Major Bleed Risk Falls with Bivalirudin vs Heparin en Route to PCI for STEMI: EUROMAX.


The 30-day risk of death or major bleeding fell significantly in ST-elevation MI (STEMI) patients treated with bivalirudin (Angiomax, the Medicines Company) compared with heparin-based management, both initiated prior to arrival at a hospital for primary PCI, in a large randomized but open-label study[1].

The bivalirudin benefit for that composite end point in the European Ambulance Acute Coronary Syndrome Angiography(EUROMAX) trial was driven by a significant drop in major bleeding, the definition of which excluded bleeding related to CABG surgery.

The heparin-based strategy consisted of either unfractionated heparin (UFH) or the low-molecular-weight heparin enoxaparin(Lovenox, Sanofi). Both groups could receive a GP IIb/IIIa inhibitor provisionally.

EUROMAX was published today in the New England Journal of Medicine with lead author Dr Philippe Gabriel Steg (Hôpital Bichat, Paris, France) to coincide with his presentation of the trial here at TCT 2013 .

http://img.medscape.com/news/2013/ih_131030_Steg_Philippe_Gabriel_TCT2013_120x156.jpg

Dr Philippe Gabriel Steg

Bivalirudin’s 40% primary-end-point relative risk reduction included a >50% drop in risk for non-CABG major bleeding. On the other hand, the relative risk of stent thrombosis with bivalirudin was nearly threefold what was seen in the heparin group, although absolute rates were very low.

At a media briefing on the trial, Steg said the excess stent thromboses with bivalirudin were driven by events in the acute phase, within 24 hours of PCI. And, he observed, they didn’t translate into more reinfarctions or ischemia-driven revascularization.

Still, “acute stent thrombosis . . . while rarely fatal and not outweighing the advantages of bivalirudin, is the only troubling issue with bivalirudin in STEMI, and we do need strategies to reduce this complication,” according to Dr Gregg W Stone (New York-Presbyterian Hospital/Columbia University Medical Center New York, NY), the assigned discussant following Steg’s formal presentation of EUROMAX.

Shades of HORIZONS AMI

The trial’s findings are reminiscent of the HORIZONS AMI trial 30-day outcomes reported about six years ago and covered then by heartwire . That trial, Steg et al observe, preceded some important changes in STEMI management and PCI technique that likely affected bleeding risk, changes that were a part of EUROMAX. These included the expansion of radial-artery PCI access, newer antiplatelet agents, reduced GP-IIb/IIIa-inhibitor use, and progressively earlier initiation of IV anticoagulants.

In the >3600-patient HORIZONS AMI, anticoagulation wasn’t started early during transport. But both it and EUROMAX with its nearly 2200 patients saw a decreased bleeding risk and increased stent-thrombosis risk with bivalirudin compared with heparin. But in contrast to EUROMAX, the earlier trial also showed a reduced risk of cardiac death in bivalirudin patients.

The two studies taken together have more to say than either alone. “I think the results of EUROMAX will heavily impact clinical use of bivalirudin in Europe,” Steg said to heartwire . “The results are very consistent wih HORIZONS AMI, even to the point of the stent-thrombosis signal” and are “reassuring enough to embrace [bivalirudin] in the prehospital setting.” That is, he added, “If you want to. [The EUROMAX results] are not mind-blowing because we don’t see a mortality reduction. But they suggest that the benefits seen in HORIZONS AMI can be extended to the contemporary prehospital setting. “

At the media briefing, Dr Bernard Gersh (Mayo Clinic, Rochester, MN), who wasn’t involved in the trial, said, “It’s not that often that you see trials that really will change clinical practice, and I think this will.”

The Role of Prehospital Diagnosis and Treatment

Gersh also said, “I’ve never seen really anything that suggests that prehospital administration [of anticoagulants] and [STEMI] diagnosis is not beneficial.”

