Antifibrinolytic therapy for preventing oral bleeding in patients with a hemophilia or Von Willebrand disease undergoing oral or dental procedures
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primarily, we aim to assess the efficacy of antifibrinolytic agents to prevent bleeding complications in people with hemophilia or VWD undergoing oral surgery.
Secondary objectives are to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy or desmopressin in people with hemophilia or VWD and further establish the effects of these agents on bleeding in oral surgery for each of these patient populations.
Background
Description of the condition
Oral surgery and dental procedures are widely performed and can be complicated by hazardous oral bleeding, especially in people with a inherited bleeding disorder such as hemophilia or Von Willebrand disease (VWD). It is important to search for alternative methods to prevent bleeding complications given that the disadvantages of commonly used perioperative measures, such as clotting factor concentrates, include the risk of developing inhibitors, the risk of transmitting infections, and the high cost of replacement factors as well as an impact on the quality of life of those needing repeated clotting factor replacement treatment by intravenous infusion. Expensive and sometimes dangerous over‐treatment with clotting factor replacement or desmopressin should be avoided. The small risk of thromboembolic events, including coronary occlusion in those with pre‐existent coronary artery disease and the risk of fluid overload and hyponatremia with desmopressin, precludes its use in individuals with certain co‐morbidities. In practice, antifibrinolytic treatment, administered either topically or systemically, is often used to achieve adequate perioperative hemostasis.
Inherited bleeding disorders impair normal hemostasis resulting in a tendency to bleed, the severity of which depends on the degree of the underlying coagulation factor deficiency. Hemophilia and VWD are the most common inherited bleeding disorders, with a prevalence of 1 in 5000 males and 1%, respectively (Rodeghiero 1987; Stonebraker 2010). Hemophilia is an X‐linked inherited bleeding disorder, caused by a deficiency of factor VIII or factor IX; VWD is a mostly dominantly inherited congenital bleeding disorder caused by a deficiency or dysfunction of Von Willebrand Factor (VWF). Factor VIII, IX and VWF are clotting proteins, necessary for the completion of primary (VWF) and secondary (FIX and FVIII) hemostasis. In addition, VWF is a carrier protein for FVIII in the circulatory system, therefore FVIII deficiency is also seen in moderate and severe VWD, with consequent additional impairment of secondary hemostasis. Severe hemophilia is defined as FVIII or FIX levels less than 1%, moderate hemophilia as 1% to 5% FVIII or FIX and mild hemophilia as 5% to 40% FVIII or FIX. Severe VWD is defined as VWF activity less than 10%, moderate VWD as 10% to 30% and mild VWD as VWF activity more than 30%. Rarer congenital deficiencies or dysfunction of other coagulation factors and platelets can also occur.
Oral surgery, including dental and peridental surgery such as tooth extraction, wisdom tooth removal, dental implant placement and soft tissue surgery in the oral cavity, are among the most common invasive surgical interventions. In undergoing this relatively minor surgery, people with congenital bleeding disorders are at an increased risk of bleeding complications during and after the procedure. If no antifibrinolytic agents and local hemostatic measures are used, postoperative bleeding has been reported to occur in 73% to 100% of people with hemophilia after oral surgery (Ramstrom 1989).
Description of the intervention
The main interventions used to prevent perioperative bleeding in people with congenital bleeding disorders are the antifibrinolytic agents tranexamic acid (TXA) or epsilon aminocaproic acid (EACA). Antifibrinolytic therapy is a cheap, safe and potentially effective therapy in preventing bleeding complications in dental surgery, in addition to other commonly used perioperative measures such as factor replacement therapy, desmopressin and local hemostatic measures. Considering the disadvantages of factor replacement therapy in this population and the wish not to use desmopressin in those at risk of thromboembolic events, it is important to look for alternative methods to prevent bleeding complications in those undergoing oral surgery. Despite the potentially beneficial effects and although it is common practice in hemophilia treatment centres, antifibrinolytic therapy has not yet become part of the standard therapeutic approach in oral surgery in these patient categories. Antifibrinolytic agents can be administered topically as a mouthwash or systemically as oral or intravenous formulations (see table below). In people with renal insufficiency a dose reduction is necessary to ensure renal clearance. Antifibrinolytic agents are contraindicated if there is active thrombotic disease.
