British Journal of Oral and Maxillofacial Surgery (2002) 40, 248252 2002 The British Association of Oral and

d Maxillofacial Surgeons doi: 10.1054/bjom.2001.0773, available online at http://www.idealibrary.com on

BRITISH

Journal of Oral and Maxillofacial Surgery

Can warfarin be continued during dental extraction? Results of a randomized controlled trial
I. L. Evans,* M. S. Sayers,* A. J. Gibbons,* G. Price,* H. Snooks, A. W. Sugar* *Maxillofacial Unit, Morriston Hospital, Swansea, UK; Mid and West Wales Research and Development Support Unit, School of Postgraduate Studies in Medical and Health Care, University of Wales, Swansea, UK SUMMARY. A randomized controlled trial was set up to investigate whether patients who were taking warfarin and had an International Normalised Ratio (INR) within the normal therapeutic range require cessation of their anticoagulation drugs before dental extractions. Of 109 patients who completed the trial, 52 were allocated to the control group (warfarin stopped 2 days before extraction) and 57 patients were allocated to the intervention group (warfarin continued). The incidence of bleeding complications in the intervention group was higher (15/57, 26%) than in the control group (7/52, 14%) but this difference was not significant. Two patients in the study required hospital review for bleeding and all other episodes of bleeding were controlled by patients at home. Continuing warfarin when the INR is :4.1 may lead to an increase in minor post-extraction bleeding after dental extractions but we found no evidence of an increase in clinically important bleeding. As there are risks associated with stopping warfarin, the practice of routinely discontinuing it before dental extractions should be reconsidered. 2002 The British Association of Oral and Maxillofacial Surgeons

INTRODUCTION Warfarin is the most commonly prescribed oral anticoagulant. At present over 300,000 people in the UK are taking oral anticoagulants1 and the treatment is underused in some conditions.2 With an ageing population in the UK and a greater proportion of this population retaining their teeth, the number of patients taking warfarin who require dental extractions is likely to increase. Therapeutic levels of warfarin are measured by the International Normalised Ratio (INR). The British Society of Haemotology has published guidelines on anticoagulant control which recommend a maximum target INR of 3.5, with a range of 34.3 For dental extractions, patients who have been taking warfarin are at an increased risk of perioperative thromboembolism if the drug is stopped but may be at an increased risk of bleeding if it is continued.4 Patients may bleed from extraction sockets and may also bleed into the medial pterygoid muscle if an inferior dental nerve block is given. A small bleed can produce trismus but a large bleed could embarrass the airway.5 On the other hand, discontinuing warfarin can cause serious embolic complications6 and may lead to a rebound hypercoagulable state.710 In addition, several antibiotics that are prescribed as prophylaxis during dental extraction against
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bacterial endocarditis may increase the effects of warfarin and the risk of bleeding. Indeed, several case reports have been published of antibiotic-induced bleeding in patients who were taking warfarin after dental procedures.11 Customary practice in the UK has been to stop warfarin treatment 2 days before extractions, to do an INR on the day of operation and to proceed if the INR is :2.1. Warfarin is started again later the same day.12 Several authors have suggested that the anticoagulant regimen does not require alteration for dental extractions if the INR is :4.0.1,1216 Additional measures that can be taken to ensure haemostasis include packing sockets with oxidized cellulose gauze and suturing all sockets.1,12 Tranexamic acid has been used as a mouth rinse to reduce haemorrhage further postoperatively.15,17 Because of the risks associated with either stopping or continuing warfarin for dental extraction, general dental and medical practitioners routinely refer patients who are taking warfarin to maxillofacial units for this procedure. If patients could be treated without altering their anticoagulant regimen, then it is possible that most dental extractions could be done in general dental practice on the same day as regular INR blood monitoring. This would often be more convenient and quicker for the patient, cost-effective and would help to reduce hospital waiting lists.

