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CLINICAL RESEARCH: MYOCARDIAL ISCHEMIA/INFARCTION

A dose-finding study of fondaparinux in patients with non–ST-segment elevation acute coronary syndromes

The Pentasaccharide in Unstable Angina (PENTUA) study

Maarten L. Simoons, MD, FESC, FACC^*,*, Inge W. G. Bobbink, MS, Jean Boland, MD, Martin Gardien, MD^*, Peter Klootwijk, MD^*, Anthonie W. A. Lensing, MD, Witold Ruzyllo, MD, FESC, FACC^||, Victor A. W. M. Umans, MD^¶, Alec Vahanian, MD, FESC, FACC^#, Frans Van De Werf, MD, FESC, FACC^**, Uwe Zeymer, MD, FESC, FACC PENTUA Investigators

^* Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands
Organon, Oss, The Netherlands
CHR Citadelle, Luik, Belgium
Academic Medical Center, Amsterdam, The Netherlands
^|| Instytut Kardiologii, Warszawa, Poland
^¶ Medisch Centrum, Alkmaar, The Netherlands
^# Hopital Bichat, Paris, France
^** University Hospital Gasthuisberg, Leuven, Belgium
Städtischen Kliniken, Kassel, Germany

Manuscript received March 12, 2003; revised manuscript received February 20, 2004, accepted February 24, 2004.

^* Reprint requests and correspondence: Dr. Maarten L. Simoons, Thoraxcenter, Room H 560, Erasmus Medical Center Rotterdam, P.O. Box 2040, 3000 CA Rotterdam, the Netherlands.
m.simoons{at}erasmusmc.nl

OBJECTIVES: In this dose-finding study, we sought to compare fondaparinux with enoxaparin in patients with acute coronary syndromes (ACS).

BACKGROUND: Fondaparinux is a synthetic pentasaccharide that selectively inhibits activated clotting factor X. It has been demonstrated as effective in preventing thromboembolic complications in orthopedic surgery.

METHODS: Four doses fondaparinux (2.5, 4, 8, or 12 mg once daily) and enoxaparin (1 mg/kg twice daily) were compared, both given for three to seven days, in patients with ACS without persistent ST-segment elevation.

RESULTS: The rates of the combined primary end point of death, myocardial infarction, or recurrent ischemia after nine days were 27.9%, 35.9%, 34.7%, 30.3%, and 35.7% in patients allocated to fondaparinux doses of 2.5, 4, 8, and 12 mg and enoxaparin, respectively (p = NS). In the per-protocol analysis (929 patients who received adequate study drug and had adequate ST-segment monitoring), these figures were 30.0%, 43.5%, 41.0%, 34.8%, and 40.2%. Again, no dose response was observed. The lowest event rates were observed in the 2.5-mg fondaparinux group, which had significantly lower rates than the enoxaparin group as well as for 4 and 8 mg fondaparinux in the per-protocol analysis (p < 0.05). Bleeding rates were low and not different among the patient groups. No differences were observed in fondaparinux concentrations in patients with or without death, myocardial infarction, recurrent ischemia, or bleeding events.

CONCLUSIONS: This dose-finding study revealed no dose response for different fondaparinux doses ranging from 2.5 to 12 mg subcutaneously and suggests that the efficacy and safety of fondaparinux may be similar to that of enoxaparin. Further studies with fondaparinux in ACS might include the lowest dose (2.5 mg) investigated in this study.

Abbreviations and Acronyms   ACS = acute coronary syndromes   CABG = coronary artery bypass graft surgery   CK-MB = creatine kinase-MB fraction   ECG = electrocardiographic   LMWH = low-molecular-weight heparin   MI = myocardial infarction   PCI = percutaneous coronary intervention   PENTUA = Pentasaccharide in Unstable Angina study

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