Safety and efficacy of pharmacological
prophylaxis for people with blunt head injury: a systematic review
Protocol
Fairleigh Reeves
Lachlan Batty
Veronica Pitt
Marisa Chau
Loyal Pattuwage
Russell Gruen
Background
Venous thromboemboilsm (VTE) refers to a spectrum of illness that encompasses deep vein thrombosis (DVT) and pulmonary embolism (PE).
Head injury is an independent risk factor for DVT (Reiff 2009). DVT occurs in up to one third of moderately to severely brain injured patients (Eker 2010) and is reported to occur in 25% of patients with isolated head injury (Denson 2007). This high incidence of DVT is significant as it is a precursor to PE which is a leading cause of death in trauma patients after the first 72 hours (Acosta 1998).
Thromboprophylaxis is an umbrella term for the preventative treatment of the spectrum of VTE.
Within this category are pharmacological interventions such as unfractionated heparin and low molecular weight heparin as well as mechanical interventions such as inferior vena cava filters, graded compression stockings or sequential compression devices.
Despite the high risk of VTE, there is reluctance among clinicians to use pharmacological prophylaxis in trauma patients due to the risk of increased bleeding (Nathens 2007), and administration of pharmacologic thromboprophylaxis in the head injured patient is controversial. A systematic review is required to establish the effectiveness and risks of
pharmacological thromboprophylaxis, over and above mechanical prophylaxis, in this subgroup of high-risk trauma patients.
Objectives
To assess the effects of thromboprophylaxis in people with blunt head injury.
Methods
Study selection criteria
Participants
Any person of any age with a blunt head injury in the acute care setting. People who have concurrent injuries (i.e. multi-trauma patients) will also be included.
We will exclude trials that only assess thromboprophylaxis in a rehabilitation or outpatient setting.
Intervention
We will include trials that report the use of any individual or combined intervention for thromboprophylaxis.
Example interventions include (but will not be limited to):
Pharmacological
o Unfractionated heparin
o Low molecular weight heparin (LMWH)
Mechanical devices
o Inferior vena cava filter (IVCF)
o Graduated compression stockings o Sequential compression devices
Comparison
We will include any of the following comparisons:
Placebo
No treatment
Alternative interventions
We will also include comparison of any one intervention versus another.
Outcomes
Primary outcomes for this review are:
Mortality (all-cause mortality and mortality from PE)
Incidence of DVT or PE during acute hospital inpatient stay (i.e. prior to participants being discharged home or to attend a rehabilitation facility)
Adverse events (e.g. bleeding complications, thrombocytopenia)
Study Types
All study designs will be included.
Search Strategy
Searches to identify studies for inclusion will not be restricted by language, date or publication status.
The following electronic databases will be searched:
Cochrane Central Register of Controlled Trials
MEDLINE
EMBASE
The following websites will also be searched to identify current and ongoing trials:
www.clinicaltrials.gov
Controlled Trials metaRegister (www.controlled-trials.com)
Reference lists of relevant publications, including clinical guidelines and systematic reviews, will also be searched to further identify any potentially relevant studies.
Data collection and analysis
Selection of studies
Citations retrieved from all sources will be merged and duplicate records removed. Two authors (FR and LB) will independently screen all titles and abstracts for eligibility. The full text of all potentially relevant studies will be retrieved. The two authors will then independently assess whether each study meets the pre-defined selection criteria. If there is any disagreement about study eligibility, this will be resolved through discussion until consensus is reached or by consulting a third author (VP). A reason for exclusion will be recorded for potentially relevant controlled trials that fail to meet all of the selection criteria.
Data extraction and management
A standardized data collection form will be developed and piloted by three authors (FR, LB and VP).
Data collection will be conducted independently by two authors (FR, LB) and will involve a two- stage process.
1. We will collect the following data from all studies: name of first author, year of publication, study design, sample size, population (head injury versus mixed trauma), intervention, comparison, outcomes measured (only those applicable to the primary outcomes of this review), timing of administration of pharmacological prophylaxis, alternative prophylaxis used.
2. We will collect the following data for controlled studies only:
o Source: title, authors, citation, country, published or not (publication type), year, language, contact details, study funding source, conflicts of interest
o Methods: study design, duration, information regarding risk of bias (see Table 1)
o Participants: sample size, inclusion and exclusion criteria, baseline
characteristics, type and severity of head injury (according to scale used by trialists), location of concurrent injuries, and severity of multi-trauma (ISS or as defined by trialists)
o Intervention: description of the intervention (e.g. dose, delivery, timing) and any comparison groups (e.g. placebo, control, alternative intervention), any
concurrent/co-interventions delivered
o Outcomes:mortality (incidence and cause), incidence of PE and DVT
(symptomatic and asymptomatic), diagnostic assessment, all adverse events, timing of outcome measurement and follow-up
o Results: number of patients in each group, losses to follow-up, summary data for each allocated group, information on subgroups, statistical methods used o Conclusions: key conclusions of study authors
In the event there are no controlled trials identified for inclusion in the review, we will tabulate the main findings of any observational studies.
Assessment of risk of bias of selected studies
Two authors (FR and LB) will independently assess the risk of bias for each controlled study using the list of items in Table 1. Each item will be assessed and judged as being a high, low, or unclear risk of bias.
