Antithrombotic Therapy With Fondaparinux in Relation to Interventional Management Strategy in Patients With ST- and Non–ST-Segment Elevation Acute Coronary Syndromes
An Individual Patient–Level Combined Analysis of the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) Randomized Trials
Background— The Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) trials evaluated fondaparinux, a synthetic factor Xa inhibitor, in patients with non–ST- and ST-segment elevation acute coronary syndromes, respectively. Combined results for these 2 trials on major efficacy and safety outcomes and data on the effects of fondaparinux in relation to interventional management strategy have not been previously reported.
Methods and Results— We performed an individual patient–level combined analysis of 26 512 patients from the OASIS 5 and 6 trials who were randomized in a double-blind fashion to fondaparinux 2.5 mg daily or a heparin-based strategy (dose-adjusted unfractionated heparin or enoxaparin). Results were stratified according to whether an early invasive, a delayed invasive, or an initial conservative management strategy was performed. Fondaparinux was superior to heparin in reducing the composite of death, myocardial infarction, or stroke (8.0% versus 7.2%; hazard ratio [HR], 0.91; P=0.03) and death alone (4.3% versus 3.8%; HR, 0.89; P=0.05). Fondaparinux reduced major bleeding by 41% (3.4% versus 2.1%; HR, 0.59; P<0.00001) and had a more favorable net clinical outcome than heparin (11.1% versus 9.3%; HR, 0.83; P<0.0001). In 19 085 patients treated with an invasive strategy, fondaparinux suppressed ischemic events to an extent similar to heparin and reduced major bleeding by more than one-half, resulting in a superior net clinical outcome (10.8% versus 9.4%; HR, 0.87; P=0.008). A similar benefit also was observed in those treated with a conservative strategy (HR, 0.74; 95% confidence interval, 0.64 to 0.85; P<0.001).
Conclusion— Compared with a heparin-based strategy, fondaparinux reduced mortality, ischemic events, and major bleeding across the full spectrum of acute coronary syndromes and was associated with a more favorable net clinical outcome in patients undergoing either an invasive or a conservative management strategy.
Received April 30, 2008; accepted August 29, 2008.
Plaque rupture with total or subtotal thrombotic occlusion of a coronary artery is common to the pathophysiology of both ST-segment elevation myocardial infarction (STEMI) and non–ST-segment elevation acute coronary syndromes (ACS).1 Unfractionated heparin (UFH) or low–molecular-weight heparin reduces nonfatal outcomes in both conditions, but at the cost of an increase in major bleeding complications and no reduction in mortality.2–5 A need exists for newer antithrombin agents that are safer than the heparins and that likewise reduce mortality across the spectrum of ACS. Fondaparinux is a synthetic inhibitor of coagulation factor X that was recently evaluated in patients with ACS and STEMI in the Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) trials.6,7 Patients undergoing an invasive management strategy or a conservative management strategy were eligible for both of these trials.
Clinical Perspective p 2046
An invasive strategy is associated with improved long-term clinical outcomes in higher-risk patients.8 The recent update to the American College of Cardiology and American Heart Association unstable angina/non-STEMI guidelines indicates that it may not be appropriate to treat all patients with this approach, particularly those with low baseline risk.9 Contemporary registry studies have demonstrated that, paradoxically, lower-risk patients are more likely to be referred for an invasive strategy compared with higher-risk patients.10,11 Because it is often not known which strategy a given patient will be treated with at the time of diagnosis, it is important that initial antithrombotic therapies be effective and safe in patients treated with either an invasive or a conservative management strategy. Thus, the goal of this analysis was to determine first the efficacy, safety, and net clinical benefit of fondaparinux compared with either UFH or enoxaparin across the spectrum of patients with ACS and second its net clinical benefit according to invasive or conservative management strategies. To accomplish this goal, we harmonized the outcomes in the OASIS 5 and 6 trials and performed an individual patient-level combined analysis of these 2 trials.
