HORIZONS AMI: Drug-Eluting Stent Safe and Effective in the Setting of STEMI

October 16, 2008

October 16, 2008 (Washington, DC) — Implanting the Taxus (Boston Scientific) drug-eluting stent in ST-segment-elevation MI (STEMI) patients reduces target lesion revascularization (TLR) and binary angiographic restenosis at one year compared with the use of the Express bare-metal stent (Boston Scientific), a new study has shown. In addition to reducing TLR rates at 12 months, the drug-eluting stent was equivalent to its bare-metal counterpart in terms of major adverse cardiovascular adverse events (MACE), including death, MI, stroke, and stent thrombosis, report investigators.

"The implantation of the paclitaxel-eluting Taxus stent compared with the bare-metal Express stent resulted in a significant 41% reduction at one year in the primary-efficacy end point of ischemia-driven TLR and a significant 56% reduction in the major secondary efficacy end point of binary restenosis," said Dr Gregg Stone (Columbia University, New York) during the late-breaking clinical-trials sessions here at the TCT 2008 meeting.

The study is ongoing, and patients will be monitored for five years, reported Stone. Commenting on the results of the study, Dr David Faxon (Brigham and Women's Hospital, Boston, MA) said the complex trial, known as HORIZONS AMI, is one the largest to date in these patients, and while it provides answers about the safety and benefits of drug-eluting stents in STEMI patients, it was not powered to address the relative risk of stent thrombosis or mortality with the different stents. "I don't think we can extrapolate the results into those two key areas," said Faxon.

Drug-Eluting Stents in STEMI Seen on the HORIZON

More than 3600 patients took part in HORIZONS AMI, from 123 centers in 11 countries. All patients had STEMI with a symptom onset of less than 12 hours. Patients were first randomized in a 1:1 fashion to unfractionated heparin plus a GP IIb/IIIa inhibitor (abciximab or eptifibatide) or to bivalirudin monotherapy plus provisional GP IIb/IIIa inhibitors for large thrombus or refractory no-flow. The 30-day results of the pharmacology study have been presented and published previously [1], and Dr Roxana Mehran (Columbia University, New York) presented the one-year results of the study at the late-breaking clinical-trials session [see sidebar].

Following emergent angiography, 3006 patients were then randomized in a 3:1 fashion to the paclitaxel-eluting stent or the bare-metal stent and followed for one year. All patients were treated with aspirin for the entire study duration, with an additional antiplatelet recommended for at least one year following PCI. Angiographic follow-up was performed at 13 months in order to not interfere with the 12-month clinical follow-up.

At 12 months, treatment with the drug-eluting stent reduced ischemic TLR, the study's primary-efficacy end point, by 41% compared with the bare-metal stent. MACE, a composite of all-cause mortality, reinfarction, stroke, and stent thrombosis, were equivalent with the two stents.

HORIZONS-AMI: Primary Efficacy and Safety End Points

End point Taxus, n=2257 (%) Express bare-metal stent, n=749 (%) Hazard ratio (95% CI)
Ischemic target lesion revascularization 4.5 7.5 0.59 (0.43–0.83)
Safety MACE 8.1 8.0 1.02 (0.76–1.36)
All-cause mortality 3.5 3.5 0.99 (0.64–1.55)
MI 3.7 4.5 0.81 (0.54–3.22)
Stroke 1.0 0.7 1.52 (0.58–4.00)

Stent thrombosis 3.1 3.4 0.92 (0.58–1.45)
Binary restenosis, per lesion, at 13 mo 10.0 22.9 0.44 (0.33–0.57)
Binary restenosis, per patient, at 13 mo 10.9 24.9 0.4 (0.33–0.57)

Stone said the study was not powered to address the relative risks of stent thrombosis or mortality with the two stents, and that is why a composite MACE end point was used. Combining this study with other studies, however, increases the number of MI patients treated with drug-eluting stents and provides reassurances about safety. Results from the Massachusetts stent registry, for example, have suggested that drug-eluting stents reduce two-year mortality in acute-MI patients, as compared with bare-metal stents.

"In that regard, I will tell you that in all those other trials, the point estimates for mortality and stent thrombosis are actually on the side favoring drug-eluting stents," said Stone. "Mortality in this study was exactly the same, and stent thrombosis was slightly on the side favoring drug-eluting stents, so when you add all of that up, you're not going to see a safety concern," he added.

Modest Benefit, But Confidence About Safety

Commenting on the study, Dr David Cohen (Saint Luke's Mid America Heart Institute, Kansas City, MO) told heartwire there have been safety concerns about drug-eluting stents in STEMI patients, particularly in putting the stents in the setting of a ruptured plaque and thrombus, which might increase the risk of subsequent events.

