Systematic Review of Outcome Measures in aSAH Protocol

This protocol has been developed in accordance with the PRISMA-P 2015 17-item checklist for the development of systematic review protocols^[¹].

Administrative information

1. Title

This is a protocol for a systematic review of outcome measures employed in clinical research into aneurysmal subarachnoid haemorrhage

2. Registration

This study has been registered prospectively with Core Outcome Measures in Effectiveness Trials (COMET) Initiative.

3. Authors

Dr Christopher Andersen (Corresponding Author)

Malcolm Fisher Department of Intensive Care Medicine

Royal North Shore Hospital

St Leonards 2065 NSW Australia

and

Northern Clinical School

University of Sydney

chris_andersen@med.usyd.edu.au

Ms Emily Fitzgerald

Malcolm Fisher Department of Intensive Care Medicine

Royal North Shore Hospital

Professor Simon Finfer

Malcolm Fisher Department of Intensive Care Medicine

Royal North Shore Hospital

and

The George Institute for Global Health, University of Sydney

CA completed the protocol with significant input and oversight by SF. CA is the guarantor of the review. This protocol has not been amended since it was published.

4. Amendments

This is the first protocol and has not been amended since initial publication.

5. Support

This systematic review has been completed without funding support.

Introduction

6. Rationale

Aneurysmal subarachnoid haemorrhage (aSAH) has an incidence of 10 to 11 cases per 100,000 /year and causes substantial morbidity and mortality. Reducing the burden associated with aSAH remains an area of ongoing interest in the medical community. there is currently no international consensus on appropriate outcome measures to use in clinical research of aSAH although a transition towards core outcome sets (COS) is occurring in other areas of clinical research. The authors have conducted a systematic review of outcome measures employed in aSAH clinical trials to provide a foundation for further research and the eventual development of a COS.

7. Objectives

The objective of this systematic review is to answer the question; What outcomes have been measured in randomized controlled trials of patients with aSAH.

Methods

8. Eligibility criteria

Randomized clinical trials that included patients exclusively with subarachnoid haemorrhage were selected for inclusion in the review. The studies included had a minimum of ten patients and reported at least one outcome. There was no restriction regarding interventions and comparators used. All studies were original research articles; we excluded review articles, letters and editorials. We limited inclusion to studies published in English.

9. Information sources

The search strategy used the following electronic databases Ovid Medline, EMBASE, CINAHL, and The Cochrane Central Register of Controlled Trials (CENTRAL). Included studies were published from January 1996, which corresponds with the publication year of the first CONSORT document^[²^].

10. Search Strategy

Search Strategy (MEDLINE – OVID and EMBASE)

exp subarachnoid hemorrhage/
exp intracranial aneurysm/
exp aneurysm, ruptured/
exp vasospasm, intracranial/
delayed cerebral ischaemia.mp
delayed cerebral ischemia.mp
2 or 3 or 4 or 5 or 6
exp intracranial hemorrhages/
7 and 8
1 or 9
humans/
exp randomized controlled trial/
exp single-blind method/
exp double-blind method/
12 or 13 or 14
10 and 11 and 15
limit 16 to yr=”1996-Current”

Search Strategy (CINAHL – EBSCO)

subarachnoid hemorrhage
randomized controlled trial
1 and 2

Search Strategy (Cochrane Central Register of Controlled Trials)

exp subarachnoid hemorrhage
limit 1 to yr = 1996 – Current

Study records

11a Data Management

Data management will be performed using the EPPI-Reviewer 4 web based program developed and maintained by Social Science Research Unit at the Institute of Education, University of London.

11b Selection process

CA performed initial screening based on the article abstract and title using the eligibility criteria. CA and EF then screened the remaining full documents independently. Following reconciliation disagreements were resolved via discussion. In the event of uncertainty SF was consulted.

11. Data collection process

The data extraction form was developed a priori and refined following testing on ten randomly selected papers. CA and EF extracted the data from each paper independently and analysis was performed to identify discrepancies. A consensus was reached when there was disagreement.