Design of OASIS 5
Details of the design and primary results of the OASIS 5 trial have been published previously.6,12 OASIS 5 was a randomized, double-blind, double-dummy trial comparing fondaparinux 2.5 mg once daily and enoxaparin 1 mg/kg twice daily (once daily for those with creatinine clearance <30 mL/min) in patients with ACS without ST-segment elevation. Patients were eligible for the study if they presented to hospital within 24 hours of symptom onset and had at least 2 of the following 3 criteria: age >60 years, ST-segment deviation, or elevated cardiac markers. Management strategy was at the discretion of the treating physician. Randomized study treatment was given for up to 8 days, with a median treatment overall of 5 days and only 2 days in those undergoing percutaneous coronary intervention (PCI). Patients were excluded from the trial if they had contraindications to low-molecular-weight heparin or if they had a creatinine of >3 mg/dL (265 μmol/L). The study was designed as a noninferiority trial with the primary outcome of death, MI, or refractory ischemia at day 9. The secondary outcomes included individual components of the primary efficacy outcome at 30 days and 6 months. The primary safety outcome was major bleeding.
Design of OASIS 6
The OASIS 6 trial was a randomized, double-blind, double-dummy comparison of fondaparinux and standard care in patients with acute STEMI.7 Patients were eligible for the study if they presented within 24 hours of symptom onset and had at least 2 mm of ST-segment elevation in the precordial leads or 1 mm of ST-segment elevation in 2 contiguous limb leads. Decisions about reperfusion therapy (ie, fibrinolytic therapy, primary PCI, or no reperfusion therapy, eg, in patients presenting late to hospital) were made by the attending physician according to local practice. The choice of the comparator agent also was at the discretion of the attending physician and may have included UFH (eg, in those patients receiving a fibrin-specific thrombolytic agent or in those patients treated with primary PCI) or placebo (eg, in those patients treated with a non–fibrin-specific thrombolytic agent). Randomized study treatment was given for up to 8 days. The primary outcome was the composite of death or MI at 30 days; the secondary outcomes included individual components of the primary efficacy outcome. The primary safety outcome was major bleeding (“severe hemorrhage”).
For efficacy, we evaluated the composite of death, MI, or stroke; for safety, we evaluated major bleeding at 30 days. The net clinical outcome was the composite of death, MI, stroke, or major bleeding at 30 days; this outcome was used to evaluate subgroups according to antithrombin therapy.
In the OASIS 5 trial, major bleeding was defined as clinically overt bleeding that was fatal (bleeding reported to cause death), symptomatic intracranial hemorrhage, retroperitoneal hemorrhage, intraocular hemorrhage leading to significant vision loss, a decrease in hemoglobin of at least 3.0 g/dL (with each blood transfusion unit counting for 1.0 g/dL hemoglobin), or bleeding requiring transfusion of ≥2 units of red blood cells or the equivalent of whole blood.6,12 In the OASIS 6 trial, the primary safety outcome was Thrombolysis in Myocardial Infarction major bleeding.7 However, to allow comparison with the OASIS 5 trial, major bleeding also was prospectively classified using the OASIS 5 criteria, and we have used the OASIS 5 major bleeding classification to pool the bleeding results of the 2 trials. The definitions used for MI and stroke in our analysis are the same as those used in the individual trials.6,7,12
An intention-to-treat analysis was used for all comparisons. To evaluate the effects of fondaparinux compared with a heparin-based strategy (UFH or enoxaparin), individual patient–level data from OASIS 5 were combined with individual patient–level data from OASIS 6 stratum 2 (in which UFH was the comparator agent). Patients enrolled in stratum 1 of OASIS 6 (ie, fondaparinux versus placebo) were excluded from this analysis. Baseline characteristics were summarized according to treatment allocation (fondaparinux or heparin). The treatment groups were compared by use of a log-rank test, with each study treated as a stratum. A stratified evaluation of the effects of fondaparinux compared with heparin (UFH or enoxaparin) by management strategy was undertaken as follows: any invasive management strategy, early invasive management strategy (with or without primary PCI included), delayed invasive management strategy, and conservative strategy (no heart catheterization during the initial hospitalization). All analyses were performed with SAS version 9.1 (SAS Institute, Inc, Cary, NC).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Baseline Characteristics, Cointerventions, and In-Hospital Medications
Overall, 26 512 patients were included in this analysis: 13 242 randomized to receive UFH or enoxaparin (the heparin group) and 13 270 to fondaparinux. Patient baseline characteristics, concomitant interventions, and in-hospital medications in the heparin and fondaparinux groups are presented in Table 1. The mean ages of patients were 65.4 and 65.5 years, respectively. Approximately two thirds of patients were male and one third were female. The diagnosis at study entry was unstable angina in 28.1% of control patients and 28.5% of fondaparinux patients, non-STEMI in 34.2% and 34.0%, respectively, and STEMI in 37.7% and 37.9%, respectively. The proportions of patients with prior revascularization, heart failure, hypertension, and diabetes mellitus were well matched between the 2 groups.
