OASIS-5: PCI results published

October 22, 2007

Hamilton, ON - Results from an analysis of patients undergoing PCI in the OASIS-5 study comparing fondaparinux (Arixtra, GlaxoSmithKline) and enoxaparin (Lovenox/Clexane, Sanofi-Aventis) in the upstream management of ACS have been published, showing a similar efficacy of the two drugs in preventing ischemic events but a significant reduction in major bleeding with fondaparinux[1].

Catheter thrombus was more common in patients receiving fondaparinux than enoxaparin but was largely prevented by using unfractionated heparin (UFH) at the time of PCI, without any increase in bleeding.

The study, published in the October 30, 2007, issue of the Journal of the American College of Cardiology, was conducted by a team led by Dr Shamir Mehta (McMaster University, Hamilton, ON), who concludes that, as in the main trial, the use of fondaparinux results in a superior net clinical benefit compared with enoxaparin in the upstream management of ACS patients undergoing PCI.

But they point out that catheter-related thrombosis can occur, albeit rarely, when either fondaparinux or enoxaparin is used as the only anticoagulant during PCI. Noting that the addition of UFH during PCI reduces the risk of catheter thrombus without increasing bleeding, they recommend that "a tailored approach of using fondaparinux in a broad range of patients with ACS as initial upstream therapy, followed by targeted therapy with UFH in those who require a PCI procedure, is an attractive strategy for the management of ACS."

The main OASIS-5 trial, published in the New England Journal of Medicine in 2006, showed that fondaparinux reduced major bleeding by 50% and 30-day mortality by 17% compared with enoxaparin in more than 20 000 ACS patients. Both drugs were given subcutaneously for a maximum of eight days. The current analysis focuses on the 6238 patients who underwent PCI during the initial hospitalization. In the fondaparinux group, intravenous fondaparinux was given for PCI. In the enoxaparin group, no additional anticoagulant was given if PCI was less than six hours from the last subcutaneous dose and additional intravenous UFH was given if PCI was conducted more than six hours after the last enoxaparin dose.

In this analysis of patients undergoing PCI, fondaparinux was still associated with a large reduction in major bleeding compared with enoxaparin. Rates of ischemic events were similar in the two groups, resulting in superior net clinical benefit (death, MI, stroke, major bleeding) with fondaparinux.

Major results of OASIS-5 PCI patients

Outcome Fondaparinux (%) Enoxaparin (%) HR p
Major bleeding at day 9 2.4 5.1 0.46 <0.00001
Net clinical benefit 8.2 10.4 0.78 <0.004
Net clinical benefit=death, MI, stroke, or major bleeding

Fondaparinux reduced major bleeding 48 hours after PCI compared with enoxaparin, irrespective of whether PCI was performed less than six hours of the last enoxaparin dose or more than six hours when UFH was given.

Major bleeding 48 hours after PCI

Group Fondaparinux (%) Enoxaparin (%) HR p
PCI <6 hr after last enoxaparin dose 1.6 3.8 0.42 <0.0001
PCI >6 hr after last enoxaparin dose (so UFH also given) 1.3 3.4 0.39 <0.0001
Catheter thrombus

Mehta et al note that after isolated reports of catheter thrombus in a small number of patients whose treatment allocation remained blinded, a protocol amendment detailed the correct method of administration of intravenous study drug and emphasized the importance of flushing all catheters and the intravenous line to ensure that the entire bolus of study drug reached the patient. In addition, centers were reminded that, at the investigator's discretion, it was permissible to give open-label UFH before PCI in addition to the study drug, and the case report forms were amended to capture all cases of catheter thrombus and to capture whether open-label UFH was given in the catheterization laboratory before PCI.

Catheter thrombus in the whole study was more common in patients receiving fondaparinux (0.9%) than enoxaparin alone (0.4%) but was largely prevented by using UFH at the time of PCI, without any increase in bleeding. Catheter thrombus occurred in 10 fondaparinux-treated patients after the protocol amendment; nine of these events occurred when no UFH was given before PCI and the remaining case occurred in a patient who received a very low dose of open-label UFH. In the enoxaparin group, there were four cases of catheter thrombosis after the protocol amendment, none of whom received UFH. Irrespective of randomized treatment group, patients who experienced catheter-related thrombus had significantly higher rates of MI (27% vs 4.2%) and stroke (5.4% vs. 0.6%) than those with no catheter thrombus.

UFH best for use during PCI itself

Mehta commented to heart wire : "Before this trial, major guideline committees recommended use of UFH in patients treated with upstream enoxaparin after a six- to eight-hour delay from the last subcutaneous dose of enoxaparin, which was why that was stipulated in the protocol. But we didn't know whether this was necessary for fondaparinux or not. Basically, we have shown that patients given upstream fondaparinux also need UFH when undergoing PCI and that UFH should be given regardless of when the last fondaparinux dose was administered."

He added that these OASIS-5 results also suggest that UFH may be the best anticoagulant to use during the PCI procedure regardless of which agent was given upstream, so long as it is given appropriately. "We showed that giving UFH during PCI did not increase bleeding in patients who had received upstream enoxaparin more than six hours previously or in patients who had received upstream fondaparinux at any time previously." The authors speculate that using bivalirudin for the PCI procedure instead of UFH and a GP IIb/IIIa antagonist may further reduce bleeding. "This strategy has the potential to result in the lowest bleeding rates we have ever seen in ACS but needs to be tested in randomized trials, which are planned," Mehta added.

Noting that these results differ from those of SYNERGY, in which patients crossed over from enoxaparin to UFH, which did show increased bleeding rates, Mehta suggested this may have been because SYNERGY was an open-label study with no set protocol on how to cross over, which could have biased the use of UFH. In contrast, OASIS-5 was a double-blind study and there was a set protocol regarding crossover.

Mehta and several of the other authors of this paper have received honoraria and consulting fees from GlaxoSmithKline, Sanofi-Aventis, and Bristol-Myers Squibb.

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