Surgery; University of Toronto

(Toronto, Canada)

Gabriel J. E. Rinkel, MD, FRCPE. Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus, University Medical Center

(Utrecht, The Netherlands)

J. Charles Victor, MSc. Institute for Clinical Evaluative Sciences; Institute of Health Policy, Management and Evaluation, University of Toronto

(Toronto, Ontario).

Timo Krings, MD, PhD. Division of Neuroradiology, Joint Department of Medical Imaging, Toronto Western Hospital, University Health

Network; University of Toronto (Toronto, Canada).

Moira K. Kapral, MD. Division of General Internal Medicine and Toronto General Research Institute, Department of Medicine, University

Health Network; Institute for Clinical Evaluative Sciences; Department of Medicine and Institute of Health Policy, Management and Evaluation,

University of Toronto (Toronto, Ontario).

Andreas Laupacis, MD. Department of Medicine, St. Michael's Hospital, Li Ka Shing Knowledge Institute, Institute for Clinical Evaluative

Sciences; Institute of Health Policy, Management and Evaluation, University of Toronto (Toronto, Ontario).

Online Supplement Contents: Table I: Risk of bias grading criteria based on Newcastle-Ottawa Scale

Table II: Risk of bias grading score based on Newcastle-Ottawa Scale

Table III: Timing categorization of included studies

Table IV: Poor outcome – distribution of confounders (poor grade SAH and age) in early versus late treatment groups

Table V: Case fatality – distribution of confounders (poor grade SAH and age) in early versus late treatment groups

Figure I: Funnel Plot – Poor Outcome

Figure II: Funnel Plot – Case Fatality

Appendix: Search Strategy

Table I: Risk of bias grading criteria based on Newcastle-Ottawa Scale

Reference: Wells GA, Shea B, O'Connell D, Peterson J, Welch V, Losos M, Tugwell P. The Newcastle-Ottawa Scale (NOS) for

assessing the quality of nonrandomised studies in meta-analyses. (Accessed July 5, 2016, at

http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.)

Categories Details Points

Selection

Representativeness of the exposed cohort

Documented SAH of aneurysmal source treated by endovascular coiling as the primary treatment modality,

without other restrictive selection criteria 1

Selection of the non exposed cohort Documented that treatment delay not due to clinical decision to delay treatment 1

Ascertainment of exposure Time to treatment defined as time from SAH ictus to treatment 1

Demonstration that outcome of interest was not present at

start of study Outcome (poor functional status/mortality) not present at baseline 1

Comparability

Comparability of cohorts on the basis of the design or

analysis

Baseline / pre-treatment neurologic status (good vs poor) similarly distributed between early and late

timing groups (statistical testing) 1

Age similar between early and late timing groups (statistical testing) 1

Outcome

Assessment of outcome Blinded / objectively reported, not survey or self-report 1

Was follow-up long enough for outcomes to occur? 6 months for poor functional outcome/mortality 1

Adequacy of follow up of cohorts loss to follow-up <10% 1

TOTAL 9

http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.

Table II: Risk of bias grading score (based on Newcastle-Ottawa Scale)

Study Selection

(4)

Comparability

(2)

Outcome

(3)

Total

(9) Notes

ApSimon

1998 2 1 1 4

In early part of study, only failed or high surgical risk aneurysms treated with coiling; uncertainty regarding

treatment delay, distribution of age unknown, short follow-up from unclear sources

Baltsavias

2000 4 0 2 6

↑ Poor grade SAH in early treatment group, uncertain age distribution; outcome assessment non-blinded/self-

report (mailed questionnaire or telephone)

Byrne 2001 2 0 2 4 Pre-1994, only non-operable patients included; ↑ poor grade SAH in early treatment group; distribution of age

not assessed; outcome assessment non-blinded

Consoli 2013 4 0 2 6 ↑Poor grade SAH in early treatment group; age distribution not assessed; outcome assessment non-

blinded/self-report (telephone)

Dorhout Mees

2012 2 0 2 4

ISAT trial cohort (not generalizable); may be underlying reasons for treatment delay; unknown distribution of

baseline variables in coiling group; outcome assessment by self-reported questionnaire

