Author + information
- Received March 12, 2003
- Revision received February 20, 2004
- Accepted February 24, 2004
- Published online June 16, 2004.
- 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‡‡
- ↵*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.
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.
Antithrombotic therapy with unfractionated heparin or low-molecular-weight heparin (LMWH) and aspirin is part of the standard care for patients with acute coronary syndromes (ACS) without persistent ST-segment elevation (1). Low-molecular-weight heparin has become the anticoagulant of choice in these patients, as it can be administered subcutaneously without the need for laboratory monitoring and subsequent dosage adaptations (1). However, despite such treatment, 5% to 15% of patients still develop myocardial infarction (MI) or die within the first weeks (2).
Fondaparinux is a new selective inhibitor of activated clotting factor X, a key enzyme in the coagulation pathway. It is a synthetic pentasaccharide that is structurally related to the antithrombin-binding site of heparin and LMWH. In contrast to heparins, which interact with several plasma components, fondaparinux selectively binds to antithrombin and causes rapid inhibition of activated factor X. It has a half-life of 15 h, with linear pharmacokinetics and low intra- and inter-individual variability, thus allowing once daily administration without laboratory monitoring (3,4). Recent studies in patients undergoing major orthopedic surgery have shown a significant reduction of venous thromboembolic events in fondaparinux-treated patients compared with those treated with LMWH (4–8). In patients with evolving MI treated with alteplase, fondaparinux yielded similar early coronary patency and a trend toward less reocclusion (p = 0.065), as compared with unfractionated heparin (9). Consequently, fondaparinux might also be an alternative to LMWH in the treatment of coronary syndromes without persistent ST-segment elevation. Hence, a dose-finding study was conducted in patients with such acute coronary syndromes, comparing four different dosages of fondaparinux with the LMWH enoxaparin.
Consecutive patients older than 21 years and weighing <120 kg with ACS without persistent ST-segment elevation were eligible for the study. Patients were required to have angina at rest or during minimal exertion, with the last episode within 24 h before enrollment and with dynamic ST-segment changes or ST-segment depression (≥0.1 mV) and/or cardiac troponin T or I concentrations above 0.1 ng/ml. Major exclusion criteria were ST-segment elevation requiring reperfusion therapy, an electrocardiographic (ECG) pattern making interpretation of ST-T changes unreliable, or the intention to proceed to percutaneous coronary intervention (PCI) within 24 h or coronary artery bypass graft surgery (CABG) within 48 h. Patients were also excluded if they had more than 12 h of therapeutic anticoagulant treatment, contraindications for anticoagulant treatment (e.g., bleeding tendency), uncontrolled hypertension, serum creatinine over 160 μmol/l, or platelet counts <100 × 109/l. All patients gave written, informed consent.
Patients were randomized to one of four fondaparinux dosages or enoxaparin in blocks of five through a central computerized service. Treatment was double-blind, using a double-dummy technique, and was administered for a minimum of three days and a maximum of seven days, to allow revascularization procedures or early patient discharge. A 12-lead continuous computer-assisted ECG monitoring system (Mortara Inc., Milwaukee, Wisconsin) was used during the first 24 to 48 h to detect (silent) myocardial ischemia (10,11). Efficacy and safety outcomes were reported for a period of 30 days. The primary efficacy evaluation was at day 9.
All potential study outcomes were reviewed by a central adjudication committee, and ECG recordings were analyzed by a central core laboratory. Both were blinded as to patient allocation. The Data and Safety Monitoring Board regularly reviewed the efficacy and safety outcomes. Discontinuation of a study arm was to be considered if the incidence of major bleeding was higher than could be expected, or when a significant difference in symptomatic recurrent ischemic events between the enoxaparin and any fondaparinux treatment group was observed. The study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization and Good Clinical Practice Guidelines, and was approved by the local institutional review boards.
