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J Am Coll Cardiol, 2003; 41:184-189 © 2003 by the American College of Cardiology Foundation |
* Thoraxcenter, University Hospital Rotterdam, Rotterdam, The Netherlands
Brigham and Women’s Hospital, Boston, Massachusetts, USA
Manuscript received May 29, 2002; revised manuscript received July 30, 2002, accepted August 19, 2002.
* Reprint requests and correspondence: Prof. Patrick W. Serruys, Head of Interventional Department, Thoraxcentre, Bd. 408, University Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands.
Serruys{at}card.azr.nl
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Abstract |
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BACKGROUND: The treatment of ISR remains a therapeutic challenge, since many pharmacological and mechanical approaches have shown disappointing results. The SESs have been reported to be effective in de-novo coronary lesions.
METHODS: Sixteen patients with severe, recurrent ISR in a native coronary artery (average lesion length 18.4 mm) and objective evidence of ischemia were included. They received one or more 18 mm Bx VELOCITY SESs (Cordis Waterloo, Belgium). Quantitative angiographic and three-dimensional intravascular ultrasound (IVUS) follow-up was performed at four months, and clinical follow-up at nine months.
RESULTS: The SES implantation (n = 26) was successful in all 16 patients. Four patients had recurrent restenosis following brachytherapy, and three patients had totally occluded vessels preprocedure. At four months follow-up, one patient had died and three patients had angiographic evidence of restenosis (one in-stent and two in-lesion). In-stent late lumen loss averaged 0.21 mm and the volume obstruction of the stent by IVUS was 1.1%. At nine months clinical follow-up, three patients had experienced four major adverse cardiac events (two deaths and one acute myocardial infarction necessitating repeat target vessel angioplasty).
CONCLUSIONS: The SES implantation in patients with severe ISR lesions effectively prevents neointima formation and recurrent restenosis at four months angiographic follow-up.
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Intracoronary radiation is the only therapy for ISR proven to be effective in randomized clinical trials (3,4). However, restenosis is not eliminated. The wide spread use of brachytherapy is limited by logistic requirements and potential side effects (5,6).
Attention is now focusing on the concept of local pharmacologic intervention by drug-eluting stents. Sirolimus has been shown to be effective in de-novo lesions with a remarkable restenosis rate of 0% in some studies (7,8). These findings provoked considerable enthusiasm (9), but also profound skepticism (10). The major criticism focused on the lack of data in complex lesions and on the lack of long-term data.
The aim of our study was to evaluate the effectiveness of sirolimus eluting stents (SESs) in preventing neointimal formation in patients with severe ISR.
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Methods |
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ISR definition
In-stent restenosis was defined as >50% diameter stenosis (DS) by quantitative coronary angiography (QCA) within a previously (at least four months) stented vessel segment. In-stent restenosis was classified as focal (<10 mm long), diffuse (>10 mm long), proliferative (>10 mm long and extending outside the stent edges), or totally occluded (11).
Procedure
All ISR lesions were predilated. Then, a SES Bx VELOCITY (Cordis Waterloo, Belgium) was implanted using conventional techniques. The stent was loaded with 140 µg sirolimus/cm2 metal surface area in a slow release formulation (>28 days drug release). All stents were 18 mm long and 2.5 to 3.5 mm in diameter. Postdilatation was performed as required.
All patients received aspirin (325 mg/day, indefinitely) and clopidogrel (300 mg loading dose immediately after stent implantation followed by 75 mg/day for two to four months at the discretion of the operator).
QCA and intravascular ultrasound (IVUS) analysis
Serial coronary angiography was performed at baseline (before and after intervention) and at four months follow-up. In-stent and in-lesion (stent plus 5 mm proximal and 5 mm distal to the stent) restenosis was defined as >50% DS at follow-up.
The QCA analysis was performed by an independent core laboratory (Brigham and Women’s Hospital, Boston, Massachusetts).
Serial IVUS was performed using motorized pullback at a constant speed of 0.5 mm/s postprocedure and at four months follow-up. The quantitative ultrasound analyses were performed by an independent core laboratory (Cardialysis BV, Rotterdam, The Netherlands).
Statistical analysis
Continuous variables are expressed as mean ± standard deviation. Because of the small sample size no statistical comparison was performed. Only the IVUS data were expressed as mean and 95% confidence interval.
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Results |
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Angiographic outcome and three-dimensional IVUS analysis
The QCA data are presented in Table 3 and the IVUS data are shown in Table 4. Satisfactory angiographic results were achieved in 15 out of 16 patients. Representative sequences of angiograms and IVUS from a single patient are shown in Figure 1.
