Low-Molecular-Weight Heparin As Bridging Anticoagulation During Interruption of Warfarin Assessment of a Standardized Periprocedural Anticoagulation Regimen

Home , Acenocoumarol, Dalteparin sodium

ORIGINAL INVESTIGATION Low-Molecular-Weight Heparin as Bridging Anticoagulation During Interruption of Warfarin Assessment of a Standardized Periprocedural Anticoagulation Regimen

James D. Douketis, MD, FRCPC; Judith A. Johnson, RN; Alexander G. Turpie, MB, FRCPC

Background: The treatment of patients at increased risk resumed on the evening of the procedure, but daltepa- for arterial thromboembolism who require temporary in- rin was not given after the procedure. terruption of warfarin sodium therapy is a common clinical problem. We investigated the efficacy and safety of a Results: Patients were followed up during the prepro- standardized periprocedural anticoagulation regimen with cedural and postprocedural period for a mean of 13.8 days low-molecular-weight heparin. (range, 10-18 days). In 542 patients who underwent a non–high-bleeding-risk procedure, there were 2 throm- Methods: We studied 650 consecutive patients with a boembolic events (0.4%), 4 major bleeding episodes mechanical heart valve, chronic atrial fibrillation, or em- (0.7%), and 32 episodes of increased wound-related blood bolic stroke who required interruption of warfarin therapy loss that precluded postprocedural dalteparin adminis- because of an invasive procedure. Warfarin was stopped tration (5.9%). In 108 patients who underwent a high- 5 or 6 days before the procedure, and patients received bleeding-risk procedure, there were 2 deaths (1.8%) pos- subcutaneous dalteparin sodium, 100 IU/kg twice daily, sibly due to thromboembolism and 2 major bleeding starting 3 days before the procedure. The risk of post- episodes (1.8%). procedural bleeding determined postprocedural anticoagulant management. In patients undergoing a non– Conclusions: In patients at increased risk for arterial high-bleeding-risk procedure who had adequate thromboembolism who require temporary interruption postprocedural hemostasis, warfarin was resumed on the of warfarin therapy, a standardized periprocedural anti- evening of the procedure, and dalteparin sodium, 100 coagulant regimen with low-molecular-weight heparin IU/kg twice daily, was resumed on the next day and con- is associated with a low risk of thromboembolic and ma- tinued until the international normalized ratio was 2.0 jor bleeding complications. or more. If postprocedural hemostasis was not secured, the resumption of dalteparin was delayed. In patients undergoing a high-bleeding-risk procedure, warfarin was Arch Intern Med. 2004;164:1319-1326

HE TREATMENT OF PA- anticoagulation strategy during interrup- tients with a mechanical tion of warfarin therapy,8-12 several au- heart valve or chronic atrial thorities1-4 and consensus groups13,14 ad- fibrillation who require vocate, for most patients, some form of temporary interruption of bridging therapy with a short-acting an- warfarinT sodium therapy because of sur- ticoagulant. The rationale for bridging an- From the Departments of gery or another invasive procedure is a fre- ticoagulation is to minimize the time be- Medicine, McMaster University quently encountered but underinvesti- fore and after a procedure that patients are (Drs Douketis and Turpie and gated clinical problem.1-4 A major gap in not receiving therapeutic anticoagula- Ms Johnson) and St Joseph’s knowledge is a lack of reliable estimates tion and, thereby, minimize the risk of Hospital (Dr Douketis), and as to the incidence of thromboembolic thromboembolism. The conventional peri- Hamilton Health Sciences, events associated with warfarin therapy in- procedural anticoagulation approach is to General Hospital (Ms Johnson terruption.1 It is well established, how- hospitalize patients 4 to 5 days before sur- and Dr Turpie), Hamilton, ever, that such events can have devastat- gery to stop warfarin and administer in- Ontario. Drs Douketis and ing clinical consequences: thrombosis of travenous unfractionated heparin while the Turpie have received honoraria a mechanical heart valve is fatal in 15% of anticoagulant effect of warfarin re- for speaking engagements and 5,6 15,16 participation in advisory patients, and embolic stroke results in cedes. Intravenous heparin is stopped committees from companies a major neurologic deficit or death in 70% 3 to 4 hours before the procedure to avoid that make low-molecular- of patients.7 Consequently, despite dis- a residual anticoagulant effect at the time weight heparin. agreement on the optimal periprocedural of the procedure. After the procedure, war-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 1. Periprocedural Anticoagulation Regimen METHODS

