Keywords Oral anticoagulant therapy Elective surgery Perioperative management. Introduction

Transcription

1 Intern Emerg Med (2007) 2: DOI /s y ORIGINAL F. Baudo F. de Cataldo G. Mostarda A. Ghirarduzzi M. Molinatti V. Pengo D. Poli A. Tosetto E. Tiraferri E. Morra on behalf of Federazione Centri per la diagnosi della trombosi e la Sorveglianza delle terapie Antitrombotiche (FCSA) Management of patients on long-term oral anticoagulant therapy undergoing elective surgery: survey of the clinical practice in the Italian anticoagulation clinics Received: 4 April 2007 / Accepted in revised form: 20 July 2007 / Published online: 23 November 2007 Abstract In the perioperative management of patients on long-term oral anticoagulant (OAC) therapy the problem is balancing the thromboembolic (TER) and the haemorrhagic risk (HR) in the perioperative period. The Federazione Centri per la diagnosi della trombosi e la Sorveglianza delle terapie Antitrombotiche (FCSA) activated an online registry from November 2001 to August 2003 in order to collect information on the management of these patients in Italy. Four hundred and eleven patients, undergoing elec- F. Baudo ( ) F. de Cataldo G. Mostarda E. Morra Thrombosis and Hemostasis Unit Niguarda Hospital Milan, Italy francesco.baudo@ospedaleniguarda.it A. Ghirarduzzi Arcispedale S. Maria Nuova Reggio Emilia Reggio Emilia, Italy M. Molinatti Maria Vittoria Hospital Turin, Italy V. Pengo University of Padua Padua, Italy D. Poli University of Florence Florence, Italy A. Tosetto Ospedale San Bortolo Vicenza, Italy E. Tiraferri Ospedale degli Infermi Rimini, Italy tive major (18%) and minor surgery (82%), from 7 centres, were registered. Three hundred and ninety-nine out of 411 patients received LMWH either once a day (310 patients) or twice a day (89 patients) during OAC therapy discontinuation. Two thromboembolic (0.48%) and 16 bleeding events (7 major; 1.7%) were reported. Notwithstanding the lower doses of heparin (54.3 U/kg o.d. and 64.4 U/kg b.i.d.), the thromboembolic complications are in line with those reported in the literature. The data of this study suggest that the intervention with LMWH may be relevant only in the high-risk patients as already proposed by others. Keywords Oral anticoagulant therapy Elective surgery Perioperative management Introduction The perioperative management of patients on long-term oral anticoagulant (OAC) therapy is an important issue in clinical practice because of the increasing number of patients requiring surgery. The problem is balancing the thromboembolic (TER) and the haemorrhagic risk (HR) in the perioperative period [1 6]. The conditions that require long-term OAC therapy and the categorisation of the associated TER according to Douketis [3] and Watts and Gibbs [4] are listed in Table 1. Direct data on TER during discontinuation of OAC therapy in the perioperative period are limited. Indirect estimates are calculated from the rates of thromboembolic events in patients at risk without OAC prophylaxis: a risk of 10 25% per year translates into the probability of 1 event/ patients x day [7, 8]. Age (>75 years), hypertension, diabetes and left ventricular insufficiency are additional risk factors. A prospective cohort study on minor invasive procedures carried out in community office practices was recently reported [9]. Perioperative low-

2 IM F. Baudo et al.: Long-term oral anticoagulant therapy and elective surgery 281 Table 1 Classification of TER according to Douketis [3] and Watts and Gibbs [4] TER Clinical conditions requiring long-term OAC therapy High Moderate/low Atrial fibrillation (AF) with mitral valvular disease or previous stroke, mechanical mitral valve prostheses, old mechanical aortic valve prostheses (caged-ball, single-leaflet tilting disc), deep venous thrombosis within the previous 3 months New generation mechanical aortic valve prostheses (bileaflet tilting disk), AF without valvular disease, previous (>3 months) venous thromboembolism requiring continuous OAC therapy. Additional risk factors Previous stroke, transient ischaemic attack or systemic embolism, left ventricular dysfunction, age >75 years, hypertension, diabetes mellitus molecular-weight heparin (LMWH), during OAC therapy interruption, was used in only 8.3% of cases; the thromboembolic rate within 30 days was 0.7%. The risk of major bleeding over a 2-day period with perioperative anticoagulation is estimated at 2 4% for major surgery, and 0 2% for minor surgery; the mortality rate of major bleeding