Leah A. Sabato, PharmD; Mentor: Michael Gulseth, PharmD, BCPS
Trial Summary
The BRIDGE trial1 was a randomized, double-blind, placebo controlled, multicenter trial in the US and Canada. The trial aimed to compare the efficacy and safety of bridging with low molecular weight heparin versus no bridging in patients who take warfarin for atrial fibrillation who required interruption of anticoagulation for surgery or a procedure. The trial included patients with both valvular and non-valvular atrial fibrillation who had at least one risk factor for stroke (hypertension, diabetes mellitus, congestive heart failure, previous ischemic stroke, systemic embolism or transient ischemic attack). Patients with a mechanical prosthetic heart valve, recent stroke or systemic embolism within 12 weeks, recent major bleeding within 6 weeks, high risk procedures such as cardiac surgery, or renal dysfunction defined as a creatinine clearance <30 mL/min were excluded. Included patients were randomized to receive either dalteparin 100 units/kg administered subcutaneously twice daily or a matching placebo. Patients were instructed to discontinue warfarin five days prior to their scheduled procedure, start the study drug three days prior to the procedure, and continue until 24 hours before the procedure. Patients resumed warfarin on the day of the procedure or immediately following, resumed the study drug between 24-72 hours after (based on bleeding risk associated with the procedure), and continued the study drug until therapeutic on warfarin. The primary efficacy endpoint was arterial thromboembolism (defined as ischemic stroke, transient ischemic attack, or systemic embolism at 30 days) and the major safety endpoint was major bleeding. The primary efficacy endpoint was designed as a non-inferiority analysis and the primary safety endpoint was designed as a superiority analysis, based on the hypothesis that no bridging would be non-inferior to bridging in terms of the primary efficacy analysis and superior to bridging in terms of the primary safety analysis. Overall, 918 patients were included in the no bridging group, and 895 patients were included in the bridging group. Most (85.1%,84.7% respectively) underwent a procedure which was categorized minor. The mean CHADS2 score was 2.3 and 86% of patients had a CHADS2 score in the range of 1-3. The major safety and efficacy endpoints are listed in the table below.
No Bridgingn=918 / Bridging
n=895 / P-value
Primary Endpoint:
Arterial Thromboembolism / 4(0.4) / 3(0.3) / 0.01Ɨ, 0.73
Stroke / 2(0.2) / 3(0.3) / -
TIA / 2(0.2) / 0 / -
Systemic embolism / 0 / 0 / -
Deep vein thrombosis / 0 / 1(0.1) / 0.25
Pulmonary embolism / 0 / 1(0.1) / 0.25
Primary Endpoint:
Major bleeding / 12.1(1.3) / 29(3.2) / 0.005
Fatal bleeding / 0 / 0 / -
Minor bleeding / 110(12.0) / 187(20.9) / <0.001
Death / 5(0.5) / 4(0.4) / 0.88
All expressed as no.(%)
Ɨp-value for noninferiority. All others represent p-value for superiority.
Follow-up Questions
- What are your thoughts on the duration of the dalteparin (8 days post, and the dose)?
The dosage of dalteparinwas appropriate for therapeutic use, however it is noteworthy that no low molecular weight heparin has demonstrated efficacy at any dose in prevention of stroke and systemic embolism in patients with atrial fibrillation. Patients received a mean of 15.7+7.4 doses of dalteparin, equivalent to approximately 8 days. The study drug was continued until warfarin was therapeutic (goal INR 2-3). Patients resumed warfarin on the day of surgery or the day immediately following at their home dose, and adjustments were made by study investigators and were not protocolized. The duration is of dalteparin is slightly longer than I would expect, which could potentially lead to a higher rate of bleeding given that the median time to a major bleeding outcome after the procedure was 7 days.
- Are you using the CHADS2 or CHADS2VASC when making your decisions about bridging?
Neither the CHADS2 or CHADS2VASC scoring system have been prospectively validated to predict perioperative thromboembolism risk. The BRIDGE trial and the CHEST guidelines for perioperative anticoagulation management stratify patients based on the CHADS2 risk scoring system, so that may be the most appropriate way. However, the CHADS2VASC score may be helpful in borderline patients to help clarify the risk/benefit ratio. Personally, I often assess both.
- Can you clarify the definition of bleeding in the trial?
The primary bleeding endpoint in the trail was major bleeding within 30 days after the procedure, which included: symptomatic (or clinically-overt) bleeding associated with transfusion of 2 units of packed red blood cells or whole blood, decrease in hemoglobin level of >2g/dL, or the need for re-operation; symptomatic or clinically-overt bleeding at a critical anatomic site, or fatal bleeding.
- What are you current thoughts on the recommendations for CHADS=4?
Overall, the means CHADS2 score was 2.3, and only 21% of included patients had a CHADS2 score of 4. Thus, this trial does not definitely answer the question. However, the thromboembolism rate was very low in both groups (0.3-0.4%) and a significant bleeding risk was identified. Overall, I do think that we can extrapolate the results to many patients in the CHADS2=4 group, recognizing that as the thromboembolic risk increases the risk:benefit ratio also changes. There are some patients in the CHADS2=4 group with strong risk factorssuch as recent stroke or with non-CHADS2 risk factors which may gain more benefit from bridging.
References
1.Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. New England Journal of Medicine 2015;373:823-33.