BRIDGE: No Benefit From Perioperative LMWH in Patients With AF

June 23, 2015

BETHESDA, MD — To bridge or not to bridge, that has been the clinical question for physicians managing warfarin-treated patients faced with an elective surgery or invasive procedure. A new National Heart, Lung, and Blood Institute (NHLBI)–sponsored study provides an answer for this specific clinical scenario, with investigators showing that a periprocedural bridging strategy with low-molecular-weight heparin (LMWH) offers no clinical advantages compared with simply stopping warfarin[1].

Specifically, for warfarin-treated patients with atrial fibrillation undergoing an elective surgery or invasive procedure, perioperative bridging with LMWH was not associated with a reduction in stroke, systemic embolism, or transient ischemic attack compared with no bridging but did significantly increase the risk of bleeding.

To heartwire from Medscape, senior investigator Dr James Douketis (St Joseph's Hospital/McMaster University, Hamilton, ON) said the results said the results of the placebo-controlled trial are likely to have an impact on the clinical guidelines for managing patients treated with warfarin who require surgery or an invasive procedure. While he admits a degree of bias, given his role in the BRIDGE trial, in his objective assessment "there's no compelling evidence that bridging mitigates the risk for stroke and thromboembolism, and there is compelling evidence that it increases the risk for bleeding."

He pointed out that certain high-risk patients—for example, a patient who needs to stop warfarin for surgery but who has had a stroke within the past 6 months—might be best bridged, but the vast majority of patients he sees in clinical practice will no longer be bridged. "I think the guidelines have to be revisited because we think this is a potentially practice-changing trial," he said. "More important, it should provide the basis for strong recommendations about bridging/no-bridging vs the weak recommendations we have had so far for everyday doctors."

The BRIDGE trial, which was led by Dr Thomas Ortel (Duke University Medical Center, Durham, NC), was presented at the International Society for Thrombosis and Haemostasis (ISTH) 2015 Congress and published simultaneously in the New England Journal of Medicine.

NHLBI-Sponsored BRIDGE Study

Speaking with heartwire , Douketis said warfarin is typically stopped 5 days before elective procedures to allow the anticoagulant effect of the drug to wear off. It is then restarted after the procedure and requires 5 to 10 days to achieve therapeutic anticoagulation. When warfarin is stopped, bridging anticoagulation with LMWH is intended to minimize the time patients do not have adequate anticoagulation and to reduce the risk of clinical events, namely stroke.

"We conceived the study over 10 years ago and at that time there was a real uncertainty about how to best manage patients on warfarin who needed surgery," said Douketis. "There were some who felt patients would need to be bridged because the risk of stroke around the time of surgery was higher than what you'd expect compared with just stopping warfarin. Others felt that wasn't the case. It was a situation we refer to as clinical equipoise—there were clinical arguments for and against bridging."

At present, the clinical guidelines for managing warfarin-treated patients undergoing an elective surgery provide "weak recommendations" for perioperative anticoagulation bridging. Douketis, who was an author of the American College of Chest Physicians (ACCP) 2012 clinical guidelines for the perioperative management of antithrombotic therapy, said the recommendations allow a great deal of leeway for clinical judgment when managing such patients.

In total, 1884 patients were enrolled in the BRIDGE trial, with 950 randomized to no bridging and 934 assigned to perioperative anticoagulation bridging. The bridging protocol involved stopping warfarin and treating patients with dalteparin 100 IU/kg twice daily from 3 days until 24 hours before the elective procedure and again from 5 to 10 days after the procedure. Patients in the no-bridging arm went off warfarin 5 days before surgery and received matching placebo subcutaneous injections before resuming warfarin within 24 hours of the procedure.

The mean age of patients in the study was 72 years, and the mean CHADS2 score was 2.3. Nearly 40% of patients in the trial had a CHADS2 score >3. In total, 44% of patients underwent a gastrointestinal procedure, while 17% of the surgery/procedures were cardiothoracic.

Regarding the primary end point at 30 days, the incidence of arterial thromboembolism was 0.4% in the no-bridging arm and 0.3% in patients bridged with LMWH (P=0.01 for noninferiority). In total, 12 major bleeding events occurred in the no-bridging arm compared with 29 major bleeds in the bridging arm, a difference that was statistically significant (1.3% vs 3.2%; P=0.005). Minor bleeding was also significantly more likely to occur among patients bridged with LMWH (12.0 vs 20.9%; P<0.001).

"The results are very gratifying to us," said Douketis. "They confirmed our a priori study hypothesis. We hypothesized that a no-bridging strategy would be noninferior to bridging with LMWH for stroke and arterial thromboembolism prevention, and that was the case. What we didn't expect was that the overall event rates were about half of what we initially anticipated."

The bridging protocol used in the study was established using past observational studies addressing the bridging/no-bridging question. The dalteparin-bridging protocol was designed to minimize the risk of bleeding while mitigating the risk of stroke and other thrombotic events. In the US, said Douketis, physicians are more likely to use enoxaparin over dalteparin, but he does not believe this affects the generalizability of the BRIDGE results.

The NHLBI of the National Institutes of Health sponsored the BRIDGE study. Ortel reports consulting fees from CSL Behring and Daiichi-Sankyo and grant support/consulting from Instrumentation Laboratory. Douketis reports consulting for Boehringer Ingelheim, Bayer, Janssen, Bristol-Myers Squibb, Pfizer, Sanofi, Daiichi-Sankyo, Actelion, Biotie, Portola, and the Medicines Company. Disclosures for the coauthors are listed on the journal website.

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