Shelley Wood

May 22, 2014

PARIS, FRANCE ( corrected )— The bivalirudin (Angiomax, the Medicines Company) controversy that first bubbled up at ACC 2014 appears to have spurred EUROMAX investigators to take a good hard look at trial patients in whom GP IIb/IIIa inhibitors (GPIs) were used only as bailout, the same as they were in the HEAT-PPCI trial.

Presenting the new, prespecified analysis here Wednesday at EuroPCR 2014 , Dr Uwe Zeymer (Institute für Herzinfarktforschung Ludwigshafen, Germany) showed that when GP IIb/IIIa inhibitors were not routinely used in EUROMAX, bivalirudin remained the superior strategy, with a significantly lower rate of death or major bleeding than heparin.

"I think this should put some heat on HEAT," he quipped.

As previously reported by heartwire , the multicenter EUROMAX trial demonstrated that STEMI patients treated with bivalirudin had lower 30-day rates of death or major bleeding than patients treated with a heparin-plus-optional-GPI strategy—the finding driven by the drop in major bleeding with the newer drug. In HEAT-PPCI, by contrast, bivalirudin was tested against heparin with no routine GPI use and found a significantly lower rate of major adverse cardiac events (MACE) with heparin over bivalirudin and no differences in bleeding complications.

Routine GPI use has emerged as a central issue, however. "There was some criticism [of EUROMAX], because nowadays not everyone is using a GPI with heparin, and it was unknown whether this advantage with bivalirudin was seen with heparin only, plus a strategy of bailout GPI," Zeymer said.

Dr Uwe Zeymer [Source: EuroPCR]

In search of answers, Zeymer and colleagues looked specifically at the 460 EUROMAX patients who received initial heparin only (41.5% of the total study population) vs the 1047 bivalirudin-treated patients.

As he showed here, for the primary end point in this new analysis, bivalirudin was still the winner, with a 30-day rate of death or major bleeds of 5.1%. By contrast, the heparin-only (with GPI bailout as needed) rate was 9.8%, a highly significant difference (p=0.0006). The rate of death/major bleeds in the heparin/routine-GP-IIb/IIIa-inhibitor group was 7.4% (p=0.0425).

For the secondary end point of death, MI, or major bleeding, bivalirudin again was lower, at 6.6% vs 10.4% (p=0.01) in the heparin-only group. As with the primary trial results, however, the rate of stent thrombosis was more than three times higher in the bivalirudin group, 1.6% vs 0.4% (p=0.09).

Bailout GPI Use Remains an Issue

Importantly, however, the use of bailout GPI was more than 25% in the heparin group, as opposed to 8% in the bivalirudin group.

Commenting on the new analysis for heartwire , Dr Rod Stables (Liverpool Heart and Chest Hospital, UK), principal investigator for HEAT-PPCI, pointed to this as a key reason for the different results between studies.

GPI use, he noted, "drives bleeding, but—almost certainly—does not confer important any additional anti-ischemic protection. You cannot compare the relative safety and efficacy of heparin and bivalirudin with confounding by differential GPI use. This basic scientific fact is immutable."

Stables believes the low GPI usage rates in the bivalirudin arm of EUROMAX "set the new benchmark," but it remains unclear what the ideal rate should be. "We do not know what the sweet spot is. I am working on information from HEAT, [but] I suspect that the rates of adverse ischemic events are not influenced by the rate of GPI use."

Heparin dosing differences between the studies also warrant scrutiny. Asked about heparin dose in the question-and-answer session following his presentation, Zeymer said the EUROMAX trial followed European Society of Cardiology guideline recommendations for heparin dosing: 70 to 100 U/kg for heparin alone and 50 to 70 U/kg when GPI use was used routinely. The published EUROMAX paper, however, gives numbers that are somewhat higher: 100 U/kg for heparin only and 60 U/kg when GPIs were used.

By contrast, in HEAT PPCI, the dose for heparin was 70 U/kg, and, said Stables, "It is a well-established fact that bleeding increases as the heparin dose goes up."

A Randomized Registry

Zeymer, asked why his analysis is so starkly different from HEAT-PPCI, hedged his bets. "So far, HEAT-PPCI has not been published, and it's always a little bit problematic to put the results of a single-center trial in a general population." Other highly positive single-center results have not been borne out when studied across multiple sites, he noted, citing the TAPAS and TASTE thrombectomy studies, also in STEMI patients. "I'm not sure if one study in a single center is really enough to oppose the results that we have seen in multicenter trials," he said.

This comment prompted Dr Gennaro Sardella (Sapienza University, Rome, Italy) to head to the microphone to turn Zeymer's own TAPAS/TASTE example against him, noting that the difference could just as easily reflect the difference between a highly selected and all-comers population.

Elaborating to heartwire , Sardella stressed that HEAT-PPCI's unique—and controversial—all-comers randomization meant that even patients with cardiogenic shock, anterior MI, high thrombus burden, etc, all ended up in the trial. It's the same kind of difference that crops up between trials and registries, and in a way, HEAT-PPCI was "a randomized registry, and the methods and recruitment of population can have an important impact on the results," Sardella said.

Asked whether the new EUROMAX analysis reassures him about bivalirudin use in STEMI, Sardella said he believes there is a role for the drug. "You cannot give bivalirudin in all patients, [but] if you have cardiogenic shock, high bleeding risk, frail patients, I think that bivalirudin maybe is better."

Zeymer disclosed receiving honoraria from the Medicines Company (<€25 000). Stables disclosed being a consultant for and receiving honoraria (<€25 000) from AstraZeneca and institutional research funding from the Medicines Company and AstraZeneca. Sardella had no disclosures.

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