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CLINICAL RESEARCH: CLINICAL TRIALS: VIEWPOINT

Actinomycin-eluting stent for coronary revascularization

A randomized feasibility and safety study: The ACTION trial

Patrick W. Serruys, MD, PhD, FACC^*,*, John A. Ormiston, MD, Georgios Sianos, MD, PhD^*, J. Eduardo Sousa, MD, Eberhard Grube, MD, Peter den Heijer, MD^||, Pim de Feyter, MD^*, Pawel Buszman, MD^¶, Albert Schömig, MD^#, Jean Marco, MD^**, Lech Polonski, MD^¶, Leif Thuesen, MD, Andreas M. Zeiher, MD, J.H. Nicholas Bett, MD, Maarten J. Suttorp, MD^||||, Helmut D. Glogar, MD^¶¶, Mark Pitney, MD^##, Gerard T. Wilkins, MD^***, Robert Whitbourn, MD, Susan Veldhof, RN, Karine Miquel, PhD, Rachel Johnson, BA, Leslie Coleman, DVM, Renu Virmani, PhD ACTION Investigators

^* Erasmus Medical Center, Rotterdam, The Netherlands
Green Lane Hospital, Auckland, Australia
Instituto Dante Pazzanese de Cardiologia, Sao Paulo, Brazil
Krankenhaus Siegburg, Siegburg, Germany
^|| Amphia Ziekenhuis, Breda, The Netherlands
^¶ Silesian Heart Disease Center, Katowice, Poland
^# Deutsches Herzzentrum München, Munich, Germany
^** Clinique Pasteur, Toulouse, France
Skejby Syghus, Aarhus, Denmark
Klinikum de J. W. Goethe Universität, Frankfurt, Germany
Prince Charles Hospital, Chermside, Australia
^|||| Sint Antonius Ziekenhuis, Nieuwegein, The Netherlands
^¶¶ Allgemeines Krankenhaus de Stadt Wien, Vienna, Austria
^## Prince of Wales Hospital, Sydney, Australia
^*** Dunedin Hospital, Dunedin, New Zealand
St. Vincent's Hospital, Melbourne, Australia
Guidant Corporation, Diegim, Belgium
Armed Forces Institute of Pathology, Washington, DC

Manuscript received November 20, 2003; revised manuscript received March 8, 2004, accepted March 17, 2004.

^* Reprint requests and correspondence: Dr. Patrick W. Serruys, Professor of Interventional Cardiology, Erasmus Medical Center, Thoraxcentre Bd 408, Dr. Molewaterplein 40, 3015 GD Rotterdam, the Netherlands (Email: p.w.j.c.serruys{at}erasmusmc.nl).

	Abstract

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OBJECTIVES: We sought to demonstrate the safety and performance of the actinomycin D-coated Multilink-Tetra stent(Guidant Corp., Santa Clara, California) in the treatment of patients with single de novonative coronary esions.

BACKGROUND: Drug-eluting stents (DES) releasing sirolimus or paclitaxel dramatically reduce restenosis. The anti-proliferative drug, actinomycin D, which is highly effective in reducing neointimal proliferation in preclinical studies, was selected for clinical evaluation.

METHODS: The multi-center, single-blind, three-arm ACTinomycin-eluting stent Improves Outcomes by reducing Neointimal hyperplasia (ACTION) trial randomized 360 patients to receive a DES (2.5 or 10 µg/cm² of actinomycin D) or metallic stent (MS). The primary end points were major adverse cardiac events (MACE) at 30 days, diameter stenosis by angiography, tissue effects, and neointimal volume by intravascular ultrasound (IVUS) at six months. When early monitoring revealed an increased rate of repeat revascularization, the protocol was amended to allow for additional follow-up for DES patients. Angiographic control of MS patients was no longer mandatory.

RESULTS: The biased selection of DES patients undergoing IVUS follow-up invalidated the interpretation of the IVUS findings. The in-stent late lumen loss and that at the proximal and distal edges were higher in both DES groups than in the MS group and resulted in higher six-month and one-year MACE (34.8% and 43.1% vs. 13.5%), driven exclusively by target vessel revascularization without excess death or myocardial infarction.

CONCLUSIONS: The results of the ACTION trial indicate that all anti-proliferative drugs will not uniformly show a drug class effect in the prevention of restenosis.

Abbreviations and Acronyms   DES = drug-eluting stent   IVUS = intravascular ultrasound   MACE = major adverse cardiac events   MI = myocardial infarction   MS = metallic stent   QCA = quantitative coronary angiography   TSR = target site revascularization   TVF = target vessel failure

	Methods

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Study design.   This was a prospective, randomized, parallel, three-arm, single-blind trial with two doses of drug compared with control. The protocol was approved by the ethics committees of all the participating institutions, and all patients gave written, informed consent.

End points.   The primary safety end points included major adverse cardiac events (MACE) at 30 days and local tissue effects (incomplete stent apposition, persisting dissection, edge stenosis, and thrombus formation) at 6 months. MACE was defined as a composite of death, myocardial infarction (MI) (more than three times the upper limit of normal creatine kinase levels), and revascularization (surgery or percutaneous coronary intervention) attributed to the target site (the stented and 5-mm persistent segments). When target vessel (the vessel containing the target site) revascularization was included in MACE, the composite end point was renamed "target vessel failure" (TVF).

The primary performance end points were the reduction of in-stent volumetric burden assessed by intravascular ultrasound (IVUS) and reduction of target site diameter stenosis by quantitative coronary angiography (QCA) at six months.

The secondary performance end points were TVF at 6 and 12 months and angiographic binary restenosis at 6 months.

