ESC: Low-dose heparin+fondaparinux does not lower peri-PCI bleeding, complications

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A low-dose regimen of unfractionalted heparin compared with standard dose did not reduce the risk of major peri-PCI bleeding or vascular access site complications in patients receiving the anticoagulant fondaparinux, which had previously been found to cut bleeding by half, according to the results of the FUTURA/OASIS-8 trial presented at the European Society of Cardiology (ESC) congress in Stockholm, and simultaneously published in the Journal of the American Medical Association.

Previously in the OASIS-5 trial, researchers found that subcutaneous fondaparinux (Arixtra, GlaxoSmithKline), a synthetic factor Xa inhibitor, was noninferior to subcutaneous enoxaparin (Lovenox, Sanofi-Aventis), an anti-thrombotic, for primary endpoints of death, MI and refractory ischemia; however, fondaparinux cut bleeding events in half.

During the FUTURA/OASIS-8 randomized trial, Sanjit S. Jolly, MD, of the Hamilton Health Sciences and McMaster University in Hamilton, Ontario, and colleagues compared the safety of two unfractionated heparin regimens in high-risk patients with non-ST-segment elevation acute coronary syndrome and undergoing PCI within 72 hours.

The 2,026 patients enrolled in the FUTURA (Fondaparinux Trial With Unfractionated Heparin During Revascularization in Acute Coronary Syndromes)/OASIS-8  trial were enrolled from 179 international hospitals between February 2009 and March 2010, and were all previously treated with fondaparinux and referred for coronary angiography. Almost 75 percent of the patients enrolled had STEMI at diagnosis, while the other 25 percent had unstable angina.

The researchers randomized patients to receive either standard active clotting time (ACT)-adjusted unfractionated heparin regimens (1,002 patients) or experimental fixed low-dose regimens or heparin (1,024 patients).

Patients who received the standard dose of unfractionated heparin during the study received 6,400 U, while those in the low-dose arm received a 3,800 U dose. Of those in the standard ACT-guided arm, 20.5 percent required an additional dose of unfractionated heparin to achieve an ACT of 300 to 350 seconds.

Patients were divided into age, sex, body mass index (BMI), creatinine clearance, access site for PCI and use of GP IIb-IIIa blockers for analysis of primary endpoints: composite peri-PCI major bleeding, minor bleeding or major vascular access site complications and researchers assessed outcomes after 48 hours (peri-PCI) and at 30 days.

According to the researchers, the median delay from symptom onset to enrollment was 19 hours and the delay from symptom onset to PCI was 27 hours. The majority of patients were on fondaparinux for a median duration of three days.

The composite endpoints occurred in 4.7 percent of the patients who received the lower doses of unfractionated heparin and in 5.8 percent of the patients who received the standard dose.

Rates of secondary outcomes including per-PCI major bleeding, death, MI and target vessel revascularization (TVR) at 30 days were 5.8 percent in patients administered a low-dose of heparin and 3.9 percent administered the standard dose.

While rates of peri-PCI major bleeding occurred at a higher rate in the patients receiving the low-dose heparin compared to those receiving standard therapy, 1.4 percent versus 1.2 percent, rates of minor bleeding were lower in the low-dose heparin group (0.7 percent) compared to the standard-dose arm (1.7 percent).

Additionally, the rates of major bleeding within 30 days were 2.2 percent in the low-dose arm compared to 1.8 percent in the standard dose arm.

However, the secondary outcomes of death, MI or TVR were higher in those patients who received a low-dose of heparin compared to those receiving the standard care, 4.5 percent versus 2.9 percent, respectively.

Five cases of catheter thrombosis occurred in the study arm where lower doses of heparin were administered, and one case of catheter thrombosis in patients administered standard doses of heparin.

“The major finding is that low fixed-dose heparin is not superior to standard ACT-guided heparin dosing (on a background of fondaparinux) in terms of preventing peri-PCI major bleeding or major vascular access-site complications,” the authors wrote.

“The findings that adding ACT-guided unfractionated heparin to fondaparinux while treating patients with acute coronary syndromes does not increase major bleeding is important in the context of modern PCI practice.”

The authors said the limitations of the trial stem from the fact that the FUTURA trial is “underpowered” to rule out moderate reductions in bleeding with the use of a low-dose of unfractionated heparin.

“Low-dose compared with ACT-guided standard-dose heparin did not reduce peri-PCI bleeding and vascular access site complications,” the authors concluded. “Therefore, patients with acute coronary syndromes treated with fondaparinux and undergoing PCI should receive the guideline-recommended ACT-guided standard dose of unfractionated heparin.”