1.  INTRODUCTION TO THE NATIONAL PATIENT SAFETY AGENCY

  The National Patient Safety Agency (NPSA) was established as a Special Health Authority in the National Health Service in July 2001 following the recommendations of the Chief Medical Officer's report on patient safety, An Organisation with a Memory1. The NPSA's role is to improve the safety of NHS patients by promoting a culture of reporting and learning from errors and systems failures, and to manage the national reporting system to support this function. By collecting and analysing data on patient safety problems, the Agency will be able to identify trends and patterns of avoidable incidents, provide feedback to organisations to enable them to change their working practices, help develop models of good practice and systems solutions at a national level, and support ongoing education and learning. Further information is available at www.npsa.nhs.uk

  A patient safety incident is any unintended or unexpected incident which could have or did lead to harm for one or more patients receiving NHS funded healthcare. This is also referred to as an adverse event/incident, mistake or clinical error, and includes near misses2.

2.  NPSA RISK ASSESSMENT PROJECT ON THE USE OF ANTICOAGULANT MEDICINES

  The NPSA is currently conducting a risk assessment project on the use of anticoagulant medicines. The risk assessment is intended to determine the extent and nature of these risks and to identify potential safety solutions that can be developed during 2005 and then introduced into the NHS IN 2006. A report on this work is planned to be published in March 2005. The NPSA wishes to inform the Parliamentary Health Committee of this work and some emerging findings in order to assist the inquiry into `The Prevention of Venous Thromboembolism in Hospitalised Patients'.

3.  EVIDENCE OF HARMS WITH ANTICOAGULANTS

  3.1  In primary care, anticoagulants are one of the three classes of drugs most commonly associated with fatal medication errors. 3 Case studies have been published to describe deaths associated with anticoagulant therapy. 4-6 A coroner and the Chief Medical Officer have recently highlighted the death of a patient from a warfarin overdose caused by misinterpretation of a doctor's handwriting. 7-9

  3.2  In secondary care warfarin and heparin errors are among the most frequently reported medication errors. 10-11

  3.3  Oral anticoagulants were included in the Department of Health Report, Making Medication Practice Safer (2004) as high risk medicines that require the implementation of additional safety controls. 12

  3.4  In the USA, 13-14 and Australia15 anticoagulants have been identified in the top five medicine classes associated with patient safety incidents with medicine.

  3.5  The NPSA contacted the medical and pharmacy defence organisations as well as the NHS Litigation Authority (Personal communications). There have been 600 patient safety incidents of harm or near harm associated with the use of anticoagulants in the UK between 1990-2002. Of these cases, 20% (120) have resulted in the death of the patient.

  3.6  Death associated with the use of warfarin is responsible for 77% (92 reports) and deaths associated with heparin is responsible 23% (28 reports).

  3.7  Further analysis of the data from the Medical Defence Union was possible. Fatal incident reports from this source concerning warfarin made up 88% (79 reports) of the total 92 reports.

  3.8  Deaths associate with the use of warfarin in primary care were 76% (60 reports) of the total reported to the MDU (79 reports). The main types of causes for these fatal incidents were (1) inadequate laboratory monitoring and (2) clinically significant drug interactions usually involving non-steroidal anti-inflammatories.

  3.9  Fatal incident reports concerning heparin in secondary care from the MDU made up 93% (26 reports) of the total of 28 reports. The main causes of these fatal incidents were (1) inadequate laboratory monitoring, (2) inappropriate cessation, (3) inappropriate use of heparin when contraindicated, (4) Dose miscalculation.

  3.10  Reports concerning heparin were not usually associated with the use of low dose heparin products used for thromboprophylaxis. However, there is the risk potential for low dose heparin products to be confused with higher dose products.

  3.11  Some thromboprophylaxis guidelines recommend the use of oral anticoagulants. Some other guidelines requiring thromboprophylaxis to commence in hospital and continue in the community. Although low dose injected heparin products may be the preferred treatment, oral anticoagulants may be substituted if the patients in the community are not able to make suitable arrangements for daily heparin injections.

4.  EMERGING FINDINGS FROM THE NPSA RISK ASSESSMENT

  A multidisciplinary healthcare team from the NHS are in the process of risk assessing systems for anticoagulant treatment in the NHS.