"This study really helps to substantially answer both of those questions," said Cohen. "It shows a revascularization benefit, but I do think the benefit is quite modest--a 3% absolute difference. You need to treat about 30 patients to benefit one in terms of repeat revascularization. I think the real strength of the study was the safety analysis, showing no difference in mortality or stent thrombosis, which does tell us in a real-world trial that we can use drug-eluting stents reasonably safely."

Cohen pointed out, however, that despite the relatively generous inclusion criteria, the results do not apply to all patients. It is a clinical-trial population, and all patients were screened to determine whether they could take dual antiplatelet therapy for at least six months. Still, at least with the Taxus stent, clinicians can be very confident saying it is safe in STEMI patients, he said.

"I think there are a lot of labs, including our own, where we use drug-eluting stents in only a minority of STEMI patients," said Cohen. "I think this is going to give us a lot of comfort and maybe go back to where we were three or four years ago, where we were using them quite a bit."

After the presentation of the HORIZONS AMI studies, an assembled panel of experts gathered on stage to discuss the findings. Dr Giles Montalescot (Hôpital La Pitie Salpetriere, Paris, France) said the findings suggest "no limitations for drug-eluting stents in STEMI patients," and Dr Eric Bates (University of Michigan Medical Center, Ann Arbor) also said the findings are reassuring. Faxon told the audience that remaining questions include assessing the risks of late-stent thrombosis and mortality, as well as how other drug-eluting stents perform in the same setting. In addition, cost remains an issue.

"We need to really understand the cost-effectiveness of the strategy, particularly in today's economic crisis," he said.

HORIZONS AMI One-Year Pharmacology Study Also Presented

Investigators also presented one-year data from the pharmacology arm of the HORIZONS AMI trial. First presented last year at the TCT meeting, 30-day results showed that bivalirudin significantly reduced net adverse clinical events--a composite of major bleeding and MACE--as well as major bleeding alone, as compared with heparin plus a GP IIb/IIIa inhibitor.

At one year, the benefits of bivalirudin monotherapy in STEMI patients undergoing primary PCI were maintained. There was a 16% reduction in the one-year rate of composite net adverse clinical events, as well as a significant 39% reduction in major bleeding.

There was also a significant 31% reduction in all-cause mortality and 43% reduction in cardiac mortality, or an absolute reduction of 1.4% and 1.7%, respectively. The type of stent used--either drug-eluting or bare-metal--did not affect any of the end points. Investigators noted that all-cause and cardiac mortality were not primary end points, but they were excited about the findings, saying they should alter clinical practice.

"I think the results are really quite striking and define a new standard of care for PCI with respect to antithrombotic therapy," said Dr Deepak Bhatt (Brigham and Women's Hospital, Boston, MA), the discussant of HORIZONS AMI during the late-breaking clinical-trials session.

Cohen agreed but added that clinicians are often slow to change entrenched pharmacologic habits. Moreover, some were likely concerned about the higher rates of acute stent thrombosis (<24 hours) observed with bivalirudin, even though there was no increased thrombosis risk observed between 24 hours and 30 days or any difference between the arms at one year.

Stone reports research support from Boston Scientific, Abbott Vascular, and the Medicines Company, as well as honoraria from Eli Lilly. Mehran reports consulting for Abbott Vascular, Cordis, Medtronic, Eli Lilly, Daiichi Sankyo, and Sanofi-Aventis. Faxon reports research support from Boston Scientific and consulting for Johnson & Johnson, Bristol-Myers Squibb, and GlaxoSmithKline. Bhatt reports research support from Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi-Aventis, and the Medicines Company. He consults for Arena Pharmaceuticals, Astellas, AstraZeneca, Bristol-Myers Squibb, Cardax, Centocor, Cogentus, Daiichi Sankyo, Eisai, Eli Lilly, GlaxoSmithKline, Johnson & Johnson, Ortho-McNeil, Medtronic, Millennium, Molecular Insights, Otsuka America, Parigenix, PDL BioPharma, Philips Medical, and Portola. Montalescot reports consulting for and receiving research support from Bristol-Myers Squibb, Guerbet Medical, Medtronic, Boston Scientific, Cordis, Stago, Centcor, Sanofi-Aventis, Eli Lilly, the Medicines Company, Schering-Plough, Merck, Sharpe & Dohme, and GlaxoSmithKline. Cohen reports research support from Cordis, Boston Scientific, Eli Lilly, Angle Medical Systems, Momenta, and Invitrox as well as consulting for Medtronic. Bates reports no conflicts of interest.

  1. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358:2218-2230. Abstract

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