Day Intervention PATIENT REGISTRY Preprocedure Starting in November 1997, a structured clinical management −7 to −10 Assess for perioperative bridging anticoagulation, protocol for patients who required temporary interruption of classify patients as undergoing high-bleeding-risk warfarin therapy was initiated at the Hamilton Health Sci- or non–high-bleeding-risk procedure ences, General Hospital, a tertiary care teaching hospital and −7 Stop aspirin (or other antiplatelet drugs) * regional center for cardiovascular and neurologic diseases in −5 or −6 Stop warfarin sodium† −3 or −4 Start subcutaneous dalteparin sodium, 100 IU/kg, Hamilton, Ontario. Patients received a standardized regimen twice daily of periprocedural bridging anticoagulation with LMWH that −1 Last preprocedural dose of dalteparin administered was administered, whenever feasible, out-of-hospital by the pa- not less than 12 h before start of surgery or tient or another caregiver. This management protocol was de- procedure veloped in response to an increasing number of elective sur- Day of Procedure gical and other invasive procedures that were being undertaken 0 Assess postoperative hemostasis after surgery or without hospitalization in patients receiving warfarin, and be- procedure; for non–high- or high-bleeding-risk cause of limited hospital bed availability that precluded peri- procedures, resume warfarin usually on evening procedural intravenous heparin administration. To assess the of or day after procedure‡ efficacy and safety of this novel periprocedural anticoagula- Postprocedure tion strategy and to allow internal auditing of patient quality of care, we established a prospective registry of patients who Non–High-Bleeding-Risk High-Bleeding-Risk received bridging anticoagulation with LMWH. Because this peri- Procedure Procedure procedural anticoagulation regimen became the standard of care +1 Start dalteparin sodium, No dalteparin at our institution, informed consent was not required for in- 100 IU/kg, twice daily§ administration clusion into this patient registry. +4 INR testing (stop dalteparin INR testing Ն if INR 2.0) PATIENTS +7 to +10 INR testing INR testing Consecutive adult patients, 18 years or older, at risk for arte- Abbreviation: INR, international normalized ratio. rial thromboembolism who were assessed in the hospital An- *After procedure, resumed on the same day as warfarin resumption. †Warfarin stopped on day −5 if target INR is 2.0 to 3.0 and on day −6 if ticoagulation Clinic between November 1, 1997, and June 30, target INR is 2.5 to 3.5. 2002, for temporary interruption of warfarin therapy were eli- ‡Warfarin resumed when the patient is able to take medications by mouth. gible for this registry. Patients satisfied the following criteria §Start of dalteparin may be delayed until hemostasis is secured. for inclusion: (1) receiving warfarin therapy, with a target international normalized ratio (INR) of 2.0 to 3.5; (2) mechani- farin and intravenous heparin are resumed, the latter ad- cal heart valve, chronic atrial fibrillation, or a previous stroke or transient ischemic attack with a presumed embolic source; ministered for 4 to 5 days until therapeutic anticoagu- and (3) undergoing an elective surgical or other invasive pro- lation with warfarin is reestablished. This approach is cedure that requires normalization of the INR. Patients were difficult to implement because of the current con- excluded from the registry if one or more of the following straints on hospital bed availability and the increasing characteristics were present: (1) renal insufficiency (serum cre- number of surgical and other invasive procedures that atinine level Ͼ2.0 mg/dL [Ͼ178 mmol/L]) that precluded thera- are being performed without hospitalization. peutic-dose LMWH administration; (2) previous heparin- An alternative periprocedural management strategy induced thrombocytopenia; (3) pregnancy; (4) treatment with is the use of low-molecular-weight heparin (LMWH) for an anticoagulant other than the prespecified LMWH regimen; bridging anticoagulation. This approach is appealing be- or (5) undergoing a minor dental procedure, such as teeth clean- ing or single-tooth extraction, in which reversal of anticoagu- cause LMWH can be administered subcutaneously, in a 27 fixed weight-based dose, and without the need for labo- lation is not required. Patients who were to receive spinal an- 17 esthesia were eligible for this registry but were excluded if they ratory monitoring, thereby