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PATIENTS AND METHODS The trial lasted from May 1999 to October 2000. A total of 117 consecutive patients who were referred by their general dental or medical practitioners to the Maxillofacial Unit at Morriston Hospital, Swansea, and its related departments at the West Wales General Hospital, Camarthen, and Neath General Hospital, who were taking warfarin and required dental extractions were included in the study. Patients who could not give informed consent, did not have access to a telephone, had an INR 94, had a history of liver disease or coagulopathies, or could not attend for follow-up were excluded from the study. At the initial consultation a full medical history was taken and an orthopantogram and clinical examination were done. Those patients who met the study criteria were given verbal and written information on the study and asked for their consent. Randomization was then by consecutive sealed envelopes containing allocation to the two study groups. A register was kept to confirm the sequence of allocation. A preoperative INR and coagulation screen were arranged on the day of operation. The intervention group continued taking warfarin as usual (anticoagulant group). If a patients INR was 94 on the day of operation they were to be withdrawn from the study. The control group stopped taking warfarin 2 days before their dental extractions. If a patients INR was 92, a further dose of warfarin was omitted and the operation was rebooked for the following day. Extractions were done only if the INR was -2. Antibiotic prophylaxis was given for patients at risk of endocarditis in both groups in accordance with British National Formulary guidelines. Dental extractions were done under local anaesthesia using 2% (20 mg/ml) lignocaine hydrochloride with 1/80,000 (12.5 g/ml) adrenaline. Local infiltrations and regional blocks were used in the mandible and maxilla as appropriate. Dental extractions were by forceps and elevators. Surgeons were instructed to use as atraumatic a technique as possible. Where a surgical approach was required the minimum size of mucoperiosteal flap was raised and the least amount of bone was removed. Each extraction socket was packed with oxycellulose dressing (Surgicel) and sutured with 3/0 polyglactin 910 (Vicryl) sutures. Patients were then given a gauze swab to bite on for 10 minutes and they were observed for a further 10 minutes before being discharged. If haemostasis was not achieved after biting on a gauze swab for 10 minutes this was recorded as an immediate bleed. All patients were given verbal and written information with a telephone number to contact the on-call maxillofacial senior house officer in case of any emergencies. A logbook was given to each patient to

record any bleeding episodes, whether pressure was used to stop bleeding, and whether professional help was required to deal with problems. Paracetomol 1 g 6 hourly as required was prescribed and patients were advised not to use any other form of analgesia. After the extractions the control (warfarin withdrawn) group were told to resume taking their warfarin on the same day. All patients were given a review appointment for a week after surgery. Those who failed to attend were sent a further appointment and, if necessary, contacted by telephone. Data were collected from the clinical notes made at each appointment and from the logbooks completed by patients. All complications were recorded and were categorized as bleeding problems, prescription of a course of antibiotics, or prescription of additional analgesia for pain. Data were analysed using the Statistical Package for Social Scientists (SPSS) on an intention to treat basis. Descriptive statistics are presented with 2 and unpaired Students t tests used to compare proportions and means as appropriate; 95% confidence intervals (CI) are also presented. Ethical approval for the study was granted by the Iechyd Morgannwg Local Research Ethics Committee. The use of tranexamic acid as a mouth rinse was not permitted by the committee.

RESULTS Of the 117 patients, 3 were excluded, one because of liver disease and 2 because they refused consent. Of the 114 patients who were randomized, 5 were withdrawn, leaving 109 who completed treatment (Table 1). Of these, 57 were allocated to the anticoagulant group and 52 to the warfarin withdrawn group. One hundred patients attended for review in clinic and 9 patients were reviewed by telephone. There were no significant differences between the groups in the mean age, proportions of men, number of teeth extracted, or the number of patients given prophylactic antibiotics. Naturally, the mean INR for the anticoagulant group was significantly higher at 2.5 than that for the control (warfarin
Table 1 Trial recruitment Parameter Withdrawn INR9 4 Stopped warfarin Withdrew consent Died before treatment Emergency extraction Extraction completed and patient followed up Continued warfarin (60 patients) 1 1 1 0 0 57 Stopped warfarin (54 patients) 0 0 0 1 1 52

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British Journal of Oral and Maxillofacial Surgery

withdrawn) group, at 1.6 (P:0.001) (Table 2). One patient who continued warfarin had an INR level 94 and should have been excluded preoperatively. Two patients in the control group had INR levels 92 (2.1 and 2.3 respectively) and should have discontinued warfarin for a further day before operation. These three patients were included in their allocated study groups on the intention to treat basis. Table 3 summarizes the main outcomes. The only two patients who sought help for bleeding were in the anticoagulant group. The first of these had an oroantral communication (OAC) that developed at the time of removal of an upper third molar; it had been closed immediately by advancing a buccal flap. Bleeding had started again from this site 6 hours later and was stopped by resuturing under local anaesthetic and applying pressure. The patient was admitted overnight for observation and had no further bleeding episodes. The second patient had bled from an upper second premolar socket, which was stopped with local anaesthetic, packing, suturing and pressure. The patient was discharged home from the accident and emergency department and had no further bleeding. The overall rate of bleeding complications in the anticoagulant group was higher than in the control group
Table 2 Baseline characteristics of patients in the two groups Parameter Number of men (%) Mean age (range) Mean number of teeth extracted (range) Prophylactic antibiotics prescribed Mean INR (range) Anticoagulant group Control group (n:57) (n:52) 36 (63) 67 (3692) 2 (17) 13 2.5 (1.24.7) 37 (71) 66 (3093) 3 (19) 12 P value

