Chicago, IL - A combination of single high-dose-bolus tirofiban combined with a sirolimus-eluting stent (SES) may solve the problem of keeping costs affordable in Europe while improving outcomes for patients undergoing PCI for AMI, new research suggests.[1] The study, which compared the tirofiban/SES strategy with a combination of abciximab/bare-metal stenting, leaves many questions unanswered but at the very least provides key randomized trial evidence supporting the use of a drug-eluting stent in the treatment of AMI, evidence of which has so far come predominantly from registry studies, experts say.

The study is published in the May 4, 2005 issue of the Journal of the American Medical Association.

"The strength of the trial lies in its stent comparison, not in the pharmacological comparison," Dr Magnus Ohman (University of North Carolina, Chapel Hill) commented to heartwire. "That to me is the important component of this trial. . . . People are [using drug-eluting stents for AMI] a lot, but we have relatively little data on the outcomes and this is the first largish, randomized trial to get published in a large, peer-reviewed journal."

Ohman and Dr Mauricio G Cohen (University of North Carolina) are the authors of an editorial appearing in the same issue of JAMA, which observes that scientific evidence is gradually catching up with how drug-eluting stents are already being used in day-to-day practice.[2] Part of their editorial deals with findings reported by Dr Marco Valgimigli (University of Ferrara, Italy) and colleagues for the tirofiban/SES combination as compared with abciximab/bare-metal stents.

As Valgimigli et al explain, their study tackles a problem faced in many European countries, where DESs are not specifically reimbursed. Current PCI guidelines recommend abciximab as adjunctive therapy in PCI, but the cost of abciximab is €1900 (US $2432), compared with tirofiban (€580, or US $742). At least one study has documented that where unrestricted use of DESs has been adopted, the use of abciximab has gone down, possibly in an attempt to offset the high cost of the SES (€1800, or US $2304) compared with a bare-metal stent (€600, or US $768).

"From a European standpoint, there is no other way to afford the use of DES," Valgimigli told heartwire. To use both abciximab and a SES would result in a 50% increase over the current average reimbursement, he says. "We are paid the same irrespective of what we are implanting, bare-metal stent or DES, plus other therapies that we administer to the patient. So it is absolutely impossible to afford both. And yet, you have to use GP IIb/IIIa inhibitors, because these kinds of drugs are giving a mortality benefit to patients, and you also would like to use DESs, but DESs are simply providing a reduction in target vessel revascularization. What we thought is that, by using a cheaper GP IIb/IIIa inhibitor, we could combine both benefits."

The authors note that the only head-to-head trial of tirofiban and abciximab, the TARGET trial, indicated that abciximab was better able to reduce periprocedural MI, but subsequent small studies, reported by heartwire, have suggested that the 10 g/kg-dose of tirofiban in that study was too low.

As such, in Valgimigli et al's study, known as the STRATEGY trial, the investigators used a higher-bolus dose of tirofiban (25 g/kg over three minutes) in the hopes of reducing periprocedural MI risk while lowering overall procedural costs. They report that, at 30 days, there were no significant differences in major adverse cardiovascular events (MACE) between the two groups: SES plus tirofiban vs bare-metal stent plus abciximab. At eight months, target vessel revascularization (TVR) and target lesion revascularization (TLR) rates were significantly lower in the SES/tirofiban group, a finding that also drove the reduction in MACE for the group. Of note, rates of thrombocytopenia were also reduced in the SES/tirofiban group.

"Our results demonstrate that a lower-cost strategy of tirofiban-supported sirolimus-eluting-stent implantation during primary PCI was safe and resulted in improved clinical and angiographic outcomes with respect to a strategy of abciximab-supported bare-metal-stent implantation," Valgimigli et al write.

To heartwire, Valgimigli said that he and his colleagues have embarked on a larger, multicenter trial testing their proposed tirofiban/SES strategy and are also using it in their regular practice. He says reception of the strategy by his European peers has been largely positive: "It's a way to afford something they otherwise could not do," he says. Others have responded less favorably, pointing out that it is impossible to tell from the study design the independent contribution of the two GP IIb/IIIa inhibitors and the SES.

This is a pragmatic trial.

Cohen and Ohman make a similar critique in their editorial, pointing out that a 2x2 factorial design would have clarified the relative merits of the different components, although such a trial would have had to have been larger and thus much more expensive. They also point out that the lack of a formal economic analysis is "somewhat surprising," given that the stated rational for the non-2x2 design was to demonstrate safety and efficacy while preserving costs. The benefit and safety of the 25-g/kg tirofiban loading dose over the standard 10-g/kg dose can also not be fully understood from these data alone, they add.

"This is a pragmatic trial," Ohman said in an interview. "I can't speak for the investigators, but it appears they took a pragmatic point of view. DESs cost more, abciximab costs more, so you wouldn't entertain to use both in a fixed healthcare system, although you could play one off the other. The issue is, of course, that it's not scientifically as clean as doing a factorial design."

Nevertheless, Ohman adds, just by virtue of being a randomized trial of DES in AMI, the STRATEGY trial, albeit small, "is very important."

Before this, he says, "Physicians have been using registry information that in general we should be cautious about using to dictate our practice. And in fact guidelines committee reviewers will consider registry information but tend to sort of downgrade it."

In this instance, Ohman emphasizes, drug-eluting stents are already widely used in clinical practice, so registry data are better than nothing when it comes to getting a snapshot of safety and efficacy. "But with registry data we cannot be absolutely sure about the risk/ benefit ratio, for example. For that you need to do a prospective randomized trial."