Dosing of antifibrinolytic agents
| Antifibrinolytic agent | Available strength | Dose (adults) | Dose (children) |
| TXA mouthwash | 50 mg/ml | 10 ml, 4‐times‐daily | ≥ 1 year: 20 mg/kg bodyweight/day in 2 to 3 doses a day |
| IV TXA | 100 mg/ml slowly IV (1 ml/min) | 500 mg to 1000 mg, 2‐ to 3‐times‐daily | ≥ 1 year: 20 mg/kg bodyweight/day in 2 to 3 doses a day |
| TXA tablets | 500 mg | 1 to 1.5 g, 2‐ to 3‐times‐daily | ≥ 1 year: 20 mg/kg bodyweight/day in 2 to 3 doses a day |
| IV EACA | 250 mg/ml | Starting dose 4 g to 5 g slowly IV (more than 1 hour), followed by continuous infusion of 1 g/hour | 100 mg/kg or 3 g/m2 slowly IV during the first hour, followed by continuous infusion 33.3 mg/kg/hour or 1 g/m2/hour |
| EACA tablets | 500 mg and 1000 mg | Starting dose 4 g to 5 g, followed by 1 to 1.25 g/hour. Maximum dose 24 g per 24 hours | starting 100 mg/kg, followed by 3 g/m2 during the first hour, followed by 33.3 mg/kg or 1 g/m2 every hour, maximum 18 g/m2 (600 mg/kg) in 24 hours |
Table legend: EACA: epsilon aminocaproic acid; IV: intravenous; TXA: tranexamic acid.
Comparator interventions include placebo or no intervention or usual care with or without placebo. Usual care in people with congenital bleeding disorders includes local hemostatic measures (e.g. suturing, local administration of fibrin glue or hemostatic gelatin sponge) except for local antifibrinolytic agents, prophylactic factor replacement therapy and temporary interruption or blockage of anticoagulation drugs. The latter are obviously rarely used in people with congenital bleeding disorders. Factor replacement therapy consists of recombinant or plasma‐derived FVIII or FIX in case of hemophilia and of plasma‐derived VWF/FVIII concentrates in case of VWD.
How the intervention might work
The antifibrinolytic agents TXA and EACA act by binding reversibly to plasminogen and blocking the interaction of plasminogen with fibrin, thereby preventing degradation of the fibrin clot which supports blood clotting. The agent TXA is more potent than EACA (Pell 1973). Bleeding in hemophilia is due not only to defective prothrombin activation but also to hyperfibrinolysis. An important role of FVIII and FIX is to consolidate and sustain the fibrin clot through the activation of thrombin activatable fibrinolysis inhibitor (TAFI). Decreased FVIII and FIX activity in hemophilia and severe VWD leads to less TAFI activation due to less thrombin generation and a consequent increase in fibrinolysis (Broze 1996). In addition, fibrinolytic activity is particularly high in oral mucosa due to the fibrinolytic activity of saliva and local t‐PA production (Sindet‐Pedersen 1990). Therefore, the inhibition of fibrinolysis with antifibrinolytic agents is a rational approach for limiting oral bleeding after surgery in people with congenital bleeding disorders (Shira 1981).
Large placebo‐controlled randomised trials have proven the effectiveness of TXA in reducing postoperative blood loss and transfusion requirements in cardiac surgery (Katsaros 1996; Later 2009; Maddali 2007). In orthopedic surgery, also associated with high perioperative blood loss, a meta‐analysis of large randomised placebo‐controlled trials demonstrated the efficacy of TXA on the same end points without an increased incidence of thrombosis (Gandhi 2013). Also in emergency surgery, TXA reduced the need for blood transfusion by 30% (Perel 2013). Fewer randomised controlled trials have been conducted in other types of surgery, including oral surgery in people with congenital bleeding disorders or in people using vitamin K antagonists (Forbes 1972; McCormack 2012; Sindet‐Pedersen 1989).
