London, UK - Two new studies released online in the Lancet February 14, 2006 constitute a one-two punch against the strategy of facilitated angioplasty, although experts refuse to call it a knockout [1,2]. It is still too soon to say that pharmacological pretreatment in some form will never have a role in ST-segment-elevation AMI patients, investigators for both studies say.

One of the two papers details the full ASSENT-4 PCI results, previously reported by heartwire at the American Heart Association 2005 meeting. In the trial, Dr Frans Van de Werf (Gasthuisberg University Hospital, Leuven, Belgium) and colleagues randomized 1667 patients—less than half of the number intended in the original trial design—to full-dose tenecteplase (TNK)-facilitated PCI or primary PCI alone. At 90 days, the primary end point of death, congestive heart failure (CHF), or shock had occurred more frequently in the facilitated-PCI arm than in the primary-PCI patients. More strokes, reinfarction, and repeat target vessel revascularization (TVR) occurred in the facilitated group, while major noncerebral bleeding was no different between the two groups. Mortality, which had early on appeared higher in the facilitated-PCI group—and was the reason the trial was halted before full enrollment—was no longer significantly different at 90 days.

In an interview with heartwire, Van de Werf emphasized that despite the clear failure of added full-dose TNK to improve on primary angioplasty, it is impossible to call this the final nail in the coffin for facilitated angioplasty, particularly since specific groups may still benefit from some form of pretreatment. Of note, mortality rates for the whole trial were lowest in patients in the facilitated-PCI group who received TNK in the ambulance but highest in those who received pretreatment at the hospital where they underwent PCI, underscoring the potential benefit of a facilitated strategy in the setting of delayed PCI. The CAPTIM trial, conducted in France, showed similar benefits in ambulance-treated patients, Van de Werf noted.

"If we had been able to randomize more people in the ambulance, at an earlier time after the onset of symptoms, the results [for the facilitated-PCI group] would probably have been much better," he told heartwire.

In fact, the original intention of ASSENT-4 PCI, Van de Werf said, was to include patients with TNK-to-PCI delay times of more than three hours, but the FDA requested that the trial design include only patients who could be treated within three hours—in keeping with current guidelines.

"If PCI follows the thrombolysis after a short period, then there is not so much time for the lytic to have a benefit," Van de Werf explained. "If the delays had been much longer with PCI, of course there is a higher chance that the group randomized to lytic therapy would have benefited from the lytic."

As well, ASSENT-4 PCI permitted neither up-front clopidogrel or heparin infusion following initial bolus dose nor GP IIb/IIIa inhibitors in the facilitated-PCI group, raising the possibility that suboptimal antithrombotic cotherapy may have contributed to the increased early thrombotic complications in the TNK-pretreatment group, he said.

The key point from ASSENT-4 PCI, Van de Werf told heartwire, is that "you should not give the therapy as it was given in this trial. With this cotherapy and with a full dose of TNK, it's not a good treatment."

In patients with longer delays to PCI or with a different pre-PCI strategy, the results might be different. "As such, we eagerly await the results of the Facilitated Intervention with Enhanced Reperfusion to Stop Events (FINESSE) trial, in which up-front abciximab alone or in combination with half-dose reteplase are compared with standard PCI," the ASSSENT-4 PCI investigators conclude.

"With a combination of GP IIb/IIIa inhibitor and half-dose lytic, it's possible they won't see the problems we saw in our trial—namely, early thrombotic complications," Van de Werf told heartwire. "On the other hand, this combination, especially in the elderly, is associated with a higher risk of bleeding complications, so I don't know what it's going to show. Certainly it will be a balance of having the benefit of abciximab on board and the higher risk of bleeding complications."

In the meantime, the second paper includes some insights into the hypothetical role of a GP IIb/IIIa-inhibitor-based strategy. In a meta-analysis of 17 trials comparing facilitated and primary PCI, Dr Ellen C Keeley (UT Southwestern, Dallas) and colleagues included trials testing GP IIb/IIIa antagonists alone or in combination with reduced-dose thrombolysis, as well as studies examining thrombolysis alone, including ASSENT-4 PCI.

As Keeley et al report, their analysis showed facilitated PCI to be associated with higher rates of death, reinfarction, urgent TVR, major bleeding, and stroke at up to 42 days. The same findings were seen when all thrombolytic-based strategies, with or without GP IIb/IIIa inhibition, were analyzed together. By contrast, the GP IIb/IIIa-inhibitor-alone strategies neither increased nor decreased rates of adverse outcomes, they note.

Importantly, Keeley et al could not assess whether patients with delays to PCI fared better with pretreatment, because 13 different "treatment delays" were measured in the 17 studies, Keeley told heartwire. However, from the available data, no one patient group had a suggestion of benefit from a facilitated approach. "From the available data, the facilitated-PCI approach is no better than primary PCI, period."

She continued, "In light of our results, the facilitated-PCI approach does not result in better clinical outcomes and in fact appears to be harmful in regimens incorporating thrombolytic therapy. This approach should not be used unless it is being studied in a randomized, controlled trial setting. Furthermore, with the data we have thus far and the data from the ASSENT-4 PCI trial, randomized trials that have treatment arms using thrombolytic therapy should consider stopping enrollment into the thrombolytic-therapy arm."

Keeley believes the findings should have an impact on clinical practice: "Many physicians have adopted the facilitated-PCI approach in the community," she told heartwire. "We can now say that this approach is not beneficial and is harmful in those regimens using thrombolytic therapy and should not be used."

Drs Gregg W Stone (Columbia University, New York, NY) and Bernard Gersh (Mayo Clinic, Rochester, MN) echo Keeley et al's conclusions in an accompanying Commentbut, like the ASSENT-4 PCI investigators, also underscore the need for a trial examining a facilitated strategy in patients facing significant PCI-transfer delays [3]. Whether any patients would benefit from a different type of pharmacological pretreatment is still unknown, they emphasize.

"Although the door cannot be completely closed on facilitated angioplasty (pending the completion of the ongoing FINESSE trial), there is currently no justification to pretreat any patient in whom primary angioplasty is intended with thrombolytic therapy or GP IIb/IIIa inhibitors or both, irrespective of the time since onset of symptoms or delays expected to catheterization," Stone and Gersh write.

To heartwire, Van de Werf predicted that FINESSE might still have something to add to the debate.

"The fact that the ethics committee for FINESSE has allowed the trial to continue suggests to me that there must be a benefit, or certainly no clear evidence of a major harm; otherwise, the trial would have been stopped."