OASIS-6: Sixth Organization to Assess Strategies in Acute Ischemic Syndromes -- Effects of Fondaparinux in STEMI Patients

Luis Gruberg, MD, FACC

Disclosures

July 20, 2006

Editorial Collaboration

Medscape &

"...these are important results that may improve the outcomes of STEMI patients, especially those who do not undergo primary PCI as a reperfusion strategy."

Presenters: Salim Yusuf, MD, DPhil, and Shamir R. Mehta, MD (McMaster University, Hamilton, Ontario, Canada)

Cardiovascular disease continues to be the leading cause of death worldwide, and 40% to 50% of these deaths are due to acute myocardial infarction (AMI). Thrombolytic therapy in conjunction with antithrombotic therapy, such as unfractionated heparin (UFH) and low-molecular-weight heparin and direct thrombin inhibitors, continues to be the mainstay of treatment for AMI. However, all of these therapies are associated with an increased risk of bleeding complications, including intracranial hemorrhage.

An alternative to these therapies is fondaparinux, a synthetic pentasaccharide that selectively binds antithrombin and rapidly inhibits factor Xa without interfering with other clotting factors. The drug is administered once daily in a fixed dose (2.5 mg) and does not require monitoring. Prior studies have demonstrated that fondaparinux is superior to enoxaparin for the prevention of venous thromboembolism and has also been shown to reduce the risk of severe and fatal bleeding, as well as ischemic events in patients with acute coronary syndromes without ST-segment elevation myocardial infarction (STEMI).[1]

The role of current antithrombotic regimens for the management of STEMI remains unclear, however.

The Sixth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-6)[2,3] trial was designed to determine whether fondaparinux is superior to usual care (placebo/UFH) in a broad range of STEMI patients. The results of the OASIS-6 trial were published simultaneously online in JAMA.[3]

Study Design

OASIS-6 was a randomized, double-blind, double-dummy trial comparing fondaparinux with usual care in 12,092 patients with STEMI within < 12 hours of symptom onset. Patients who had contraindications to anticoagulant therapy, had an INR > 1.8, were pregnant, or had intracranial hemorrhage within < 12 months were excluded from the study. There was no age cut-off for the trial.

Eligible patients were treated with a variety of background therapies, including streptokinase, tissue plasminogen activator (t-PA), tenecteplase (TNK), reteplase (r-PA), primary percutaneous coronary intervention (PCI), or no reperfusion (ie, presented late or had a contraindication to thrombolytic agents). Patients were stratified according to the need for UFH treatment and were randomized to receive either fondaparinux (2.5 mg SC daily), regardless of UFH use, or UFH or placebo (depending on whether UFH was indicated). Patients assigned to the fondaparinux group were treated with the study drug for 8 days, whereas UFH was administered for 48 hours.

Primary Efficacy Endpoint

Composite of death and reinfarction at 30 days.

Primary Safety Outcome

Severe bleeding.

Balance of Efficacy and Safety

Composite of death, MI, and severe bleeding.

Secondary Endpoint

Same outcomes and individual components assessed at 9 days and at 3 and 6 months.

Results

A total of 12,092 patients with STEMI within < 12 hours of symptom onset were randomized at 447 centers in 41 countries between September 2003 and September 2005 to receive placebo or UFH (n = 6056) or to receive fondaparinux (n = 6036). Final follow-up was done in January 2006, and complete data are available for 99.9% of patients. Baseline clinical characteristics, including time from pain to study entry (median 4.8 hours), were well balanced between the 2 groups (Table 1).

Table 1. OASIS-6: Baseline Characteristics
Placebo/UFH
(n = 6056)
Fondaparinux
(n = 6036)
Age (yrs) 62 62
Male gender (%) 72 73
Diabetes (%) 18 18
Hypertension (%) 55 54
Current or former smoker (%) 57 59
S/P MI (%) 12 13
S/P PCI or CABG (%) 4 4
Unstable angina (%) 37 37
STEMI > 2 mm (%) 62 60
Time from pain to study entry (median hrs) 4.8 4.8
In-hospital procedures
Coronary angiography (%) 43 44
PCI (%) 37 37
Thrombolysis (%) 45 45
CABG surgery (%) 1.3 1.1
No reperfusion (%) 23 24
Background medical therapy
Aspirin (%) 96 97
Clopidogrel/ticlopidine (%) 59 59
ACE inhibitors/ARBs (%) 80 79
ACE = angiotensin converting enzyme; ARB = angiotensin receptor blockers; CABG = coronary artery bypass graft; MI = myocardial infarction; PCI = percutaneous coronary intervention; S/P = status-post; STEMI = ST-segment elevation myocardial infarction

The composite of death or MI at 9 and at 30 days (primary endpoint), as well as at the end of the study, was significantly reduced in patients randomized to fondaparinux (Figure 1). The individual endpoints of death and reinfarction were also significantly lower in patients treated with fondaparinux (Figure 2 and Figure 3).

