Antifibrinolytic agent tranexamic acid for nasal haemorrhage (epistaxis)
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To determine the effectiveness of tranexamic acid compared with placebo or no additional intervention in the management of patients with epistaxis.
To compare the morbidity and mortality associated with tranexamic acid with that associated with placebo or 'usual care'.
Background
Description of the condition
Epistaxis (nosebleed) is extremely common, with a pronounced bimodal distribution. It is common in childhood and then becomes less frequent before the incidence rises again in the sixth decade (McGarry 2008). Its prevalence in random samples of the population was found in one study to be 10% to 12% at any given time (Shaheen 1967). The cause of epistaxis is unknown in 70% to 80% of cases (Stell 1977) and is termed idiopathic epistaxis. However, epistaxis may be secondary to a number of causes such as surgery, trauma, hypertension (high blood pressure), coagulation (clotting) abnormalities, hereditary haemorrhagic telangiectasia (inherited blood vessel abnormality) and the use of medications such as aspirin and warfarin (McGarry 2008).
Most epistaxis is self‐limiting or settles with simple measures such as compression by pinching the nose, and could be ideally managed at home without further medical interference. More severe cases may require medical attention.
Two basic methods are used: cauterisation to seal the bleeding vessel if visualised, and when this is not possible, the use of various materials packed into the nose to arrest the blood flow. In anterior epistaxis, which is the most common type, a bleeding point is often visible and can be cauterised under local anaesthetic by either a locally applied chemical such as silver nitrate or by electrocautery (hot wire). In some cases this is not sufficient and nasal packing is required with materials such as ribbon gauze, nasal tampons, balloons or inflatable packs. Posterior epistaxis is more common in older adults with hypertension and arteriosclerosis (Burton 2004). In these cases a bleeding point cannot be identified and nasal packing is often necessary. This packing usually stays in for one to two days and applies pressure to the bleeding site thereby stopping the bleeding.
Rebleeding may occur after initial management, which often results in a more prolonged hospital stay and further treatments including further nasal packing, surgery and embolisation.
If an epistaxis persists or recurs despite nasal packing then surgical intervention may be necessary. Surgery usually involves examining the nose under a general anaesthetic which is easier than when the patient is awake. Any bleeding points are cauterised and a more effective pack can be inserted. In addition blood vessels can be tied off either through the nose or by a skin incision. Embolisation involves performing an angiogram and then occluding feeding vessels to the bleeding area which usually stops the epistaxis, however there is a small risk of stroke associated with this treatment.
Patients admitted with a severe epistaxis, whether anterior or posterior, may face significant morbidity; in particular, nasal packing is uncomfortable. There is also a very small risk of death from a number of causes including uncontrollable epistaxis, hypoxia (breathing difficulties) from nasal packs and from a complication of general anaesthetic.
Description of the intervention
Tranexamic acid is useful in a wide range of haemorrhagic conditions. It helps to prevent clot breakdown (fibrinolysis) and thus reduces blood loss. The requirement for blood to coagulate is very important in controlling any form of bleeding. A blood clot is made up of molecules of fibrin and is the end point of the coagulation cascade. A blood clot is broken down (fibrinolysis) by the binding of plasminogen to fibrin, converting plasminogen to its active derivative plasmin. Tranexamic acid can help stabilise blood clots by competitively inhibiting the binding of plasminogen to fibrin preventing fibrinolysis. This antifibrinolytic effect is routinely used to prevent excessive bleeding in many clinical situations such as following cardiac surgery when cardiopulmonary bypass is used and in acute upper gastrointestinal bleeding (Dunn 1999). Tranexamic acid may therefore have a role to play in the management of epistaxis as an adjunct to usual therapies such as nasal cautery or packing to improve clotting and prevent rebleeding. This will reduce the need for further interventions with all their attendant risks. It can be taken orally, intravenously and topically and is administered over a number of days. It is contra‐indicated in patients with thromboembolic disease such as stroke and heart attack.
Why it is important to do this review
The effectiveness of tranexamic acid in preventing significant bleeding has been shown in many clinical settings, however there remains uncertainty as to its role in the treatment of epistaxis. White 1988 investigated the use of oral tranexamic acid in epistaxis while Tibbelin 1995 investigated the efficacy of its topical preparation. There are also citations related to its use in the control of epistaxis in patients with hereditary haemorrhagic telangiectasia (Klepfish 2001; Sabba 2001). The recent CRASH‐2 study on tranexamic acid for trauma highlights the positive effect of tranexamic acid as a life‐saving adjunct to treatment (CRASH‐2 2010). We aim to perform the first review of all the available evidence and assess the effectiveness of this treatment.
Objectives
To determine the effectiveness of tranexamic acid compared with placebo or no additional intervention in the management of patients with epistaxis.
To compare the morbidity and mortality associated with tranexamic acid with that associated with placebo or 'usual care'.
Methods
Criteria for considering studies for this review
Types of studies
All identified randomised controlled trials (RCTs) which fulfil the criteria outlined below.
