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16th Interventional Cardiology Symposium

Montreal, Quebec / June 14-16, 2007

In the last decade, numerous medical and technical advances have reduced negative outcomes in patients with acute coronary syndromes (ACS). Notably, increased use of antithrombin and antiplatelet agents and broader application of percutaneous coronary intervention (PCI) have reduced death, myocardial infarction (MI), recurrent stroke and heart failure. However, this progress has come at a cost as patients have been subjected to an increased risk of bleeding and associated adverse outcomes including ischemia, transfusion and death.

“Initially, because of the benefits shown in trials, bleeding was written off as something minor and reversible. However, it has reached limits that are becoming completely unacceptable both for patients and institutions,” observed Dr. Shamir R. Mehta, Director of Interventional Cardiology, Hamilton Health Sciences, and Associate Professor of Medicine, McMaster University, Hamilton, Ontario.

“The question now is how to refine our [anticoagulant] therapies to make them safer while preserving efficacy in an era of routine invasive management. A lot of work has gone into devising new compounds that are more effective and that more specifically target various parts of the coagulation cascade,” continued Dr. Mehta. Two synthetic antithrombin agents, fondaparinux and bivalirudin, which target factor Xa and IIa, respectively, have shown efficacy comparable to or better than those of established medications. This result has been accompanied by substantially lower rates of bleeding, particularly when fondaparinux is used in initial upstream therapy of ACS.

Efficacy with Significantly Less Bleeding

The OASIS-5 (Fifth Organization to Assess Strategies for Ischaemic Syndromes) study of more than 20,000 patients with ACS without ST-segment elevation (N Engl J Med 2006;354:1464-76) demonstrated that both in patients undergoing PCI and those treated more conservatively, fondaparinux was non-inferior to enoxaparin in reducing death/MI/recurrent ischemia, death/MI, and mortality at nine days. Moreover, it led to a significant 17% reduction in all-cause mortality after one month (P=0.02) and significant decreases in death and ischemic outcomes at six months. Fondaparinux-treated patients also experienced a 48% reduction in major bleeding over nine days of therapy, with differences apparent as early as the first day of dosing, Dr. Mehta summarized. Among patients who were treated for shorter periods, about 30% fewer bleeding episodes occurred with fondaparinux vs. enoxaparin. “It doesn’t matter what tertile [the patient was] in, in terms of bleeding. There were significant reductions,” he confirmed.

OASIS-5 data support the preference expressed by most interventional cardiologists for the use of unfractionated heparin (UFH) during cardiac catheterization. Although catheter thrombus was initially more common with fondaparinux than with enoxaparin, a study protocol amendment suggesting the use of UFH in combination with fondaparinux (it was already being used with enoxaparin in patients going to catherization after more than six hours) effectively prevented this complication (Table 1). Even with UFH, bleeding rates in patients undergoing PCI were more than 50% lower with fondaparinux than with enoxaparin. Furthermore, according to an analysis by Dr. Mehta presented at the European Society of Cardiology last fall, abrupt or threatened artery closure was significantly reduced in both OASIS-5 treatment arms with the addition of UFH. Fondaparinux is also compatible with glycoprotein (GP) IIb/IIIa inhibition at the time of PCI.

Table 1. Effective Prevention of Catheter Thrombus

New Option for Percutaneous Coronary Intervention

The recent ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial (Stone et al. N Engl J Med 2006;355:2203-16) compared three treatment regimens in 13,819 patients with ACS undergoing invasive management: UFH/enoxaparin plus GP IIb/IIIa inhibition; bivalirudin plus GP IIb/IIIa inhibition; and bivalirudin alone. The study revealed a “significant reduction in major bleeding with bivalirudin vs. heparin plus GP IIb/IIIa, suggesting that you can spare the use of a GP IIb/IIIa antagonist in patients with ACS,” Dr. Mehta indicated.

Similarly, the REPLACE-2 (Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events) study (Gibson et al. Am J Cardiol 2007;99(12):1687-90) demonstrated that it is safe to switch patients from other anticoagulants to bivalirudin at cardiac catheterization/PCI. In addition, patients at high risk who would typically be considered candidates for GP IIb/IIIa inhibition can benefit equally from and have a lower risk of bleeding with bivalirudin. “One of the issues with bivalirudin is you should make sure you have platelet inhibition on board. Patients should be pretreated with a thienopyridine. If they are not pretreated with a thienopyridine, you should probably use a GP IIb/IIIa antagonist,” Dr. Mehta advised.

Updated Guidelines

Recently published guidelines from the European Society of Cardiology (Eur Heart J 2007;28(12):1462-536) indicate that fondaparinux is a first-line agent for ACS while a decision between early invasive or a conservative strategy is pending. Enoxaparin may be used if the patient’s risk of bleeding is low. Guidelines from the American Heart Association/American College of Cardiology, expected shortly, will likely contain similar advice. According to Dr. Mehta, the recommended protocol is to administer fondaparinux in the emergency room along with acetylsalicylic acid, clopidogrel, a statin, a beta blocker and nitroglycerine as required. Based on data from OASIS-6, fondaparinux is also indicated for emergency treatment of ST-elevation MI, he noted. “We are using it across the spectrum of ACS.”

Table 2 lists the recommended steps for the transition of a patient who has received fondaparinux to the cardiac catherization laboratory. The transition can take place as per institutional protocol, Dr. Mehta told listeners. “You do not need to delay because fondaparinux does not increase bleeding vs. placebo. However, if the usual practice with enoxaparin is to wait six hours, that can also be done with fondaparinux.” At PCI, interventional cardiologists may employ a UFH or bivalirudin, with or without GP IIb/IIIa inhibition. “The nice thing about fondaparinux is that it allows the interventional cardiologist to use those agents in PCI that they have been using in the past and are comfortable with, plus new agents such as bivalirudin which has also been shown to lower bleeding. So to start with fondaparinux, and then, if the patient needs a PCI, to use bivalirudin, seems like a logical strategy [and is one] we are currently adopting in significant numbers of our patients,” he stated.

Table 2. Procedure for Transitioning Patients Initiated on Fond
terization Laboratory

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Summary

In his closing remarks, session chair Dr. Jean-François Tanguay, Director, Montreal Heart Institute, Quebec, emphasized the utility of this strategy for transitioning patients to the catheterization laboratory. The use of fondaparinux in upstream therapy of ACS and bivalirudin in patients undergoing PCI is a strategy that has the potential to lead to optimally lower rates of bleeding in ACS.