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(Circulation. 2004;110:1658-1663.)
© 2004 American Heart Association, Inc.

Vascular Medicine

Single-Arm Study of Bridging Therapy With Low-Molecular-Weight Heparin for Patients at Risk of Arterial Embolism Who Require Temporary Interruption of Warfarin

M.J. Kovacs, MD, FRCPC; C. Kearon, MD, FRCPC; M. Rodger, MD, FRCPC; D.R. Anderson, MD, FRCPC; A.G.G. Turpie, MD, FRCPC; S.M. Bates, MD, FRCPC; L. Desjardins, MD, FRCPC; J. Douketis, MD, FRCPC; S.R. Kahn, MD, FRCPC, SMBD; S. Solymoss, MD, FRCPC; P.S. Wells, MD, FRCPC

From the London Health Sciences Centre, London, Ontario (M.J.K.); Hamilton Health Sciences Centre, Hamilton, Ontario (C.K.); Ottawa Hospital, Ottawa, Ontario (M.R.); Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia (D.R.A.); Hamilton Health Sciences-General Hospital, Hamilton, Ontario (A.G.G.T.); McMaster University Medical Centre, Hamilton, Ontario (S.M.B.); Hospital University Laval, Sainte Foy, Quebec (L.D.); St Joseph’s Health Centre, Hamilton, Ontario (J.D.); Jewish General Hospital, Montreal, Quebec (S.R.K.); St Mary’s Hospital, Montreal, Quebec (S.S.); and Ottawa Hospital, Ottawa, Ontario (P.W.), Canada.

Correspondence to Dr Michael J. Kovacs, London Health Sciences Centre, 800 Commissioners Rd E, London, Ontario, Canada N6A 4G5. E-mail michael.kovacs{at}lhsc.on.ca

Received April 9, 2004; revision received July 7, 2004; accepted July 14, 2004.

	Abstract

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Background— When warfarin is interrupted for surgery, low-molecular-weight heparin is often used as bridging therapy. However, this practice has never been evaluated in a large prospective study. This study was designed to assess the efficacy and safety of bridging therapy with low-molecular-weight heparin initiated out of hospital.

Methods and Results— This was a prospective, multicenter, single-arm cohort study of patients at high risk of arterial embolism (prosthetic valves and atrial fibrillation with a major risk factor). Warfarin was held for 5 days preoperatively. Low-molecular-weight heparin was given 3 days preoperatively and at least 4 days postoperatively. Patients were followed up for 3 months for thromboembolism and bleeding. Eleven Canadian tertiary care academic centers participated; 224 patients were enrolled. Eight patients (3.6%; 95% CI, 1.8 to 6.9) had an episode of thromboembolism, of which 2 (0.9%; 95% CI, 0.2 to 3.2) were judged to be due to cardioembolism. Of these 8 episodes of thromboembolism, 6 occurred in patients who had warfarin deferred or withdrawn because of bleeding. There were 15 episodes of major bleeding (6.7%; 95% CI, 4.1 to 10.8): 8 occurred intraoperatively or early postoperatively before low-molecular-weight heparin was restarted, 5 occurred in the first postoperative week after low-molecular-weight heparin was restarted, and 2 occurred well after low-molecular-weight heparin was stopped. There were no deaths.

Conclusions— Bridging therapy with subcutaneous low-molecular-weight heparin is feasible; however, the optimal approach for the management of patients who require temporary interruption of warfarin to have invasive procedures is uncertain.

Key Words: blood vessel prosthesis • bridging therapy • fibrillation • heparin, low-molecular-weight

	Introduction

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Oral anticoagulant therapy presents a problem when the need for surgery arises because anticoagulation is associated with bleeding from the operative site, patients have an increased risk of thromboembolism when therapy is interrupted, and the antithrombotic effect of warfarin takes 4 to 5 days to recede after it is stopped and to reestablish after it is restarted.^1–3 To reduce the risk of thromboembolism, it is often recommended that such patients receive intravenous heparin before and after surgery during the period when they do not have a therapeutic effect from warfarin.^1,4–6 The practice of giving perioperative heparin therapy to patients who have warfarin temporarily interrupted is referred to as bridging therapy. Intravenous heparin is attractive as bridging therapy because it has a rapid onset of action and a short half-life and because its use minimizes the amount of time in the perioperative period that patients are not anticoagulated.⁷ The disadvantages of using intravenous heparin as bridging therapy are that it is costly because it requires admission to hospital and it may increase the risk of postoperative bleeding. It has been estimated that it costs more than $600 000 to prevent 1 thromboembolic event in patients with prosthetic heart valves receiving intravenous heparin as bridging therapy.⁸ For these reasons, bridging therapy is usually reserved for patients who have a high risk of arterial embolism such as those who have mechanical heart valves or atrial fibrillation with additional risk factors.^4–6 Despite its historical use in this situation, the efficacy and safety of bridging therapy with unfractionated heparin are unknown.¹