  Anticoagulants treatments include injectable heparin products and oral anticoagulants eg warfarin. The clinical effectiveness of anticoagulants is monitored by routine blood tests; the International Normalised Ratio (INR) for Warfarin and Activated Partial Thromboplastin Test (APTT) for sodium or calcium heparin products. Anticoagulant doses are adjusted following the results of these tests. Low molecular weight heparin products do not usually require blood tests or dose adjustment.

  The following are emerging as the high risk issues in the current error-prone anticoagulant system.

  4.1  Failure to initiate anticoagulant therapy where indicated.

—  Inadequate consideration of thrombosis in pre-operative assessment.

—  Inadequate consideration of thrombosis in medical assessment.

—  Misdiagnosis.

—  Failure to check the requirement for anticoagulant therapy in higher risk patients.

—  Service capacity issue—reluctance to increase patient numbers on anticoagulants—continue to use aspirin when patient may benefit from warfarin therapy.

—  Lack of knowledge and use of treatment guidelines when therapy should be initiated.

—  Conflicting treatment guidelines.

—  Inadequate review of previous medical history.

—  Absent or incomplete medical and medication history available.

—  Wrong information or lack of information.

—  Fear/reluctance to prescribe due to risk of bleeding/stroke—especially in the elderly.

—  Failure of patient to seek treatment.

  4.2  Lack of information and confusion over treatment plan, increasing risk of wrong or delayed treatment, dose or duration of therapy.

—  Absent, incomplete or unclear record indicating reason for treatment, target INR, duration of therapy/planned cessation date and medication history.

—  Failure to record and communicate plan to nurses, pharmacists, receptionist, anticoagulant clinic/GP. Discharge/handover information incomplete. Pre-screening information/treatment cessation plan missing.

—  Lack of clarity over which member of the hospital medical team is responsible for recording this information and when this information should be recorded. This could be either at the same time the anticoagulant is prescribed or before or at the same time the patient is discharged from hospital.

—  NHS pressures of discharge. Lack of time, lack of knowledge, inability to find template referral forms or poor documentation system, or assumption that some other member of the team is responsible or failure to understand the importance of recording this information for the safe and effective anticoagulant treatment. No treatment plan. Discussions / decisions not recorded.

  4.3  Patient has appointment with anticoagulant service but long time period between discharge and clinic appointment.

—  Risk to patient that dosing is incorrect due to delay between clinical review during anticoagulant induction therapy.

—  Patient may be required to return to hospital ward for blood test and dosing—ad hoc arrangement "on duty" staff who may not know or expect the patient are required to manage care on an interim basis. Patients' care record may no longer be on the ward. Patient may not attend due to confusion over arrangements.

  4.4  Patient is discharged on loading dose.

—  Loading dose may be continued in error.

—  Poor inpatient documentation.

—  Unclear, incomplete or wrong completion of yellow book eg, loading doses recorded in yellow book, delay in appointment for anticoagulant clinic, no further doses recorded in yellow book, patient assumes that they are to continue with previous dose until seen in the anticoagulant clinic.

—  Lack of awareness of regime by junior doctor.

  4.5  Prescribe wrong dose or no dose of anticoagulant.

—  Mis-communication of intended dose of anticoagulant between members of the clinical team, the laboratory and the clinical team, the hospital and the GP surgery. Healthcare staff and the patient or carer. Doses may frequently be communicated verbally.

—  Oral anticoagulants may be prescribed by the "number" of tablets to taken rather than mg dose. There are 5mg, 3mg, 1mg and 0.5mg tablets available.

—  Healthcare organisations and practitioners may have standardised on the use of one or more strengths of anticoagulant product. This may cause confusion as neighbouring healthcare organisations and practitioners may has standardised on different strength products.

—  Dose does not appear on prescription but held separately eg at the back of a hospital prescription care or on a separate anticoagulant prescription form.

—  The laboratory results may be matched to the incorrect patient and used to determine new dose of anticoagulant.

—  No baseline INR measured before commencing induction doses of oral anticoagulants. The selected doses may be inappropriate for the patients for this reason.

—  The first INR test undertaken on day three, the patient may already be discharged from the hospital and this may cause difficulty in arranging the test and adjusting the dose before the patient is transferred into the care of the outpatient anticoagulant service of GP service.

—  Poor dosing decisions by prescribers based on INR and other factors.

—  Lack of standardisation of loading dose regimens between healthcare organisations and practitioners.

—  Anticoagulant doses are prescribed on a daily basis by junior doctors in hospitals. Prescriptions for these daily doses are frequently omitted and this can lead to dose omission as nursing staff have no information as to what dose to administer.

