OASIS-6: Fondaparinux benefits in STEMI

March 14, 2006

Atlanta, GA -The factor Xa inhibitor antithrombotic fondaparinux reduced mortality and reinfarction without increasing bleeding, compared with usual care (unfractionated heparin [UFH] or no antithrombotic therapy) in the Sixth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-6) trial in a broad population of patients with ST-elevation MI (STEMI).

The drug was of benefit in all groups, apart from those patients undergoing primary PCI, who showed similar outcomes with both fondaparinux and unfractionated heparin but had a higher risk of catheter thrombosis with the Xa inhibitor.

Dr Salim Yusuf

The trial was presented at the American College of Cardiology 2006 Scientific Sessions on March 14 and was published simultaneously online in the Journal of the American Medical Association[1]

Lead author Dr Salim Yusuf (McMaster University, Hamilton, ON) told heart wire : "Fondaparinux clearly has advantages over other antithrombotics in STEMI—it saves lives and prevents recurrent heart attacks, without increasing bleeding." But he says it is not suitable for use in primary PCI. "Fondaparinux does not seem to be enough on its own to reduce thrombus in primary PCI—these patients do seem to need a factor II inhibitor (present in heparin)."

In an editorial accompanying the paper, Dr Robert Califf (Duke Clinical Research Institute, Durham, NC) questions the relevance of OASIS-6 to North America, where primary PCI has been established as the preferred treatment for STEMI, saying that fondaparinux will be more preferred in settings in which the use of angiographic-based reperfusion is not routine[2].

But Yusuf responded to hea rt wire : "Despite all the hype, only about 20% of patients actually get primary PCI in the US." He further points out: "While fondaparinux should not be the primary antithrombotic in primary PCI (heparin may be the best drug during the procedure), it is still beneficial if used for the few days after the procedure." He added: "Use of fondaparinux for about 10 days after primary PCI was associated with a strong trend toward fewer ischemic events in OASIS-6. So we are learning how to use these drugs. . . . No single drug is perfect in all situations."

In the paper, Yusuf et al note that trials of unfractionated heparin, direct thrombin inhibitors, and enoxaparin have thus far failed to demonstrate mortality reductions in STEMI patients, and bleeding is substantially increased when these agents are used with aspirin and thrombolytic therapy. Therefore, there is a clear need for an effective, inexpensive, and safe antithrombotic agent for patients with STEMI.

The OASIS-6 trial enrolled 12 092 patients with STEMI from 41 countries. They were randomized to fondaparinux (2.5 mg once daily given for up to eight days) or usual care—just placebo for those in whom unfractionated heparin was not indicated (stratum 1) or unfractionated heparin for up to 48 hours followed by placebo for up to eight days (stratum 2).

The primary end point—a composite of death or reinfarction at 30 days—was significantly reduced in the fondaparinux group. Significant reductions in this end point were also seen at the secondary assessment times of nine days and final follow-up (three or six months). Mortality was also significantly reduced throughout the study.

OASIS-6 primary end point: Death/reinfarction

Time point Fondaparinux (n=6036) (%) Control (n=6056) (%) HR 95% CI p
30 d (primary end point) 9.7 11.2 0.86 0.77-0.96 0.008
9 d 7.4 8.9 0.83 0.73-0.94 0.003
3 - 6 mo 13.4 14.8 0.88 0.79-0.97 0.008

There was no heterogeneity of the effects of fondaparinux in the two strata by planned heparin use. However, there was no benefit in the 3789 patients who underwent primary percutaneous coronary intervention. Compared with other patients who received unfractionated heparin, fondaparinux was superior to unfractionated heparin in preventing death or reinfarction at 30 days and at study end.

OASIS-6 stratum 1: Fondaparinux vs placebo, death/reinfarction

Time point Fondaparinux (%) UFH (%) HR 95% CI
30 d 11.2 14.0 0.79 0.68-0.92
9 d 8.5 11.1 0.76 0.64-0.89
3-6 mo 15.9 17.3 0.87 0.76-0.99

OASIS-6 stratum 2: Fondaparinux vs UFH, death/reinfarction in patients not undergoing primary PCI

Time point Fondaparinux (%) UFH (%) HR (95% CI) p
30 d 11.5 13.8 0.82 (0.66-1.02) 0.08
9 d 9.5 10.9 0.87 (0.69-1.10) 0.25
3-6 mo 14.9 19.0 0.77 (0.64-0.93) 0.008

OASIS-6 stratum 2: Fondaparinux vs UFH, death/reinfarction in patients undergoing primary PCI

Time point Fondaparinux (%) UFH (%) HR (95% CI) p
30 d 6.1 5.1 1.20 (0.91-1.57) 0.19
9 d 4.2 4.1 1.01 (0.74-1.38) 0.96
3-6 mo 8.5 8.2 1.06 (0.84-1.33) 0.61

Significant benefits of fondaparinux were observed in patients receiving thrombolytic therapy (HR 0.79; p=0.003) and those not receiving any reperfusion therapy (HR 0.80; p=0.03). And the results on both efficacy and safety were also consistent, regardless of whether patients received unfractionated heparin prior to randomization.

