Stockholm, Sweden - Fondaparinux, the new anti-Xa inhibitor, is as effective as enoxaparin in reducing cardiovascular events in the short term, while causing half the amount of bleeding, according to results of OASIS-5/Michelangelo, the largest ACS trial conducted to date.

Dr Salim Yusuf

By 30 days this benefit in bleeding had translated into a significant reduction in mortality,Dr Salim Yusuf (McMaster University, Hamilton, ON) told the European Society of Cardiology (ESC) Congress 2005 today, These results, according to Yusuf, should lead to fondaparinux becoming the new preferred antithrombotic drug used in ACS patients

"We have shown that bleeding causes death, and we have shown a striking reduction in bleeding. This was shown in all subgroups—there was no subgroup in which enoxaparin looked better," Yusuf said. The benefit of fondaparinux was seen both in hospitals with cath labs and those without and was irrespective of whether patients received unfractionated heparin at any time either before or after randomization, he reported. "Fondaparinux will reduce bleeding irrespective of the type of hospital you practice in or, in contrast to SYNERGY, whether you switch antithrombotic therapy," he commented.

Dr Shamir Mehta

Noting that the price of fondaparinux is currently around 70% that of enoxaparin, he added: "This new drug therefore has a net clinical benefit at no greater financial cost." Yusuf calculated that treating 1000 ACS patients with fondaparinux instead of enoxaparin would prevent 10 deaths, four strokes, and 25 major bleeds.

Co-lead investigator Dr Shamir Mehta (McMaster University, Hamilton, ON) commented to heartwire: "Fondaparinux had a net clinical benefit in both the conservative medical approach and in the aggressive interventional approach. Everyone will be happy with this drug—noninterventional cardiologists, interventional cardiologists, and hospital administrators. There is no doubt in my mind that this drug is preferable to enoxaparin. Physicians will have to think twice or thrice before prescribing enoxaparin after seeing these reductions in bleeding and mortality with fondaparinux."

Dr Robert Califf

Discussant of the trial at the ESC hotline session, Dr Robert Califf (Duke University, Durham, NC) said that fondaparinux was an "excellent regimen" and appeared to have a unique profile as an antithrombotic drug. He explained that while all previous antithrombotics have a trade-off, with both efficacy and bleeding increasing as the dose increases, fondaparinux appears to have a dose-related effect on bleeding but not on efficacy, so the lowest dose is the most effective one. "This is a great situation that we have previously only dreamed about," he commented.

Study design

OASIS-5, the largest ACS trial ever conducted, randomized 20 078 patients within 24 hours of an ACS to fondaparinux (2.5 mg sc once daily) or enoxaparin (1 mg/kg twice daily) for two to eight days. The primary efficacy outcome was a composite of death/MI/refractory ischemia at day nine. The primary safety outcome was the rate of major bleeding at day nine. Yusuf reported that the primary efficacy end-point curves were "superimposable." The hazard ratio for the primary efficacy end point with fondaparinux was 1.01 (95% CI 0.90-1.13), and fondaparinux clearly met the "noninferiority" criterion.

Efficacy results at day nine

End point	Enoxaparin, n=10 021 (%)	Fondaparinux, n=10 057 (%)
Death/MI/refractory ischemia*	5.8	5.9
Death/MI	4.1	4.1
Death	1.9	1.8
MI	2.7	2.7
Refractory ischemia	1.9	2.05

But major bleeding at day nine showed a dramatic difference between the two treatment groups, with a 47% reduction in the fondaparinux arm, and an "extreme" p value that Yusuf said "would go off the slide if all the zeros were included."

Bleeding results at day nine

End point	Enoxaparin, n=10 021 (%)	Fondaparinux, n=10 057 (%)	HR (95% CI)	p
Total bleeds	7.0	3.2	0.44 (0.39-0.51)	<<0.0001
Major bleeds	4.0	2.1	0.53 (0.45-0.62)	<<0.0001
TIMI major bleeds	1.3	0.7	0.54 (0.41-0.73)	<<0.0001
Minor bleeds	3.1	1.1	0.35 (0.28-0.43)	<<0.0001

Categories of major bleeds at day nine (numbers of patients)

Category of major bleed	Enoxaparin	Fondaparinux	p
Total major bleeding	404 (4%)	215 (2.1%)	<<0.0001
Intracranial	5	6
Surgery required to stop bleed	74	41	0.0001
Retroperitoneal	37	9	0.0001
Hb reduced by 3g/dL or more	312	150	0.0001
Transfusion of 2 units or more	275	162	0.0001

The investigators also reported the net clinical benefit—a combination of the efficacy and bleeding results—at nine days, which showed a clear benefit of fondaparinux (hazard ratio 0.82 [95% CI 0.74-0.90]; p<<0.00001).