—  Heparin products are prescribed mg/kg body weight or unit/kg body weight. A body weight may not be available or may be incorrectly estimated. The dose of heparin may be miscalculated due to an arithmetic errors.

—  Low molecular heparin products have different licensed clinical indications and the dose and dose frequency differs with indication. These factors can cause confusion and the wrong product, dose or frequency is prescribed for a specific indication.

—  Poorly hand written prescriptions for heparin in "units" can be misinterpreted as dose zeros causing dose errors of factors of 10.

  In Primary Care for oral anticoagulants.

—  Repeat prescriptions for oral anticoagulants are generated via patient/carer request alongside requests for other medicines. There is no additional safety checks for oral anticoagulants.

—  There are less safety checks for anticoagulants as no dose or frequency or duration information is included on prescription. It is assumed that dosing information is provided to the patient by the anticoagulant clinic.

—  INR results may not be recorded in GP case record.

—  Current oral anticoagulant dose information may not be recorded in GP case record.

—  Routine checks of the continued appropriateness of treatment, recent and safe INR, the current dose, appropriateness of the dose or quantity requested or date of next appointment with the anticoagulant clinic may not be included in the repeat prescription process in GP's surgeries.

  4.6  Prescription and labels for oral anticoagulants include the instruction "as directed".

—  Prescription for discharge and repeat supplies of oral anticoagulants include the instruction "as  directed". There is a separation of responsibilities—those prescribing the "supply" of anticoagulants to those "dosing" anticoagulants.

—  Once discharged from hospital, the patient held record called "the yellow book" is the only information source that provides information about the current dosage. The yellow book is not regarded as a prescription but rather "supplementary clinical information".

—  The information in the patient held record especially the dose and the latest INR result is not usually checked by the GP prescribing maintenance supplies or the pharmacist when dispensing maintenance supplies of oral anticoagulants.

  4.7  Failure to monitor anticoagulant therapy to adjust dose to effect.

—  Lack of time, or poor documentation system, or assumption that some other member of the team is responsible for monitoring and dose adjustment.

—  Failure to understand the importance of communicating to the team for the safe and effective anticoagulant treatment.

—  Inadequate follow-up of patients who do not attend the anticoagulant clinic to have a blood test and dose of oral anticoagulant adjusted as appropriate.

  4.8  Dose adjustment for surgery/dentistry/endoscopy/cardioversion.

—  Different guidelines, opinion and practice on how to manage patients on anticoagulants requiring surgery,dental treatment, endoscopy or cardioversion.

—  Anticoagulant clinics frequently expected to manage patients therapy before and after treatment without any guidance from the surgeon or dentist or investigating clinician as to what is required.

—  Blood test frequently undertaken immediately prior procedure, the operation or procedure is cancelled and delayed if INR is not correct, even when the patient an anticoagulant clinic have not been informed what was required.

  4.9  Unconsidered co-prescribing of non-steroidal anti-inflammatories and other interaction medicines with oral anticoagulants.

—  Lack of knowledge, time, professional judgement of prescriber.

—  Lack of use of cytoprotective agents.

—  Incomplete or unavailable medication history.

—  Patients self prescribing/taking over the counter supplies of nonsteroidals

  4.10  Incorrect selection and preparation of heparin products

—  There are many different types and strength of heparin products and there may be a mis-selection error.

—  Heparin products are prescribed mg/kg body weight or unit/kg body weight. A body weight may not be available or may be incorrectly estimated. The dose of heparin may be miscalculated due to an arithmetic errors.

—  Sodium Heparin—supplied as concentrate that requires dilution. Mis-selection and arithmetic calculation errors.

—  Incorrect physical syringe measurement of dose.

—  Incorrect dilution of concentrate.

—  For heparin infusions incorrect calculation of rate of administration. Confusion over mls/hour, units/hour.

—  For heparin infusions incorrect operation of infusion pump when programming rate of administration to be delivered.

  4.11  Inappropriate dispensed supply of oral anticoagulants.

—  There are less safety checks for anticoagulants as no dose or frequency or duration information is included on prescription. It is assumed that dosing information is provided to the patient by the anticoagulant clinic.

—  Routine checks of the continued appropriateness of treatment, recent and safe INR, the current dose, appropriateness of the dose or quantity requested or date of next appointment with the anticoagulant clinic are not usually included in the repeat dispensing process.

—  A review of the patient held record is not usually included when supplies of anticoagulants are dispensed.