Table 1 Items to assess risk of bias for different study designs Study design Item
RCT* Sequence generation
Allocation concealment Blinding
Incomplete outcome data Selective outcome reporting Cohort Study# Prospective/retrospective
Comparability of groups Blind assessment of outcome
Identification and adjustment for confounding factors Sufficient duration of follow-up for outcome to occur Adequate follow-up of cohorts (number lost to follow-up) Case-control Study# Adequate case definition
Adequate selection and definition of controls
Comparability of case and controls
Identification and adjustment for confounding factors Non-response rate
*Adapted from Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008)
# Adapted from the Newcastle-Ottawa Quality Assessment Scale (http://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf)
Measures of treatment effect
For dichotomous outcomes we will determine the relative risk (RR) and 95% confidence interval (CI) and use measures of absolute risk (AR) to calculate number needed to treat (NNT) and number needed to harm (NNH). For continuous outcomes we will calculate the mean difference (MD) and 95% CI where the same scales have been used or, where studies have used different scales to measure the same outcome, we will calculate the standardised mean difference (SMD) and 95% CI.
Dealing with missing data
We will attempt to contact authors for missing data in controlled trials.
Some studies may have missing summary data. Where proportions are reported for dichotomous outcomes (e.g. percentages), these will be used to estimate the number of events or the number of people assessed for an outcome. For continuous measures, missing standard deviation (SD) values will be imputed from other measures such as standard error (SE), P values or confidence intervals wherever possible or we will use SD values based on similar trials. All data imputations will be reported.
Assessment of heterogeneity
Individual studies will be assessed for similarity according to participant characteristics, type of intervention, comparison group, and outcomes.
If a meta-analysis is undertaken we will also assess statistical heterogeneity by visual inspection of the scatter of effect estimates on forest plots and by using the I2 statistic (Higgins 2003).
Assessment of reporting bias
If there are sufficient controlled trials (at least ten) we will use funnel plots to assess for potential small study effects.
Data synthesis
Where appropriate, we will attempt to pool results from controlled trials in a meta-analysis.
Studies assessing the same outcome will be grouped together based on similarity between the type of intervention and the comparison. Results will only be pooled if the studies are judged to be sufficiently similar.
Where we are unable to pool summary data in a meta-analysis, we will tabulate the results and a narrative synthesis will be undertaken.
If there are no controlled studies, we will tabulate the main findings from observational studies and the strengths and limitations of the evidence will be presented in the text.
Subgroup analysis
If data is sufficient, the following subgroup analyses will be undertaken:
Participant:
o Isolated head trauma compared to multi-trauma
o Severity of head injury (by GCS or other scales used by trialists)
Intervention:
o Early (within 48 hours or as defined by trialists) or late intervention (after 48 hours or as defined by trialists)
Outcome:
o All-cause mortality or mortality from PE
o Asymptomatic compared to symptomatic DVT or PE o Timing of outcome measurement
Sensitivity analysis
In the event a meta-analysis is undertaken, we will conduct a sensitivity analysis to examine the effects of excluding non randomised studies from the analysis.
References
Acosta JA, Yang JC, Winchell RJ et al. Lethal injuries and time to death in a level 1 trauma centre. Journal of the American College of Surgeons 1998; 186: 528-33.
Denson K, Morgan D, Cunningham R, et al. Incidence of venous thromboembolism in patients with traumatic brain injury. Am J Surg. 2007; 193:380-383
Ekeh A, Dominguez K et al. Incidence and Risk Factors for DVT after moderate and severe brain injury
Greenfield LJ et al. Posttrauma thromboembolism prophylaxis, J Trauma. 1997; 42:100-
103 Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Intervensions.
Version 5.0.1 [updated September 2008]. The Cochrane Collaboration, 2008
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta- analyses. BMJ 2003; Vol. 327, issue 7414:557-60
Kim J, Gearheart MM, Zurick A et al. Preliminary report on the safety of Heparin for deep venous thrombosis prophylaxis after severe head injury. 2002. J Trauma; 53: 38-43
Levy AS, Salottolo K, Bar-Or R et al. Pharmacological thromboprophylaxis is a risk factor for haemorrhage progression in a subset of patients with traumatic brain injury. J Trauma. 2010; 68: 886-894
Liberati A, Altman D, Tetzlaff J et al. The PRISMA Statement for Reporting Systematic Reviews and Meta-Analyses of Studies That Evaluate Health Care Interventsion:
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Nathens AB, McMurray MK, Cuschieri J, et al. The practice of venous thromboembolism prophylaxis in the major trauma patient. J Trauma 2007; 62: 557-562
Norwood S, McAuley C, Berne J et al. Prospective evaluation of the safety of enoxaparin prophylaxis for venous thromboembolism in patients with intracranial haemorrhagic injuries. Arch Surg. 2002; 137: 696-702
Reiff DA et al. Traumatic brain injury is associated with the development of deep vein thrombosis independent of pharmacological prophylaxis. 2009: 66: 1436-1440
Wells GA , Shea B, O'Connell D, Peterson J, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. Department of Epidemiology and Community Medicine, University of Ottawa, Canada.
(http://www.ohri.ca/programs/clinical_epidemiology/nosgen.pdf)