12. Data Items

See the attached data extraction form (Appendix 1) for the data items collected.

13. Outcomes and prioritization

The design of this study is to examine the different outcomes employed in clinical trials. All reported outcomes in the selected randomized controlled trials would therefore be included. Both primary and secondary outcomes will be recorded.

14. Risk of bias

There was a wide range of different outcomes across multiple domains and therefore assessment of selection bias, performance bias and an overall assessment of risk of bias in individual studies was not attempted. Attrition bias and the handling of missing data however may represent a measure of functionality with respect to outcome measures and was therefore assessed. Detection bias and selective reporting bias also provide relevant insights to the use of outcome measures and was also included in the analysis.

15. Data Synthesis

The data synthesis will primarily consist of the frequency of reported outcomes, individually, between different domains and within domains.

16. Meta-biases

All studies will be assessed for protocol registration. Where possible an assessment of selective reporting of outcomes will be made.

17. Confidence in cumulative evidence

This study is primarily descriptive with multiple different interventions and comparators included across multiple domains and as such no attempt was made to assess the strength of the evidence.

Bibliography

1 Shamseer et al., “Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation,” BMJ, vol. 349, no. g7647, January 2015.

2 C Begg et al., “Improving the quality of reporting of randomized controlled trials. The CONSORT statement.,” JAMA, vol. 276, no. 8, pp. 637-9, 1996.

Appendix 1 Data Extraction Form

CA = Christopher Andersen

EF = Emily Fitzgerald

Abstract and Title Screening [CA]

EXCLUDE on Study Type [Exclude]

Exclude if non RCT study design

EXCLUDE on Date [Exclude]

Exclude if study published pre 1996

EXCLUDE on Study Participants [Exclude]

Exclude if <10 study participants

EXCLUDE on Language [Exclude]

Non English papers excluded

EXCLUDE on Full Paper Availability [Exclude]

EXCLUDE on Study Population [Exclude]

Study not based on a population of patients with aSAH

EXCLUDE on Duplicate study [Exclude]

INCLUDE based on Abstract and Title [Include]

No obvious exclusion criteria based on the abstract and title – for screening based on full report

Full Reference Screening [CA & EF]

EXCLUDE on Study Type [Exclude]

Study not a randomised controlled trial. Trials which are observational in nature based on a previous RCT (substudies) are also excluded. Trials which look at additional outcomes from a previously published RCT (different duration of follow up, other outcome measures such as resource use) and maintain the same intervention and comparator are not excluded.

EXCLUDE based on Abstract Only, Presentation or Poster Only [Exclude]

Articles which are not published in a peer reviewed journal have been excluded from the study including abstract only, oral presentations or conference posters

EXCLUDE on Date [Exclude]

Studies published before 1996

EXCLUDE on Study Participants [Exclude]

Studies with <10 patients are excluded

EXCLUDE based on Language [Exclude]

Studies not published in English are excluded

EXCLUDE based on Full Paper Availability [Exclude]

If full report not available then study is excluded

EXCLUDE based on Study Population [Exclude]

Studies which do not look at aSAH specifically, or have a clearly defined subgroup identified at baseline of aSAH are excluded

EXCLUDE based on Duplicate Study [Exclude]

INCLUDE based on Full Reference Screening [Include]

Study Characteristics [CA & EF]

Trial phase

Phase II

Phase III

` Not stated

Trial Location

Single Centre

Multi-Centre

International

Not stated

Funding Source

Industry

Government/University

Other non industry funding

Not stated

Intervention

Pharmaceutical.

Invasive

Physiological parameter target

Process of care

Comparator

Standard Care

Placebo controlled

Other comparator

Participants

0-50 participants

51-500

>501

Sub study

In the info describe the parent study

Risk of Bias [CA & EF]

Selection bias

Method of Randomisation

Low risk of bias

The investigators describe a random component in the sequence generation process such as: Referring to a random number table; Using a computer random number generator; Coin tossing; Shuffling cards or envelopes; Throwing dice; Drawing of lots; Minimization*.

