The following slides highlight a discussion and analysis of presentations in the Late-Breaking Clinical Trials session from the 55th Annual Scientific Session of the American College of Cardiology (ACC) in Atlanta, Georgia, March 11-14, 2006. The original presentations were by: S. Yusuf, MB; SR Mehta, MD; CP Cannon, MD; and JJ Popma, MD. The presentations were reported and discussed by Dr. Michael R. Freeman in a Cardiology Scientific Update. Patients with acute coronary syndromes (ACS) have significantly improved outcomes with the application of evidence-based therapy using thrombolytic agents, primary percutaneous coronary intervention (PCI), antithrombotic drugs, and early cardiac catheterization. Nevertheless, patients continue to have recurrent ischemic events and therapy is complicated by significant bleeding. Fondaparinux is the first of a new class of antithrombotic drugs, a selective factor-Xa inhibitor. Two large trials in ACS patients have demonstrated the efficacy of fondaparinux in reducing death and recurrent ischemic events with a reduction in bleeding complications; these were the Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS)-5 and -6 trials: • OASIS-5 – Fondaparinux in patients with non-ST-elevation myocardial infarction (NSTEMI) • OASIS-6 – Fondaparinux in patients with ST-elevation MI (STEMI). The issue of Cardiology Scientific Update presented the highlights of these trials.

There is an increasing volume of data demonstrating the relationship between bleeding and mortality in ACS. Thus, the 30-day benefit in bleeding in OASIS-5 translated into a significant reduction in mortality. Several studies expanding on the benefits of fondaparinux in NSTEMI patients were presented at the ACC meeting. One analysis of the OASIS registry, OASIS-2, and CURE data, demonstrated the adverse effects of bleeding in patients with NSTEMI. There was a >4-fold increase in 30-day mortality in patients with bleeding. A similar analysis of the OASIS-5 study demonstrated that major bleeding resulted in a 5-fold increased risk of death at 30 days, and even minor bleeding increased the risk by >2-fold. Fondaparinux was associated with less bleeding and access site complications than the low-molecular-weight heparin, enoxaparin, in patients undergoing percutaneous coronary inter-vention( PCI) for NSTEMI. However, death and MI were similar in both treatment groups (7.2% vs. 6.9%) who had PCI during hospitalization. Renal dysfunction appears as an important marker of high risk in patients with ACS. The OASIS-5 study demonstrated a close relationship between rising creatinine levels, death, and bleeding. In all quartiles of renal function, there was a higher event rate in patients treated with enoxaparin than in those treated with fondaparinux. At the highest creatinine level (>1.19), the mortality rate was 11.38% vs 9.53%, p<0.023. The major bleeding rate in this highest quartile was greater in the enoxaparin group (8.2%) than in the fondaparinux group (5.5%). In OASIS-5, as summarized in the above slide, the net clinical benefit (endpoint of death/MI/refractory ischemia/major bleeding) at 9 days was similar for both enoxaparin and fondaparinux in patients aged <65 years (6.1% vs. 5.8%, respec-tively). However, in patients aged >65 years, the event rates were significantly higher with enoxaparin (12.3%) than with fondaparinux (9.3%). In the overall population at 30 days, the death/MI/revascularization/ major bleeding rates were reduced by 19% with fondaparinux as compared to enoxaparin, p<0.00001.

The OASIS-6 trial enrolled 12,092 patients with STEMI from 41 countries and the results are summarized in the above slide. All were randomized to fondaparinux (2.5 mg once daily given for up to 8 days) or usual care, depending on the presentation and initial therapy was according to the investigator’s judgment. The first group of patients (designated Stratum 1) received either fondaparinux or placebo (since unfractionated heparin [UFH] was not indicated due to late presentation) or a nonfibrin-specific thrombolytic agent (n=5658). The second group of patients (designated Stratum 2) received fibrin-specific thrombolytic therapy or primary PCI and they were randomized to fondaparinux for up to 8 days or UFH for up to 48 hours, followed by placebo for up to 8 days (n=6434). Patients with contraindications to anticoagulation or with a creatinine >265.2 mg/dL were excluded. UFH was administered as an intrave-nous bolus of 60 IU/kg (maximum, 4000 U), followed by an intravenous infusion at 12I U/kg/hr for 24-48 hours. The primary endpoint was a composite of death or reinfarction (recurrent symptoms with ST elevation and/or significant enzyme rise depending upon timing of the event) at 30 days, with secondary assessment at 9 days and 3 months in all, and at 6 months in 6976 patients. Major bleeds were identified up to day 9 and were centrally adjudicated with standard criteria, including fatal hemorrhage, intracranial hemorrhage, cardiac tamponade, or a fall in hemoglobin of >5 g/dL (TIMI criteria). Follow-up was concluded in January 2006 and was over 99% complete. Patients were equally randomized within each stratum, the median age was 62 years, 72% were male, 44% underwent cardiac catheterization, 29% with primary PCI, and 45% with thrombolytic therapy. No reperfusion therapy was given to 24% of the total population.