Overall, 19 085 patients (72%) underwent an invasive strategy, 13 250 (50%) within 72 hours of randomization. A total of 7427 patients (28%) were treated conservatively, with no heart catheterization during the initial hospitalization.
More than 97% of patients in each treatment group received aspirin, and more than two thirds in each group also received a thienopyridine. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were used in >70% of patients, β-blockers in >86% of patients, and statins in >78%.
Overall Efficacy and Safety Outcomes
At 30 days, 8.0% of patients in the heparin group experienced a death, MI, or stroke compared with 7.2% of patients in the fondaparinux group (hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.83 to 0.99; P=0.03; Table 2 and Figure 1A). Fondaparinux also reduced all-cause mortality compared with heparin (4.3% versus 3.8%; HR, 0.89; 95% CI, 0.79 to 1.00; P=0.05; Figure 1B), and consistent reductions were seen in both MI and stroke (Table 2). These benefits were maintained at the 6-month follow-up (Table 2).
For safety, a significant reduction was found in major bleeding with fondaparinux compared with heparin (3.7% versus 2.2%; HR, 0.58; 95% CI, 0.50 to 0.68; P<0.00001; Table 2). Importantly, fatal bleeding (ie, bleeding resulting in death of the patient) was significantly lower with fondaparinux compared with heparin (40 fatal bleeds versus 24; HR, 0.60; 95% CI, 0.39 to 0.99; P=0.04). Fondaparinux also reduced the proportion of patients with hemoglobin drops of ≥3 g/dL (406 versus 255; HR, 0.63; P<0.001), those requiring >2 units of red blood cell transfusion (382 versus 277; HR, 0.62; P<0.001), and those requiring surgical intervention to stop the bleeding (82 versus 49; HR, 0.60; P<0.004; Table 2).
Results According to Management Strategy
Invasive Management Strategy
In the 19 085 patients undergoing an invasive management strategy, the net clinical outcome of death, MI, stroke, or major bleeding occurred in 10.8% of patients in the heparin group compared with 9.4% in the fondaparinux group (HR, 0.86; 95% CI, 0.79 to 0.94; P=0.001; Table 3). This benefit was due mainly to a reduction in major bleeding in favor of fondaparinux (5.0% versus 3.5%; HR, 0.70; 95% CI, 0.61 to 0.81; P<0.0001) with similar rates of ischemic events (7.0% versus 6.8%; HR, 0.97; 95% CI, 0.87 to 1.08; P=0.63) in the randomized treatment groups. In those patients undergoing an early invasive management strategy (ie, within 72 hours of randomization), a 13% reduction occurred in the net clinical benefit outcome (11.3% versus 9.9%; HR, 0.87; 95% CI, 0.78 to 0.96; P<0.0001; Table 3 and Figure 2). When patients undergoing primary PCI for STEMI were excluded from this group, the net benefit favoring fondaparinux was even more marked compared with heparin, with a 22% relative risk reduction in the net clinical outcome (13.1% versus 10.3%; 95% CI, 0.69 to 0.88; P<0.0001, P<0.001; Table 3 and Figure 2).