(26% compared with 14%, 2 2.8, P:0.1; 95% CI 027%). The difference was not significant. The three immediate bleeds were controlled with additional sutures and pressure and all but the two delayed bleeds described above were controlled by patients biting on gauze squares at home. Five patients had other complications (Table 2). In the anticoagulant group two patients were prescribed antibiotics and one was prescribed additional analgesia by clinicians unconnected with the study. One patient in each group was prescribed antibiotics for mild local infections of the extraction sockets by clinicians involved in the study. We found no association between the risk of bleeding and the giving of prophylactic antibiotics. Antibiotics were given to 7 of 22 patients who experienced a bleeding complication compared with 18 of 84 patients who did not ( 2 1.23, P:0.3). In addition, no association was found between the risk of bleeding and the number of teeth extracted. Those who experienced bleeding after extraction had a mean of three teeth extracted, compared with a mean of two in the patients who did not experience bleeding (P:0.2). However, the numbers of patients were low, and small to moderate associations would not be identified.

DISCUSSION
0.38 0.48 0.24 0.26

1.6 (1.22.3) :0.001

Table 3 Comparison of complications in study groups Complications Sought help for bleeding at hospital Sought help for bleeding at hospital and admitted Immediate postoperative bleeding Delayed postoperative bleeding treated by patient at home Sought help for bleeding by telephone at home Postoperative antibiotics prescribed Additional analgesia given for pain None Total Anticoagulated group 1 1 3 9 1 3 1 38 57 Control group 0 0 0 7 0 1 0 44 52 Total 1 1 3 16 1 4 1 82 109

Previous prospective trials comparing perioperative anticoagulant regimens for dental extractions have been too small to detect significant differences in bleeding5,12,14 or have not been adequately randomized.17 In our study there was a higher risk of bleeding in the anticoagulant group (15 patients in the anticoagulant group and 7 patients in the control group), although the difference was not significant. All but two of the bleeding complications were dealt with by the patients at home, suggesting that even if postoperative bleeding episodes do occur more commonly when patients continue anticoagulant treatment, most can be controlled by the patient with no professional help. This supports previous research findings. Bailey and Fordyce5 found a delayed bleeding tendency in patients who continued to take warfarin, but all episodes were controlled by local measures. Devani et al.12 found a very low incidence of postoperative bleeding in anticoagulated patients undergoing dental extractions. Wahl6,13 in a review found there was little or no difference in terms of blood loss after dental surgery between patients who were receiving anticoagulants and those whose coagulation was normal. In 2400 documented dental operations, he found that only 12 patients experienced bleeding that was uncontrolled by local measures. In 7 of these 12 the

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extent of anticoagulation was above recommended therapeutic limits. We have not found any reports of patients experiencing serious harm from postoperative bleeding after dental extractions while continuing anticoagulants.6 On the other hand, stopping warfarin does not lead to a predictable fall in INR. The INR often falls below 1.5 and exposes the patient to risks of thromboembolism.12 Four patients have been reported to have had fatal embolic complications after anticoagulant treatment was withdrawn,1821 supporting the view that anticoagulant treatment should not be stopped before dental extractions without good reason. We did not find a connection between taking prophylactic antibiotics and increased bleeding. Various authors have suggested that antibiotics may cause an increase in bleeding in patients taking warfarin and having dental operations.11,22 The effects of warfarin may be magnified by the suppression by antibiotics of intestinal bacterial flora that can provide a supplementary source of vitamin K when the patients intake is low. In addition, erythromycin stimulates liver enzymes and potentiates the effects of warfarin, and metronidazole inhibits the metabolism of warfarin, again potentiating its effects. Multiple extractions of teeth are generally considered to be a good test of the efficacy of the haemostatic mechanism.5 However, we found no correlation between postoperative bleeding and the number of teeth removed. Tranexamic acid used as a mouth rinse has been shown to prevent bleeding after oral surgery in patients who are taking anticoagulants by inhibiting plasminogen activation and fibrinolysis and acting as a clot stabilizer.17,23 In animal experiments tranexamic acid mouth rinses combined with Surgicel packing proved effective in reducing blood loss.24 In human trials, Blinder et al. did not find this technique better at reducing bleeding than gelatin sponge and sutures alone.14 However, Ramstrom et al. found that in patients who continued taking warfarin at the time of dental extractions, those who used tranexamic mouth rinses had significantly less bleeding than those who did not.25 More recently the use of Surgicel soaked in tranexamic acid, sutures and tranexamic acid mouth rinses has proved particularly effective in preventing postoperative bleeding.26 The use of tranexamic acid mouth rinse was considered in the current study. However, and somewhat surprisingly, tranexamic acid does not have a product licence for use as a mouth rinse in the UK27 and can be used only for named patients. The local research ethics committee therefore did not think its use was appropriate. Our study has shown that although there may be an increase in the number of patients experiencing postoperative bleeding when anticoagulation is continued, this does not appear to be a clinically important problem. Nearly all patients controlled bleeding by simple pressure

and in the two cases that did require professional help, bleeding was stopped by local treatment of the extraction socket. The cost and inconvenience of referring a patient to hospital to have dental extractions is justified only if there is a substantial benefit to the patient. Patients who take warfarin would certainly benefit if dental extractions could be performed safely in general practice. Our study has shown that dental extractions can be done safely in a hospital without stopping warfarin treatment if the patients INR is :4.1. It remains to be established if this finding can be translated to general dental practices.