complication is 8% [7, 8]. The current therapeutic options are (1) in the low TER discontinuation of OAC therapy to obtain an INR value 1.5 at surgery and its resumption within 24 h after surgery; (2) in the intermediate/high TER replacement of OAC therapy with prophylactic or therapeutic dose of heparin (bridging therapy), during the period of the subtherapeutic INR. OAC therapy is discontinued 4 6 days before surgery in patients with an INR target of 2.5 and 3.5 respectively in order to obtain an adequate INR. In older patients a longer time of OAC therapy discontinuation may be required. LMWH is added when the INR is subtherapeutic and discontinued 24 h before surgery; the INR is tested again on the day before surgery. Anticoagulation (LMWH and OAC) is resumed h after surgery when the haemostasis is safe [10 12]. The American College of Chest Physicians recommends bridging with full doses of heparin only in high-ter patients: recommendations are based on the results of observational studies and on the opinions of experts [10]. To date no controlled, randomised trial has been reported. The Federazione Centri per la diagnosi della trombosi e la Sorveglianza delle terapie Antitrombotiche (FCSA) established a registry to carry out a prospective observational study on the management of the patients on longterm OAC therapy requiring elective surgery. The purpose of this survey is to report on the management procedures in current clinical practice in Italy. 2. to determine the distribution of the patients according to the type of surgery (major or minor); 3. to determine the distribution of the patients according to the risk factors of bleeding (high and low risk) and of arterial and venous thromboembolic complications (high, moderate low risk); 4. to determine the adherence to the current recommendations; 5. to record thromboembolic and haemorrhagic events; 6. to collect information on schedule and dose of heparin. The data were collected with an on-line questionnaire. A standard definition of major and minor surgery is lacking. We adopted, as empirical criterion, the invasiveness of the procedure: abdominal, thoracic, orthopaedic prostheses and neurosurgery were considered major procedures. An empirical criterion was also adopted for the HR. The high HR is related either to the particular site of the intervention (e.g., neurosurgery, major cancer and vascular surgery) or to technical difficulty for an effective surgical haemostasis (e.g., transurethral prostatectomy, polypectomy in the gastrointestinal tract or bladder, renal and liver biopsy). Major bleeding in the perioperative period includes fatal haemorrhage, bleeding in particular sites (intracranial, retroperitoneal, ocular with reduced vision, major joints) or requiring reoperation, causing Hb reduction 2 g/dl and requiring transfusion of 2 or more RBC Units. Any bleeding event not fitting into the above categories was defined as minor [13]. The TER definition is that reported in the literature [3, 4] (Table 1). The following information was required on registration: age, sex, body weight, indications of OAC therapy, associated risk factors for thrombosis and haemorrhage, type of surgery, time of OAC therapy discontinuation before surgery and its resumption after the procedure, INR value at the time of heparin inception and at surgery, heparin schedule in the perioperative period, vitamin K administration, surgical bleeds, early (within two months) and late thrombotic complications (clinical and/or instrumental diagnosis as indicated); arterial, cardiac valvular or mural thrombus; stroke or transient ischaemic attack (TIA); peripheral arterial thromboembolic event; and venous, deep vein thrombosis and pulmonary embolism. Patients and methods The purposes of the registry were: 1. to collect information on the management of the patients on long-term OAC therapy undergoing elective surgery, outside clinical trials, in surgical departments affiliated with the FCSA centres. All the patients were managed according to the local policy. Results The registry was activated in November 2001 and closed in August We have no information on the consecutiveness of accrual. Four hundred and seventy-seven patients from 7 Italian FCSA centres were registered. Sixty-six cases