obviating the need for hos- had an indwelling epidural catheter after the procedure for an- pitalization to administer anticoagulants. Furthermore, this algesia, which precluded coadministered LMWH.28 Patients who strategy has the potential to substantially reduce health care required rapid reversal of anticoagulation because of an ur- costs.18 However, there is little evidence to support the ef- gent procedure were not included in this registry. ficacy and safety of LMWH as bridging anticoagulation. Previous studies of periprocedural anticoagulation are lim- PERIPROCEDURAL ited because no standardized anticoagulant regimen was ANTICOAGULANT MANAGEMENT investigated,19-22 anticoagulants other than LMWH were investigated,19-23 or studies of LMWH as bridging therapy Patients received a standardized anticoagulation regimen, as out- involved fewer than 30 patients.24-26 lined in Table 1, that involved therapeutic-dose LMWH as We report on a prospective registry of 650 patients bridging therapy because less intense regimens, with low- at risk for arterial thromboembolism who required tem- dose LMWH, had not been previously assessed for efficacy. Pa- tients were instructed in subcutaneous self-injection of LMWH porary interruption of warfarin therapy and received bridg- by the Anticoagulation Clinic nurse practitioner, and syringes ing anticoagulation with LMWH. This is the first large- were prefilled to minimize dose errors. Patients were provided scale study, to our knowledge, assessing the efficacy and with information about potential bleeding and thromboem- safety of a standardized periprocedural anticoagulation bolic complications, and were asked to report such events if regimen with LMWH. they occurred or were suspected. A 24-hour telephone con-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 tact number was provided if patients had difficulty with the over 24 hours; transfusion of2Uormore of packed red blood LMWH injections or other health-related concerns. If a pa- cells; or bleeding at a critical site (retroperitoneal, intracranial, tient or caregiver was unable to administer LMWH, it was un- or body cavity).29 Patients who had a decrease in hemoglobin dertaken by a visiting nurse. level or received a blood transfusion because of expected pro- For preprocedural anticoagulation, in general, warfarin cedure-related blood loss, but with no clinically overt bleeding, therapy was interrupted on the fifth day before the procedure were not considered to have major bleeding. Death was docu- in patients receiving warfarin with a target INR of 2.0 to 3.0, mented on the basis of information from patients’ medical and on the sixth day before the procedure in patients receiv- records or death certificate, and if it occurred suddenly, it was ing warfarin with a target INR of 2.5 to 3.5. The INR testing classified as possibly due to thromboembolism. was done on the third or fourth day before the procedure. If A secondary clinical outcome was increased wound- the INR was less than 2.5, treatment was initiated with daltepa- related blood loss, which was assessed only in patients under- rin sodium, 100 IU/kg twice daily by subcutaneous injection, going non–high-bleeding-risk procedure in whom the presence with the first dose supervised by the Anticoagulation Clinic of increased blood loss would delay or suspend the postproce- nurse. If the INR was 2.5 or more, thereby precluding the ini- dural resumption of dalteparin therapy. This subjective out- tiation of dalteparin therapy, an injection of isotonic sodium come was characterized by greater-than-expected oozing from chloride solution was administered subcutaneously to ob- a wound site or blood accumulation in a wound drain. serve the patient’s self-injection technique, and the first dose Patients underwent follow-up from the time warfarin of dalteparin was given on the next day. To minimize the like- therapy was interrupted before the procedure until therapeu- lihood of a residual anticoagulant effect at the time of the pro- tic anticoagulation with warfarin, defined by an INR 2.0 or more, cedure, the last preprocedure dalteparin dose was adminis- was reestablished after the procedure. Subsequent warfarin tered not less than 12 hours before the start of the procedure, dosing was undertaken by the Anticoagulation Clinic or the and if the INR was 3.0 or more on the third or fourth day be- patient’s primary care physician. fore the procedure, patients received phytonadione, 1 mg orally. If