Tranexamic acid for reducing mortality in emergency and urgent surgery
This is the protocol for a review and there is no abstract. The objectives are as follows:
To assess the effects of tranexamic acid on mortality in adult patients undergoing emergency surgery.
Description of the condition
An estimated 234 million people undergo major surgical procedures every year worldwide, of which almost seven million will have major complications, including one million who will die (Weiser 2008). Emergency or urgent surgery, which can be defined as a surgery which must be done promptly to save life, limb, or functional capacity, is associated with a high risk of bleeding and death (Karkouti 2004; Pearse 2006).
Although there are not accurate figures regarding the epidemiology of emergency surgeries, it is estimated that they represent a larger relative proportion in low- and middle-income countries, in comparison to high-income countries. The Disease Control Priorities in Developing Countries Project estimated the burden of disease for conditions that require surgery. They found that low- and middle-income regions present the highest burden of disease for surgical conditions, and the highest proportion of emergency surgical conditions, such as injuries or obstetric complications (Debas 2006). For example, surgical conditions in Africa represent 38 disability adjusted life years (DALYs) per 1000 population, of which 60% are emergencies, while for Europe surgical conditions represent 25 DALYs per 1000 population, of which only 30% are emergencies (Debas 2006). Although perioperative mortality has been declining over the past 50 years, the mortality rate is twice higher in countries with a low human development index (Bainbridge 2012).
Bleeding is a leading complication of surgery, and has been shown to be associated with increased mortality (Karkouti 2004). In addition, perioperative bleeding is one of the main indications for blood transfusions, which is associated with further complications (Goodnough 2008). Although the safety of red blood cell transfusion has improved dramatically during the past decades, major complications (such as haemolysis, infection with HIV or hepatitis viruses, and acute lung injury) are still possible (Klein 2007). This knowledge has led to increased interest in the identification of interventions for reducing perioperative bleeding and the need for blood transfusion.
Description of the intervention
To reduce perioperative bleeding, the effect of antifibrinolytic drugs such as epsilon aminocaproic acid (EACA) and tranexamic acid (TXA) have been studied extensively. Antifibrinolytics promote blood clotting by preventing blood clots from breaking down. TXA and EACA are synthetic derivatives of the amino acid lysine that act as inhibitors of fibrinolysis by blocking the lysine binding sites on plasminogen molecules, inhibiting the formation of plasmin (Okamoto 1997). TXA is about ten times more potent than EACA and binds much more strongly to both the strong and weak sites of the plasminogen molecule than EACA (Mannucci 2007).
How the intervention might work
TXA has been shown to reduce blood transfusion in adult patients scheduled for elective surgery. A Cochrane review showed that compared with placebo, TXA reduced the probability of receiving a red blood cell transfusion by 39% (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.53 to 0.70), and was associated with a non-significant reduction in risk of reoperation (RR 0.80, 95% CI 0.55 to 1.17) and mortality (RR 0.60, 95% CI 0.33 to 1.10) (Henry 2011). However, this review did not include trials assessing the effect of TXA use in emergency surgery.
Why it is important to do this review
It is important to evaluate the effect of TXA in emergency surgery as these procedures are associated with a higher risk of bleeding and mortality. In addition, the recent CRASH-2 trial assessed the effects of TXA in 20,211 trauma patients and found a reduction in all-cause mortality (RR 0.91, 95% CI 0.85 to 0.97) and death due to bleeding (RR 0.85, 95% CI 0.76 to 0.96) with TXA use (CRASH-2 2010). Almost half of the patients in the CRASH-2 trial required surgery, many of whom might have been in the emergency setting, which raises the possibility that TXA could be effective in emergency surgery.
To assess the effects of tranexamic acid on mortality in adult patients undergoing emergency surgery.
Criteria for considering studies for this review
Types of studies
We will include randomised controlled trials.
Types of participants
Adult patients (over 18 years old) undergoing emergency or urgent surgery. We considered the surgery as "emergency or urgent" if the authors used this definition, if the surgeries were conducted within 48 hours of hospital admission, or if because the nature of the condition is implicitly understood that patients will require emergency surgery (e.g. long bone fracture, hip fracture or acute aortic dissection).
Types of interventions
Tranexamic acid compared to placebo or no tranexamic acid.
Types of outcome measures
Search methods for identification of studies
We will not limit the searches by date, language or publication status.
We will search the following electronic databases.
The Cochrane Injuries Group Specialised Register (latest version).
The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue).
MEDLINE (Ovid SP) 1950 to present.
EMBASE (Ovid SP) 1980 to present.
ISI Web of Science: Conference Proceedings Citation Index - Science (CPCI-S) 1990 to present.
ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) 1970 to present.
We will also search the following online trials register to identify unpublished studies that are complete or ongoing.
We will base the searches on the MEDLINE search strategy in Appendix 1 and adapt them, where necessary, for the other databases.
Searching other resources
We will search the Research and Development website of Pfizer: https://www.pfizer.com/research/.
In addition, we will check the reference lists of all relevant trials and previously published reviews identified through the search.