Conservative Management Strategy
In the 7427 patients treated conservatively during the initial hospitalization (ie, no heart catheterization), fondaparinux was superior to a heparin in reducing the net clinical composite of death, MI, stroke, or major bleeding (12.0% versus 9.0%; HR, 0.74; 95% CI, 0.64 to 0.85; P<0.0001; Table 3 and Figure 2). Death, MI, or stroke was significantly reduced with fondaparinux compared with heparin (10.5% versus 8.4%; HR, 0.69 to 0.92; P=0.003), as was major bleeding (3.0% versus 1.6%; HR, 0.53; 95% CI, 0.38 to 0.73; P=0.0001). In terms of the net clinical outcome, no significant heterogeneity in the effects of fondaparinux was found in patients undergoing an invasive or a conservative strategy.
Patients Undergoing PCI
In the subgroup of patients treated with PCI for non–ST-segment elevation ACS or rescue, routine, or facilitated PCI for STEMI, the net clinical outcome significantly favored fondaparinux compared with any heparin-based comparator (12.2% versus 10.0%; HR, 0.81; 95% CI, 0.70 to 0.94; P<0.01; Table 4). The benefit was due primarily to a reduction in major bleeding, with similar rates of ischemic events between groups. Analysis in which fondaparinux was compared separately with enoxaparin or with UFH gave similar and consistent results regardless of agent (Table 4).
Catheter-related thrombus occurred in 0.89% of patients receiving fondaparinux versus 0.22% receiving any heparin (HR, 3.98; 95% CI, 1.74 to 9.09; Table 4). In OASIS 5, mortality was not significantly different in those who had catheter thrombus compared with those who did not (2.7% catheter thrombus versus 2.1% no catheter thrombus; relative risk, 1.31; 95% CI, 0.19 to 9.17), but higher rates of MI (27% versus 4.2%; relative risk, 6.51; 95% CI, 3.78 to 11.20) and stroke (5.4% versus 0.6%; relative risk, 9.48; 95% CI, 2.37 to 38.0) were found at 30 days in those who had catheter thrombus. Despite this finding, no difference was found in the composite of death, MI, or stroke between groups (7.9% heparin versus 7.9% fondaparinux; Table 4). Open-label UFH was given before the PCI procedure in 306 of 3298 patients receiving enoxaparin/UFH and 306 of 3336 patients receiving fondaparinux. Open-label UFH seemed to reduce the risk of catheter thrombus in patients undergoing PCI with either fondaparinux alone (only 1 case was reported with very-low-dose open-label UFH, 500 IU/kg) or enoxaparin (no cases of catheter thrombus when UFH was used before PCI). In OASIS 6, no cases of catheter thrombus were reported in either group undergoing nonprimary PCI, for whom UFH was recommended by protocol for PCI anticoagulation.
In patients receiving open-label UFH before PCI, major bleeding occurred in 5.3% in the heparin group compared with 3.7% in the fondaparinux group (HR, 0.70; 95% CI, 0.32 to 1.51), which is consistent with the bleeding reduction in those patients not receiving open-label UFH before PCI (HR, 0.53; 95% CI, 0.41 to 0.68; P for heterogeneity=0.497).
The net clinical outcome was consistently superior with fondaparinux compared with heparin in multiple predefined subgroups (Figure 3). These subgroups included patients ≥65 and those <65 years of age, men and women, patients with diabetes and those without diabetes, patients with prior stroke and no prior stroke, and those with creatinine clearance greater than and less than the median. Importantly, fondaparinux demonstrated superior net clinical benefit compared with heparin in those patients concurrently treated with thienopyridines and glycoprotein IIb/IIIa antagonists. A consistent benefit of fondaparinux was also found in patients receiving other evidence-based treatments, including statins, blockers of the renin-angiotensin system, and β-blockers.
This analysis demonstrates that in patients treated with an invasive management strategy, fondaparinux resulted in a significantly improved net clinical outcome compared with heparin. Similarly, in patients treated with a conservative strategy, fondaparinux had a more favorable net clinical outcome compared with heparin. The benefit of fondaparinux versus a heparin-based strategy in patients managed invasively and those managed conservatively underscores the wide therapeutic potential of this agent.