Gu 2012 4 2 1 7 Outcome assessment non-blinded, loss to follow-up

Johansson

2004 3 0 2 5 Elderly patients only; unknown distribution of baseline clinical variables; outcome assessment not blinded

Lawson 2010 4 2 1 7 Assessed outcome at discharge (ie: inadequate follow-up), not blinded

Luo 2015 3 2 1 6

Restricted to poor grade patients; clearly documented that delayed treatment was not due to clinical decision

but other factors; no statistical difference in age and WFNS bw groups; some patients interviewed over

telephone for outcomes; no mention of loss to follow up (patients without routine follow up were excluded )

Norback 2005 4 0 2 6 Unknown distribution of baseline clinical variables; outcome assessment not blinded

Oudshoorn

2014 (UMC) 3 2 2 7 No information on why treatment delayed; short follow-up

Oudshoorn

2014 (ISAT) 2 1 1 4 ISAT cohort; WFNS not equally distributed; outcome by self reported questionnaires, short follow-up

Phillips 2011 3 0 1 4 Coiling not primary treatment modality, unknown distribution of baseline clinical variables; outcome

assessment non-blinded, loss to follow-up

Qian 2014 2 2 1 5 Excluded cases with diagnostic CT performed >6-hours post SAH; uncertain whether coiling primary modality

and reasons for treatment delay, outcome assessment not blinded, loss to follow-up

Sandstrom

2013 3 1 2 6 Restricted to poor grade patients; age distribution uncertain; loss to follow-up

Sluzewski

2003 2 0 1 3

In early part of study, only high surgical risk aneurysms treated with coiling; unknown distribution of baseline

clinical variables; outcome assessment not blinded; only mean follow-up time provided

Wikholm

2000 3 1 1 5

Rejected clipping as first choice, age distribution unknown, no mention of blinding, outcomes assessed at

discharge

Table III: Timing categorization of included studies

Abbreviations: NS – not specified

STUDY

Number of timing

categories

Upper limit of earliest timing

category (days)

Upper limit of next timing

category (days)


category (days)


category (days)

ApSimon 1998 4 4 14 28 NS

Baltsavias 2000 3 2 10 30 .

Byrne 2001 2 6 30 . .

Consoli 2013 3 0.5 2 NS .

Dorhout Mees 2012 4 2 4 10 NS

Gu 2012 2 1 NS . .

Johansson 2004 3 3 10 21 .

Lawson 2010 2 3 10 . .

Luo 2015 2 1 NS . .

Norback 2005 3 3 10 21 .

Oudshoorn 2014 (UMC) 2 1 3 . .

Oudshoorn 2014 (ISAT) 2 1 3 . .

Phillips 2011 4 1 3 10 NS

Qian 2014 4 1 3 10 NS

Sandstrom 2013 2 1 NS . .

Sluzewski 2003 2 3 60 . .

Wikholm 2000 2 2 15 . .

Table IV: Poor outcome – distribution of confounders (poor grade SAH and age) in early versus late treatment groups

Definition of "early"

(days) STUDY

Definition of “late"

(h/d)

Poor grade SAH early

group (%)

Poor grade SAH late

group (%)

P-value (Chi-

Square)

Mean age early

group (SD)

Mean age late

group (SD)

P-value (t-

test)