See p 1518

Low-molecular-weight heparin is usually given subcutaneously once or twice daily in fixed weight-adjusted doses without laboratory monitoring. The convenience of this regimen makes low-molecular-weight heparin suitable for use out of hospital, and it is now widely used to treat patients with acute deep vein thrombosis at home.^9–11 Thus, therapeutic-dose low-molecular-weight heparin is an attractive alternative to intravenous heparin for bridging therapy. Although it is used in clinical practice, the efficacy and safety of bridging therapy with low-molecular-weight heparin are uncertain.^12,13 There are concerns that bridging with low-molecular-weight heparin may not be effective at preventing arterial embolism and may be associated with perioperative bleeding,¹ although therapeutic low-molecular-weight heparin has been shown to be superior to unfractionated heparin in patients with acute coronary syndrome.¹⁴ To date, there are no large, prospective, multicenter trials of bridging therapy. We performed a prospective, multicenter cohort study to assess the efficacy and safety of bridging therapy with low-molecular-weight heparin initiated out of hospital in patients who had a high risk of arterial embolism.

	Methods

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Study Sample
Consecutive consenting patients who had a prosthetic heart valve or had atrial fibrillation and at least 1 major risk factor for cardiac embolism and who required temporary interruption of warfarin for elective noncardiac surgery or an invasive procedure were potentially eligible. Major risk factors for cardiac embolism with atrial fibrillation were defined as previous transient ischemic attack or stroke, high blood pressure, diabetes, age >75 years, or left ventricular dysfunction. Patients were excluded if there was evidence of active bleeding before warfarin was stopped, platelet count <100x10⁹/L, planned eye surgery (excluding cataract surgery) or neurosurgery, life expectancy of <3 months, serum creatinine >150 µmol/L, or presence of an active duodenal ulcer.

The study protocol was reviewed and approved by the Institutional Review boards of each participating center. Written informed consent was obtained from all patients. At the time of consent, all patients were registered with the coordinating center. The study was supported by an unrestricted grant from Pharmacia Corp.

Treatment Regimen
The treatment protocol was based on a pilot study,¹⁵ consensus of the investigators, and previous assessment of warfarin reversal (Figure).¹⁶

View larger version (36K): [in this window] [in a new window]   Bridging protocol.

Preoperative Management of Anticoagulation
Warfarin therapy was stopped 5 days before the procedure (ie, patients missed 5 doses). Dalteparin, a low-molecular-weight heparin, was administered at a dose of 200 IU/kg sc (maximum, 18 000 IU) the morning of the third and second days before the procedure. On the morning before surgery, a dalteparin dose of 100 IU/kg (maximum, 9000 IU) was used. A daily dose of 200 IU/kg with this low-molecular-weight heparin is the same as the dose used for initial treatment of acute venous thromboembolism.⁹

On the day before surgery, an international normalized ratio (INR) was obtained. If the INR was >1.4, the patient was given 1 mg oral vitamin K. If the INR was >1.7, the patient was given 2 mg oral vitamin K. If vitamin K was given, the INR was repeated on the day of surgery. If the INR was >1.4 on the day of surgery, postponement of surgery was considered. Aspirin was stopped 7 days before surgery. All preoperative management was given as outpatient therapy.

Postoperative Management of Anticoagulation
If possible, warfarin was given the evening of surgery at twice the patient’s usual daily dose. No low-molecular-weight heparin was given the day of surgery. The day after surgery, patients resumed their preoperative dosage of warfarin and started once-daily low-molecular-weight heparin. Low-molecular-weight heparin (dalteparin) was administered at a dose of 200 IU/kg daily or at a set dose of 5000 IU daily if the physician judged that the patient was at high risk for postoperative bleeding. Low-molecular-weight heparin was continued for at least 4 days and until the INR was >1.9. The INR was measured on the second and fourth postoperative days. Patients did not remain in hospital to receive low-molecular-weight heparin if they were otherwise capable of being managed as outpatients. Low-molecular-weight heparin was administered to outpatients by the patient, a relative, or a nurse. In patients in whom it was required, aspirin was restarted the day after surgery.

Follow-Up
While in hospital, patients were assessed daily for bleeding and thrombosis. Patients were familiarized with the signs and symptoms of thrombosis and bleeding and were encouraged to call study personnel if either was suspected after leaving hospital. All patients were followed up for 3 months.