Patients in the fondaparinux (Arixtra, NV Organon, Oss, the Netherlands; Sanofi-Synthélabo, Paris, France) groups received one of four dosages (2.5, 4, 8, or 12 mg) once daily subcutaneously, with the first dose given intravenously. Patients with a body weight <50 kg received lower dosages: 2, 3, 6, or 9 mg, and those heavier than 100 kg received 3, 5, 10, or 15 mg. The selection of the lowest dosage of 2.5 mg was based on the consideration that this dosage was effective as thromboprophylaxis in high-risk patients (4), whereas dosages of 4, 8, or 12 mg, as administered in the Synthetic Pentasaccharide as an Adjunct to Fibrinolysis in ST-Elevation Acute Myocardial Infarction (PENTALYSE) study (9), appeared equally effective. The latter suggested that the minimally effective dose of fondaparinux would be lower than 4 mg. The highest dosage of 12 mg was selected, because in studies of healthy volunteers, higher dosages showed a tendency toward hemorrhage at puncture sites. Patients in the enoxaparin (Clexane/Lovenox, Aventis Pharmaceuticals, Bridgewater, New York) group received 1 mg/kg twice daily subcutaneously, according to the manufacturer's instructions (12–14). To ensure double-blinding, fondaparinux-treated patients also received placebo-enoxaparin injections twice daily, and enoxaparin-treated patients received a placebo-fondaparinux injection once daily, with the first dose give intravenously (double-dummy method). In addition, all patients received 75 to 160 mg/day aspirin, preceded by a loading dose if indicated.
Study medication was stopped before any coronary interventional procedure. Heparin, glycoprotein IIb/IIIa blockers, ticlopidine, and clopidogrel during such intervention were allowed. Prohibited concomitant medications were oral anticoagulants, fibrinolytic agents, LMWH, and therapeutic doses of unfractionated heparin other than during interventions.
Efficacy end points
The primary efficacy end point was the composite of mortality, acute MI, or recurrent symptomatic or asymptomatic myocardial ischemia up to day 9. In order to distinguish between thrombotic events (possible lack of efficacy) and bleeding events (possible overdose), death related to bleeding was not included in the primary efficacy end point. Secondary efficacy end points were each of the components of the primary efficacy end point and revascularization procedures. In addition, the outcome in the treatment groups was analyzed at 30 days.
Myocardial infarction was defined as an elevation of creatine kinase-MB fraction (CK-MB) ≥2 times the upper limit of normal (≥3 times after PCI; ≥5 times after CABG) or new Q waves or new left bundle branch block. In addition, a more sensitive diagnosis of MI was applied, including any elevation of CK-MB above the upper limit of normal (15).
Recurrent ischemia was defined as at least 1 mm (0.1 mV) ST-segment depression for at least 1 min during continuous 12-lead ECG monitoring (10,11), chest pain in combination with at least 1 mm (0.1 mV) ST-segment depression or elevation (symptomatic episodes), or re-admission to the hospital due to unstable angina.
Safety end points
The primary safety end point was major bleeding up to day 9. Major bleeding included any overt bleeding associated with death, a life-threatening condition, (re)operation to manage bleeding (retroperitoneal, intracranial, or in another critical organ), or a drop in hemoglobin of more than 1.2 mmol/l (2.0 g/l) or requiring a transfusion of 2 U or more of whole blood or packed cells or other intervention. Overt bleeding episodes that did not qualify as major were considered a secondary safety end point (minor bleeding). Minor bleeding at subcutaneous injection sites was considered not clinically relevant and was not included in this safety end point.
Plasma concentrations of fondaparinux (mg/l) were determined in samples obtained at baseline, at 1 to 2 h after the dose on several days during treatment, and before dosing on day 3. Measurements were performed in a central laboratory by a validated assay based on the anti-Xa activity of the antithrombin III-fondaparinux complex. In this assay, the amount of hydrolysis of a chromogenic substrate, which is inversely proportional to the fondaparinux concentration, is determined after the addition of a known quantity of factor Xa, in the presence of an excess of antithrombin.
Based on an expected event rate for the primary efficacy end point of 36% in the highest dose group and 50% in the lowest dose group, it was estimated that the study would have a power of 80%, with one-sided type I error of 2.5%, to detect a positive dose-response relationship for fondaparinux if 190 evaluable patients per group were available (Cochran-Armitage trend test). To allow for missing primary outcome data, the sample size was set at 215 patients per group. The analysis was by the intention-to-treat principle for all randomized patients, regardless of whether they received any study drug or not. In addition, a per-protocol analysis was defined as the primary analysis for efficacy in order to select a dose for further studies with fondaparinux in ACS.