Data from this analysis suggest that the use of fondaparinux instead of a heparin-based strategy in a broad range of ACS patients would be expected to save 5 lives and 3 additional MIs or strokes in every 1000 patients treated. This benefit is clinically worthwhile, considering that use of fondaparinux in place of a heparin also prevents 10 major bleeding events per 1000 patients treated. This efficacy-to-safety profile is truly unique among anticoagulants and has not been consistently observed with UFH or low-molecular-weight heparin. Bivalirudin reduces bleeding and improves net clinical benefit compared with UFH and a glycoprotein IIb/IIIa antagonist,13 but few contemporary data exist in patients with ACS or STEMI demonstrating a lower rate of bleeding in direct comparison with heparin given in conventional doses.
The net clinical benefit of fondaparinux was observed consistently in those undergoing both an early invasive and a delayed invasive management strategy and was due primarily to a reduction in major bleeding. These benefits were even more marked after the exclusion of patients referred for primary PCI for STEMI, for whom data from the OASIS 6 trial demonstrated no tangible benefit of fondaparinux over heparin.7 For all other patients receiving an invasive strategy, it appears that fondaparinux is at least as good an option, if not a better one, than either unfractionated or low-molecular-weight heparin. These data support the recent American College of Cardiology/American Heart Association and European Society of Cardiology guidelines for management of unstable angina and non-STEMI, in which fondaparinux is cited as a class I recommendation for either an invasive or a conservative management strategy.9,14
Importantly, the net clinical outcome was consistent with fondaparinux regardless of whether it was coadministered with other effective antithrombotic drugs (including thienopyridines and glycoprotein IIb/IIIa antagonists) and other therapies such as statins and blockers of the rennin-angiotensin system. Among patients undergoing PCI for ACS without ST-segment elevation and rescue, routine, or facilitated PCI for STEMI, fondaparinux reduced bleeding with similar rates of death, MI, or stroke compared with heparin. The small absolute excess in catheter thrombus when fondaparinux was used as the sole anticoagulant (≈7 per 1000 patients) did not seem to translate into an increase in clinical ischemic events between groups. This finding suggests that the reduction in bleeding with fondaparinux may have offset any increase in the risk of major events related to catheter thrombus. Furthermore, the risk of catheter thrombus was essentially eliminated when adjunctive UFH (50 to 60 IU/kg) was administered in the catheterization laboratory immediately before the PCI procedure. Thus, it is recommended that adjunctive UFH be given if a PCI procedure is performed in patients receiving upstream fondaparinux.9,14,15
The strengths of our study are that we analyzed a very large data set of >26 500 patients among whom were reported >2000 primary efficacy outcomes and almost 1000 major bleeds. This allowed us to obtain robust estimates of the benefits and risks of fondaparinux in the overall study population, according to interventional management strategy, and in key subgroups. We used the same definition of ischemic and bleeding events to pool the results from both trials, and no heterogeneity was found in the results. Our study provides robust outcome data on >19 085 patients undergoing an invasive management strategy and 7427 patients undergoing an initial conservative strategy. Therefore, it reflects a broad spectrum of patients with ACS that can be generalized to real-world clinical practice.
Although the use of UFH in a dose of 50 to 60 IU/kg for PCI in fondaparinux-treated patients appears to be safe and effective, a limitation of our data is that the number of patients treated with this approach remains relatively modest. The protocol amendment to allow the routine use of UFH before PCI was not instituted until ≈60% of the patients had been randomized into OASIS 5. In the OASIS 6 trial, UFH was recommended by protocol for PCI anticoagulation in those undergoing nonprimary PCI, and no cases of catheter thrombus were seen in either group, but the number of patients is modest. Future trials are therefore needed to identify the optimal dose of UFH to be used in fondaparinux-treated patients. The Fondaparinux Trial With UFH During Revascularization in Acute Coronary Syndromes (FUTURA) OASIS 8 trial will randomize 2000 fondaparinux-treated ACS patients undergoing PCI to receive 2 doses of UFH (standard, activated clotting time guideline–recommended doses versus empirical low-dose UFH).