5.  ISSUES FOR THROMBOPROPHYLAXIS OF HOSPITAL PATIENTS ARISING FROM RISK ASSESSMENT

  It is important that the use of any anticoagulant products for thromboprophylaxis should be as safe as possible and forms part of an anticoagulant system that has identified and minimised risks. Identified risks in section 4 will help the NPSA develop safety solutions for the anticoagulant system during 2005. Specific risks concerning thromboprophylaxis for further discussion are included in this section.

5.1  Failure to treat or undertreatment

  The indications for thromboprophylaxis and recommended drug regimens have been reasonably well  established and there is a range of guidance available15-19. Failure to treat or suboptimal thromboprophylaxis has been identified during the NPSA risk assessment process. This risk has also been identified in published studies in the UK and internationally (Table 1) 20-26.

  Failure to use thromboprophylaxis is particularly poor in patients admitted to nonsurgical areas of the hospital. Most acutely ill medical patients are at risk for venous thromboembolism, at least 75% of fatal pulmonary emboli occur in this group. Medical patients are at significant risk of thromboembolic disease. Patients over 75 years of age, a history of venous thrombosis with chronic respiratory disease, congestive heart failure, and infectious disease and with a diagnosis of cancer are at high risk of symptomatic venous thromboembolism (VTE), particularly pulmonary embolism. Most medically ill patients in the hospital do not receive any form of venous thromboembolism prophylaxis despite evidence that their venous thromboembolism risk is similar to surgical patients. Many patients recently discharged from the hospital remain at high risk for thrombosis27-29. Recent studies have identified the risk factor profiles in this group of patients, and a risk assessment model for medical patients has been developed. Risk stratification will help to ensure that patients receive appropriate thromboprophylaxis27.

  In a publication concerned with the application of the American College of Chest Physicians Seventh National Guidelines on Antithrombotic and Thrombolytic Therapy recommendations for appreciable resources to be devoted to the distribution of educational materials, computer generated reminders and to patient mediated interventions as these methods are judged to be effective30. The authors suggest that few resources are devoted to educational meetings, audit, feedback and educational outreach as these methods do not appear to be very effective in applying the agreed guidelines in practice.

5.2  Management of patients on oral anticoagulants for dental procedures, surgical procedures and other procedures

  Another reason for patients requiring thromboprophylaxis not to be treated or undertreated is due to a widespread belief among healthcare practitioners that oral anticoagulation therapy must be discontinued before dental treatment, minor surgery and other procedures to prevent serious bleeding.

  The scientific literature does not support routine discontinuation of oral anticoagulation therapy for dental patients. Use of warfarin sodium as it relates to dental or oral surgical procedures has been well-studied. Some dental studies of antiplatelet therapy are consistent with the findings in warfarin sodium studies. Dental therapy for patients with medical conditions requiring anticoagulation or antiplatelet therapy must provide for potential excess bleeding. Routine discontinuation of these drugs before dental care, however, can place these patients at unnecessary medical risk. The coagulation status—based on the International Normalized Ratio—of patients who are taking these medications must be evaluated before invasive dental procedures are performed. Any changes in anticoagulant therapy must be undertaken in collaboration with the patient's prescribing physician31.

  In an Australian study of 70 patients who were on warfarin treatment requiring minor oral surgical procedures were treated in the Oral Surgery Department. A control group of 35 had their warfarin stopped prior to the minor oral surgical procedure. The other 35 formed the study group. Patients with an International Normalized Ratio outside the therapeutic range of two to four, or with history of liver disease or on drugs affecting liver function were excluded from the study32. Any incidences of post-operative bleeding were recorded. None of the patients in either control or study group had any serious bleeding complications.

  In a systematic review peri-operative management of patients receiving oral anticoagulants 31 published studies were found. Although the quality of the identified reports was generally poor; and no randomized controlled trials have been performed and duration of follow-up was typically not stated. The reports indicated that most patients can undergo dental procedures, arthrocentesis, cataract surgery, and diagnostic endoscopy without alteration of their regimen.

  For other invasive and surgical procedures, oral anticoagulation needs to be withheld, and the decision whether to pursue an aggressive strategy of peri-operative administration of intravenous heparin or subcutaneous low-molecular-weight heparin should be individualized. The reviewers emphasised that the current literature is limited and further and more rigorous studies are needed to better inform treatment with anticoagulants in these clinical situations33.