1

Oudshoorn 2014

(UMC) 24-72h 32.8 23.9 0.27 55.1 (12.2) 56.6 (14.3) 0.49

Oudshoorn 2014

(ISAT) 24-72h 16.7 4.9 0.005* 49.4 (10.9) 50.8 (10.7) 0.82

Phillips 2011 24-72h N/A N/A 0.81 N/A N/A 0.50

Qian 2014 24-72h 4.1 6.4 0.49 56.2 56.3 NS

Gu 2012 >24h 28.6 22.5 0.50 74.5 75.7 0.20

Luo 2015 >24h 100 100 - 62.6 55.6 0.11

Phillips 2011 >24h N/A N/A N/A* N/A N/A N/A*

Qian 2014 >24h 4.1 5.6 0.47 56.2 55.5 NS

Sandstrom 2013 >24h 100 100 - N/A N/A N/A*

2

Baltsavias 2000 3-30d 29.9 19.5 0.005* 48.9 51.4 N/A*

Consoli 2013 >48h 33.0 13.4 0.0001* N/A N/A N/A*

Dorhout Mees 2012 >2d N/A N/A N/A* N/A N/A N/A*

3

Johansson 2004 4-21d N/A N/A N/A* N/A N/A N/A*

Lawson 2010 4-10d 29.4 35.7 0.32 58 53 0.26

Norback 2005 4-21d N/A N/A N/A* N/A N/A N/A*

Phillips 2011 >72h N/A N/A N/A* N/A N/A N/A*

Qian 2014 >72h 4.5 5.4 0.72 56.2 55.4 NS

Sluzewski 2003 4-60d N/A N/A N/A* N/A N/A N/A*

4 ApSimon 1998 >4d 15.0 3.2 0.29 N/A N/A N/A*

6 Byrne 2001 6-30d 29.2 19.4 0.048* N/A N/A N/A*

Abbreviations: h – hours; d – days; NS – not statistically significant (p-value not provided); N/A – not available, cannot be calculated

from provided data

Annotations:

* Comparability of groups not demonstrated (statistically significant difference between groups, or data not available)

Table V: Case fatality – distribution of confounders (poor grade SAH and age) in early versus late treatment groups

Definition of "early"

(days) STUDY

Definition of “late"

(h/d)

Poor grade SAH early

group (%)

Poor grade SAH late

group (%)

P-value (Chi-

Square)

Mean age early

group (SD)

Mean age late

group (SD)

P-value (t-

test)

1

Oudshoorn 2014

(UMC) 24-72h 32.8 23.9 0.27 55.1 (12.2) 56.6 (14.3) 0.49

Oudshoorn 2014

(ISAT) 24-72h 16.7 4.9 0.005* 49.4 (10.9) 50.8 (10.7) 0.82

Qian 2014 24-72h 4.1 6.4 0.49 56.2 56.3 NS

Qian 2014 >24h 4.1 5.6 0.47 56.2 55.5 NS

2 Baltsavias 2000 3-30d 29.9 19.5 0.005* 48.9 51.4 N/A*

Consoli 2013 >48h 33.0 13.4 0.0001* N/A N/A N/A*

Wikholm 2000 3-15d N/A N/A NS N/A N/A N/A*

3 Lawson 2010 4-10d 29.4 35.7 0.32 58 53 0.26

Qian 2014 >72h 4.5 5.4 0.72 56.2 55.4 NS

Abbreviations: h – hours; d – days; NS – not statistically significant (p-value not provided); N/A – not available, cannot be calculated

from provided data

Annotations:

* Comparability of groups not demonstrated (statistically significant difference between groups, or data not available)

Figure I: Funnel Plot – Poor Outcome

Figure II: Funnel Plot – Case Fatality

Appendix: Search Strategy (up to date as of August 12, 2015)

Database: Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) <1946 to Present>

Search Strategy:

--------------------------------------------------------------------------------

1 exp Subarachnoid Hemorrhage/ (15993)

2 intracranial hemorrhages/ or cerebral hemorrhage/ (29936)

3 intracranial aneurysm/ (20870)

4 rupture, spontaneous/ (17187)

5 3 and 4 (1846)

6 aneurysm, ruptured/ (5401)

7 exp brain/ or exp meninges/ (965694)

8 6 and 7 (465)

9 ((subarachnoid or arachnoid) adj6 (haemorrhage$ or hemorrhage$ or bleed$ or blood$)).tw. (17720)

10 vasospasm, intracranial/ (2192)

11 ((cerebral or intracranial or cerebrovascular) adj6 (vasospasm or spasm)).tw. (3806)

12 sah.tw. (6744)

13 1 or 2 or 5 or 8 or 9 or 10 or 11 or 12 (53224)

14 exp Endovascular Procedures/ (78724)

15 exp Embolization, Therapeutic/ (28470)

16 coil$.ti,ab. (40619)

17 14 or 15 or 16 (140601)

18 13 and 17 (2727)

19 exp Time Factors/ (977585)

20 Early.ti. (203591)

21 (same adj2 day).ti,ab. (9082)