A systematic review on studies reporting outcomes after oral surgery in people receiving oral anticoagulation therapy, excluding antiplatelet agents, found few bleeding complications, which were controlled with local hemostatic measures including TXA mouthwashes (Madrid 2009). However, high‐quality published evidence to support the use of antifibrinolytic agents in people with coagulation disorders undergoing oral surgery is limited. We are unaware of any recent systematic review or meta‐analysis specifically reporting on antifibrinolytic therapy in this population.
Why it is important to do this review
Within this review, we aim to analyse the evidence base for the use of antifibrinolytic agents in people with hemophilia or VWD undergoing oral surgery. Given their low cost, high tolerability, effectiveness and safety, these agents are an attractive alternative to prevent perioperative bleeding in oral surgery. We hope to find sufficient scientific evidence to support the use of antifibrinolytic agents in people with congenital bleeding disorders undergoing oral surgery, and that this treatment will become part of the general standard therapeutic approach, potentially sparing patients from the inconvenience of postoperative bleeding without the disadvantages and high costs of clotting factor replacement therapy or desmopressin.
Objectives
Primarily, we aim to assess the efficacy of antifibrinolytic agents to prevent bleeding complications in people with hemophilia or VWD undergoing oral surgery.
Secondary objectives are to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy or desmopressin in people with hemophilia or VWD and further establish the effects of these agents on bleeding in oral surgery for each of these patient populations.
Methods
Criteria for considering studies for this review
Types of studies
Randomised and quasi‐randomised controlled trials in people with hemophilia or VWD undergoing oral or dental procedures.
Types of participants
People of all ages with hemophilia or VWD undergoing any type of oral surgery. In order to avoid too much heterogeneity and very small subgroups of people with rarer coagulation disorders, we are restricting our review to these common congenital bleeding disorders. We will define VWD as VWF activity less than 40% and hemophilia A or B as FVIII or FIX levels less than 40%.
Oral surgery is defined as surgery related to teeth (tooth extraction including third molar removal and implant placement), periodontal tissues, or soft tissues in the oral cavity.
Types of interventions
Main intervention
Use of the antifibrinolytic agents (TXA or EACA) to prevent perioperative bleeding in people with hemophilia or VWD undergoing oral surgery at any dose, mode of delivery (topical, oral or intravenous), frequency and duration of administration, whether started before, during or immediately after the intervention.
Comparison interventions
Placebo or no intervention or usual care with or without placebo in people with hemophilia or VWD.
Usual care includes local hemostatic measures except for local antifibrinolytic agents and prophylactic factor replacement therapy. Trials using co‐interventions such as additional preventive coagulation factor replacement and local hemostatic measures will be included if these co‐interventions are equally distributed among the intervention and comparison groups and do not seriously hamper the interpretation of the separate effect of the antifibrinolytic agents.
Types of outcome measures
Primary outcomes
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Number of postoperative bleeding episodes requiring intervention*
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Side effects or other adverse events
*Intervention is defined as any additional treatment or medical attention needed in addition to usual care to halt postoperative bleeding directly up to 10 days post surgery. Postoperative bleeding episodes include immediate postoperative bleeds, defined as bleeding within 24 hours after surgery, as well as delayed postoperative bleeds, defined as bleeding 24 hours to 10 days after surgery. Usual care to halt bleeding consists of local pressure. This includes both clinically relevant (non‐major) bleeding requiring medical attention (e.g. wound dressing or additional sutures) and major bleeding requiring transfusion of packed red blood cells. Side effects are mainly gastro‐intestinal and will only be considered clinically relevant if it leads to discontinuation or change of therapy.
Secondary outcomes
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Number of minor postoperative bleeding episodes (defined as self‐limiting, usually with local pressure, that does not require medical attention)
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Number of immediate (less than 24 hours) and delayed (24 hours to 10 days) postoperative bleeding episodes requiring intervention
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Any postoperative complication except bleeding, such as wound infection
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Change in hemoglobin level from baseline
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Major bleeding, requiring transfusion of packed red blood cells
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Bleeding duration (minutes, all types of bleeding minor and major)
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Amount of postoperative blood loss (ml)
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Need for and dose of clotting factor concentrates
Search methods for identification of studies
Electronic searches
The Cystic Fibrosis and Genetic Disorders (CFGD) Group will identify relevant studies from the Group's Coagulopathies Trials Register.
