title: Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions.
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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  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.
  
  
  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.
  
  
  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.
authors.affiliation: Van Creveldkliniek / Department of Haematology, University Medical Centre Utrecht, Heidelberglaan 100, Utrecht, Netherlands, 3584CT.
authors.forename: Karin P M
authors.initials: KP
authors.lastname: van Galen
authors.forename: Eveline T
authors.initials: ET
authors.lastname: Engelen
authors.forename: Evelien P
authors.initials: EP
authors.lastname: Mauser-Bunschoten
authors.forename: Robert J J
authors.initials: RJ
authors.lastname: van Es
authors.forename: Roger E G
authors.initials: RE
authors.lastname: Schutgens
mesh_terms: D015119:Aminocaproic Acid / Q000627:therapeutic use; D000933:Antifibrinolytic Agents / Q000627:therapeutic use*; D016063:Blood Loss, Surgical / Q000517:prevention & control; D005164:Factor IX / Q000008:administration & dosage; D005169:Factor VIII / Q000008:administration & dosage; D006467:Hemophilia A / Q000150:complications / Q000188:drug therapy*; D002836:Hemophilia B / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D013511:Minor Surgical Procedures / Q000009:adverse effects; D006472:Oral Hemorrhage / Q000209:etiology / Q000517:prevention & control*; D019106:Postoperative Hemorrhage / Q000209:etiology / Q000517:prevention & control*; D016032:Randomized Controlled Trials as Topic; D013515:Surgery, Oral; D014081:Tooth Extraction / Q000009:adverse effects*; D014148:Tranexamic Acid / Q000627:therapeutic use; D014842:von Willebrand Diseases / Q000150:complications / Q000188:drug therapy*
chemical_list: D000933:Antifibrinolytic Agents; D014148:Tranexamic Acid; D005169:Factor VIII; D005164:Factor IX; D015119:Aminocaproic Acid