patients were receiving antiplatelet therapy, usually aspirin, STATISTICAL ANALYSIS this was interrupted 7 days before the procedure. The postprocedural anticoagulation regimen was deter- Statistical analyses were done with SAS 8.2 software (SAS In- mined on the basis of 2 considerations: (1) the bleeding risk stitute Inc, Cary, NC). Baseline patient characteristics and peri- associated with the procedure and (2) the adequacy of postprocedural anticoagulation regimens were expressed as a mean procedural hemostasis. Patients were classified as being at high with a corresponding standard deviation. Clinical outcome rates risk or nonhigh risk of postprocedural bleeding. This classifi- were based on the number of patients with a thromboembolic cation of bleeding risk was based on a subjective assessment or bleeding event divided by the number of patients at risk and of the anticipated procedure-related bleeding, which was de- were expressed as a proportion with a corresponding 95% con- termined by input from the anticoagulation physician and nurse- fidence interval. practitioner and the attending surgeon or interventionist. The adequacy of postprocedural hemostasis was determined by the RESULTS same caregivers and was based on a subjective assessment of wound-related blood loss. In patients undergoing a high-bleeding-risk procedure, war- PATIENTS farin therapy was resumed on the evening after the procedure, Of 798 patients at risk for arterial thromboembolism who but patients did not receive dalteparin at any time after the pro- were assessed for temporary interruption of warfarin be- cedure. In patients undergoing a non–high-bleeding-risk procedure who had adequate postprocedural hemostasis, warfarin cause of an elective surgical or other invasive proce- was resumed on the evening of procedure, and dalteparin so- dure, 104 were excluded from the registry because the dium, 100 IU/kg twice daily, was resumed on the day after the patient was undergoing a minor dental procedure (n=89), procedure, with the first dose administered approximately 24 had renal insufficiency (n=14), or had previous heparin- hours after the procedure. Dalteparin was continued until the induced thrombocytopenia (n=1). Of 694 registry pa- INR was 2.0 or more. In patients undergoing a non–high-bleeding- tients who were scheduled to receive the prespecified an- risk procedure who had inadequate postprocedural hemostasis, ticoagulation regimen, 35 were excluded because they the resumption of warfarin was delayed until the first postpro- received an LMWH other than dalteparin before or after cedural day, and dalteparin was delayed until the second or third the procedure, and 9 were excluded because they re- postprocedural day when hemostasis was secured. In all pa- ceived intravenous heparin after the procedure at the dis- tients, the initial postprocedural dose of warfarin corresponded to the patient’s usual dose for that day of the week, and anti- cretion of the treating physician (Figure). Thus, there platelet therapy was resumed on the same day as dalteparin. were 650 patients scheduled to receive the prespecified anticoagulation regimen, of whom 542 (83%) were un- CLINICAL OUTCOMES AND dergoing a non–high-bleeding-risk procedure, and 108 PATIENT FOLLOW-UP (17%) were undergoing a high-bleeding-risk procedure. The baseline patient characteristics are described Three primary clinical outcomes were assessed in all patients: in Table 2. The type of procedure patients underwent (1) thromboembolism, (2) major bleeding, and (3) death. Throm- and the associated bleeding risk category are described boembolism was defined as a stroke or transient ischemic at- in Table 3. All patients received out-of-hospital daltepa- tack, an acute coronary syndrome, or systemic embolism involv- rin injections before the procedure, which was admin- ing a limb or viscera that was ascertained on the basis of clinical findings and objective diagnostic testing. Major (or clinically im- istered by the patient (self-injection), a family member, portant) bleeding was defined as bleeding that was clinically overt, or a visiting nurse in 88%, 7%, and 5% of cases, respec- with new symptoms (eg, hematemesis) or signs (eg, wound he- tively. After the procedure, dalteparin was administered matoma), and was associated with one or more of the following by the patient, a family member, or a visiting nurse in characteristics: hemoglobin level decrease of more than 20 g/L 85%, 7%, and 8% of cases, respectively.

