Chourmouzios A. Arampatzis

Unrestricted Utilization of Sirolimus-Eluting Stents Compared With Conventional Bare Stent Implantation in the “Real World” The Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) Registry

Background—The effectiveness of sirolimus-eluting stents in unselected patients treated in the daily practice is currently unknown. Methods and Results—Sirolimus-eluting stent implantation has been used as the default strategy for all percutaneous procedures in our hospital as part of the R apamycin-E luting S tent E valuated A t R otterdam C ardiology H ospital (RESEARCH) registry. Consecutive patients with de novo lesions (n=508) treated exclusively with sirolimus-eluting stents (SES group) were compared with 450 patients who received bare stents in the period just before (pre-SES group). Patients in the SES group more frequently had multivessel disease, more type C lesions, received more stents, and had more bifurcation stenting. At 1 year, the cumulative rate of major adverse cardiac events (death, myocardial infarction, or target vessel revascularization) was 9.7% in the SES group and 14.8% in the pre-SES group (hazard ratio [HR], 0.62 [95% CI, 0.44 to 0.89]; P =0.008). The 1-year risk of clinically driven target vessel revascularization in the SES group and in the pre-SES group was 3.7% versus 10.9%, respectively (HR, 0.35 [95% CI, 0.21 to 0.57]; P <0.001). Conclusions—Unrestricted utilization of sirolimus-eluting stents in the “real world” is safe and effective in reducing both repeat revascularization and major adverse cardiac events at 1 year compared with bare stent implantation.

Clinical, Angiographic, and Procedural Predictors of Angiographic Restenosis After Sirolimus-Eluting Stent Implantation in Complex Patients An Evaluation From the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) Study

Background—The factors associated with the occurrence of restenosis after sirolimus-eluting stent (SES) implantation in complex cases are currently unknown. Methods and Results—A cohort of consecutive complex patients treated with SES implantation was selected according to the following criteria: (1) treatment of acute myocardial infarction, (2) treatment of in-stent restenosis, (3) 2.25-mm diameter SES, (4) left main coronary stenting, (5) chronic total occlusion, (6) stented segment >36 mm, and (7) bifurcation stenting. The present study population was composed of 238 patients (441 lesions) for whom 6-month angiographic follow-up data were obtained (70% of eligible patients). Significant clinical, angiographic, and procedural predictors of post-SES restenosis were evaluated. Binary in-segment restenosis was diagnosed in 7.9% of lesions (6.3% in-stent, 0.9% at the proximal edge, 0.7% at the distal edge). The following characteristics were identified as independent multivariate predictors: treatment of in-stent restenosis (OR 4.16, 95% CI 1.63 to 11.01; P <0.01), ostial location (OR 4.84, 95% CI 1.81 to 12.07; P <0.01), diabetes (OR 2.63, 95% CI 1.14 to 6.31; P =0.02), total stented length (per 10-mm increase; OR 1.42, 95% CI 1.21 to 1.68; P <0.01), reference diameter (per 1.0-mm increase; OR 0.46, 95% CI 0.24 to 0.87; P =0.03), and left anterior descending artery (OR 0.30, 95% CI 0.10 to 0.69; P <0.01). Conclusions—Angiographic restenosis after SES implantation in complex patients is an infrequent event, occurring mainly in association with lesion-based characteristics and diabetes mellitus.

Coronary Restenosis After Sirolimus-Eluting Stent Implantation Morphological Description and Mechanistic Analysis From a Consecutive Series of Cases

Background We describe the clinical and morphological patterns of restenosis after sirolimus‐eluting stent (SES) implantation. Methods and Results From 121 patients with coronary angiography obtained >30 days after SES implantation, restenosis (diameter stenosis >50%) was identified in 19 patients and 20 lesions (located at the proximal 5‐mm segment in 30% or within the stent in 70%). Residual dissection after the procedure or balloon trauma outside the stent was identified in 83% of the proximal edge lesions. Lesions within the stent were focal, and stent discontinuity was identified in some lesions evaluated by intravascular ultrasound. Conclusions Sirolimus‐eluting stent edge restenosis is frequently associated with local trauma outside the stent. In‐stent restenosis occurs as a localized lesion, commonly associated with a discontinuity in stent coverage. Local conditions instead of intrinsic drug‐resistance to sirolimus are likely to play a major role in post‐SES restenosis. (Circulation. 2003; 108:257‐260.)