22 24 hour$.ti,ab. (106482)

23 48 hours.ti,ab. (33847)

24 delay$.ti. (50671)

25 timing.ti,ab. (79625)

26 Late.ti. (58017)

27 or/19-26 (1402951)

28 18 and 27 (320)

29 remove duplicates from 28 (319)

30 limit 29 to case reports (70)

31 29 and case report.ti. (23)

32 30 or 31 (74)

33 29 not 32 (245)

***************************

Database: EBM Reviews - Cochrane Database of Systematic Reviews <2005 to December 2013>, EBM Reviews - ACP Journal

Club <1991 to January 2014>, EBM Reviews - Database of Abstracts of Reviews of Effects <1st Quarter 2014>, EBM Reviews

- Cochrane Central Register of Controlled Trials <January 2014>, EBM Reviews - Cochrane Methodology Register <3rd

Quarter 2012>, EBM Reviews - Health Technology Assessment <1st Quarter 2014>, EBM Reviews - NHS Economic

Evaluation Database <1st Quarter 2014>

Search Strategy:

--------------------------------------------------------------------------------

1 exp Subarachnoid Hemorrhage/ (361)

2 intracranial hemorrhages/ or cerebral hemorrhage/ (658)

3 intracranial aneurysm/ (317)

4 rupture, spontaneous/ (100)

5 3 and 4 (28)

6 aneurysm, ruptured/ (87)

7 exp brain/ or exp meninges/ (7910)

8 6 and 7 (10)

9 ((subarachnoid or arachnoid) adj6 (haemorrhage$ or hemorrhage$ or bleed$ or blood$)).tw. (1188)

10 vasospasm, intracranial/ (88)


12 sah.tw. (383)

13 1 or 2 or 5 or 8 or 9 or 10 or 11 or 12 (2016)

14 exp Endovascular Procedures/ (5050)

15 exp Embolization, Therapeutic/ (559)

16 coil$.ti,ab. (611)

17 14 or 15 or 16 (6112)

18 13 and 17 (94)

19 exp Time Factors/ (46862)

20 Early.ti. (15763)


22 24 hour$.ti,ab. (15607)

23 48 hours.ti,ab. (4502)

24 delay$.ti. (2841)


26 Late.ti. (2470)

27 or/19-26 (160154)

28 18 and 27 (20)

***************************

Database: Embase Classic+Embase <1947 to 2014 Week 06>

Search Strategy:

--------------------------------------------------------------------------------

1 exp subarachnoid hemorrhage/ (30989)

2 brain artery aneurysm rupture/ or brain hemorrhage/ or brain vasospasm/ (70157)

3 (intracranial aneurysm/ or brain artery aneurysm/) and (rupture/ or artery rupture/ or rupture$.tw.) (6599)

4 aneurysm rupture/ and (exp brain/ or exp meninx/) (1572)

5 ((subarachnoid or arachnoid$) adj6 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$ or blood$)).tw.

(25456)

6 ((brain or cereb$ or intracranial) adj3 aneurysm$ adj3 ruptur$).tw. (3768)


8 sah.ti,ab. (9613)

9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 (101458)

10 exp coil embolization/ (6288)

11 coil$.ti,ab. (52481)

12 exp endovascular surgery/ (17896)

13 10 or 11 or 12 (70230)

14 9 and 13 (4957)

15 time/ (437888)


17 Time Factor$.ti,ab. (2428)

18 Early.ti. (272672)


20 24 hour$.ti,ab. (162815)

21 48 hour$.ti,ab. (57250)

22 delay$.ti. (64268)

23 Late.ti. (76303)

24 or/15-23 (1111704)

25 14 and 24 (380)

26 limit 25 to (letter or note or report) (11)

27 case report.ti. (213881)

28 26 or 27 (213892)

29 25 not 28 (349)

30 remove duplicates from 29 (334)

***************************

Web of Science 301

TOPIC: (subarachnoid hemorrhage) AND TOPIC: (coil*) AND TOPIC: (time or timing)

Refined by: DOCUMENT TYPES=( ARTICLE OR PROCEEDINGS PAPER OR REVIEW )

Indexes=SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH Timespan=All years

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