High risk of bias

The investigators describe a non-random component in the sequence generation process. Usually, the description would involve some systematic, non-random approach, for example: Sequence generated by odd or even date of birth; Sequence generated by some rule based on date (or day) of admission; Sequence generated by some rule based on hospital or clinic record number.

Unclear risk of bias

Insufficient information about the sequence generation process to permit judgement of ‘Low risk’ or ‘High risk’.

Allocation concealment

Low risk of bias

Participants and investigators enrolling participants could not foresee assignment because one of the following, or an equivalent method, was used to conceal allocation: Central allocation (including telephone, web-based and pharmacy-controlled randomization); Sequentially numbered drug containers of identical appearance; Sequentially numbered, opaque, sealed envelopes.

High risk of bias

Participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias, such as allocation based on: Using an open random allocation schedule (e.g. a list of random numbers); Assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or nonopaque or not sequentially numbered); Alternation or rotation; Date of birth; Case record number; Any other explicitly unconcealed procedure.

Unclear risk of bias

Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’. This is usually the case if the method of concealment is not described or not described in sufficient detail to allow a definite judgement – for example if the use of assignment envelopes is described, but it remains unclear whether envelopes were sequentially numbered, opaque and sealed.

Ascertainment bias (outcome assessment)

Low risk of bias

Any one of the following: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; Blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.

High Risk of Bias

Any one of the following: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; Blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.

Unclear risk of bias

Any one of the following: Insufficient information to permit judgement of ‘Low risk’ or ‘High risk’; The study did not address this outcome.

Attrition Bias

Low risk of bias

Any one of the following: No missing outcome data; Reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); Missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; Missing data have been imputed using appropriate methods.

High Risk of Bias

Any one of the following: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; For continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘As-treated’ analysis done with substantial departure of the intervention received from that assigned at randomization; Potentially inappropriate application of simple imputation

Unclear risk of bias

Any one of the following: Insufficient reporting of attrition/exclusions to permit judgement of ‘Low risk’ or ‘High risk’ (e.g. number randomized not stated, no reasons for missing data provided); The study did not address this outcome.

Loss to follow up

Comment on the loss to follow up for long term outcomes in text box

Reporting bias

Trial registered propectively

Yes

Evidence of selective reporting of outcomes

Yes

No

Unclear

Unclear/No

Primary outcome [CA & EF]

Domain

Functional or Life Impact

Pathophysiology

Health care resource use

Composite Measure

No stated primary outcome

Mortality

Surrogate outcome

a laboratory measurement or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful end point that is a direct measure of how a patient feels, functions, or survives

Clinically meaningful endpoint

Mortality [CA & EF]

Not reported

Survival (time to event analysis)

This is identified in the article when there is a cox analysis of the time to event of survival. It is useful for assessing what is the proportion of a population which will survive past a certain time.

Landmark mortality

Discharge

ICU Discharge

Hospital Discharge

All-cause mortality versus Disease specific

Disease specific mortality

All-cause mortality

Functional or Life Impact [CA & EF]

Method of ascertainment

Phone interview

Face to face interviews

Combined phone/face to face

Mailed questionnaire

Other

Unclear

Functional outcome measures

Glasgow Outcome Scale

Dichotomised

Extended Glasgow Outcome Scale

Dichotomised

Modified Rankin Score

Dichotomised

Barthel’s Index

MMSE

Neuropsychological testing

NIHSS

GCS (as outcome measure)

Karnofsky scale

Other

Patient reported outcomes

Short Form 36 Health Survey

Neuro-QoL

Satisfaction and Life Scale

Patient Health Questionnaire (PHQ-9)

Sickness Impact Profile

EQ-5D

Other

Discharge disposition

This refers to the discharge facility such as own residence, inpatient rehabilitation, nursing home, death