Bridging Raises Bleeding Risk in Atrial Fibrillation Patients on Warfarin

June 29, 2015
Michael R. Page, PharmD, RPh

A practice-changing study suggests bridging anticoagulation does more harm than good in atrial fibrillation (AF) patients treated with warfarin.

A practice-changing study suggests bridging anticoagulation does more harm than good in atrial fibrillation (AF) patients treated with warfarin.

Bridging involves starting a short-acting blood thinner such as low-molecular-weight heparin (LMWH) after warfarin is stopped, usually 5 days before surgery. After the procedure, the bridging therapy is administered with warfarin for up to 5 days as the latter drug establishes or reestablishes its therapeutic effect.

The reason for this practice lies in basic pharmacology.

Warfarin inhibits the production of coagulation factors II, VII, IX, X, as well as proteins C and S. Of these factors, II, VII, IX, X have procoagulant effects, while proteins C and S have a counterbalancing anticoagulant effect in the clotting cascade.

Proteins C and S also have the shortest half-lives in the blood. As a result, warfarin depletes these more quickly than procoagulant factors II, VII, IX, and X.

By inhibiting the production of anticoagulant proteins C and S early in therapy and leaving procoagulant proteins unchecked, warfarin is thought to slightly increase the risk of thromboembolism during the first few days of therapy.

To counteract this effect, patients at high risk for blood clots often receive bridging therapy. Nevertheless, there is no consistent practice guidance detailing which patients should receive it, and there is little evidence to establish when it is helpful or potentially harmful.

“Bridging has been controversial because there has been a lack of data demonstrating that it’s necessary, so people don’t know what to do,” said Thomas L. Ortel, MD, PhD, chief of the Division of Hematology at Duke University, in a press release. “You can go to 5 different doctors, and some will bridge and others won’t. It just depends on what they feel they can safely do.”

The 2014 AHA/ACC/HRS Guideline for the Management of Patients with Fibrillation states, “Bridging therapy with unfractionated heparin or LMWH is recommended for patients with AF and a mechanical heart valve undergoing procedures that require interruption of warfarin. Decisions on bridging therapy should balance the risks of stroke and bleeding.”

Because so little evidence exists on the risks and benefits, however, inconsistent treatment is the norm.

Now, the results of the BRIDGE study led by Duke researchers published in the New England Journal of Medicine, show AF patients who resume warfarin after elective surgery may not benefit from bridging after all.

All 1884 patients in the BRIDGE study had either AF or atrial flutter, had interrupted warfarin therapy before undergoing a surgical procedure, and were randomized in a 1:1 ratio to receive bridging therapy with either warfarin and dalteparin or warfarin and placebo.

After up to 37 days of follow-up, 0.3% of those who received warfarin and dalteparin had arterial blood clots, which was comparable to the 0.4% of patients who received warfarin alone. The risk of clot formation was not significantly different between the groups.

While no benefit was seen, there was evidence of harm. For instance, 3.2% of those receiving bridging therapy experienced major bleeding events, compared with 1.3% of those receiving warfarin alone. Overall, major bleeding events were nearly 3 times less likely to occur in patients taking warfarin alone than in those receiving bridging therapy with warfarin and dalteparin.

These results suggest that AF patients undergoing elective surgical procedures do not require bridging therapy with an injectable blood thinner when warfarin is reestablished.

“This is the first study to provide high-quality clinical trial data demonstrating that for patients with AF who need a procedure and who need to come off warfarin, they can simply stop and restart,” Dr. Ortel stated.

Although bridging may be inadvisable for AF patients, it remains an appropriate option in certain groups of patients at high risk for thromboembolic events. In addition, this study did not offer evidence on the value of bridging therapy in patients with indications for warfarin therapy other than AF, or in those taking anticoagulants other than warfarin.

Despite these limitations, BRIDGE is an important practice-changing study, as it suggests that adding an injectable anticoagulant to oral warfarin before and after surgery does more harm than good.

References

1. Douketis JD, Spyropoulos AC, Kaatz S, et al. Perioperative Bridging Anticoagulation in Patients with Atrial Fibrillation. N Engl J Med. 2015.

2. January CT, et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: Executive Summary. J Am Coll Cardiol. 2014;64(21):2246-2280.