Leuven, Belgium - Many experts in the field of acute MI have said they are mystified as to why the ASSENT 4 PCI trial could be showing higher event rates that are not attributed to bleeding in the group receiving thrombolysis plus PCI.

The trial, which is comparing use of the thrombolytic tenecteplase (TNK) before PCI with PCI alone, has suspended enrollment after a planned interim analysis showed the mortality rate in those treated with thrombolysis plus PCI, while consistent with that observed in large-scale thrombolytic trials, was higher than the PCI-alone arm.

The ASSENT 4 steering committee today released a statement reporting that the trial was suspended on April 21, 2005, after the enrollment of 1635 of the planned 4000 patients, because of "an unexpectedly superior outcome in patients randomized to the direct PCI-only arm." That being said, "the rates of death and of [intracerebral hemorrhage] in the TNK-facilitated PCI arm are consistent with prior ASSENT fibrinolytic-alone studies," it added.

The statement continues: "As would be the case with any ongoing trial, this decision was based on preliminary and still-accumulating data. At this juncture, the executive committee is rapidly collecting missing and incomplete outcome data. We are also acquiring additional prognostically relevant information concerning the baseline characteristics and time to treatment of the two study groups that will assist in better understanding the results. Once these analyses are complete, further communication concerning the future of the trial will be forthcoming. We wish to emphasize that current treatment for STEMI as recommended in contemporary STEMI guidelines is not affected by these results."

Lead investigator of the study, Dr Frans van de Werf (University of Leuven, Belgium), told heartwire that he would prefer to wait for the analyses before giving any further comments. He did point out, however, that recruitment has been suspended but a decision to stop the trial has not yet been taken. He also confirmed that the reason to suspend recruitment was not due to any difference in bleeding rates. This has surprised many experts, as it was expected that if there were a problem with the dual regimen it would be likely to involve increased bleeding complications.

One physician who has not expressed surprise at the announcement is Dr Eric Topol (Cleveland Clinic, OH). "For some time, there have been data that suggested that any lytic combination with PCI may not be the way to go, such as GUSTO-V, but we have needed definitive trials to prove it. The strategy of a 'bridge' lytic is practical and attractive, but the prothrombotic effects of lytics with vascular intervention appear to be overriding," he commented to heartwire.

The prothrombotic effect he refers to is the activation of platelets that can occur with thrombolysis and is the reason aspirin is always given with a thrombolytic. But not everyone is convinced that this is the culprit.

Dr Gabriel Steg (Hôpital Bichat, Paris, France) explained that pretreatment with thrombolysis upstream of PCI may, at least in theory, be associated with intraplaque hemorrhage and enhanced platelet activation, which could lead to "paradoxical" increases in adverse outcomes. "Although I am uncertain that platelet activation is enhanced to the same extent by TNK as compared with first-generation lytic agents," he added.

Steg told heartwire he felt the suspension of the trial was a "huge surprise, especially since intracranial bleeds do not appear to account for the difference in event rates." But he said it was necessary to wait for more detail to interpret the decision to suspend enrollment.

Dr Duane Pinto (Beth Israel Deaconess Medical Center, Boston, MA) was also mystified by the announcement. "That is really surprising," he commented to heartwire. "People after lytics die of intracranial hemorrhage, recurrent MI, and heart failure. If bleeding weren't higher, PCI should take care of the recurrent-MI problem, and CHF should be, if anything, less, because infarct size would be smaller with the combination. It is really weird," he said.

Pinto was also skeptical that the activation of platelets could be the reason behind the increase in event rate. "Activation of platelets—this is true, but the PCI should take care of that," he noted, adding that since everyone who received a stent after PCI in ASSENT 4 got clopidogrel, there should have been a double protection from the prothrombotic effect of lytics. "Basically, the prothrombotic effect would be manifest as stent thrombosis—an unlikely event and even less likely to detect a difference between the two arms, since they both got postprocedure clopidogrel," he asserted.
Dr Tim Henry (Minneapolis Heart Institute Foundation, MN) gave a similar view. "We should remember the trial is just on hold at the moment. I, too, would like to reserve judgment until there has been a more complete analysis," he commented. But he added, "To me, it doesn't make a lot of sense that the combination arm would have more events if they are not bleeding events. It is possible that it is due to different patient characteristics—so it may not be real effect."

The approach of giving a thrombolytic before PCI is known as "facilitated PCI." It is being investigated to try to increase the window of opportunity in which primary PCI can be performed. At present, primary PCI is believed to be superior to thrombolysis in reducing mortality after an MI, but only if it is performed quickly, so this strategy can be implemented only for patients living relatively near a cath-lab facility. It was hoped that by giving thrombolysis first (possibly in the ambulance) this would enable the time-to-PCI to be increased so patients from farther away could also benefit.

Henry pointed out that if the effect seen in ASSENT 4 is real, it is very disappointing. "The idea of being able to open the artery on the way to the cath lab was a very attractive hypothesis. And there have been some small trials that support this approach." Pinto echoed this sentiment. "We are still in need of a widely accessible, safe, pharmacologic strategy that will preserve the benefits of PCI in our STEMI patients, particularly if there are substantial delays," he commented.

Dr Chris Cannon (Brigham and Women's Hospital, Boston, MA) pointed out that the combination of lytic and PCI did not perform well in early trials. "It seems that TAMI 1, TIMI 2A, and ECSG 1 had it right—lysis and early PCI don't mix very well. We all look forward to learning more."

Cannon said his take-home message was: "If you are within two hours of a cath lab go with primary PCI with aspirin, clopidogrel 600 mg, weight-adjusted heparin, and a GP IIb/IIIa inhibitor in the emergency department (and tell transport or the ambulance driver to step on the gas to get to the cath lab). If no early cath is available, the patient should receive aspirin, clopidogrel 300 mg, weight-adjusted heparin, and tenecteplase."

Two other large-scale trials are under way to evaluate the combination of thrombolysis followed by PCI. These are FINESSE and CARESS. As Pinto notes: "We may have to wait for the results of FINESSE and CARESS before we can give a final verdict."