ACKNOWLEDGEMENTS
We thank Kathy Wareham, clinical research scientist, Clinical Research Unit, School of Postgraduate Studies, University of Wales Swansea, for methodological advice at the outset of the study; Alan Watkins, senior lecturer in statistics, European Business Management School, University of Wales Swansea, for providing statistical advice; Simon Hodder, consultant maxillofacial/head and neck surgeon, Morriston Hospital for permission to recruit his patients into the study and Judy Jones, research secretary, Maxillofacial Unit, Morriston Hospital, for organizing data collection and recording.

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British Journal of Oral and Maxillofacial Surgery 27. Evans IL, Sugar AW. Re: Management of anticoagulation in patients with prosthetic heart valves undergoing oral and maxillofacial operations. Br J Oral Maxillofac Surg 2001; 39: 245.

16. Beirne OR, Koehler JR. Surgical management of patients on warfarin sodium. J Oral Maxillofac Surg 1996; 54: 11151118. 17. Souto JC, Oliver A, Zuazu-Jausoro, Vives A, Fontcuberta J. Oral surgery in anticoagulated patients without reducing the dose of oral anticoagulant; a prospective randomized study. J Oral Maxillofac Surg 1996; 54: 2732. 18. Akbarian M, Austen WG, Yurchak PM, Scannell JG. Thromboembolic complications of prosthetic cardiac valves. Circulation 1968; 37: 826831. 19. Behrman SJ, Wright IS. Dental surgery during continuous anticoagulation therapy. J Am Dent Assoc 1961; 62: 172180. 20. Marshall J. Rebound phenomena after anticoagulant therapy in cerebrovascular disease. Circulation 1963; 28: 329332. 21. Ogiuchi H, Ando T, Tanaka M et al. Clinical reports on dental extractions from patients undergoing anticoagulant therapy. Bull Tokyo Dent Coll 1985; 26: 205212. 22. Bandrowsky T, Vorono AA, Borris TJ, Marcantoni HW. Amoxicillin-related postextraction bleeding in an anticoagulated patient with tranexamic acid rinses. Oral Surg Oral Med Oral Pathol 1996; 82: 610612. 23. Sindet-Pedersen S, Ramstrom G, Bernvil S, Blomback M. The effect of tranexamic acid mouthrinse in anticoagulant treated patients undergoing oral surgery. N Engl J Med 1989; 320: 840843. 24. Vinckier F, Vermylen J. Blood loss following dental extraction in anticoagulated rabbits: effects of tranexamic acid and socket packing. Oral Surg Oral Med Oral Pathol 1985; 59: 25. 25. Ramstrom G, Sindet-Pedersen S, Hall G, Blomback M, Alander U. Prevention of postsurgical bleeding in oral surgery using tranexamic acid without dose modification of oral anticoagulants. J Oral Maxillofac Surg 1993; 51: 12111216. 26. Bal BJ, Hardee PS. Efficacy and cost effectiveness of tranexamic acid mouthrinse for oral surgery in warfarinized patients. Br J Oral Maxillofac Surg 2000; 38: 390.

The Authors
I. L. Evans BSc, FDS, RCS(Eng) M. S. Sayers FDS, RCS(Edin) Senior House Officers A. J. Gibbons MA(Cantab), FDS, RCS(Edin), FRCS(Edin) Specialist Registrar G. Price RGN Sister A. W. Sugar FDS, RCS(Eng), FDS, RCS(Edin) Consultant Oral and Maxillofacial Surgeon Morriston Hospital Swansea, Wales, UK H. Snooks PhD Senior Lecturer in Health and Social Care Research Mid and West Wales Research and Development Support Unit Morriston Hospital Swansea, Wales, UK Correspondence and request for offprints to: Mr A. W. Sugar FDS, RCS, Consultant in Oral and Maxillofacial Surgery, Maxillofacial Unit, Morriston, Swansea, SA6 6NL, UK. Tel:;44(0) 1792 703077; Fax:;44(0) 1792 703068; E-mail: adrian.sugar@swansea-tr. wales.nhs.uk Accepted 6 December 2001