3 282 F. Baudo et al.: Long-term oral anticoagulant therapy and elective surgery Table 2 Patient distribution according to indications of OAC therapy OAC therapy indications Patient number Prosthetic mechanical heart valve Aortic 57 Mitral 28 Prosthetic biological heart valve Aortic 5 Mitral 5 Atrial fibrillation Non-valvular 221 Non-valvular+other risk factors 5 Venous thrombosis prophylaxis 67 Stroke 4 Coronary heart disease 4 Valvulopathy 7 Dilatative cardio-myopathy 7 Intracardial thrombosis 1 Table 3 Patient distribution in relation to type of surgery, TER and treatment. Number of patients (%) High TER Low TER 44 (11.0) 355 (89.0) LMWH dose o.d. b.i.d. o.d. b.i.d. Major surgery 4 (25.0) 12 (75.0) 41 (67.2) 20 (32.8) Minor surgery 11 (39.2) 17 (60.8) 253 (86.0) 41 (14.0) o.d., once a day; b.i.d., twice a day One patient in high TER and 11 patients in the low TER, undergoing minor surgery, were not treated with heparin Thromboembolic events: 2/253 patients in the low TER group undergoing minor surgery Table 4 Perioperative management (median and range) OAT discontinuation before surgery (days) a 5 (4 7) Heparin inception before surgery (days) b 5 (1 7) Heparin discontinuation before surgery (hours) 24 (1 24) Heparin inception after surgery (hours) 24 (10 72) OAT inception after surgery (days) 1 (1 10) INR at inception of heparin 2.1 ( ) INR at surgery 1.3 ( ) Patients requiring vitamin K c 54 Patients without heparin 12 Type of LMWH Enoxaparin 27 patients Nadroparin 372 patients LMWH o.d.: number of patients 309 Units/kg 54.3 ( ) LMWH b.i.d: number of patients 90 Units/kg 64.4 ( ) a 15 patients discontinued OAT >7 days and b 12 initiated heparin >7 days before surgery; no further information; the patients were excluded in the calculation c Vitamin K was administered in two centres to shorten the time to the targeted INR before surgery of cataract surgery were excluded and 411 patients were included in the analysis: 251 males, median age 72 years (range 25 97). The distribution of the patients according to the OAC therapy indication is reported in Table 2. Seventyseven patients (16 high TER and 61 low TER) underwent major surgery (orthopaedic 22, GI tract 16, urologic 13, gynaecologic 11, vascular 4, others 11). Four and 12 high- TER patients received LMWH o.d. or b.i.d. respectively; 41 and 20 low-ter patients received LMWH o.d. or b.i.d. respectively (Table 3). Three hundred and thirty-four patients (29 high TER and 305 low TER) underwent minor surgery or minor procedures: endoscopies with or without biopsy (158), non-invasive surgery (132), deep and superficial biopsy (39) and device implantation (Pace maker, Porta-Cath) (5). Eleven and 17 high-ter patients received LMWH o.d. or b.i.d. respectively (1 patient untreated); 253 and 41 low-ter patients received LMWH o.d. and b.i.d. respectively (11 patients untreated) (Table 3). The perioperative management is reported in Table 4. The median time of OAC therapy discontinuation and heparin inception before surgery is 5 days. The INR value at inception of heparin was 2.1. The o.d. and b.i.d. dose of heparin per kilogram was 54.3 and 64.4 respectively either pre- or postoperatively (data not shown). Vitamin K was administered in 54 patients to correct the INR before surgery. Two thromboembolic events (0.5%) and 1 death were recorded. A 71-year-old man (aortic mechanical valve, low TER) on treatment with LMWH 51.4 U/kg o.d. suffered a TIA, 3 days after a laparoscopic colecistectomy; a 43- year-old woman (mitral valvulopathy, low TER) on treatment with LMWH 49.4 U/kg o.d. suffered an arterial embolus in the right leg 4 days after mastectomy. An 86- year-old man with high TER (AF, left ventricular insufficiency, cancer of pancreas) on treatment with LMWH 80 U/kg b.i.d. died 13 days after endoscopic retrograde colangio pancreatography because of a sudden cardiac arrest. Twenty-six patients with high HR and 51 patients with low HR underwent major surgery. Forty-eight patients with high HR and 286 patients with low HR underwent minor surgery. Seven patients (1.7%) experienced major, non-fatal haemorrhages: 3 high HR patients receiving o.d. heparin; 4 low HR patients, 1 receiving o.d. and 3 b.i.d. heparin (INR at surgery 1.5). Nine minor haemorrhages (2.2%) were recorded: 1 high HR and 8 low HR patients (INR at surgery 1.5). No patients received antiplatelet drugs. Discussion The ACCP guidelines recommend: (1) bridging with full doses of unfractionated or LMWH in high TER; (2) discontinuation of warfarin in low TER with post-surgery