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Two other patients showed 59% and 62% in-lesion DS, respectively, at follow-up without evidence of cardiac ischemia. The first patient had received two SESs. Both IVUS and angiographic analysis revealed a gap of 
2.2 mm between the two SESs. Neointimal hyperplasia (NIH) occurred precisely at the bare segment between the two stents (Fig. 2). A repeat intervention was not performed because the patient was asymptomatic, intracoronary pressure measurement showed a fractional flow reserve of 0.80, and the stenosis was assessed as 50% DS by online QCA. The second case was the heart transplanted recipient who had a 62% DS proximal to the stent. The vessel, which had Thrombolysis In Myocardial Infarction (TIMI) grade 1 flow prior to implantation of the SESs, had been extensively ballooned during the procedure and the injured area was not completely covered by SES. As the patient had no evidence of ischemia by radionuclide scintigraphy, repeat revascularization was not performed. All other patients showed only minimal late lumen loss.
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Nine months clinical outcome
The major adverse cardiac events are summarized in Table 5. One patient with severe three-vessel disease died suddenly 3.5 months after successful implantation of two overlapping SESs in the right coronary artery. Unfortunately, no clinical or autopsy information is available.
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The third patient, who had failed brachytherapy, had no evidence of NIH at a four months follow-up IVUS, but died due to congestive heart failure 9.5 months after the index procedure. This 79-year-old man with left main coronary artery disease and congestive heart failure had undergone bypass surgery twice and had percutaneous coronary intervention four times before the index procedure.
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Discussion |
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Important clinical findings. Despite our relatively small patient population, we witnessed some remarkable phenomena. First, we observed NIH in a gap between two SESs and at a site of injury that was not completely covered by the SES. This case illustrates the therapeutic power of SESs, since the patient serves as his own control (Fig. 2).
Second, we monitored the treatment of a patient with severe transplant vasculopathy. The patient presented with a small, diffusely diseased vessel and impaired flow (TIMI grade 1) and received two sequential, overlapping 2.5 mm diameter SESs at the site of ISR. The vessel segment proximal to the stents was treated by balloon dilation. At follow-up there was only minimal NIH within the SESs, and angiographic restenosis occurred at the proximal adjacent vessel segment, outside the stents.
Third, we examined the treatment of patients after failed brachytherapy. We treated four patients who had failed brachytherapy, two of whom developed clinical events. The third patient revealed a reappearance of the "black hole" at follow-up IVUS; nonetheless, no significant stenosis was seen at follow-up angiography. Brachytherapy failure patients were responsible for one-third of all adverse events and represent a particular challenge. These patients can have prolonged endothelial dysfunction that can increase the risk of thrombosis; there are no current data available on the combined effect of radiation and cytostatic drug therapy in coronary arteries.
Late vessel occlusion occurred in two additional patients who had not been treated with brachytherapy. One patient with five drug-eluting stents experienced acute vessel closure and developed myocardial infarction after follow-up angiography and IVUS three weeks after discontinuing clopidogrel. Intravascular ultrasound performed at the time of the acute myocardial infarction showed no evidence of NIH within the stents and thrombus formation as the cause for the occlusion. The second patient who had received two SESs died suddenly and we have to consider this as an acute cardiac and possibly thrombotic event. Therefore, it seems wise to propose that patients receiving more than one SES for the treatment of ISR, particularly in the setting of failed brachytherapy, total vessel occlusion, or poorly deployed stents, should receive clopidogrel for an extended period.
Study limitations
This is a small observational study and only lesions with vessel diameter between 2.5 to 3.5 mm were enrolled. Therefore, the results need to be confirmed by randomized and multicenter trials. Additionally, the study comprises four months angiographic and IVUS follow-up. However, the recently reported long-term data, which demonstrated that the four months results are preserved at one year in de-novo lesions, support the notion that our four months data may be predictive of the long-term findings (13).
Conclusions
Sirolimus eluting stent implantation is an effective treatment for patients with complex ISR, even when they are at an intrinsically high risk for complications. As the use of drug-eluting stents increases, their complexity and the range of indications will expand towards higher risk patient populations. In this setting, stenting the whole area injured by the balloon, overlapping SESs properly, and good stent deployment with low residual stenosis, as well as an appropriate anti-platelet regimen will be the keys to successful treatment. When more than one eluting stent is used to treat long in-stent restenotic lesions, IVUS guidance may be advisable to optimize complete coverage of previously implanted bare metal stents and to ensure that the edges of implanted stents are overlapped.
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Acknowledgments |
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Footnotes |
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