Early Outcome After Sirolimus-Eluting Stent Implantation in Patients With Acute Coronary Syndromes Insights From the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) Registry

OBJECTIVES This study evaluated the early outcomes of patients with acute coronary syndromes (ACS) treated with sirolimus-eluting stents (SES). BACKGROUND The safety of SES implantation in patients with a high risk for early thrombotic complications is currently unknown. METHODS Sirolimus-eluting stents have been utilized as the device of choice for all percutaneous procedures in our institution, as part of the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) registry. After four months of enrollment, 198 patients with ACS had been treated exclusively with SES (64% of those treated in the period) and were compared with a control group composed of 301 consecutive patients treated with bare stents in the same time period immediately before this study. The incidence of major adverse cardiac events (MACE) during the first month was evaluated (death, nonfatal myocardial infarction [MI], or re-intervention). RESULTS Compared with control patients, patients treated with SES had more primary angioplasty (95% vs. 77%; p < 0.01), more bifurcation stenting (13% vs. 5%; p < 0.01), less previous MI (28% vs. 45%; p < 0.01), and less glycoprotein IIb/IIIa inhibitor utilization (27% vs. 42%; p < 0.01). The 30-day MACE rate was similar between both groups (SES 6.1% vs. control patients 6.6%; p = 0.8), with most complications occurring during the first week. Stent thrombosis occurred in 0.5% of SES patients and in 1.7% of control patients (p = 0.4). In multivariate analysis, SES utilization did not influence the incidence of MACE (odds ratio 1.0 [95% confidence interval: 0.4 to 2.2]; p = 0.97). CONCLUSIONS Sirolimus-eluting stent implantation for patients with ACS is safe, with early outcomes comparable with bare metal stents.

Sirolimus-Eluting Stent Implantation in ST-Elevation Acute Myocardial Infarction A Clinical and Angiographic Study

Background—Sirolimus-eluting stents (SES) have recently been proven to reduce restenosis and reintervention compared with bare stents. Safety and effectiveness of SES in acute myocardial infarction remain unknown. Methods and Results—Since April 16, 2002, a policy of routine SES implantation has been instituted in our hospital, with no clinical or anatomic restrictions, as part of the RESEARCH (Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital) registry. During 6 months of enrollment, 96 patients with ST-elevation acute myocardial infarction underwent percutaneous recanalization and SES implantation; these patients comprise the study population. The incidence of major adverse cardiac events (death, nonfatal myocardial infarction, reintervention) was evaluated. Six-month angiographic follow-up was scheduled per protocol. At baseline, diabetes mellitus was present in 12.5% and multivessel disease in 46.9%. Primary angioplasty was performed in 89 patients (92.7%). Infarct location was anterior in 41 (42.7%) of the cases, and 12 patients (12.5%) had cardiogenic shock. Postprocedural TIMI-3 flow was achieved in 93.3% of the cases. In-hospital mortality was 6.2%. One patient (1.1%) had reinfarction and target lesion reintervention the first day as a result of distal dissection and acute vessel occlusion. During follow-up (mean follow-up of 218±75 days), 1 patient died (1.1%), no patient had recurrent myocardial infarction, and there were no additional reinterventions. No early or late stent thromboses were documented. At angiographic follow-up (70%), late loss was −0.04±0.25, and no patient presented angiographic restenosis. Conclusions—In this study, sirolimus-eluting stent implantation for patients with ST-elevation acute myocardial infarction was safe without documented angiographic restenosis at 6 months.

Post-sirolimus-eluting stent restenosis treated with repeat percutaneous intervention: late angiographic and clinical outcomes.