Types of participants
All patients with nosebleeds requiring intervention by a medical professional. Different subgroups include the following.
The age group of patients:
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child;
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adult.
The type of patient:
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inpatient;
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outpatient.
The site of the nosebleed:
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anterior (bleeding point identified);
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posterior (bleeding point not identified).
The type of 'usual care' intervention:
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cauterisation;
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nasal packing;
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surgery;
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embolisation.
Exclusion criteria:
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anyone with a clotting disorder.
Types of interventions
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Tranexamic acid (oral, topical and intravenous) with given doses, frequencies and durations plus 'usual care' (cauterisation, nasal packing, surgery, embolisation) versus placebo plus 'usual care'.
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Tranexamic acid (oral, topical and intravenous) with given doses, frequencies and durations plus 'usual care' (cauterisation, nasal packing, surgery, embolisation) versus 'usual care' alone.
Types of outcome measures
Primary outcomes
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Effectiveness in control of epistaxis. Frequency and/or severity of rebleeds with a measure of blood loss.
Secondary outcomes
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Further intervention (repacking, surgery, embolisation).
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Need for blood transfusions.
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Length of hospital stay.
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Adverse and/or side effects.
Search methods for identification of studies
We will conduct systematic searches for randomised controlled trials of tranexamic acid treatment versus placebo or 'usual treatment'. There will be no language, publication year or publication status restrictions. We may contact original authors for clarification and further data if trial reports are unclear and we will arrange translations of papers where necessary.
Electronic searches
We will identify published, unpublished and ongoing studies by searching the following databases from their inception: the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, current issue); PubMed; EMBASE; CINAHL; LILACS; KoreaMed; IndMed; PakMediNet; CAB Abstracts; ISI Web of Science; BIOSIS Previews; CNKI; mRCT (Current Controlled Trials); ClinicalTrials.gov; ICTRP (the World Health Organization International Clinical Trials Registry Platform) and Google Scholar.
Subject strategies for databases will be modelled on the search strategy designed for CENTRAL (see Appendix 1). Where appropriate, we will combine subject strategies with adaptations of the highly sensitive search strategy designed by The Cochrane Collaboration for identifying randomised controlled trials and controlled clinical trials (as described in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1, Box 6.4.b. (Handbook 2008)).
Searching other resources
We will scan reference lists of identified publications for additional trials and contact authors if necessary. We will search PubMed, TRIPdatabase, NHS Evidence ‐ ENT & Audiology, NHS Evidence ‐ Cancer and Google to retrieve existing systematic reviews possibly relevant to this systematic review, so that we can scan their reference lists for additional trials.
We will contact the pharmaceutical company manufacturing tranexamic acid. We will scan reference lists from identified publications and contact authors as necessary.
Data collection and analysis
Selection of studies
Two authors will scan the initial search results to identify trials which loosely meet the inclusion criteria. We will then review the full texts of the retrieved trials and apply the inclusion criteria. We will only include randomised trials, focusing mainly on those that are cluster‐randomised.
Data extraction and management
We will extract data from the studies using standardised data forms. We will extract data so as to allow an intention‐to‐treat analysis. Where data are missing, we will write to the authors of the study requesting the missing data.
Assessment of risk of bias in included studies
Two authors will undertake independent assessment of the risk of bias of the included trials as part of the data extraction process. The following will be taken into consideration, as guided by the Cochrane Handbook for Systematic Reviews of Interventions (Handbook 2008):
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sequence generation;
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allocation concealment;
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blinding;
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incomplete outcome data;
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selective outcome reporting; and
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other sources of bias.
We will use the Cochrane 'Risk of bias' tool in RevMan 5 (RevMan 2008), which involves describing each of these domains as reported in the trial and then assigning a judgement about the adequacy of each entry. This involved answering a pre‐specified question whereby a judgement of 'Yes' indicated low risk of bias, 'No' indicated high risk of bias, and 'Unclear' indicated unclear or unknown risk of bias.
Data synthesis
Data analysis will be by intention‐to‐treat. If data are of sufficient quality they will be combined to give a summary measure of effect, otherwise data will not be combined. We will use study quality in a sensitivity analysis.
Data permitting, we will analyse patients with different nosebleed sites (anterior or posterior), aetiologies and treatments separately.
For ease of analysis of the different groups, we will initially treat the data as dichotomous, noting whether any further bleeding occurred or not in the intervention and control arms of the studies. This will allow us to perform a risk analysis and a number needed to treat (NNT) calculation. We will then analyse the count data, noting the number and type of events occurring in each group. Following this we will make a comparison of the difference in the mean number of events (the mean difference) between the intervention and control arms.
We will determine heterogeneity using the Chi2 test. We will use a random‐effects meta‐analysis model in the event that heterogeneity exists. We will also undertake an investigation into the cause of the heterogeneity.
We will be using the services of an expert statistician to help further with data synthesis.