But whether they are achievable in the field varies by country, even within Europe. Interviewed, Steg pointed out that at most participating centers, there were no physicians in the ambulances. It does take some expertise to interpret the ECGs, unless the tracings can be transmitted to a center for remote reading. But, he said, “It’s been shown in other trials if you have good trained paramedics, they do just as well if not better than physicians.”

Also speaking at the briefing as a EUROMAX observer, Dr Philippe Généreux (NewYork-Presbyterian Hospital/Columbia University Medical Center, New York, NY) said prehospital STEMI diagnosis and treatment initiation could make the most difference in countries like Canada, “where there aren’t cath labs on every corner” and it might take 45 to 60 minutes for an ambulance to reach a PCI center.

Prospects for prehospital management in the US seem more remote, observers agreed. Dr James B Hermiller, Jr (St Vincent Hospital/The Heart Center of Indiana, Indianapolis,) said at the briefing, “The barrier to this in the US is very great. It’s difficult just to  get ECGs in the field, let alone administer anticoagulants, but we need to get there because this is very important.”

The Open-Label Randomization

EUROMAX randomized patients at centers in nine European countries presenting within 12 hours of onset of symptoms from electrocardiographically defined STEMI, on an open-label basis, to the bivalirudin or heparin strategies. Treatment was initiated in the ambulance or at a non-PCI hospital with subsequent transport to a PCI center.

For the 1089 patients who received bivalirudin, the drug was started as a 0.75-mg/kg bolus followed by an infusion of 1.75 mg/kg/h continued for at least four hours after PCI. The 1109 control patients received UFH at either 100 IU/g or 60 IU/kg with a GP IIb/IIIa inhibitor or were allowed to have enoxaparin at 0.5 mg/kg. Adjuvant GP IIb/IIIa inhibitors were allowed at physicians’ discretion. All patients received aspirin plus a P2Y12 inhibitor.

Relative Risk (95% CI) for Outcomes, Bivalirudin vs Heparin Strategies for STEMI Initiated During Emergency Transport to Primary PCI

End points

RR (95% CI)

p

30-day death from any cause or non-CABG major bleedinga

0.60 (0.43–0.82)

0.001

30-day death from any cause, reinfarction, or non-CABG major bleeding

0.72 (0.54–0.96)

0.02

Non-CABG major bleeding

0.43 (0.28–0.66)

<0.001

Major bleeding (TIMI definition)

0.62 (0.32–1.20)

0.15

Severe or life-threatening bleeding (GUSTO definition)

0.61 (0.22–1.68)

0.33

Definite stent thrombosisb

2.89 (1.14–7.29)

0.02

a. Primary end point 
b. Academic Research Consortium criteria

No significant differences were seen at 30 days for the composite of death, reinfarction, ischemia-driven revascularization, or stroke, or for any stroke or ischemic stroke. A committee blinded to treatment assignment adjudicated bleeding episodes and clinical events.

As discussant, Stone pointed out that PCI via the radial artery, rather than the femoral artery, was done in only 6% of cases in HORIZONS AMI but in 47% of EUROMAX patients. Some predicted that the greater proportion of radial procedures would lead to a much lower major bleeding rate and make it hard for bivalirudin to show an effect. A EUROMAX subgroup analysis found, however, that the benefits of bivalirudin over the heparin-based strategy were consistent for different kinds of patients, including whether their PCI was by the radial or femoral routes.

“Therefore, bivalirudin is beneficial regardless of the access site, and this is because most bleeding in the STEMI and ACS setting is not access-site related,” he said. It’s the non–access-site bleeds to pose the greater threat to later outcomes. So, he said, “the advantages of bivalirudin are present in patients undergoing radial as well as femoral intervention, and radialists should pay attention to this.”

Stone said EUROMAX raises the question of whether using cangrelor (the Medicines Company) as part of the accompanying antiplatelet therapy might help prevent stent thrombosis with bivalirudin, and that’s being addressed in HORIZONS-AMI-2, which is starting soon.

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