5.3  Extended thromboprophylaxis

  Prolonged thromboprophylaxis with LMWH for up to 35 days after major orthopaedic surgery has been recommended33. The American College of Chest Physicians (ACCP) recommendation for a minimum of seven to 10 days of prophylaxis after hip and knee replacement, even if patients are discharged from the hospital within seven days of surgery. As risk of VTE persists for up to three months after surgery, patients at high risk for postoperative VTE may benefit from extended prophylaxis (eg, an additional three weeks after the first seven to 10 days). Extended prophylaxis with low-molecular-weight heparin (LMWH) reduces the frequency of post discharge VTE by approximately two thirds after hip replacement; however, the resultant absolute reduction in the frequency of fatal pulmonary embolism is small (ie, estimated at one per 2,500 patients). Indirect evidence suggests that, compared with LMWH, efficacy of extended prophylaxis after hip replacement is greater with fondaparinux, similar with warfarin, and less with aspirin. Extended prophylaxis is expected to be of less benefit after knee than after hip replacement. In keeping with current ACCP recommendations, at a minimum, extended prophylaxis should be used after major orthopaedic surgery in patients who have additional risk factors for VTE (eg, previous VTE, cancer). If anticoagulant drug therapy is stopped after seven to 10 days, an additional month of prophylaxis with aspirin should be considered19, 35.

  Cancer patients receiving radiotherapy. The duration of prophylaxis should usually last for the period of treatment, except in the case of pelvic or cerebral radiotherapy where it is continued for four to 12 months beyond the treatment period36.

  Arranging for the continuation of thromboprophylaxis after discharge from hospital can be complicated and if not arranged carefully may cause many of the risks described in section 4. Safe models of practice need to be developed and promoted to enable the safe extended thromboprophylaxis in the community using injected low dose heparin products and where appropriate oral anticoagulants.

6.  SUMMARY

  The NPSA has identified the use of anticoagulants in hospital and in the community as a high risk process, The NPSA is currently conducting a risk assessment project to determine the extent, nature and prioritise these risks and to identify potential safety solutions. A report is planned to be published in March 2005. The NPSA intends to develop the safety solutions during 2005 for introduction into the NHS IN 2006.

  Specific issues associated with thromboprophylaxis of hospital patients have been identified as high risk issues in the emerging findings from the NPSA risk assessment. This includes failure to treat or undertreatment with anticoagulants for thromboprophylaxis, lack of clarity over how patients on oral anticoagulants should be managed for dental, surgical and other procedures and issues associated with the safe treatment when thromboprophylaxis is required following discharge from hospital.

  The NPSA would be pleased to provide oral evidence on the 9 December and provide any additional information that would assist the Health Committee complete work on this topic

REFERENCES:

  1  Department of Health (England). An organisation with a memory. 2000

  2  National Patient Safety Agency. Seven steps to patient safety.

  3  Medical Defence Union 1996. Problems in General Practice—medication errors. The Medical Defence Union 1996.

  4  Machin S J. Medico legal problems associated with oral anticoagulant services. In Oral anticoagulation management and stroke prevention: The primary care perspective. Editors D A Fitzmaurice and E T Murray. Newmarket: Hayward Medical Communications. 2002; p50-57.

  5  Reardon M, Burns B, Brewer B, O'Sullivan J P. Deaths associated with warfarin in elderly patients. Br J Clin Pract 1995; 49:322-3.

  6  Ferner. R E, Whittington, R M. Coroner's cases of death due to errors in prescribing or giving medicines or to adverse drug reactions: Birmingham 1986-91. Journal of the Royal Society of Medicine. 1994; 87: 145-148.

  7  Eaton L. Coroner highlights prescribing error after patient dies from warfarin overdose. Br Med J. 2002; 325: 922.

  8  Anon. Warfarin safety. Br J Gen Pract. 2002; 52: 102.

  9  Department of Health. Patient Safety, medication error and handwriting. Chief medical Officer's Update 2003; 53: 10-12 www.doh.gov.uk/cmo/cmo—35.htm.

10  Cousins D H, Upton D R. Medication Errors: A national standard for supply of warfarin tablets? Pharmacy in Practice 1997; 7; 570.

11  Cousins, D H, Upton D R. Medication Errors: Risk assess your dispensing. Pharmacy in Practice 1998; 8; 253-256.

12  Department of Health (England). Improving medication safety. 2004.

13  Anon. Joint Commission IDs five high-alert meds. ED Manage 2000, 12:21-2.

14  Anon. High alert medications and patient safety. Int J Qual Health Care 2001, 13:339-40.

15  Runciman W B, Roughead E E, Semple S J. Adams R J. Adverse drug events and medication errors in Australia. In J Qual Care 2003, 15 Suppl. 1:i49-59.