The CFGD Coagulopathies Trials Register is compiled from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE and the prospective handsearching of one journal ‐ Haemophilia. Unpublished work is identified by searching the abstract books of major conferences: the European Haematology Association conference; the American Society of Hematology conference; the British Society for Haematology Annual Scientific Meeting and Haemostasis and the Congress of the World Federation of Hemophilia. The search term 'antifibrinolytics' will be added to this trials register. For full details of all searching activities for the register, see the relevant section of the Cystic Fibrosis and Genetic Disorders Group Module.
Furthermore, we will search the ongoing trials registers: ClinicalTrials.gov (http://www.clinicaltrials.gov/); and the WHO International Clinical Trials Registry Platform (ICTRP) (http://www.who.int/ictrp/en/), abstract books of the annual scientific meeting of the International Society for Thrombosis and Haemostasis, the CINAHL database of nursing and allied health services, trial registries and the Proquest dissertation database using database specific search terms equivalent to those indicated for the CFGD Coagulopathies register. We will use existing highly sensitive search strategies (filters) to identify randomised trials if available in the trial registers.The final search strategies will be published in the appendices.
Searching other resources
In order to find additional relevant trials, we will screen the reference lists of all included trials by hand. Furthermore, we will try to contact the manufacturers of antifibrinolytic agents and authors of included studies to ask wether they are aware of and willing to share any other (un)published studies that meet the inclusion criteria. The final search strategies will be published as appendices.
Data collection and analysis
Selection of studies
Two authors (EE content area expert, KG content area expert and methodologist) will independently screen titles and abstracts of all articles obtained through the search strategy and identify abstracts of trials that appear to be potentially relevant. Of the identified trials, full texts will be obtained and two authors (EE, KG) will independently assess these trials for inclusion based on the previously described selection criteria. For this purpose we will use a separate data collection form for assessing trial eligibility. Multiple reports of the same trial will be identified by comparing authors of the reports, trial dates, trial durations, number of participants, details on the interventions and location and setting of the reported trials. When multiple reports on one or more trials are identified these reports will be linked together. A third author (RS content area expert, supervising author) will verify the assessment of trials identified for inclusion. We will resolve any disagreement by discussion between three authors (EE,KG,RS). When necessary, to clarify the eligibility of certain trials, we will try to request further information for the original authors. Duplicate records of the same reports will be removed using reference manager software (RefMan® 2005). We will record the articles retrieved from the search databases in the RevMan software (RevMan 2011). Excluded trials will be listed, except if obviously not fulfilling the selection criteria of this review and the primary reason for exclusion will be given.
Data extraction and management
Two authors (EE, KG) will independently extract data from published reports using a data extraction form that lists characteristics of the included trials and trial participants, all outcome measures and a risk of bias table. We will prepare the data extraction form using the general template for ‘Summary of findings’ tables and a Cochrane checklist of items to consider in data collection or data extraction (Higgins 2011a), which will be authorized by all authors. A third author will verify the data extraction of trials identified for inclusion (RS). If there are any disagreements, we plan to resolve these by discussion between three authors (EE, KG, RS). If possible, the primary outcome measure of the number of postoperative bleedings needing intervention will be extracted from the included trials. When necessary to clarify data from certain trials, we will try to request further information for the original authors.
Assessment of risk of bias in included studies
We will assess the methodological quality of the included trials by using a risk of bias table that includes judgments of the adequacy of the sequence generation (selection bias), allocation concealment (selection bias), blinding of the outcomes assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias) and other potential sources of bias (Higgins 2011b). This table will be completed for each included trial by two authors (EE, KG) independently. We will resolve any disagreements by discussion between three authors (EE, KG, RS). We will rate the risk of bias for each domain as low, unclear or high and summarize this information in a 'risk of bias' plot.