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 For preprocedural anticoagulation, warfarin therapy 798 Patients Assessed for Bridging Anticoagulation was interrupted a mean of 5.7 days before the procedure, and patients received a mean of 5.4 doses of dalteparin. 104 Patients Excluded From Registry: Minor Dental Procedure (89) For postprocedural anticoagulation, in 108 pa- 694 Patients Scheduled to Receive Renal Insufficiency (14) tients who underwent a high-bleeding-risk procedure and Prespecified Periprocedural Heparin-Induced Bridging Anticoagulation With Thrombocytopenia (1) were not scheduled to receive only postprocedural daltepa- Dalteparin Sodium, 100 IU/kg SC BID rin, warfarin was resumed on the evening of or the day 44 Patients Excluded From Analysis: after the procedure. In the 542 patients who underwent Received Intravenous Heparin (9) Received Different LMWH (35) a non–high-bleeding-risk procedure, there was exces- Stratification of Patients According to sive postprocedural bleeding in 32 patients that pre- Bleeding Risk Associated With Procedure cluded postprocedural dalteparin administration, and these patients received only warfarin, starting the day after the procedure. In 510 patients who underwent a non– 542 Patients Underwent 108 Patients Underwent high-bleeding-risk procedure and received postproce- Non–High-Bleeding-Risk Procedure High-Bleeding-Risk Procedure dural dalteparin, it was resumed on the first postprocedure (Scheduled to Receive Preprocedural (Scheduled to Receive Only and Postprocedural Dalteparin Preprocedural Dalteparin Sodium, day in 454 patients (89%), at least 24 hours after the pro- Sodium, 100 IU/kg SC BID) 100 IU/kg SC BID) cedure, on the second postprocedural day in 46 patients (9%), on the third postprocedural day in 5 patients (1%), and on the fourth postprocedural day in 5 patients (1%). Resumption of Dalteparin: Suspension of Dalterparin: 454 Patients on Day + 1 After Procedure 32 Patients Did Not Receive This delay in resumption of postprocedural dalteparin 46 Patients on Day + 2 After Procedure Postprocedural Dalteparin in 56 patients was necessitated by delayed hemostasis (23 5 Patients on Day + 3 After Procedure (Increased Wound-Related 5 Patients on Day + 4 After Procedure Blood Loss) patients) and concerns about bleeding after implantation of a permanent pacemaker or internal cardiac defib- Perioperative anticoagulant management. SC indicates subcutaneously; BID, rillator (30 patients) or bowel polypectomy (3 patients). twice daily; and LMWH, low-molecular-weight heparin. PATIENT FOLLOW-UP AND ADVERSE CLINICAL OUTCOMES Table 2. Characteristics of 650 Registry Patients Patients underwent clinical follow-up during the pre- Characteristic Finding procedural and postprocedural period for a mean of 13.8 Mean age (range), y 67.8 (28-88) days (range, 10-18 days). The rates of adverse clinical out- Mean weight (range), kg 80.2 (55-99) comes are outlined in Table 5. In 108 patients under- Sex, No. (%) going a high-bleeding-risk procedure who received only Men 417 (64) preprocedural dalteparin, there were 2 nonfatal major Women 233 (36) bleeding episodes (1.8%) (upper gastrointestinal tract Reason for warfarin sodium therapy, No. (%) bleeding and wound hematoma), neither of which was AF 306 (47) AF and valvular heart disease 22 (3) fatal; no confirmed thromboembolic events; and 2 deaths AF and cardiomyopathy 18 (3) (1.8%) (cardiac arrests) possibly due to thromboembolism. In 542 patients undergoing a non–high-bleeding- Any AF 346 (53) risk procedure who were scheduled to received prepro- Mechanical AVR 108 (17) cedural and postprocedural dalteparin, there were 4 major Ͻ Mechanical AVR and Bental procedure 2 ( 1) bleeding episodes (0.7%) (3 wound hematomas and a rec- Mechanical AVR and AF 33 (5) Mechanical MVR 29 (4) tus abdominus sheath hematoma), none of which were Mechanical MVR and AF 17 (3) fatal; 2 thromboembolic events (0.4%) (systemic embo- Mechanical AVR and MVR 26 (4) lism and transient ischemic attack); and 32 episodes Any mechanical heart valve 215 (33) (5.9%) of excessive wound-related bleeding that precluded postprocedural administration of dalteparin. The Previous stroke/TIA and AF 70 (11) adverse clinical outcomes, which all occurred during the Previous stroke/TIA and mechanical AVR 9 (1) Previous stroke/TIA and mechanical MVR 6 (1) postprocedural period, are described in Table 6. Previous stroke/TIA and mechanical AVR and MVR 4 (Ͻ1) Any previous stroke 89 (14) COMMENT