Bleeding reduction turns into mortality reduction

Yusuf noted that while the entire difference in bleeding between the two groups occurred in the first few days and then remained the same, the efficacy curves gradually diverged over time, showing benefits favoring fondaparinux by 30 days, which became more obvious by six months. By six months, the end points of death, death/MI, stroke, and the composite of death/MI/stroke were all significantly reduced in the fondaparinux group.

Efficacy end points at 30 days

End point	Enoxaparin, %	Fondaparinux, %	p
Death/MI/refractory ischemia	8.8	8.1	NS
Death/MI	6.9	6.2	0.077
Death	3.5	2.9	0.022
MI	4.2	3.9	NS
Refractory ischemia	2.3	2.2	NS

Efficacy end points at six months

End point	Enoxaparin (%)	Fondaparinux (%)	p
Death/MI/refractory ischemia	13.1	12.1	0.055
Death/MI	11.2	10.3	0.036
Death	6.3	5.6	0.037
MI	6.3	6.0	0.33
Stroke	1.6	1.3	0.029
Death/MI/stroke*	12.3	11.1	0.005

Yusuf showed data illustrating that the reduction in mortality in the fondaparinux group at 30 days was directly linked to the reduction in bleeding with this drug and that of the 57 extra deaths in the enoxaparin group at 30 days, 39 (68%) were attributed to bleeding.

Catheter thrombosis: An issue with PCI?

The only issue with fondaparinux appeared to be an increase in catheter thrombus in patients undergoing PCI, although other PCI procedural complications such as pseudoaneurysm and large hematoma were reduced with the Xa inhibitor.

Yusuf noted that the increase in catheter thrombus might be explained by the fact that many more patients in the enoxaparin group received unfractionated heparin (UFH) during PCI, and that when a small dose of unfractionated heparin was given to the fondaparinux patients during PCI, this problem was "virtually eliminated."

PCI procedural complications at 30 days

Event	Enoxaparin, n=3089 (%)	Fondaparinux, n=3118 (%)	p
Any UFH during PCI	53.8	18.8
Any coronary complication	8.6	9.6	0.18
Abrupt closure	1.1	1.5	0.20
Vascular access site complication	8.1	3.3	<<0.0001
Pseudoaneurysm	1.6	1.0	0.039
Large hematoma	4.4	1.6	<<0.0001
Catheter thrombus	0.5	1.3*	0.001

Yusuf noted that before this amendment of the protocol to give a small dose of UFH to the fondaparinux patients undergoing PCI, there was a slight increase in death/MI in this group, whereas after the amendment there was a reduction, and when the results are taken together, there was no difference in death/MI between the enoxaparin and fondaparinux groups in patients undergoing PCI regardless of when the PCI was performed.

Major events at 30 days in all patients undergoing PCI

Event	Enoxaparin, n=3089 (%)	Fondaparinux, n=3118 (%)	p
Death	1.2	1.2	0.87
MI	5.0	5.2	0.66
Death/MI	5.8	6.2	0.51
Major bleed	5.1	2.3	<0.0001
Death/MI/major bleed	10.1	8.1	<0.001

Major events at 30 days in patients undergoing PCI within 24 hours

Event	Enoxaparin, n=867 (%)	Fondaparinux, n=865 (%)	p
Death	2.2	2.1	0.88
Death/MI/refractory ischemia	8.1	7.1	0.43
Major bleed	4.7	2.9	0.048
Death/MI/major bleed	11.6	9.5	0.14

Was the dose of enoxaparin too high for all?

In his discussion of the trial, Califf suggested that enoxaparin may have been used in this study at too high a dose for all patients, which may have worsened its bleeding profile, although he noted the dose used in OASIS was the dose recommended in the labeling "Patients with reduced creatinine clearance may need a lower dose of enoxaparin, but this is something the manufacturer needs to address," he commented.

OASIS-6 next year

Califf also said the catheter-thrombus issue will probably still bother interventional cardiologists until more data become available. Such data will be available next year with the results of OASIS-6, which is evaluating fondaparinux in ST-elevation patients, including a large subset undergoing primary PCI.