Author + information
- Received November 20, 2003
- Revision received March 8, 2004
- Accepted March 17, 2004
- Published online October 6, 2004.
- 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
- ↵*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
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/cm2of 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.
Restenosis after stent implantation remains a major limitation of efficacy. Drug-eluting stents (DES) with sirolimus (1) and paclitaxel (2) have significantly reduced restenosis in simple lesions, compared with the metallic stent (MS). Actinomycin D affects the “S” phase of the cell cycle by forming a stable complex with double-stranded deoxyribonucleic acid inhibiting ribonucleic acid synthesis and is a powerful inhibitor of cell proliferation (3). To create the eluting stent, actinomycin was coated onto the stainless-steel Multilink Tetra stent in a polymer. We aimed to test the safety and efficacy of two doses of actinomycin D compared with the MS.
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.
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 mm3in 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.
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.
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/cm2of 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
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 ttest. 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.
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.
Procedural characteristics and clinical outcomes in the hospital and at one month
The procedural success rate was 99%. In-hospital MACE was confined to the four patients (1.1%) with non–Q-wave MI. The MACE rates at 30 days ranged from 0.8% to 2.5%, without differences between groups.
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.
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.
Clinical outcomes at 12 months
At 12 months, MACE and TVF were higher in the DES than in the MS patients, mainly due to increased TSR (Table 3).Of the 2 deaths, the 1 with a MS was sudden at 44 days, and the 1 with low-dose DES was due to MI at 306 days. After 30 days, there were 2 additional non–Q-wave MIs in the low-dose and 1 in the high-dose DES arm. To 1 year, there were 14 DES patients who had a second re-intervention, and in 2, a third re-intervention (Fig. 1).
There was late-acquired incomplete stent apposition in six patients in the low-dose group and seven in the high-dose group. At variance with the angiographic findings, there were apparently no differences between groups in volumetric obstruction measured by IVUS. This discrepancy is the result of a biased selection of DES patients undergoing IVUS during follow-up, as demonstrated by the higher binary “vessel segment” restenosis rate (32% and 47.8%) in the DES patients who did not undergo IVUS follow-up, compared with those who did (25.8% and 23.7%) (Table 4).This biased selection invalidated interpretation of the IVUS findings.
This trial showed that while in-hospital and one-month outcomes were similar in each group, by six months there was increased restenosis, late lumen loss, and TSR in the DES arm. Despite this increased rate of restenosis, mortality and MI rates were very low.
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.
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).
- Abbreviations and acronyms
- drug-eluting stent
- intravascular ultrasound
- major adverse cardiac events
- myocardial infarction
- metallic stent
- quantitative coronary angiography
- target site revascularization
- target vessel failure
- Received November 20, 2003.
- Revision received March 8, 2004.
- Accepted March 17, 2004.
- American College of Cardiology Foundation
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