Measures of treatment effect
The treatment effect is the proportion of participants with postoperative bleedings needing intervention, immediate as well as delayed postoperative bleedings lumped together, in the intervention group compared to the control group. For meta‐analysis, we will express this treatment effect as a risk ratio (RR) with corresponding 95% confidence interval (CI). We can also convert this measure to a number needed to treat (NNT), after calculation of the absolute risk reduction (ARR) using the RR and the control group risk (CGT), which is the risk of postoperative bleeding in the control group. The NNT will be useful for better interpretation of the results of our meta‐analysis. In the event that there are included trials where no events are observed in both groups, these trials will be added to the forest plot.
Formulas: ARR = 100 x CGR x (1‐RR), NNT = 100/ARR.
Should events happen more than once in individual participants, i.e. postoperative bleeding needing intervention, side effects, adverse events, the rate of events in the two groups will be calculated dividing one by the other, expressed as rate ratios with corresponding 95% CIs and analysed using Poisson regression.
Likewise, the difference of the effect measures for the secondary outcomes regarding the number of minor postoperative bleedings, postoperative complications except bleeding, major bleeding requiring blood transfusion and the need for clotting factor concentrates between the intervention group compared and the control group will be expressed as a rate ratio with corresponding 95% CIs.
For the secondary outcome measurements (change in hemoglobin level, duration of bleeding, amount of postoperative blood loss and dose of clotting factor concentrates), we will calculate the mean difference (MD) with corresponding 95% CIs between the two groups. If necessary, we will transform the outcome measurements for these continuous data in different studies to the same scale (i.e. bleeding duration in minutes, amount of blood loss in ml) (Deeks 2011).
Unit of analysis issues
We will include trials with non‐standard randomised controlled designs (other than parallel patient‐control designs), given the rare occurrence of hemophilia and VWD.
Cross‐over trials
In this specific patient population, cross‐over trials are especially advantageous because fewer participants are required to obtain the same power and because the intervention evaluated has a temporary effect in the treatment of the stable, chronic condition of a congenital bleeding disorder. Furthermore, it is likely that single patients need comparable dental procedures more than once at different times. When the interventions are sufficiently spaced in time there is no risk of a carry over effect. Furthermore, every participant receives the intervention and control treatment, which allows the determination of the best treatment or preference for an individual participant (Higgins 2011c). Data from cross‐over trials will be included in the meta‐analysis as if the trial were a parallel group trial.
Studies with multiple treatment groups
When included clinical trials randomise participants to one of several intervention groups, only the groups where the intervention consists of the administration of antifibrinolytic agents to prevent bleeding in oral surgery and the comparison groups with placebo, no intervention or usual care with or without placebo will be included in the meta‐analysis using the same treatment effect measure as in the included parallel group trials. If possible and if the inclusion criteria are met, we will present the effect measure separately in the meta‐analysis when more than two groups are relevant with regard to differences in the administration of antifibrinolytic agents, using a proportional part of the comparison group, to allow for any subgroup analyses (Higgins 2011c).
Cluster‐randomised trials
If cluster‐randomised trials are included special attention will paid in the risk of bias assessment to the possibility of recruitment bias, baseline imbalances, loss of clusters, incorrect analysis, herd effect and contamination (Higgins 2011c). In the meta‐analysis we will use the same treatment effect measure as in the included parallel group trials if the original analysis properly accounts for the cluster design, based for example on a multilevel model or generalized estimating equations (GEEs) and seek for statistical advice if needed.
Dealing with missing data
Possible sources of missing data are: missing outcomes; selective or incomplete reporting; and lack of intention‐to‐treat analysis. To deal with missing data we will contact the original investigators to request missing data whenever possible. Data will be assumed to be missing at random and will therefore not be included in the meta‐analysis. We will address the potential impact of missing data on the findings in the 'Discussion' section (Higgins 2011c) of our final review.
Assessment of heterogeneity
Expected differences in the specific interventions and participant characteristics will give rise to clinical heterogeneity between the included trials. We will consider a visual inspection of the forest plot to see whether CIs overlap. In addition, significant statistical heterogeneity arises from methodological differences between studies (Deeks 2011). To quantify inconsistency between studies the I2 statistic will be calculated to describe the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance) (Higgins 2003).