Abbreviations: AF, atrial fibrillation, AVR, aortic valve replacement; In this registry of 650 patients at increased risk for arte- MVR, mitral valve replacement; TIA, transient ischemic attack. rial thromboembolism who required temporary interruption of warfarin therapy for an elective procedure, a PERIPROCEDURAL ANTICOAGULANT standardized bridging anticoagulation regimen with MANAGEMENT LMWH was associated with a low risk of thromboembolic (Ͻ1%) and major bleeding (1%-2%) complica- The periprocedural anticoagulation dosing regimen pa- tions in the immediate periprocedural period, and was tients received is outlined in Table 4 according to pa- feasible for out-of-hospital administration. This antico- tients’ indications for warfarin therapy and their corre- agulation strategy involved 2 main components: (1) pre- sponding target INR. procedural and postprocedural dalteparin sodium therapy,

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 3. Classification of Bleeding Risk Associated With Procedure

Bleeding Risk Category Surgical or Other Invasive Procedure No. of Procedures (%) High Heart valve replacement ± coronary artery bypass 61 Coronary artery bypass 6 Abdominal aortic aneurysm repair 5 Neurosurgical cancer surgery 2 Urogynecologic cancer surgery 3 Head and neck cancer surgery 4 Intra-abdominal and breast cancer surgery 5 Bilateral knee replacement 2 Laminectomy 9 Transurethral prostate resection 10 Kidney biopsy 1 Total 108 (17) Nonhigh (surgical procedure) Cholecystectomy 17 Bowel resection 6 Abdominal hernia repair 21 Hemorrhoidal surgery 4 Bowel polypectomy 5 Axillary node dissection 1 Abdominal hysterectomy 2 Dilation and curettage 3 Hydrocele repair 1 Hand surgery 6 Carpal tunnel repair 4 Skin cancer excision 16 Knee replacement 4 Hip replacement 2 Shoulder surgery 4 Foot surgery 5 Pacemaker insertion 56 Sternotomy wire removal 4 Internal cardiac defibrillator insertion 11 Endarterectomy or carotid bypass surgery 9 Noncataract eye surgery 6 Cataract eye surgery 17 Dental surgery 3 Total 205 (31) Nonhigh (nonsurgical procedure) Coronary angiography ± percutaneous coronary intervention 223 Electrophysiologic testing 11 Noncoronary angiography 8 Gastrointestinal endoscopy ± biopsy 64 Bronchoscopy ± biopsy 3 Arthroscopy 7 Central venous catheter removal 1 Biopsy (prostate, bladder, thyroid, breast, lymph node, pancreas, myocardial thyroid) 21 Total 337 (52)

100 IU/kg twice daily, to minimize the duration with- tion8,11,12 or cointerventions such as periprocedural as- out therapeutic anticoagulation; and (2) avoidance of post- pirin therapy that could influence the risk of thrombo- procedural dalteparin in patients at high risk of bleed- embolic and bleeding events.32,33 Second, patients ing or with inadequate postprocedural hemostasis, and underwent a standardized duration of clinical follow- delay in dalteparin resumption in patients with delayed up, thereby limiting variability in patient surveillance hemostasis. The second component was of paramount that would influence the likelihood of capturing clinical importance because the development of postprocedural outcomes. Third, unlike most registries that allow major bleeding would delay the resumption of antico- broad patient eligibility criteria, this registry assessed a agulation and, thereby, increase the time that patients prespecified patient group at increased risk for arterial would be exposed to the risk of thromboembolism. thromboembolism, in whom most physicians would This patient registry has several features that sup- consider some form of periprocedural bridging antico- port the validity of the results. First, unlike most regis- agulation.1-4,13,14 tries in which patient treatment is left to the discretion Clinically important (or major) bleeding complica- of the treating physician,30,31 patients in this registry re- tions were infrequent, occurring in 1% to 2% of pa- ceived a standardized periprocedural anticoagulation regi- tients. The low incidence of major bleeding is likely at- men. This would reduce the potential for variability in tributable to 3 factors. First, 52% of patients underwent the aggressiveness of periprocedural anticoagula- nonsurgical invasive procedures, such as cardiac cath-

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Downloaded From: https://jamanetwork.com/ on 09/29/2021 Table 4. Periprocedural Anticoagulation Regimen

Mean ± SD

Patient Group (Target INR) Anticoagulation Management Before Procedure After Procedure Atrial fibrillation (2.0-3.0) Warfarin stopped, d 5.6 ± 1.4 NA INR when warfarin stopped 2.1 ± 0.6 NA Dalteparin sodium injections, No. 5.4 ± 1.9 5.1 ± 1.1 First dalteparin sodium dose, IU 8071 ± 1781 8055 ± 1763 Mechanical heart valve (2.5-3.5) Warfarin stopped, d 6.2 ± 1.6 NA INR at time of stopping 6.2 ± 1.6 NA Dalteparin sodium injections, No. 5.1 ± 1.7 5.1 ± 1.1 First dalteparin sodium dose, IU 7767 ± 1468 7782 ± 1459 Previous stroke or TIA (2.0-3.0) Warfarin stopped, d 5.8 ± 1.3 NA INR when warfarin stopped 2.1 ± 0.7 NA Dalteparin sodium injections, No. 4.9 ± 1.3 5.1 ± 1.1 First dalteparin sodium dose, IU 7523 ± 1788 7523 ± 1788

Abbreviations: INR, international normalized ratio; NA, not applicable; TIA, transient ischemic attack.