16  Prophylaxis of Venous Thromboembolism SIGN Publication No 62. Scottish Intercollegiate Guidelines Network. 2002. http://www.sign.ac.uk/guidelines/fulltext/62/index.html.

17  Royal College of Obstetrics and Gyanecology. Thromboprophylaxis during pregnancy, labour and vaginal delivery. 2004.

18  Oates-Whitehead R M, D'Angelo A, Mol B. Anticoagulant and aspirin prophylaxis for preventing thromboembolism after major gynaecological surgery (Cochrane Review). The Cochrane Library, Issue 4, 2004.

19  Geerts W H, Pineo G F, Heit J A, Bergqvist D, Lassen M R, Colwell C W, Ray J G. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep; 126(3 Suppl):338S-400S.

20  Burns P J, Wilsom R G, Cunningham C. Venous thromboembolism prophylaxis used by consultant general surgeons in Scotland. J R Coll Surg Edinb. 2001 Dec; 46(6):329-33.

21  Fassiadis N, Stavrianakis C, Moghraby O S, Gandhi P, Smedley F H. Venous thromboembolism. Prophylaxis on a Saturday morning in a district hospital. Int Angiol. 2002 Dec; 21(4):330-2.

22  Gidiri M, Sant M, Philips K, Lindow S W. Thromboprophylaxis for caesarean section—how can uptake and coverage be improved? J Obstet Gynaecol. 2004 Jun;24(4):392-4.

23  Deep K, Jigajinni M V, Fraser M H, McLean A N. Prophylaxis of thromboembolism in spinal injuries—survey of practice in spinal units in the British Isles. Injury. 2002 May; 33(4):353-5.

24  Wright G, Elliott K, Wilkie C, Cuschieri R J, Bittiner B, Hughes K B. A prospective audit of hospital-acquired deep vein thrombosis and pulmonary embolism. Int J Clin Pract. 1999 Oct-Nov; 53(7): 497-504.

25  Aujesky D, Guignard E, Pannatier A, Cornuz J. Pharmacological thromboembolic prophylaxis in a medical ward: room for improvement. J Gen Intern Med. 2002 Oct; 17(10): 788-91.

26  Stark J E, Kilzer W J. Venous thromboembolic prophylaxis in hospitalized medical patients. Ann Pharmacother. 2004 Jan; 38(1): 36-40.

27  Alikhan R, Cohen AT, Combe S, Samama M M, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Olsson C G, Turpie A G; MEDENOX Study. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med. 2004 May 10; 164(9): 963-8.

28  Cohen A T. Discoveries in thrombosis care for medical patients. Semin Thromb Hemost. 2002 Aug; 28 Suppl 3:13-7.

29  Michota F A. Venous thromboembolism prophylaxis in medical patients. Curr Opin Cardiol. 2004 Nov; 19(6):570-4.

30  Schunemann H J, Cook D, Grimshaw J, Liberati A, Heffner J, Tapson V, Guyatt G. Antithrombotic and thrombolytic therapy: from evidence to application: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep; 126(3 Suppl):688S-696S.

31  Jeske A H, Suchko G D. Lack of a scientific basis for routine discontinuation of oral anticoagulation therapy before dental treatment. J Am Dent Assoc. 2003 Nov; 134(11):1492-7.

32  Cannon P D, Dharmar V T. Minor oral surgical procedures in patients on oral anticoagulants—a controlled study. Aust Dent J. 2003 Jun; 48(2):115-8.

33  Dunn A S, Turpie A G. Perioperative management of patients receiving oral anticoagulants: a systematic review. Arch Intern Med. 2003 Apr 28; 163(8):901-8.

34   Cohen A T, Khushal A. Extended thromboprophylaxis following lower limb arthroplasty: what do the clinical trials mean? Haemostasis. 2000;30 Suppl 2:88-94; discussion 82-3.

35  Kearon C. Duration of venous thromboembolism prophylaxis after surgery. Chest. 2003 Dec; 124 (6 Suppl):386S-392S.

36  Thodiyil P A, Walsh D C, Kakkar A K. Thromboprophylaxis in the cancer patient. Acta Haematol. 2001; 106(1-2):73-80.