For the per-protocol analysis, the following exclusion criteria were prespecified: patients with incomplete administration of study treatment (missing one or more active injections during the first 3 days), use of prohibited concomitant medication, or inadequate continuous ECG monitoring (less than 12 h recording) in the absence of a symptomatic end point. The safety analysis was based on all patients who received study medication.
Incidences and their 95% confidence intervals were calculated for the primary efficacy and safety end points. Pairwise comparisons between treatment groups were performed using the Fisher exact test. The time to the first event was analyzed for the primary efficacy parameter using Kaplan-Meier analysis. Analyses for trend over dosages were performed using the Cochran-Mantel-Haenszel test or the Cochran-Armitage test for trend, as appropriate. When applicable, odds ratios and their 95% confidence intervals were calculated to estimate the impact of covariates. No corrections were made for multiple comparisons in this dose-finding study.
During the period of July 1999 to January 2001, a total of 1,138 patients were randomized (intention-to-treat population), of whom 929 had complete follow-up information, including adequate ST-segment monitoring and three days of treatment with study drug (per-protocol analysis). Four patients did not receive the allocated dose of fondaparinux or enoxaparin.
This report describes the efficacy and safety results for the intention-to-treat group (n = 1,138), as well as efficacy for the per-protocol analysis (n = 929). The baseline characteristics and outcome patterns were similar in the different analyses (Table 1): 47% of patients had dynamic ECG changes at baseline, 54% showed ST-segment depression, 41% had elevated cardiac troponin T (>0.1 ng/ml), 22% of patients (n = 252) had troponin T levels >0.3 ng/ml, and 20% had both elevated troponin (>0.1 ng/ml) and an abnormal ST-segment. At enrollment in the study, 58% of patients had already received aspirin, 42% had received unfractionated heparin or LMWH, and 5% had received lipid-lowering drugs. The fondaparinux and enoxaparin treatment groups were comparable regarding these characteristics. After randomization, all patients received aspirin and most patients received nitrates (95%) and beta-blockers (91%). Lipid-lowering drugs were given in 54%: angiotensin-converting enzyme inhibitors in 45%, calcium channel blockers in 40%, thienopyridines in 19%, and glycoprotein IIb/IIIa receptor blockers in 3.4% of patients. There were no significant differences in medication among the treatment groups.
Adequate ST-segment monitoring data were not available during at least 12 h in 71 patients who did not show symptomatic ischemia, MI, or death within nine days. Furthermore, 21 patients received pre-study medication that was not allowed, 110 patients received prohibited medication during the first nine days of the study, and 22 patients had one or more missed injections with active study drug during the first three days. As specified in the protocol of this dose-finding study, these patients were excluded from the per-protocol analysis.
The median duration of study treatment was five days (range three to eight days). Treatment was discontinued in 211 patients (178 patients in the per-protocol group) because of the occurrence of an end point (n = 19 [1.7%]), a serious adverse event (n = 6 [0.5%]), urgent coronary revascularization (n = 54 [4.7%]), unusual bleeding (n = 6 [0.5%]), withdrawal of consent (n = 4 [0.3%]), and other reasons, including planned coronary revascularization (n = 122 [10.7%]). Discontinuation of study treatment was similar among the treatment groups.
Mortality was low (1.1%), and no fatal bleedings occurred. Myocardial infarction was reported in 1.7%, using a threshold of CK-MB ≥2 times the upper limit of normal, and in 7.0%, using the more sensitive definition (including any CK-MB elevation) (15).