Outcome Measures
The primary efficacy outcome was the frequency of symptomatic arterial or venous thromboembolism from 5 days preoperatively (the first day that warfarin was not taken before surgery) until 90 days after surgery. Arterial thromboembolism was defined as ischemic stroke, transient ischemic attack, myocardial infarction, or systemic embolism. Venous thromboembolism was defined as deep vein thrombosis or pulmonary embolism as previously described.¹⁰ The primary safety end point was major hemorrhage. Major hemorrhage was defined as (1) overt bleeding with a hemoglobin decrease of >20 g /L within a 24-hour period or transfusion of at least 2 units of blood; (2) intracranial, intraspinal, intraoccular, retroperitonial, or pericardial bleeding; and (3) fatal bleeding.

All suspected outcome events were reviewed by a central adjudication committee using predefined criteria.

Statistical Analysis
The sample size was determined by the need to obtain reasonably precise estimates (ie, narrow 95% CIs) of the frequency with which thromboembolism and major bleeding occurred. With an expected frequency for thromboembolism of 1% (95% CI, 0.3 to 3.6) and for major bleeding of 5% (95% CI, 2.7 to 9.0), it was judged that a study of 200 patients would be necessary. The 95% CIs were calculated with the Wilson Score Method.¹⁷

	Results

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Patients
Two hundred twenty-four eligible and consenting patients from 11 tertiary care academic centers were enrolled and registered with the coordinating center from January 2001 to October 2001. Seven patients were excluded: 5 for creatinine >150 µmol/L, 1 for planned neurosurgery, and 1 for platelet count <100x10⁹/L. No patients were lost to follow-up. The baseline characteristics are given in Table 1. Mean age was 70 years; 62% were men. By chance, 112 patients had prosthetic valves, and 112 patients had atrial fibrillation without a prosthetic valve. The most common procedures were cardiac catheterization (n=42), genitourinary surgery (n=33), dental procedures (n=25), and major orthopedic surgery (n=25).

View this table: [in this window] [in a new window]   TABLE 1. Baseline Characteristics and Reason for Interruption of Warfarin

Perioperative Management
Fifteen patients (6.7%) had an INR of >1.5 on the day before their procedure and required vitamin K; however, no surgery was postponed (Table 2). Postoperatively, 170 patients (76%) received full doses of low-molecular-weight heparin, 35 patients (16%) received low-dose (ie, 5000 IU daily) low-molecular-weight heparin, and 19 patients (8.5%) received no low-molecular-weight heparin. The mean time to achieve an INR of 2.0 was 4.6 days (range, 2 to 10), and the mean duration of postoperative low-molecular-weight heparin was 4.2 days. Ninety-two patients (41%) required >4 days of low-molecular-weight heparin. There were no differences in the time required to achieve an INR of 2.0 or the number of days of postoperative low-molecular-weight heparin use between valve and atrial fibrillation patients.

View this table: [in this window] [in a new window]   TABLE 2. Perioperative Management

Thromboembolism
Of the 224 patients, 8 (3.6%; 95% CI, 1.6 to 6.9) had an episode of thromboembolism between the time warfarin was stopped and 90 days after having surgery (Tables 3 and 4). Of these 8 episodes, 2 (0.9%; 95% CI, 0.2 to 3.2) were judged highly likely to be due to cardioembolism (a stroke on day 42 and a transient ischemic attack on day 14) (Table 4), 5 were judged unlikely to be due to cardioembolism (5 myocardial infarctions), and 1 was judged not to be due to cardioembolism (a deep vein thrombosis). Four of the episodes of thromboembolism occurred in patients who had a delay between surgery and the restarting of warfarin because of intraoperative or early postoperative bleeding (including the transient ischemic attack mentioned above), and 2 occurred after warfarin was stopped because of bleeding during the 3-month postoperative follow-up period (including the stroke on day 42). Therefore, 6 of 8 episodes of thromboembolism occurred in patients who had warfarin therapy deferred or withdrawn because of bleeding. No episodes of thromboembolism occurred preoperatively. None of the 15 patients who had an INR 1.5 on the day before surgery had a thromboembolic event. Two of the 19 patients (10.5%; 95% CI, 2.9 to 31.4) who received no postoperative low-molecular-weight heparin and 2 of the 35 patients (5.7%; 95% CI, 1.6 to 18.6) who received low-dose low-molecular-weight heparin had thromboembolic events.