The above slide summarizes the overall outcome of death or MI at 9 days, 30 days (primary), and at the end of follow-up. At 30 days, the hazard ratio (HR) of 0.86 was highly significant, demonstrating the efficacy of fondaparinux in the whole population for reducing death and MI. The absolute difference was 1.5% at 30 days. The significant reduction in mortality was due to a reduction in cardiac mortality, from 9.5% to 8.2%, and these events included death as a result of reinfarction, congestive heart failure, cardiogenic shock, and asystole.

The survival curves in the total patient population at various time periods and according to the type of event are shown in the above slide. When comparing the two strategies, similar results were demonstrated if the events considered were death, MI, and severe bleeding. Thus, at 30 days, the study demonstrated a significant overall relative reduction of 14% in the primary endpoints of mortality and reinfarction. With respect to bleeding at 30 days, there was a nonsignificant reduction in bleeding for the fondaparinux group when compared with both the placebo and UFH groups, revealing an HR (hazard ratio) of 0.79, but an absolute difference of only 0.3%. There was a significant reduction in myocardial rupture, a nonsignificant reduction in fatal bleeding, no differences in intracranial hemorrhage or retroperitoneal bleeding, and a hemoglobin drop of >5 g/dL. In the overall population, there was a significant reduction in total events, including death, MI, stroke, and major bleeding. The HR of 0.88 was highly significant (p<.009), indicating the overall efficacy of fondaparinux in STEMI.

The ExTRACT-TIMI 25 study (also reported at the ACC) was similar to the thrombolysis-treated Stratum 2 patients in the OASIS-6 trial and should considered when making decisions for the appropriate therapy of STEMI patients. EXTRACT-TIMI 25 randomized 20,506 patients receiving thrombolysis for STEMI and compared treatment with a new dosing regimen of the low molecular weight heparin (LMWH), enoxaparin, for up to 8 days versus UFH for at least 48 hours, as shown in the above slide. The new regimen of enoxaparin involved lower doses in elderly patients and in those with renal dysfunction. The dose of enoxaparin was reduced to three-quarters of the standard dose, with no bolus in patients aged ≥75 years and to once-daily in those who had a clinically significant impairment in renal function. Although enoxaparin did not reduce mortality alone as compared to UFH in EXTRACT-TIMI 25 (6.9% vs 7.5%), it did reduce the primary endpoint of death or nonfatal recurrent MI (by one-third) (9.9% vs. 12.0%) urgent revascularization (2.1% vs 2.8%) at 30 days and was associated with a net clinical benefit when the efficacy and bleeding results were combined (11.0% vs 12.8%, p<0.001). However, major bleeding was significantly increased by 53% with enoxaparin and fatal bleeding was increased by 80% (p<0.001). The improved efficacy likely was related to the superior antithrombotic effect of enoxaparin, the longer duration of therapy, and the previously documented rebound thrombosis that may occur with discontinuation of UFH. The investigators concluded that for every 1,000 patients treated with the enoxaparin strategy, there would be 15 fewer nonfatal reinfarctions, 7 fewer episodes of urgent revascularization, and 6 fewer deaths, at the cost of 4 additional episodes of nonfatal major bleeding.

The OASIS-5 and -6 trials in patients presenting with ACS without severe renal dysfunction demonstrate that fondaparinux is a safe and efficacious antithrombotic agent. Fondaparinux affords a simple regimen that can be used as a single-fixed dose, with no requirement for monitoring. Improved outcomes are associated with reduced bleeding complications and low cost; however, it is important to clearly define the patient population who benefits from this therapy. There is a question about whether the OASIS-6 data are relevant in centres where primary PCI has been established as the preferred treatment for STEMI; fondaparinux may be preferable in settings where the use of angiographic-based reperfusion is not routine. In patients requiring rescue PCI or other PCI after admission, initial management with fondaparinux followed by standard UFH during PCI, is adequate to prevent adverse events. These important trials presented at the ACC meeting and subsequently published demonstrate that antithrombotic therapy in ACS patients with either NSTEMI or STEMI reduces the composite endpoints of death, recurrent MI, and recurrent ischemia. Fondaparinux is as effective as enoxaparin in NSTEMI patients, but with significantly reduced bleeding, particularly in the elderly and in those with an elevated creatinine. Fondaparinux and enoxaparin are more effective than UFH in patients with STEMI receiving thrombolytic therapy for reducing death, MI, and recurrent ischemic events. However, fondaparinux appears to have no adverse effects on bleeding as compared to enoxaparin and likely improves 30-day survival. In patients undergoing PCI or rescue PCI, UFH appears to be superior to fondaparinux.