Chicago, IL - High-dose tirofiban was "noninferior" to abciximab in terms of resolution of ST-segment elevation at 90 minutes in STEMI patients undergoing primary PCI in the MULTISTRATEGY trial. The study also found that the use of sirolimus-eluting stents appeared safe and reduced target vessel revascularization (TVR) in this population.

The results of the MULTISTRATEGY trial were presented at the American College of Cardiology (ACC) 2008 Scientific Sessions/i2 Summit-SCAI Annual Meeting today and were simultaneously published online in the Journal of the American Medical Association [1].

Dr Marco Valgimigli

Presenting the study, Dr Marco Valgimigli (University of Ferrara, Italy) noted that abciximab has shown benefits over placebo in patients undergoing primary PCI, with better ST-segment resolution and reduced mortality. In a previous head-to-head trial (TARGET), abciximab was shown to be superior to tirofiban in coronary stenting, but it was subsequently suggested that the bolus dose of tirofiban used (10 µg/kg) was suboptimal. They therefore conducted this study to compare a higher bolus dose (25 µg/kg) of tirofiban plus standard infusion with abciximab.

In addition, he explained that there is little evidence available on the use of drug-eluting stents in the STEMI population and that there are concerns about their use in this indication because STEMI patients are thought to be at higher risk for stent thrombosis, a problem that has been associated with drug-eluting stents. The MULTISTRATEGY trial therefore also compared the use of drug-eluting and bare-metal stents in STEMI patients.

The open-label 2x2 factorial study comprised 745 STEMI patients who underwent two randomizations: first to either high-dose tirofiban or abciximab, and second to either sirolimus-eluting stent or uncoated-stent implantation.

For the drug comparison, the main outcome measure was at least 50% ST-segment-elevation resolution at 90 minutes postintervention. Results with the two GP IIb/IIIa blockers were similar, and tirofiban was found to fulfill the criteria for noninferiority to abciximab.

Percent of patients with at least 50% ST-segment resolution at 90 minutes postintervention

At least 50% ST-segment resolution	Abciximab (n=372)	Tirofiban (n=372)	Relative risk (97.5% CI)	p for noninferiority
Patients (%)	83.5	85.3	1.020 (0.958-1.086)	<0.001

Ischemic and hemorrhagic outcomes were similar in the tirofiban and abciximab groups.

For the stent comparison, the major outcome was the rate of major adverse cardiac events, defined as the composite of death from any cause, reinfarction, and clinically driven TVR within eight months. There was a significant reduction in the sirolimus-coated-stent group, which was driven by a reduced rate of TVR. Valgimigli pointed out that the stent-thrombosis rate was similar between the two groups and the incidence of death/MI was not increased in the sirolimus-coated-stent group; there was actually a trend toward a reduction, which he said was "reassuring" for the safety of the use of drug-eluting stents in the STEMI population.

Event rates for uncoated vs sirolimus-eluting stents

Event	Uncoated stent, n=372 (%)	Sirolimus stent, n=372 (%)	p (between stents)
Death/re-MI/TVR	14.5	7.8	0.004
Death	4.0	3.0	0.42
MI	4.6	3.2	0.34
TVR	10.2	3.2	<0.001
Definite/probable stent thrombosis	4.0	2.7	0.31

The discussant for the trial, Dr Magnus Ohman (Duke Clinical Research Institute, Durham, NC), said that this was an important study with an efficient design but that it was probably not big enough to be practice-changing. However, he added that the study "would add to our understanding of optimal therapy in primary PCI and will be important for meta-analysis."

Limited experience with high-dose tirofiban

In the drug comparison, he noted that tirofiban was used in less than 4% of PCI cases in the US, and there were very few data available on this new high-dose regimen. He pointed out that the main end point for the comparison between the two drugs was a surrogate end point, that the trial was really too small to provide definite information on clinical events and safety, and that tirofiban was associated with a numeric (but not statistically significant) increase in bleeding and blood transfusions. "This leaves one to question how safe this new regimen of tirofiban may be," he commented.

Responding to this at an ACC/SCAI press conference, Valgimigli countered that although there was a slight increase in bleeding in the tirofiban group, it was nonsignificant and should not be overinterpreted.

Need longer follow-up for stent comparison

In the stent comparison, Ohman pointed out that the follow-up of eight months was not really long enough to know for sure about the safety of drug-eluting stents in STEMI patients. "I would suggest that death/MI at two years would be a better end point, given the risk of late stent thrombosis in these patients," he said. He added that everyone was waiting for the much larger HORIZONS AMI trial, which will provide more information on the comparison between bare-metal and drug-coated stents in STEMI patients. These results are expected to be presented later this year, probably at the Transcatheter Cardiovascular Therapeutics meeting.

Valgimigli agreed that eight months of follow-up was too short for conclusive answers, but said they would continue to follow the patients long term. He added that the protocol of the MULTISTRATEGY trial mandated dual-antiplatelet treatment for at least three months after stent placement and that more than 60% of patients in the sirolimus-eluting-stent group had stopped taking thienopyridines by eight months, but no increase in stent thrombosis or death/MI was seen in this group. "We have shown that there is nothing to pay for the reduction in restenosis at least up to eight months," he added.

Valgimigli told heartwire that drug-eluting stents were being used in STEMI patients even though there was little evidence for this particular indication. "In some US registries, drug-eluting stents are being used in up to 50% of STEMI patients. But it appears that practice has changed without the science to support it. I would say this figure would be much lower in Europe—more in the region of 10%," he commented.

Press-conference moderator Dr William Knopf (Atlanta Cardiology Group, GA) said that the use of drug-coated stents in STEMI patients is "a very controversial subject. It is not [a] widespread [belief] that drug-eluting stents are safe in AMI patients. I personally believe that they are, but we need more information on stent thrombosis. These data from the MULTISTRATEGY trial are very encouraging," he added.