View this table: [in this window] [in a new window]   TABLE 3. Summary of Outcome Events During 90 Days of Follow-Up

View this table: [in this window] [in a new window]   TABLE 4. Details of Thromboembolic Events

Bleeding
There were 15 major hemorrhages (6.7%; 95% CI, 4.1 to 10.8), of which 8 occurred intraoperatively or <6 hours postoperatively before warfarin or dalteparin were restarted and hence were unlikely to be related to bridging therapy (Table 3). Five major bleeds (2.2%; 95% CI, 1.0 to 5.1), all in patients who were receiving full-dose low-molecular-weight heparin postoperatively, occurred within a week of operation/surgery. One of these 5 bleeds occurred 2 days after a skin graft operation in a patient who had an INR of 1.5 on the day before surgery and did not receive oral vitamin K. Two major bleeds occurred >4 weeks after the operative procedure and were unlikely to be related to bridging therapy. Finally, there were no episodes of major hemorrhage preoperatively.

Mortality
There were no deaths in the 3-month follow-up period.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This prospective, multicenter cohort study found that patients with prosthetic heart valves or atrial fibrillation have a substantial risk of thromboembolism and bleeding when warfarin is temporarily interrupted and surgery is performed. Thromboembolism occurred in 3.6% and major bleeding occurred in 6.6% of patients within 3 months of surgery. However, of 8 episodes of thromboembolism, only 2 were judged to be due to cardioembolism. Five episodes of thrombosis were myocardial infarctions that were probably related to a high prevalence of coronary artery disease in this older population with known cardiac disease, although interruption of antithrombotic therapy may have contributed to these events.^18,19 Of the 15 episodes of major bleeding, 8 occurred intraoperatively or immediately after surgery before low-molecular-weight heparin therapy was restarted. Because the last preoperative dose of low-molecular-weight heparin was reduced to half the usual daily dose and was given at least 24 hours before surgery, it is unlikely that bridging therapy contributed to these 8 bleeds. Finally, given that there were no preoperative events of thrombosis or bleeding, this aspect of the bridging protocol likely does not need modification for this patient population. However, use of bridging with full-dose low-molecular-weight heparin may have contributed to the 5 episodes of bleeding that occurred within a week of surgery. Because 2 of these 5 patients subsequently had thromboembolism, we cannot exclude the possibility that the higher postoperative low-molecular-weight heparin dose of the bridging therapy indirectly contributed to these thrombotic events.

Three previous studies evaluated the use of low-molecular-weight heparin as bridging therapy.^15,20,21 Of a total of 126 patients in those 3 studies, 1 had thromboembolism¹⁵ and 2 had a major episode of bleeding.^20,21

Strengths of the present study include its prospective design, use of explicit inclusion and exclusion criteria, registration and complete follow-up of all enrolled patients, standardized evaluation of outcomes by a central adjudication committee, and large size compared with previous studies that evaluated bridging therapy. For these reasons, the findings of this study are expected to be valid and generalizable.

The main limitation of this study is the lack of a comparison group. Without an untreated control group, we are unable to determine whether bridging therapy with low-molecular-weight heparin reduced the frequency of thromboembolism or increased the frequency of bleeding. There is concern that low-molecular-weight heparin is ineffective at preventing stroke caused by atrial fibrillation²² and at preventing thromboembolic complications associated with prosthetic heart valves during pregnancy.²³ Similarly, without a comparison group that received perioperative intravenous heparin, the relative efficacy and safety of bridging therapy using intravenous heparin and subcutaneous low-molecular-weight heparin are uncertain. Different patient subgroups may require different postoperative strategies that are determined by the patient’s risk of cardioembolism and risk of hemorrhage (ie, the type of surgery). Despite the fact that this study lacks a control group, this is the first large, multicenter, prospective study of bridging therapy. To date, there remains no accepted standard for bridging therapy.²⁴ The protocol and outcomes from this study can serve as a basis for future randomized studies.

We conclude that bridging therapy with subcutaneous low-molecular-weight heparin is feasible, but the optimal approach to management of patients who require temporary interruption of warfarin for invasive procedures is uncertain and deserves evaluation by randomized controlled trials.

	Acknowledgments

 
Dr Kovacs is an internal scholar, Department of Medicine, University of Western Ontario. Dr Kearon is an investigator for the Canadian Institutes of Health Research. Dr Anderson is a clinical scholar, Faculty of Medicine, Dalhousie University. Dr Bates is a recipient of the New Investigator Award, Canadian Institutes of Health Research, University-Industry (bioMerieux, Inc) Program. Dr Rodger holds the Maureen Andrew New Investigator Award from the Heart and Stroke Foundation of Canada (Ontario). Philip Wells is a Canada Research Chair. We are indebted to Susan Finkenbine, Gertrude Kells, Laura Radey, Melinda Robbins, Barbara St Jacques, Pamela Stevens, and Eileen Whyte for their help with study coordination.

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