4 IM F. Baudo et al.: Long-term oral anticoagulant therapy and elective surgery 283 Table 5 Prospective observational studies: haemorrhagic and thrombotic complications Author Patient (n) High-dose LMWH (%) Thromboembolism (%) Major bleedings (%) Kovacs [17] a 3.6 d 2.2 d Dunn [18] b 1.5 d 3.5 d Douketis [19] c 0.6 d 0.9 e Malato [20] c 3.1 d 2.6 d Spyropoulos [21] c 0.9 d 3.3 f LMWH dose: a 200 U/kg o.d.; b 1.5 mg/kg o.d.; c 100 U/kg b.i.d. d LMWH high doses: 2/542 (0.4%); no heparin 2/108 (1.8%) e LMWH high doses: 4/542 (0.7%); no heparin 2/108 (1.8%) f No differences between low and high doses heparin prophylaxis in patients undergoing an intervention that carries a high TER; (3) pre- and post-surgery heparin prophylaxis in intermediate TER [10]. Two studies on the adherence of practising physicians to current recommendations have recently been published [14, 15]. The method in both studies was to inquire by a questionnaire on how clinicians would manage different clinical scenarios of mitral and aortic valvular prosthesis with different TERs in major or minor surgery. The discordance was related mainly to the use of full doses in the low-risk scenarios. In the Ageno et al. survey, sponsored by FCSA, the questionnaires were distributed during the annual meeting. In the high-ter scenarios patients would receive full doses of heparin pre- and post-operatively, regardless of major or minor surgery; post-surgery prophylactic doses were preferred by 16.7 and 22.2% of the responders in major and minor surgery respectively. In the low-risk scenarios full doses were preferred pre-surgery and prophylactic doses post-surgery; discontinuation of warfarin without heparin was chosen by 11.1 and 16.7% in major and in minor surgery respectively. In Table 3 we have summarised the results of our study in order to evaluate how the choices of Ageno s enquiry translate into clinical practice. The majority of the patients underwent minor surgery (334/411; 81.3%) and both in the major and in the minor surgery groups, were classified as low TER (79.2 and 88.0%). The FCSA recommends therapeutic dose of heparin ( lower than that currently recommended [1 5, 8, 10, 16]. In our observational study heparin dosage was the same pre- and post-surgery. In the high TER the majority of the patients, regardless of the type of surgery, were managed by LMWH b.i.d., but LMWH o.d. was also selected. In the patients with low TER the lower doses were preferred either pre- or post-operatively. One high- TER and 11 low-ter patients undergoing minor surgery discontinued warfarin without addition of heparin. Fifteen high-risk patients received one dose/day and 61 low-risk patients received two doses/day. We have no information to interpret these discrepancies. OAC therapy discontinuation and heparin inception before surgery were concomitant: the median value of the INR was 2.1 (range ), indicating that many patients were either under- or over-treated with OAC therapy. In the literature thromboembolic and haemorrhagic events are in the ranges % and % respectively (Table 5) [17 21]. In our survey the occurrence of thromboembolic and haemorrhagic events was low. The two thromboembolic events occurred in two patients with low TE risk who underwent minor surgery. In spite of the lower doses of heparin, the thromboembolic complications are in line with those reported in the literature, suggesting that the intervention with LMWH may be relevant only in the minority of highrisk patients as already proposed by others [1, 5]. This study has important limitations; it is observational, limited numbers of patients are included, and the majority of the patients have low TER and underwent minor surgical procedures. References 1. Kearon C, Hirsh J (1997) Managing anticoagulation before and after surgery in patients who require oral anticoagulants. N Engl J Med 336: Heit JA (2001) Perioperative management of the chronically anticoagulated patient. J Thromb Thrombolysis 12: Douketis JD (2003) Perioperative anticoagulation management in patients who are receiving oral anticoagulant therapy: a practical guide for clinician. Thromb Res 108: Watts SA, Gibbs NM (2003) Outpatient management of the chronically anticoagulated patient for elective surgery. Anaesth Intensive Care 31: Mannucci C, Douketis JD (2006) The management of patients who require temporary reversal of vitamin K antagonist for surgery: a practical guide for clinicians. Intern Emerg Med 1: Spyropoulos AC, Turpie AGG (2005) Perioperative bridging interruption with heparin for the patient receiving long-term anticoagulation. Curr Opin Pulm Med 11: Kearon C (2003) Management of anticoagulation before and after elective surgery. Hematology

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