Table 5. Adverse Clinical Outcome Rates

Patient Group, % (95% CI)

Patients Undergoing Patients Undergoing Non–High-Bleeding-Risk Procedure High-Bleeding-Risk Procedure All Patients Clinical Outcome* (n = 542)† (n = 108)‡ (n = 650) Thromboembolism 0.37 (0.04-1.32) None 0.31 (0.04-1.00) Thromboembolism (including possible events) 0.74 (0.20-1.87) 1.85 (0.23-6.52) 0.62 (0.17-1.57) Major bleeding 0.74 (0.20-1.87) 1.85 (0.23-6.52) 0.92 (0.34-2.00) Increased wound-related blood loss§ 5.90 (4.07-8.23) NA NA

Abbreviations: CI, confidence interval; NA, not applicable. *All clinical outcomes occurred after the procedure. †Scheduled to receive preprocedural and postprocedural bridging anticoagulation with dalteparin sodium. ‡Scheduled to receive only preprocedural bridging anticoagulation with dalteparin. §Precluded scheduled postprocedural administration of dalteparin.

eterization or gastrointestinal endoscopy, which are as- tion,44,47 as it included only clinically overt bleeding. There sociated with a low risk of bleeding complications.34,35 is a need for a bleeding classification scheme specific for Second, measures were taken to minimize the risk of the postprocedural clinical setting that differentiates be- bleeding. Postprocedural dalteparin was avoided in pa- tween clinically important bleeding that requires a change tients undergoing a high-bleeding-risk procedure such in clinical management (eg, reoperation) and increased as open heart surgery,36 abdominal vascular surgery,37 neu- wound-related blood loss that is expected and may re- rosurgery,38 major cancer surgery,39,40 or procedures in- quire transfusion but is, otherwise, self-limiting and with- volving the prostate or kidney.41-43 In patients undergo- out clinical consequences.50 ing a non–high-bleeding-risk procedure, the start of Thromboembolic complications were also infre- dalteparin was delayed for 24 hours until the day after quent. There was 1 episode of systemic embolism to the the procedure, when there was adequate wound hemo- lower extremities, 1 transient ischemic attack and 2 deaths, stasis. This was done because in patients who receive possibly due to thromboembolism, yielding an overall in- LMWH after a surgical procedure, more than 90% of ma- cidence of 0.6%. Reliable estimates of periprocedural jor bleeding episodes occur at the surgical wound site,44-46 thromboembolic complications during temporary inter- and such bleeding is more likely to occur with early post- ruption of warfarin treatment are limited. It is postu- procedural initiation of anticoagulant therapy, 4 to 12 lated that the absolute risk of thromboembolic events dur- hours after surgery, than delayed initiation of anticoagu- ing the 2- to 4-day period after warfarin interruption, when lation, more than 12 hours after surgery.23,47 Further- there is no anticoagulant effect present, is a small frac- more, the start of dalteparin was delayed or suspended tion of the 5% to 15% annual risk of thromboembolic in patients with inadequate postprocedural hemostasis, events.8 However, thromboembolic risk may be higher and in those undergoing pacemaker or cardiac defibril- than expected because after interruption of warfarin lator implantation or bowel polypectomy, who might be therapy a transient hypercoagulable state may develop at increased risk of bleeding complications with early post- owing to a rebound increase in thrombin generation or procedural initiation of anticoagulation.48,49 Third, our platelet activation.51,52 Furthermore, a surgical proce- definition of major bleeding was narrower than that used dure may induce a hypercoagulable state through mecha- in other studies involving postoperative anticoagula- nisms that include vessel-wall injury and fibrinolysis

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Patient Age, y/ Reason for Periprocedural Clinical Outcome Sex Warfarin Sodium Therapy Procedure Anticoagulation (Days After Procedure) 72/M Chronic AF Gastrointestinal endoscopy Preprocedural and postprocedural Stroke, lower-limb embolism (5) dalteparin sodium 82/F Chronic AF Cataract removal Preprocedural and postprocedural TIA (8) dalteparin 72/F Chronic AF Pacemaker insertion Preprocedural and postprocedural Wound hematoma (2) dalteparin 62/M Previous embolic stroke Abdominal hernia repair Preprocedural and postprocedural Wound hematoma (3) dalteparin 68/M Chronic AF Coronary angiography Preprocedural and postprocedural Wound hematoma (2) dalteparin 76/F MVR, chronic AF Dental surgery Preprocedural and postprocedural Rectus abdominus sheath dalteparin hematoma (3) 72/F Chronic AF, previous TIA Bilateral knee replacement Preprocedural dalteparin Upper gastrointestinal tract bleeding (5) 74/F Previous embolic stroke Intra-abdominal cancer surgery Preprocedural dalteparin Wound hematoma (2) 75/F AVR, MVR, chronic AF Lumbar laminectomy Preprocedural dalteparin Cardiac arrest (6) 70/M Chronic AF, valvular heart Heart valve replacement, coronary Preprocedural dalteparin Cardiac arrest (7) disease bypass