No dose response was observed among the fondaparinux dosage groups, neither in the intention-to-treat analysis nor in the per-protocol analysis (test for trend: p = 0.70 and p = 0.40, respectively). The lowest event rate in the per-protocol analysis was observed in the 2.5 mg fondaparinux groups, which had a significantly lower rate than that in the 4 or 8 mg fondaparinux and enoxaparin groups (Fig. 1). The most frequent event was recurrent ischemia, as detected by continuous 12-lead ECG monitoring. In the intention-to-treat analysis, the same pattern was apparent, but the differences were not statistically significant. Differences in combined events (death, MI, and recurrent ischemia), as observed among the treatment groups, were already apparent during the first three days and sustained throughout the 30-day study period (Fig. 2). These differences were mainly due to a lower rate of recurrent ischemia. There were no significant differences in death or death and MI at 9 or 30 days (Table 2). At 30-day follow-up, mortality rates (intention to treat) were 1.3%, 3.2%, 1.3%, 2.6%, and 1.4%, respectively, for 2.5, 4, 8, and 12 mg fondaparinux and enoxaparin. Per protocol, these figures were 1.5%, 3.9%, 0.6%, 3.2%, and 1.6%, respectively. For the combined end point of death, MI, and recurrent ischemia, the 30-day outcomes were 32.3%, 38.2%, 36.0%, 33.8%, and 38.7% (intention to treat) versus 33.8%, 44.9%, 42.4%, 37.8%, and 43.6% (per protocol), respectively.
In-hospital revascularization procedures were performed in 18% (PCI) and 3% (CABG) of patients (Table 2). Again, no dose response was observed among the fondaparinux treatment groups. One patient died five days after PCI; the other deaths up to day 9 occurred in patients not undergoing revascularization. Two MIs were reported within 24 h of PCI, six occurred before PCI or CABG, and nine in patients not undergoing revascularization. No relationship was observed between the timing of these events and the study drug.
The incidence of major and minor bleeding episodes is shown in Table 3. Bleeding rates were low, and no significant differences between the treatment groups were observed. No major bleeding episodes occurred in patients receiving 2.5 mg fondaparinux or enoxaparin.
A dose-dependent increase was observed in both the predose and post-dose fondaparinux plasma concentrations determined on day 3 of treatment. The mean post-dose concentrations were 0.41, 0.65, 1.15, and 1.61 mg/l for patients receiving 2.5, 4, 8, and 12 mg fondaparinux, respectively. Within each dosage group, the fondaparinux plasma concentrations in patients with a primary end point were similar to those of patients without death, MI, or recurrent ischemia. Similarly, no significant differences were observed in fondaparinux plasma concentrations between patients with and those without bleeding. As expected, there was considerable overlap in plasma concentrations among the four dosage groups. When patients were regrouped according to the post-dose plasma concentration at day 3, the lowest rates of death, MI, or recurrent ischemia were observed for patients with plasma concentrations in the lowest range, whereas no correlation with plasma concentration was observed for bleeding events.
The Pentasaccharide in Unstable Angina study (PENTUA) dose-finding study showed no dose response among the four doses of fondaparinux and suggests overall similar efficacy and safety with the synthetic pentasaccharide fondaparinux and enoxaparin for management of patients admitted with ACS without persistent ST-segment elevation. No major bleeding events were observed in patients receiving 2.5 mg/day fondaparinux or enoxaparin. The absence of a dose response among the four doses of fondaparinux was consistent for different end points, including death, MI, symptomatic recurrent ischemia, any recurrent ischemia, and revascularization.
The lowest event rate (death, MI, and recurrent ischemia) at day 9, as well as day 30, was observed in patients receiving 2.5 mg fondaparinux, which, in the per-protocol analysis at day 9, was significantly lower than that with enoxaparin (Fig. 1). However, there is no known physiologic argument to explain why a lower dose of fondaparinux (2.5 mg) would be more effective than higher dosages (4 to 12 mg). Accordingly, the apparent differences among the four dose groups may be a play of chance, and further studies are required to assess whether fondaparinux given as 2.5 mg/day, or even lower doses, will be as effective as, or perhaps superior to, the usual regimen of enoxaparin in patients with ACS.
Assessment of the optimal dose regimen is a major challenge in drug development. In patients with ACS, effective therapies have been established, including aspirin, heparin (16,17), LMWH (12,13,18,19), and, more recently, clopidogrel (20). Accordingly, we considered it unethical to include a true placebo group in the present study, and we selected a lowest dose of fondaparinux, which, based on other studies, was likely to be effective.
