BARCELONA — The selective factor Xa inhibitor fondaparinux proved superior to enoxaparin or unfractionated heparin for the treatment of the full spectrum of acute coronary syndrome, from unstable angina through ST-elevation MI, in a weighty new combined analysis of two randomized trials totaling more than 32,000 patients, Dr. Shamir Mehta reported at a joint meeting of the European Society of Cardiology and the World Heart Federation.
In acute coronary syndrome (ACS) patients not undergoing percutaneous coronary intervention (PCI), fondaparinux conferred significantly lower rates of the composite end point of mortality, repeat MI, or stroke as well as less major bleeding than either enoxaparin or unfractionated heparin (UFH) in the combined analysis of the fifth and sixth Organization to Assess Strategies for Ischemic Syndrome (OASIS-5 and −6) trials. (See box.)
In those participants who did undergo PCI, fondaparinux (Arixtra) was as effective as enoxaparin (Lovenox, Clexane) and had a markedly lower associated risk of major bleeding, added Dr. Mehta of McMaster University, Hamilton, Ont.
Adding UFH in the catheterization lab at the time of PCI in patients treated upstream with fondaparinux essentially eliminates catheter thrombosis, a concern when patients went to PCI on fondaparinux alone. The incidence of catheter thrombosis was just 0.3% in patients on fondaparinux and UFH. Moreover, the incidence of abrupt or threatened abrupt closure in the cath lab was 6.2% with enoxaparin alone, 5.9% with fondaparinux alone, 4.3% with enoxaparin plus UFH, and comparably low with fondaparinux plus UFH.
“These data suggest that unfractionated heparin is a good anticoagulant for PCI and probably better than using enoxaparin or fondaparinux alone,” the cardiologist said.
A caveat is that there were no primary PCIs in OASIS-5 and −6, Dr. Mehta noted, adding that he doesn't recommend using fondaparinux in that setting.
Fondaparinux is approved in the U.S and Europe for the prevention of venous thromboembolism in patients undergoing major orthopedic or abdominal surgery and for treatment of acute deep vein thrombosis and acute pulmonary embolism. It is not approved for ACS patients; however, GlaxoSmithKline reported in October that the Food and Drug Administration has accepted a supplemental new drug application based on OASIS-5 and −6 for priority review, for the use of fondaparinux in “a broad spectrum of patients with acute coronary syndromes.”
The results of OASIS-5 were presented at the annual congress of the European Society of Cardiology in September 2005 and published in April 2006 (N. Engl. J. Med. 2006;354:1464–76); those of OASIS-6 were presented at the annual meeting of the American College of Cardiology in March 2006 and published in April (JAMA 2006;295:1519–30). The new combined analysis was performed in order to strengthen the power of the findings and address questions that had arisen when the individual studies were presented.
One question many physicians asked when the individual OASIS studies were presented was this: Is fondaparinux safe in patients on clopidogrel or a glycoprotein IIb/IIIa inhibitor? The answer is now in: With more than 18,000 patients in the combined analysis on clopidogrel or ticlopidine, the rate of major bleeding at 9 days was 2.2% in fondaparinux-treated patients, vs. 3.8% treated with enoxaparin or UFH. And in more than 5,400 patients on a glycoprotein IIb/IIIa inhibitor, the major bleeding rate was 3.6% with fondaparinux and 5.6% in the comparator group.
Some interventional cardiologists had argued that comparing fondaparinux to enoxaparin plus UFH in the PCI setting was misleading because switching from enoxaparin to UFH in the cath lab resulted in increased bleeding, compared with rates with either alone. The combined analysis shows that's not so. When UFH was given at least 6 hours after the last enoxaparin dose as specified in the OASIS protocols, bleeding did not increase. The bleeding risk of fondaparinux is so low that unlike with enoxaparin, there is no need for a delay before giving UFH, Dr. Mehta said.
Fondaparinux costs less than half as much as enoxaparin, he said. “Plus you have lower rates of bleeding complications with all their related costs, plus the reductions in mortality, MI, and stroke.”
Dr. Mehta has served as a consultant for and on the speaker's bureau of GlaxoSmithKline, which sponsored the OASIS trials.