Abbreviations: AF, atrial fibrillation; AVR, aortic valve replacement; MVR, mitral valve replacement; TIA, transient ischemic attack.

inhibition.53-55 In 3 prospective studies that have inves- cause of the potential for bioaccumulation.58 Additional tigated periprocedural bridging anticoagulation with studies are needed to confirm our findings in patients who LMWH,25,26,56 thromboembolic events occurred in 1 have a longer duration of postprocedural follow-up and (0.8%) of 128 of patients, an event rate that is consis- to identify high-bleeding-risk procedures in which post- tent with our findings. procedural anticoagulation should be used with cau- There are limitations of this study that should be ad- tion. Furthermore, there is a need for clinical trials to com- dressed. First, we acknowledge that postprocedural pa- pare our periprocedural anticoagulation regimen with less tient follow-up was limited to about 1 week in most pa- intense strategies (eg, low-dose LMWH) or alternative tients. Consequently, our findings may underestimate the oral anticoagulants such as direct thrombin inhibitors, risk of thromboembolic events because clinical manifes- which, because of a short half-life, may obviate the need tations of periprocedural thrombus formation, such as for bridging therapy with LMWH.59 embolic stroke or valve thrombosis, may be delayed for To summarize, in patients at increased risk for arte- several weeks after warfarin interruption.23 However, it rial thromboembolism who require temporary interrup- is likely that most clinically overt bleeding episodes at- tion of warfarin therapy, a standardized periprocedural an- tributed to periprocedural bridging anticoagulation would ticoagulant regimen with LMWH is associated with a low be captured, as they are most likely to occur during the risk of thromboembolic and major bleeding complica- first week after a procedure.33,44-46,56 Second, we acknowl- tions in the immediate periprocedural period, and is fea- edge that our classification of patients according to the sible for outpatient administration. Additional studies are procedure-related bleeding risk, which determined needed to confirm these findings and investigate alterna- whether postprocedural dalteparin was given, was sub- tive periprocedural anticoagulation strategies. jective and has not been validated. Such a classification of patients was deemed necessary to minimize postpro- Accepted for publication August 25, 2003. cedural bleeding and was supported by studies that have There was no funding for this study. Dr Douketis is a identified high-bleeding-risk procedures.36-43 There are recipient of a Research Scholarship from the Heart and Stroke no clinical prediction rules, to our knowledge, that stratify Foundation of Canada, Ottawa, Canada. patients according to the risk of postprocedural bleed- We express sincere gratitude to Nicole Archer for es- ing.57 Third, because this patient registry did not in- tablishing the patient registry database and to Nicole Zytaryk clude a control group, we cannot comment on the effi- and Lauren Griffith for statistical assistance. We also thank cacy or safety of our periprocedural anticoagulation Mark Crowther, MD, MSc, and Clive Kearon, MD, PhD, regimen compared with other strategies that might in- for their helpful reviews of the manuscript. volve intravenous heparin,11,12 or warfarin interruption Corresponding author: James D. Douketis, MD, FRCPC, without bridging anticoagulation.8,9 Finally, because this Department of Medicine, St Joseph’s Hospital, Room F-541, registry was undertaken at a single center that does not 50 Charlton Ave E, Hamilton, Ontario, Canada L8N 4A6 have a major focus on pulmonary or renal disease, there (e-mail: [email protected]). was underrepresentation of patients undergoing respi- ratory or nephrologic procedures. Consequently, our findings may not be generalizable to such patients, espe- REFERENCES cially those with significant renal insufficiency in whom 1. Dunn AS, Turpie AG. Perioperative management of patients receiving oral anti- therapeutic-dose LMWH should be used with caution be- coagulants: a systematic review. Arch Intern Med. 2003;163:901-908.

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