Data collection and analysis
Selection of studies
Two authors (PP and KK) will independently examine titles, abstracts, and keywords of citations from electronic databases for eligibility. We will obtain the full-text of all potentially relevant records. Because the definition of emergency surgery is challenging, a third author (CM) will independently (and blinded from outcomes) assess whether or not the studies selected included emergency surgeries.
Data extraction and management
Two authors (PP and KK) will extract data on the number, age and sex of trial participants, type of surgery, dose and timing of tranexamic acid, type of comparator, and outcome data. We will resolve any uncertainties regarding inclusion through discussion with the third author (IR).
Assessment of risk of bias in included studies
Two authors (PP and KK) will assess the risk of bias in included studies using the Cochrane Collaboration's tool described in Higgins 2011. We will assess the following domains for each study: sequence generation, allocation concealment, blinding, incomplete outcome data, and selective outcome reporting. We will attempt to obtain the protocols for the included studies in order to assess selective outcome reporting bias. We will complete a 'Risk of bias' table, incorporating a description of the study's performance against each of the above domains and our overall judgement of the risk of bias for each entry, as follows: 'Low risk’, ‘High risk’ or ‘Unclear risk’ of bias. As the risk of bias for blinding and incomplete outcome data may vary according to outcome, we will assess this separately for mortality, transfusion and adverse events. We will resolve any uncertainties regarding inclusion through discussion with a third author (IR).
Measures of treatment effect
For dichotomous outcomes, we will calculate risk ratios (RRs) and 95% confidence intervals (CIs) for each study. For the continuous outcome 'units of blood transfused', we will calculate the mean difference (MD) and 95% CIs. If the results are reported in millilitres we will convert them into units by dividing by 300.
Unit of analysis issues
The patient will be the unit of analysis.
Dealing with missing data
We will contact the original investigators to obtain any missing data.
Assessment of heterogeneity
We will examine trial characteristics in terms of participants, interventions and outcomes for evidence of clinical heterogeneity. We will examine statistical heterogeneity using both the I2 statistic and Chi2 test. The I2 statistic describes the percentage of total variation across studies due to heterogeneity rather than chance. A value of 0% indicates no observed heterogeneity, and larger values show increasing heterogeneity; substantial heterogeneity is considered to exist when I2 > 50% (Higgins 2011). For the Chi2 test, we will use a P value of < 0.10 to indicate the presence of statistically significant heterogeneity.
Assessment of reporting biases
We will investigate the presence of reporting (publication) bias using funnel plots if there are at least ten studies for the same outcome in the review.
If we judge that the studies are clinically and statistically homogenous, we will pool the data using the fixed-effect model.
Subgroup analysis and investigation of heterogeneity
We are not planning to conduct any subgroup analyses.
We will conduct sensitivity analyses according to the risk of bias judgement for allocation concealment ('high' versus 'unclear' versus 'low'), and for fixed-effect versus random-effects models for data synthesis.
We thank the referees for their comments on the manuscript.
Appendix 1. MEDLINE search strategy
MEDLINE (Ovid) 1950 to present
1 exp Antifibrinolytic Agents/
2 (anti-fibrinolytic* or antifibrinolytic* or antifibrinolysin* or anti-fibrinolysin* or antiplasmin* or
anti-plasmin* or ((plasmin or fibrinolysis) adj3 inhibitor*)).ab,ti.
3 exp Tranexamic Acid/
4 (tranexamic or Cyclohexanecarboxylic Acid* or Methylamine* or amcha or trans-4-aminomethyl-cyclohexanecarboxylic
acid* or t-amcha or amca or kabi 2161 or transamin* or exacyl or amchafibrin or anvitoff or spotof or cyklokapron or
ugurol oramino methylcyclohexane carboxylate or aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic
acid or AMCHA or amchafibrin or amikapron or aminomethyl cyclohexane carboxylic acid or aminomethyl
cyclohexanecarboxylic acid or aminomethylcyclohexane carbonic acid or aminomethylcyclohexane carboxylic acid or
aminomethylcyclohexanecarbonic acid or aminomethylcyclohexanecarboxylic acid or aminomethylcyclohexanocarboxylic acid or
aminomethylcyclohexanoic acid or amstat or anvitoff or cl?65336 or cl65336 or cyclocapron or cyclokapron or cyklocapron
or exacyl or frenolyse or hexacapron or hexakapron or tranex or TXA).ab,ti.
7 randomized controlled trial.pt.
8 controlled clinical trial.pt.
10 clinical trials as topic.sh.
13 6 or 7 or 8 or 9 or 10 or 11 or 12
14 (animals not (humans and animals)).sh.
15 13 not 14
16 5 and 15
Protocol first published: Issue 11, 2012
Contributions of authors
All authors contributed to the development of the protocol.
Declarations of interest
PP,CM and KK: None known.
IR: LSHTM has received funds from pharmaceutical companies to pay for the drug and placebo used in RCTs of tranexamic acid in acute severe bleeding. These funds are delared in the relevant publications.