Drugs that prevent oral bleeding in people with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions

Review question

We reviewed the evidence about whether antifibrinolytic medicine (drugs that promote blood clotting) such as tranexamic acid or epsilon aminocaproic acid, can prevent oral bleeding in people with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions.

Background

Haemophilia and Von Willebrand disease are inherited bleeding disorders. People with these disorders have an increased risk of bleeding complications during and after oral surgery or dental extractions, even if these are relatively minor and commonly performed. The number of bleeds and the severity of each depend on disease-related factors (such as the severity of the haemophilia), as well as patient-related factors (such as inflammation of the gums or blood vessel diseases) and intervention-related factors (such as the type and the number of teeth extracted or how big the surface of the wound is). Measures such as giving clotting factors directly into the blood stream, are commonly used before, during or after surgery to prevent bleeding complications. However, these measures are costly and have risks such as the formation of inhibitors and the transmission of infections. Therefore, it is important to search for alternative methods to prevent bleeding complications. In routine practice antifibrinolytic medicine is often used before, during and after surgery. However, there is currently no clear scientific evidence for this practice .

Search date

The evidence is current to: 14 December 2015.

Trial characteristics

We did not find any trials of antifibrinolytic medicine to prevent bleeding after minor oral surgery or dental extractions in people with Von Willebrand disease. The review does include two trials published in the 1970's in 59 people with haemophilia undergoing dental extraction. In one trial the people were aged between 13 and 65 years and in the second trial the people had an average age of 34 years. One trial lasted five days and used tranexamic acid; the second trial lasted 10 days and used epsilon aminocaproic acid tablets. Both trials compared the active medicine with a substance that contained no medication (a placebo) in addition to clotting factor concentrates.

Key results

Overall, the two included trials showed a reduction in the number of bleeds after dental extraction, in the amount of blood loss, and in the need for clotting factor concentrates in the people treated with tranexamic acid or epsilon aminocaproic acid tablets compared to those who received a placebo. When combining the results of both trials it appeared that antifibrinolytic medication roughly halves the bleeding rate after dental extraction and the trials reported. Side effects of the antifibrinolytic medicine rarely occurred and led to discontinuation of epsilon aminocaproic acid tablets in only one case.

Quality of the evidence

In the epsilon aminocaproic acid trial, the trial physicians assigned each person to receive a placebo or the active treatment based on a pair-matching technique for age, factor-assay and the number of extractions. The fact that the trial physicians made this decision may have introduced a selection bias. However, we do not think that this had a major impact on the trial's conclusions. Overall, the two trials were small and differed from each other in terms of how many of the people taking part had severe haemophilia , the simultaneous use of clotting factor concentrates and the different antifibrinolytic treatment schedules. We rated the overall quality of the evidence as low for using antifibrinolytic medicine to prevent bleeding in people with haemophilia after minor oral surgery or dental extractions. No evidence was found for people with Von Willebrand disease. It could however be argued that, if antifibrinolytic medicine works for people with haemophilia, it is likely that the medicine will also work for people with other bleeding disorders undergoing dental extractions or minor oral surgery.

Authors' conclusions: 

Despite the discovery of a beneficial effect of systemically administered tranexamic acid and epsilon aminocaproic acid in preventing postoperative bleeding in people with haemophilia undergoing dental extraction, the limited number of randomised controlled trials identified, in combination with the small sample sizes and heterogeneity regarding standard therapy and treatment regimens between the two trials, do not allow us to conclude definite efficacy of antifibrinolytic therapy in oral or dental procedures in people with haemophilia. No trials were identified in people with Von Willebrand disease.

Read the full abstract...
Background: 

Minor oral surgery or dental extractions (oral or dental procedures) are widely performed and can be complicated by hazardous oral bleeding, especially in people with an inherited bleeding disorder such as haemophilia or Von Willebrand disease. The amount and severity of singular bleedings depend on disease-related factors, such as the severity of the haemophilia, both local and systemic patient factors (such as periodontal inflammation, vasculopathy or platelet dysfunction) and intervention-related factors (such as the type and number of teeth extracted or the dimension of the wound surface). Similar to local haemostatic measures and suturing, antifibrinolytic therapy is a cheap, safe and potentially effective treatment to prevent bleeding complications in individuals with bleeding disorders undergoing oral or dental procedures. However, a systematic review of trials reporting outcomes after oral surgery or a dental procedure in people with an inherited bleeding disorder, with or without, the use of antifibrinolytic agents has not been performed to date.

Objectives: 

The primary objective was to assess the efficacy of local or systemic use of antifibrinolytic agents to prevent bleeding complications in people with haemophilia or Von Willebrand disease undergoing oral or dental procedures. Secondary objectives were to assess if antifibrinolytic agents can replace or reduce the need for clotting factor concentrate therapy in people with haemophilia or Von Willebrand disease and to further establish the effects of these agents on bleeding in oral or dental procedures for each of these populations.

Search strategy: 

We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, compiled from electronic database searches of the Cochrane Central Register of Controlled Trials (CENTRAL), of MEDLINE and from handsearching of journals and conference abstract books. We additionally searched the reference lists of relevant articles and reviews. We searched PubMed, Embase and The Cochrane Library. Additional searches were performed in ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP).

Date of last search of the Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 14 December 2015.

Selection criteria: 

Randomised and quasi-randomised controlled trials in people with haemophilia or Von Willebrand disease undergoing oral or dental procedures using antifibrinolytic agents (tranexamic acid or epsilon aminocaproic acid) to prevent perioperative bleeding compared to no intervention or usual care with or without placebo.

Data collection and analysis: 

Two authors independently screened the titles and abstracts of all identified articles. Full texts were obtained for potentially relevant abstracts and two authors independently assessed these for inclusion based on the selection criteria. A third author verified trial eligibility. Two authors independently performed data extraction and risk of bias assessments using standardized forms.

Main results: 

While there were no eligible trials in people with Von Willebrand disease identified, two randomised, double-blind, placebo-controlled trials (total of 59 participants) in people with haemophilia undergoing dental extraction were included. One trial of tranexamic acid published in 1972 included 28 participants with mild, moderate or severe haemophilia A and B and one of epsilon aminocaproic acid published in 1971 included 31 people with haemophilia with factor VIII or factor IX levels less than 15%. Overall, the two included trials showed a beneficial effect of tranexamic acid and EACA, administered systemically, in reducing the number of bleedings, the amount of blood loss and the need for therapeutic clotting factor concentrates. Regarding postoperative bleeding, the tranexamic acid trial showed a risk difference of -0.64 (95% confidence interval -0.93 to - 0.36) and the EACA trial a risk difference of -0.50 (95% confidence interval 0.77 to -0.22). The combined risk difference of both trials was -0.57 (95% confidence interval -0.76 to -0.37), with the quality of the evidence (GRADE) for this outcome is rated as moderate. Side effects occurred once and required stopping epsilon aminocaproic acid (combined risk difference of -0.03 (95% CI -0.08 to 0.13). There was heterogeneity between the two trials regarding the proportion of people with severe haemophilia included, the concomitant standard therapy and fibrinolytic agent treatment regimens used. We cannot exclude that a selection bias has occurred in the epsilon aminocaproic acid trial, but overall the risk of bias appeared to be low for both trials.

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