Figure 1. OASIS-6: death/reinfarction at 9 day, 30 days, and at study end (3-6 months).
Figure 2. OASIS-6: individual rates of death and reinfarction at 9 days, 30 days, and at study end (3-6 months).

Compared with control, the use of fondaparinux was associated with a 14% relative risk reduction in the incidence of the study's primary endpoint (HR 0.86 [CI 95% 0.77-0.96]; P = .008). In addition, fondaparinux reduced the risk of death and reinfarction by 13% and 19%, respectively (Table 2). The benefit of fondaparinux was observed early and was maintained throughout the follow-up period.

Table 2. OASIS-6: Events at 30 Days (primary endpoint), 9 Days, and at Study End
Event Placebo/UFH
(n = 6056)
Fondaparinux
(n = 6036)
HR CI 95% P
30 Days
Death or reinfarction (%) 11.2 9.7 0.86 0.77-0.96 .008
Death (%) 8.9 7.8 0.87 0.77-0.98 .026
Reinfarction (%) 3.0 2.5 0.81 0.65-1.01 .057
9 Days
Death or reinfarction (%) 8.9 7.4 0.83 0.73-0.94 .003
Death (%) 7.0 6.1 0.87 0.75-1.00 .043
Reinfarction (%) 2.3 1.6 0.67 0.52-0.88 .004
Study End (3 or 6 months)
Death or Death or reinfarction (%) 14.8 13.4 0.88 0.79-0.97 .008
Death (%) 11.6 10.5 0.88 0.79-0.99 .029
Reinfarction (%) 4.6 3.8 0.81 0.67-0.97 .026
CI = confidence interval; HR = hazard ratio; MI = myocardial infarction; UFH = unfractionated heparin

The results remained consistent regardless of whether patients received placebo or UFH. The highest benefit regarding death and reinfarction was observed in patients who did not undergo reperfusion therapy, whereas in those patients who underwent primary PCI, there was no benefit from the addition of fondaparinux (Figure 3).

Figure 3. OASIS-6: Death/reinfarction at study end (3-6 months) by reperfusion therapy.

There was no increase in severe bleeding associated with fondaparinux at 9 days, regardless of whether patients were treated with lytics or primary PCI (Figure 4). There was a trend toward fewer fatal bleeds in the fondaparinux group relative to control (35 vs 49, respectively; HR 0.72 [CI 95% 0.47-1.10]; P = .13), and no difference in the rate of intracranial hemorrhage between the 2 groups. In addition, the incidence of cardiac tamponade was significantly lower in the fondaparinux group (48 vs 28, respectively; P = .02) (Table 3).

Figure 4. OASIS-6: Severe hemorrhage at study end (3-6 months).
Table 3. OASIS-6: Severe Hemorrhage at 9 Days
Event (%) Placebo/UFH Fondaparinux HR CI 95% P
Severe hemorrhage 79 61 .77 0.55-1.08 .13
Fatal hemorrhage 49 35 .72 0.47-1.20 .13
ICH 10 11 1.10 0.47-2.60 .82
Cardiac tamponade 48 28 0.59 0.37-0.93 .02
CI = confidence interval; HR = hazard ratio; ICH = intracranial hemorrhage; UFH = unfractionated heparin
Conclusions
  1. Fondaparinux significantly decreases mortality and reinfarction in STEMI patients without increasing bleeding compared with placebo or UFH.

  2. The benefits merge at 9 days and are sustained out to 180 days.

  3. Fondaparinux had no benefit in patients who underwent primary PCI.

  4. The benefits are marked in those patients who did not receive reperfusion therapy and in patients who received thrombolytics, with lower severe bleeding complications relative to placebo.

  5. Fondaparinux significantly reduced mortality.

Viewpoint

The results of OASIS-6 show a clear-cut reduction in the incidence of 2 hard endpoints, mortality and reinfarction, in patients with STEMI without an increase in the risk of bleeding. This effect was mainly due to a reduction in cardiac death and was already observed at 9 days and persisted during the follow-up period. Of interest, patients who underwent angioplasty as a reperfusion strategy did not derive any benefit. As reported in JAMA,[3] there was a higher incidence of thrombotic complications (guiding catheter) during the coronary intervention. Another issue is the prolonged therapy with fondaparinux, up to 8 days, which usually is longer than the average hospitalization.

Nevertheless, these are important results that may improve the outcomes of STEMI patients, especially those who do not undergo primary PCI as a reperfusion strategy.

References
  1. The Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:1464-1476.

  2. Mehta SR, Yusuf S, for the OASIS-6 Investigators. The impact of fondaparinux, a synthetic factor Xa inhibitor, on mortality and reinfarction in patients with acute ST segment elevation myocardial infarction: results of the Michelangelo-Organization To Assess Strategies For Ischemic Syndromes (OASIS)-6 trial. Program and abstracts from the American College of Cardiology 55th Annual Scientific Session; March 11-14, 2006; Atlanta, Georgia. Abstract 422-7.

  3. The OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction. The OASIS-6 randomized trial. JAMA. 2006;295:1519-1530.

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