Power calculation and sample size.   To detect a difference of 6.6% in diameter stenosis and of 11.5 mm³ in intimal hyperplasia, with a significance level of 0.05 and 90% power, 110 patients would be needed in each of the three arms. A sample size of 120 patients was chosen.

Patient selection.   Patients with stable angina pectoris or silent ischemia and a single de novolesion in a native coronary artery 3.0 mm and 4.0 mm in diameter that could be covered by an 18-mm stent were enrolled. Randomization was done by a telephone allocation service.

Study device.   The three components of the investigational device were the Multilink Tetra stent, a polymeric coating, and an anti-proliferative drug—actinomycin D (3)—in two doses (2.5 and 10 µg/cm² of metal stent surface area). The eluting profile of actinomycin D is targeted to release 80% of drug in 28 days. Stents were 18 mm in length and 3.0, 3.5, or 4.0 mm in diameter.

QCA and IVUS.   The QCA and IVUS analyses were performed as previously described (4,5). Coronary aneurysms were angiographically defined as localized coronary artery dilation 1.5 times the reference diameter (4).

Statistical analysis.   All analyses were based on the intent-to-treat principle. For continuous variables, the mean value ± SD was presented; differences between the treatment groups were evaluated with the Student t test. Discrete variables were expressed as counts and percentages and were analyzed with the Fisher exact test. Event-free survival times were analyzed using the Kaplan-Meier method. Differences between the groups were compared with the use of both the Wilcoxon and log-rank tests.

	Results

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Patient baseline characteristics.   In total, 360 patients were randomly assigned to receive a DES with a dose of 2.5 µg/cm² (n = 120) or 10 µg/cm² (n = 121) or a MS (n = 119). Three patients were de-registered because they did not receive either a DES or control stent. Baseline clinical and angiographic characteristics are presented in Table 1. The significant difference in minimal lumen diameter after the procedure between the MS and DES groups could not be accounted for by procedural differences.

However, early monitoring of a subset of 39 DES patients revealed an increased rate of target site revascularization (TSR), suggesting that the investigational device was not performing as intended. After the sponsor informed the principal investigator and the Data Safety Monitoring Board, the following recommendations were made: 1) accelerated angiographic follow-up for DES patients; 2) a second angiographic and clinical follow-up visit six months later; 3) possible re-intervention for moderate restenosis (>30% DS); 4) extension of clopidogrel administration for at least a further six months for DES patients; and 5) angiographic and IVUS follow-up was no longer mandatory for MS patients, as primary performance end points could not be reached. Consequently, only 65 of 118 MS patients underwent imaging, and 101 had clinical follow-up at 6 months.

Angiographic outcomes.   The in-stent and in-lesion late loss and restenosis rates at six months were higher in both DES groups than in the MS group (Table 2). Aneurysm formation was infrequent, with two cases (3.1%) in the MS group and five (2.2%) in the DES groups.

View larger version (30K): [in this window] [in a new window]   Figure 1 Kaplan-Meier estimates of survival free of repeated target site revascularization up to 365 days among patients who received actinomycin-eluting 2.5 and 10 µg/cm2 stents and those who received the metallic stent. The rate of event-free survival was significantly higher in the control stent group than in the actinomycin stent groups (p < 0.05 by both the Wilcoxon and log-rank tests). Solid circles = control (n = 104); open circles = drug-coated, 2.5 µg/cm2 drug-eluting stent (n = 120); squares = drug-coated, 10 µg/cm2 drug-eluting stent (n = 119).

	Discussion

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The safety of the polymer was demonstrated in the porcine coronary model, where the histologic response was similar to MS to 180 days. Drug-eluting stents with four doses of actinomycin D (2.5, 10, 40, and 70 µg/cm²) were evaluated in preclinical studies in the porcine coronary model by angiography, histomorphometry, and histopathology at 28 days. At this time, all vessels were patent, and there was marked suppression of neointimal formation above the stent with all doses. Neointimal thickness above the internal elastic lamina was decreased in all dose groups compared with the MS control. Medial thinning and necrosis were observed in the high-dose groups, as was positive remodeling. Intimal fibrin deposition and inflammation were present with all doses, but most marked with the higher doses. Based on these preclinical findings, the two lower doses were considered safe for further evaluation in humans, with three months of data pending, which was the practice for MS extended to DES at the time. This trial has demonstrated that 28-day animal data do not provide sufficient information to judge the safety and efficacy of DES.

Conclusions.   This trial demonstrates that not all anti-proliferative drugs are effective in the prevention of restenosis. It has become clear that promise in early preclinical studies (30 days) does not necessarily translate into clinical effectiveness at 6 months and that late safety animal data (90 days) is a prerequisite for clinical investigation (6).

	References

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1. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization N Engl J Med 2002;346:1773-1780.[Abstract/Free Full Text]
2. Grube E, Silber S, Hauptmann KE, et al. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions Circulation 2003;107:38-42.[Abstract/Free Full Text]
3. Muller W, Crothers DM. Studies of the binding of actinomycin and related compounds to DNA J Mol Biol 1968;35:251-290.[CrossRef][Medline]
4. Serruys PW, Degertekin M, Tanabe K, et al. Intravascular ultrasound findings in the multi-center, randomized, double-blind RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) trial Circulation 2002;106:798-803.[Abstract/Free Full Text]
5. Hamers R, Bruining N, Knook M, et al. A novel approach to quantitative analysis of intravascular ultrasound images Comput Cardiol 2001;28:589-592.
6. Schwartz RS, Edelman ER, Carter A, et al. Drug-eluting stents in preclinical studies: recommended evaluation from a consensus group Circulation 2002;106:1867-1873.[Free Full Text]

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