The interpretation of the I2 values will be as follows (Higgins 2003):
0% to 40% indicates unimportant levels of heterogeneity;
30% to 60% indicates moderate heterogeneity;
50% to 90% indicates substantial heterogeneity;
75% to 100% indicates considerable heterogeneity.
Assessment of reporting biases
To address reporting bias, the literature search will be as comprehensive as possible to prevent missing trials that meet the eligibility criteria. We will also search the trial registration database (www.clinicaltrials.gov) for this purpose. We plan to construct a funnel plot only if enough trials (10 or more) are included. When asymmetry occurs, the possibility that this provides evidence of small‐study effects and publication bias will be considered as only one of the possible explanations (Sterne 2011). We will attempt to understand the source of any small‐study effects and consider their implications in sensitivity analyses.
Data synthesis
We assume that included trials use different outcome definitions of postoperative bleeding. We will try to distillate the number of postoperative bleedings needing intervention if possible, which is suitable for the meta‐analysis. All kinds of interventions with antifibrinolytic agents will be combined. Given that small study populations are expected, based on the rare occurrence of congenital bleeding disorders and expected heterogeneity between the trials due to different outcome measures and differences in the administration of antifibrinolytic agents and use of co‐interventions, we choose to use a random‐effects model for meta‐analysis. If we cannot undertake a meta‐analysis because of too much heterogeneity between the included trials, we will only enter extracted data in the 'Summary of findings' table and provide a narrative synthesis.
Subgroup analysis and investigation of heterogeneity
We will conduct planned subgroup analyses if sufficient trials are included to allow for subgroup analysis as a means of investigating heterogeneous results, to answer specific questions about particular patient groups, types of interventions and types of trials (Deeks 2011).
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Hemophilia versus VWD
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Severe versus moderate versus mild forms of hemophilia, defined as FVIII or FIX levels of < 1%, 1% to 5%, and 6% to 40% respectively
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Severe versus moderate versus mild forms of VWD, defined as VWF activity of < 10%, 10% to 30%, and > 30% respectively
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Administration form of antifibrinolytic agents: topical versus systemic
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Antifibrinolytic agent used: TXA versus EACA
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Different outcome definitions of perioperative bleeding: clinically significant versus minor versus major postoperative bleedings; and immediate versus delayed postoperative bleedings
Sensitivity analysis
If sufficient trials are included in the meta‐analysis, we will perform sensitivity analyses aimed at determining whether conclusions are robust regarding:
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the risk of bias: high risk of bias versus unclear and low risk of bias;
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abstracts whose results cannot be confirmed in subsequent publications versus full text papers;
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differences in usual care: local hemostatic measures versus coagulation factor replacement or desmopressin;
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methodological aspects: blinded versus non‐blinded randomised controlled trials and standard randomised controlled trials versus non‐standard designs;
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reporting bias: including versus excluding small trials.
Other issues suitable for sensitivity analysis that are identified during the review process based on different decisions made during the process.
If any sensitivity analysis identifies particular decisions or missing information that greatly influenced the findings of the review, we will deploy greater resources to try and resolve uncertainties and obtain extra information from the original authors. If this cannot be achieved, we will interpret the results with a certain degree of caution, which will be stated in the 'Discussion' section (Deeks 2011). We will reporting on the sensitivity analyses by producing a summary table.
Summary of findings table
The findings of the included trials will be presented in the 'Summary of findings' table that will contain the primary outcome measure and the secondary outcome measures major bleeding, amount of postoperative blood loss (ml), any postoperative complication except bleeding and need for clotting factor concentrates, a measure of the typical burden of these outcomes (illustrative risk on control intervention), the absolute and relative magnitude of the effect (risk ratio (95% CI) and absolute risks), the numbers of participants and studies addressing these outcomes, risk of bias assessment, source of any external information ('assumed risk' column) and quality assessment for each outcome measure according to the GRADE approach (high, moderate, low or very low) and space for comments (Schünemann 2011a; Schünemann 2011b).