The results of our study have important implications for clinical practice. More than 1.5 million patients in North America are admitted to hospital each year with ACS with or without persistent ST-segment elevation on the presenting ECG, the great majority of whom receive antithrombin therapies, most commonly UFH or low-molecular-weight heparin. Extrapolation from registry and randomized trial data suggests that ≈50 000 individuals experience major bleeding and perhaps as many as 150 000 receive a blood transfusion each year in North America16 at a cost of at least $5000 per bleed.17 A halving of the risk of bleeding achieved by switching to the routine use of fondaparinux in place of enoxaparin or UFH would translate into a savings of $100 million each year in North America alone and many millions more worldwide. These savings do not include the reduced acquisition costs of fondaparinux compared with enoxaparin in most regions of the world. Even more important for patients, however, is the reduction in death and nonfatal ischemic events that can be expected with fondaparinux use in a broad range of patients with ACS.
The OASIS 5 and 6 trials were sponsored by Sanofi-Synthelabo Reserche, Organon NV, and GlaxoSmithKline. The studies were conducted independently of the sponsors at the Population Health Research Institute, McMaster University, and were overseen by an international steering committee of academic physicians and experts in the field. The sponsors had no role in the analysis or content of this manuscript. Drs Mehta, Boden, Eikelboom, Flather, Steg, Avezum, Piegas, Faxon, Widimsky, Budaj, Rupprecht, Jolly, Granger, Fox, Bassand, and Yusuf have received honoraria and/or research grants from GlaxoSmithKline and Sanofi-Aventis. The other authors report no conflicts.
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The Fifth and Sixth Organization to Assess Strategies in Ischemic Syndromes (OASIS 5 and 6) trials evaluated fondaparinux, a synthetic factor Xa inhibitor, in patients with non–ST- and ST-segment elevation acute coronary syndromes, respectively. Combined results for these 2 trials on major efficacy and safety outcomes and data on the effects of fondaparinux in relation to interventional management strategy have not been previously reported. This report describes an individual patient–level combined analysis of 26 512 patients from the OASIS 5 and 6 trials who were randomized in a double-blind fashion to fondaparinux 2.5 mg daily or a heparin-based strategy (dose-adjusted unfractionated heparin or enoxaparin). The results were then stratified according to whether an early invasive, a delayed invasive, or an initial conservative management strategy was performed. Fondaparinux was found to be superior to heparin in reducing the composite of death, myocardial infarction, or stroke (8.0% versus 7.2%; hazard ratio [HR], 0.91; P=0.03) and death alone (4.3% versus 3.8%; HR, 0.89; P=0.05). Fondaparinux also was safer; it reduced major bleeding by 41% (3.4% versus 2.1%; HR, 0.59; P<0.00001) and had a more favorable net clinical outcome than heparin (11.1% versus 9.3%; HR, 0.83; P<0.0001). In 19 085 patients treated with an invasive strategy, fondaparinux suppressed ischemic events to an extent similar to heparin and reduced major bleeding by more than one-half, resulting in a superior net clinical outcome (10.8% versus 9.4%; HR, 0.87; P=0.008). A similar benefit also was observed in those treated with a conservative strategy (HR, 0.74; 95% confidence interval, 0.64 to 0.85; P<0.001). Therefore, compared with a heparin-based strategy, fondaparinux reduces mortality, ischemic events, and major bleeding across the full spectrum of acute coronary syndromes and is associated with a more favorable net clinical outcome in patients undergoing either an invasive or a conservative management strategy. These data underscore the wide therapeutic potential of fondaparinux in patients with acute coronary syndromes.
Guest Editor for this article was Gianni Tognoni, MD.
Clinical trial registration information—URL: www.clinicaltrials.gov. Unique identifiers NCT0013915 and NCT00064428.