Different dosages of fondaparinux, ranging from 0.75 to 8.0 mg, were tested for prevention of deep vein thrombosis after total hip replacement (4). In that study, a clear dose response was observed, with low event rates for doses between 3.0 and 8.0 mg/day and higher event rates for 0.75 and 1.5 mg/day fondaparinux. Furthermore, there was a gradual increase in major bleeding complications at increasing dosages of fondaparinux (4). Based on these findings, a dose of 2.5 mg/day fondaparinux was subsequently tested in four studies for prevention of venous thromboembolism after different types of orthopedic surgery (5–8). Taken together, these studies in more than 7,000 patients consistently showed a 55% relative risk reduction for venous thromboembolic events (odds ratio 0.45, 95% confidence interval 0.37 to 0.54) (21). In the present study, the same dose (2.5 mg) of fondaparinux appeared to have similar or slightly better efficacy as enoxaparin for the treatment of ACS without persistent ST-segment elevation.
In the PENTALYSE study, fondaparinux was given as an adjunct to fibrinolytic therapy with alteplase (9). Doses of 4, 8, and 12 mg fondaparinux resulted in similar angiographic patency as alteplase with standard unfractionated heparin for 48 to 72 h. No dose response was observed among these fondaparinux doses, as in the present study.
Surprisingly, little difference was observed for major and minor bleeding complications among the doses tested, and fondaparinux plasma concentrations were similar in patients with and without bleeding, suggesting that fondaparinux will be relatively safe at doses up to 12 mg/day.
The absence of a dose response between 2.5 and 12 mg fondaparinux in PENTUA, as well as similar findings for 4, 8, and 12 mg fondaparinux in PENTALYSE (9), suggests that all doses were at the flat part at the top of the dose-response curve for this compound. Therefore, it may be argued that the optimal dose of fondaparinux in ACS might be <2.5 mg. However, when the PENTUA study was designed, it was argued by some physicians that the 2.5 mg dose was already too low to be investigated (22). The assumption was made that treatment of arterial thrombosis (as in ACS) would require a higher dose than prevention of venous thrombosis (as in orthopedic surgery). There are, however, sparse data to support this notion. The dosage of enoxaparin, as registered for treatment of ACS (1 mg/kg twice daily) is about three to five times higher than the dose used for prevention of venous thromboembolism after orthopedic surgery (40 mg/day or 30 mg twice daily). However, the dose-finding information on enoxaparin in ACS is limited to one study in 630 patients with ACS (12). Based on these findings, the dose of 1 mg/kg twice daily was chosen for subsequent phase III studies and shown to be more effective to prevent death, MI, and recurrent ischemia, as compared with unfractionated heparin infusion (13,14). Larger studies with lower doses of enoxaparin, similar to those used in orthopedic surgery, have not been conducted; thus, it remains uncertain whether lower doses might be equally effective. In view of its observed efficacy to prevent deep vein thrombosis (4), we decided to include 2.5 mg fondaparinux as the lowest dose in the PENTUA study.
Recurrent ischemia, MI, and death
In this study, as in other studies (13,14,20,23), the most frequent end point was recurrent ischemia, whereas MI and death were relatively infrequent. A specific feature of the PENTUA study is the use of 24-h continuous 12-lead ECG recording to detect myocardial ischemia. The incidence of symptomatic and silent ischemia detected in this manner varied from 30% to 42% among the treatment groups within the first nine days. As in other studies, approximately half of the ischemic episodes were silent (11). We required adequate recording of a continuous 12-lead ECG for the per-protocol analysis in the present study, because it provides more consistent assessment of recurrent ischemia than recurrent chest pain. In earlier studies, we demonstrated a strong relationship between recurrent ischemia and the risk of subsequent MI (11). Thus, an end point of recurrent ischemia in a phase II dose-finding study is an appropriate choice, while it has also been chosen as part of the primary end point in larger phase III studies (2,13,14).