Maybe not for primary PCI

Although the rate of death and MI and severe bleeds did not differ significantly between the two groups in patients undergoing primary PCI, there was a higher rate of guiding catheter thrombosis and more coronary complications (abrupt coronary artery closure, new angiographic thrombus, catheter thrombus, no reflow, dissection, or perforation) with fondaparinux. But addition of UFH with fondaparinux during PCI largely avoided these complications. The OASIS authors say: "Given the very limited time for antithrombotic therapy prior to the procedure and the need for UFH during the procedure, there is probably little advantage in using fondaparinux as the initial treatment in patients in whom primary PCI is intended." But they add: "In all other patients (including those who may need a rescue PCI or other PCI after admission), initial management with fondaparinux followed by standard UFH during PCI is an attractive choice."

Trend toward less bleeding

There was a tendency to fewer severe bleeds with fondaparinux, particularly in stratum 1 (vs placebo), an observation that the authors describe as "puzzling." There were also significantly fewer cardiac tamponades with the factor Xa inhibitor, which the authors attribute to less intrapericardial bleeding or a smaller infarct size, leading to fewer cases of myocardial rupture.

OASIS-6: Severe bleeding at 9 days

Group Fondaparinux (%) Placebo/UFH (%) HR p
All cases 1.0 1.3 0.77 0.13
Stratum 1 vs placebo 1.0 1.6 0.63 0.06
Stratum 2 vs UFH 1.1 1.1 0.95 0.82
Cardiac tamponade 0.5 0.8 0.59 0.02

The investigators say that this pattern of reduction in mortality and reinfarction, without an increase in bleeds, is unique among antithrombotic agents. They point out that the benefits were most marked in those not undergoing PCI and those who were at higher risk, with 34 deaths or reinfarctions prevented for every 1000 individuals treated with fondaparinux in this high-risk subgroup.

Consistent with OASIS-5

The authors also point out that these results are consistent with those from OASIS-5. "Collectively the data from both trials indicate that fondaparinux is an attractive antithrombotic agent in terms of efficacy and safety in patients with varying presentations of acute coronary syndrome and treated with different pharmacologic modalities (other than primary PCI)." Noting that fondaparinux can be used as a single fixed dose, they conclude: "The simplicity of this regimen, lack of monitoring, and its safety and efficacy in the full spectrum of acute coronary syndrome facilitates the use of fondaparinux in a range of settings. It may even be applicable in the prehospital or posthospital settings in appropriate patients."

Was it the drug or the longer treatment time that gave the benefit?

In his editorial, Califf suggests there are several different ways of interpreting these new data. The benefit could reflect the superiority of fondaparinux, which he says has now been established as a leading antithrombotic drug in the treatment of acute coronary syndromes, whose value is further enhanced by the remarkable reduction in bleeding observed in both OASIS-5 and -6.

But he points out that if outcomes are compared for fondaparinux and unfractionated heparin during the time patients were receiving active drug in both groups, the result in this case is not as encouraging for fondaparinux, with roughly the same outcomes seen in the two groups during the first 72 hours. "Thus, a skeptic could argue that OASIS-6 provides valuable proof that anticoagulation reduces death and MI when compared with no anticoagulation but that there is no convincing evidence of difference between agents in this trial," Califf writes. He adds that this raises the larger question of whether anticoagulation should be continued for longer than 48 to 72 hours in all patients with STEMI.

Yusuf responded to heart wire : "This discussion is a bit academic; nobody uses UFH for a week or 10 days, as there are significant bleeding risks if it is used for a prolonged duration, plus a significant risk of heparin-induced thrombocytopenia, which can be a very nasty complication." He added: "In OASIS-6, there was a trend in favor of fondaparinux during the first three days, which became clearly significant with longer treatment duration and led to a significant reduction in mortality. So, we can definitely say that fondaparinux given the way we did was superior to UFH the way it is used and safer. Given how inexpensive (about $15 a day) and safe fondaparinux is, it is hard to not recommend its use."

OASIS-5 published in New England Journal of Medicine

The OASIS-5 results of fondaparinux in non-ST-elevation ACS, first presented at the European Society of Cardiology meeting in Stockholm last year, have also been published today in the New England Journal of Medicine[3]. The largest ACS trial to date, OASIS-5 was hailed as groundbreaking and showed that a daily dose of fondaparinux 2.5 mg was as effective as enoxaparin in reducing cardiovascular events in the short term, while causing half the amount of bleeding.

This benefit in bleeding also translated into a significant reduction in morbidity and mortality—fondaparinux was associated with a significantly reduced number of deaths at both 30 and 180 days. The investigators note that fondaparinux had a net clinical benefit in both the conservative medical approach and in the aggressive interventional approach. This comes at no greater financial cost, they observed in Stockholm, although there are no specific discussions about the costs of the drug in the paper.

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