Safety of Heparin "Bridge" Questioned When Warfarin Is Stopped

January 17, 2008 — Patients on chronic warfarin who go off the drug for up to five days while they undergo a minor invasive procedure appear to have a <1% risk of experiencing a thromboembolic event, suggests a prospective study that, moreover, pointed to a substantial risk of clinically important bleeding when some form of heparin is given as "bridge" therapy in warfarin's stead [1].

The findings speak to the dilemma providers face when taking patients off oral anticoagulation while they undergo a colonoscopy, dental procedures, or other such outpatient procedures, according to lead author Dr David A Garcia (University of New Mexico Health Sciences Center, Albuquerque). Many want to give short-acting parenteral anticoagulation during such procedures, accepting a potential for more bleeding complications in exchange for a reduced risk of potentially devastating thromboembolic events, he observed for heartwire. But prospective data for guiding such decisions have been in short supply.

"If there's an overriding message from our study, it's perhaps that the hemorrhagic risk associated with heparinlike perioperative anticoagulation is greater than previously appreciated, and that it needs to be considered carefully in any risk/benefit analysis that one is doing around an interruption of warfarin for an elective procedure," Garcia said. "We don't have good data about the benefit of perioperative heparin, whereas we are getting increasingly more evidence that perioperative heparin certainly comes with a risk."

Anyway, he observed, the risk of thromboembolic complications during warfarin interruption appears to be quite low, at least in populations like the one his group studied: "outpatients undergoing elective, relatively minor invasive procedures, most of whom had their warfarin interrupted for only brief intervals, three to five days." Less than one-tenth of the study's > 1000 patients had received bridge anticoagulation.

The group's findings, published in the January 14, 2008 issue of Archives of Internal Medicine, are consistent with those of other studies and with current guidelines "proposed by the American College of Chest Physicians, suggesting that low-risk patients may undergo four to five days of warfarin-therapy interruption without bridging therapy."

Their analysis covered 1293 instances of warfarin interruption in 1024 patients who underwent such outpatient procedures as colonoscopy, oral or dental surgery, or ophthalmic surgery. The patients averaged 72 years in age, and most had been on warfarin due to atrial fibrillation or mechanical heart valves or for management of venous thromboembolism. Only 8.3% of cases of warfarin interruption involved bridge anticoagulation therapy, which was nearly always with a low-molecular-weight heparin, according to the authors. Outcomes included the following:

1	There were only seven instances of thromboembolism (0.7%) within 30 days of the procedure. The rate was the same after exclusion of patients who received bridge therapy.
2	The rate of thromboembolism was 0.4% when the warfarin interruption lasted five days or less and 2.2% for those of seven or more days.
3	Six patients (0.6%), including four who had received bridge therapy, suffered a major bleeding complication, defined as hemorrhage that led to death or to hospitalization with a transfusion ≥ 2 U red packed cells or at a "critical" site (including, for example, intracranial or retroperitoneal bleeding).
4	Another 17 patients (1.7%), including 10 who had received bridge therapy, experienced "clinically significant, nonmajor bleeding."

Bleeding complication risk among patients who received or did not receive bridge anticoagulation therapy

Complication	Bridge anticoagulation (%)	No bridge anticoagulation (%)
Major hemorrhage	3.7	0.2
Significant nonmajor hemorrhage	9	0.6

"Although our paper doesn't provide any definitive answers, it questions whether the risk of bridging therapy, even in outpatients, can be justified by the potential benefit," Garcia said, cautioning that it doesn't apply to patients undergoing major surgery or are hospitalized for an invasive procedure, whose thrombotic and bleeding risks would likely be higher. Randomized, placebo-controlled trials are now needed, he added, to settle the issue.

The study was funded by Bristol-Myers Squibb. Dr. Garcia has disclosed receiving consulting honoraria and research support from Bristol-Myers Squibb, AstraZeneca, and sanofi-aventis. Coauthor Dr. Elaine M. Hylek (Boston University School of Medicine, Massachusetts) has disclosed having served on advisory boards for Bristol-Myers Squibb and receiving research support from AstraZeneca and Bristol-Myers Squibb.

Source
Garcia DA, Regan S, Henault LE, et al. Risk of thromboembolism with short-term interruption of warfarin therapy. Arch Intern Med. 2008;168 63-69.

Clinical Context

Significant uncertainty surrounds the treatment of patients who must discontinue warfarin sodium therapy before an invasive procedure. In part, the uncertainty results from the lack of published information about the risk for thromboembolism associated with short-term interruption of warfarin therapy. The patient and clinician have 3 options: (1) continue warfarin therapy, (2) withhold therapy for some time before (and after) the procedure, or (3) temporarily withhold warfarin therapy while also providing a short-acting (bridging) anticoagulant during the perioperative period. The current guidelines from the American College of Chest Physicians suggest that if the annual risk for thromboembolism is low, warfarin therapy may be held for 4 to 5 days before the procedure without bridging and may be restarted shortly thereafter.
The aim of this study was to assess the frequency of thromboembolism and bleeding in patients whose warfarin therapy was temporarily withheld for an outpatient invasive procedure.

Study Highlights

1	In this prospective, observational cohort study, enrollment was conducted from April 4, 2000, to March 6, 2002, and was performed at 101 sites (primarily community-based physician office practices) in the United States.
2	A total of 1293 episodes of interruption of warfarin therapy in 1024 low- to intermediate-risk individuals were included.
3	The mean (SD) age of the patients was 71.9 (10.6) years; 438 (42.8%) were women.
4	The most common indications for anticoagulant therapy were atrial fibrillation (n = 550), venous thromboembolism (n = 144), and mechanical heart valve (n = 132).
5	The most common procedures were colonoscopy and oral and ophthalmic surgery. Other reasons for withholding warfarin therapy were epidural injection, prostate biopsy, breast biopsy, and dermatologic procedures.
6	The main outcome measures were thromboembolism or clinically significant hemorrhage within 30 days of interruption of warfarin therapy.
7	Perioperative heparin or low-molecular-weight heparin was used in 8.3% of cases overall.
8	Results demonstrated that 7 (0.7%) patients (95% confidence interval [CI], 0.3% - 1.4%) experienced postprocedure thromboembolism within 30 days; 4 of the thromboembolisms were arterial and 3 were venous.
9	Among patients whose warfarin therapy was interrupted for 5 days or less, the proportion experiencing thromboembolism was 0.4% vs 2.2% for those with an interruption interval of 7 days or more.
10	None of the 7 patients who experienced thromboembolism received periprocedural bridging therapy.
11	6 (0.6%) patients (95% CI, 0.2% - 1.3%) experienced major bleeding, whereas an additional 17 (1.7%) patients (95% CI, 1.0% - 2.6%) experienced a clinically significant, nonmajor bleeding episode.
12	Of these 23 patients who had bleeding episodes, 14 received periprocedural heparin or low-molecular-weight heparin.

Pearls for Practice

1	According to the American College of Chest Physicians, current recommendations suggest that if the annual risk for thromboembolism is low, warfarin therapy may be held for 4 to 5 days before the procedure without bridging.
2	For many patients receiving long-term anticoagulation who need to undergo a minor outpatient intervention, a brief (≤ 5 days) periprocedural interruption of warfarin therapy is associated with a low risk for thromboembolism and bleeding.