At 30 days, the end point of death or MI varied between 2.9% and 6.2%, which is lower than that in some previous studies in patients with ACS (2,23–25), but similar to the recent findings in the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study (20). As expected, event rates were higher when the new, more sensitive European Society of Cardiology/American College of Cardiology consensus definition for MI was applied (15). The relatively low event rates in the PENTUA study (as in CURE study) are most likely related to the selection of patients for whom at enrollment the physician decided that early revascularization would not be necessary. Nevertheless, it should be appreciated that the rate of revascularization at 30 days was relatively high, ranging from 31% to 43% among the different patient groups. This figure is similar to other recent studies in patients with ACS (2,20,24,25).
The apparent lower event rate with 2.5 mg fondaparinux was mainly due to a lower rate of recurrent ischemia. Differences in death and MI among the five treatment groups were small and probably due to chance. For example, when comparing 2.5 mg fondaparinux and enoxaparin, the end point of death and/or MI was slightly lower in the former group, using a threshold of CK-MB exceeding two times the upper limit of normal, and higher using a more sensitive threshold (Table 2). Similar nonsignificant differences were observed at 30-day follow-up (data not shown). Yet, it should be appreciated that small, statistically not significant differences in phase II studies may relate to unfavorable outcomes in larger phase III studies (26). Careful monitoring in subsequent studies with fondaparinux in ACS will be appropriate, particularly in view of the slightly higher mortality in patients receiving fondaparinux.
It should be appreciated that this was a phase II study designed to determine the dose for future studies with fondaparinux in patients with ACS. Thus, no definite conclusions about the relative benefit of fondaparinux versus enoxaparin can be drawn. Other limitations include the missing data for ECG monitoring and use of medications not allowed in the protocol in some of the patients. Multiple comparisons were made using different end points on an intention-to-treat as well as per-protocol analysis. Thus, the statistically significant findings may be due to chance. However, it is not likely that these limitations have had a significant impact on the outcome of the study, as the absence of a dose-response relationship was apparent both in the intention-to-treat and per-protocol analyses, whereas lower event rates at nine days in patients allocated to 2.5 mg fondaparinux were consistently observed in different analyses at days 9 and 30.
This phase II dose-finding study indicates that fondaparinux in dosages between 2.5 and 12 mg/day may have similar efficacy as enoxaparin to prevent early recurrent ischemia, MI, or death in patients with ACS not undergoing early revascularization (<48 h). Bleeding complications were infrequent. These encouraging results should be a basis for subsequent phase III studies with fondaparinux in patients with ACS, including patients who will undergo early coronary revascularization. In such studies, a 2.5 mg/day fondaparinux regimen should be investigated in combination with aspirin, clopidogrel, and glycoprotein IIb/IIIa receptor blockers, as currently recommended (1).
- acute coronary syndromes
- coronary artery bypass graft surgery
- creatine kinase-MB fraction
- low-molecular-weight heparin
- myocardial infarction
- percutaneous coronary intervention
- Pentasaccharide in Unstable Angina study
- Received March 12, 2003.
- Revision received February 20, 2004.
- Accepted February 24, 2004.
- American College of Cardiology Foundation
- Bertrand M.E.,
- Simoons M.L.,
- Fox K.A.A.,
- et al.
- Boersma E.,
- Harrington R.A.,
- Moliterno D.J.,
- et al.
- Bauer K.A.
- PENTATHLON 2000 Study Steering Committee,
- Turpie A.G.G.,
- Bauer K.A.,
- Eriksson B.I.,
- et al.
- European Pentasaccharide Hip Elective Surgery Study (EPHESUS) Steering Committee,
- Lassen M.L.,
- Bauer K.A.,
- Eriksson B.I.,
- et al.
- Coussement P.K.,
- Bassand J.P.,
- Convens C.,
- et al.
- Klootwijk P.,
- Meij S.,
- Melkert R.,
- et al.
- Akkerhuis K.M.,
- Klootwijk P.A.,
- Lindeboom W.,
- et al.
- The Thrombolysis In Myocardial Infarction (TIMI) 11A Trial Investigators
- Antman E.M.,
- McGabe C.H.,
- Gurfunkil E.P.,
- et al.
- The Joint European Society of Cardiology/American College of Cardiology Committee
- Sheldon T.
- The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRIMS-PLUS) Study Investigators
- Leebeek F.W.G.,
- Boersma E.,
- Cannon C.P.,
- van de Werf F.J.,
- Simoons M.L.