Background—We evaluated the clinical and angiographic outcomes of patients presenting with restenosis after sirolimus-eluting stent (SES) implantation treated with repeated percutaneous intervention. Methods and Results—A total of 24 consecutive patients have undergone repeated percutaneous intervention to treat post-SES restenosis (27 lesions). The restenosis was located within the stent in 93% of lesions. From the 27 lesions, 1 (4%) was re-treated with a bare stent, 3 (11%) were treated with balloon dilatation, and the remaining 23 lesions (85%) were treated with repeated drug-eluting stent implantation (SES in 12 lesions [44%], paclitaxel-eluting stents in 11 lesions [41%]). The event-free survival rate was 70.8% after a median follow-up of 279 days from the post-SES treatment. The overall recurrent restenosis rate was 42.9%. The risk of recurrent restenosis was increased for patients with hypercholesterolemia, previous angioplasty, failed brachytherapy, post-SES restenosis needing early (<6 months) treatment, and post-SES restenosis treated with balloon dilatation. The recurrent restenosis rate of originally de novo lesions re-treated with drug-eluting stents was 18.2%. Conclusions—Even though de novo lesions treated with SES at baseline and re-treated with drug-eluting stents had reasonably better outcomes than other lesion types and strategies, our study shows that the treatment of post-SES restenosis is currently suboptimal and warrants further investigation.

A prospective, randomized trial of intravascular-ultrasound guided compared to angiography guided stent implantation in complex coronary lesions: The AVIO trial

BACKGROUND No randomized studies have thus far evaluated intravascular ultrasound (IVUS) guidance in the drug-eluting stent (DES) era. The aim was to evaluate if IVUS optimized DES implantation was superior to angiographic guidance alone in complex lesions. METHODS Randomized, multicentre, international, open label, investigator-driven study evaluating IVUS vs angiographically guided DES implantation in patients with complex lesions (defined as bifurcations, long lesions, chronic total occlusions or small vessels). Primary study endpoint was post-procedure in lesion minimal lumen diameter. Secondary end points were combined major adverse cardiac events (MACE), target lesion revascularization, target vessel revascularization, myocardial infarction (MI), and stent thrombosis at 1, 6, 9, 12, and 24 months. RESULTS The study included 284 patients. No significant differences were observed in baseline characteristics. The primary study end point showed a statistically significant difference in favor of the IVUS group (2.70 mm ± 0.46 mm vs. 2.51 ± 0.46 mm; P = .0002). During hospitalization, no patient died, had repeated revascularization, or a Q-wave MI. No difference was observed in the occurrence of non-Q wave MI (6.3% in IVUS vs. 7.0% in angio-guided group). At 24-months clinical follow-up, no differences were still observed in cumulative MACE (16.9%vs. 23.2 %), cardiac death (0%vs. 1.4%), MI (7.0%vs. 8.5%), target lesion revascularization (9.2% vs. 11.9%) or target vessel revascularization (9.8% vs. 15.5%), respectively in the IVUS vs. angio-guided groups. In total, only one definite subacute stent thrombosis occurred in the IVUS group. CONCLUSIONS A benefit of IVUS optimized DES implantation was observed in complex lesions in the post-procedure minimal lumen diameter. No statistically significant difference was found in MACE up to 24 months.

Effectiveness of sirolimus-eluting stent for treatment of left main coronary artery disease.

The present study reports on the clinical outcome of 31 consecutive patients with left main coronary artery disease treated with a sirolimus-eluting stent. The implantation of this stent was associated with abolition of post-discharge fatal events and percutaneous reintervention.

Routine sirolimus eluting stent implantation for unselected in-stent restenosis: insights from the rapamycin eluting stent evaluated at Rotterdam cardiology hospital (RESEARCH) registry

Objective: To assess the effectiveness of routine sirolimus eluting stent (SES) implantation for unselected patients with in-stent restenosis and to provide preliminary information about the angiographic outcome for lesion subgroups and for different in-stent restenosis patterns. Design: Prospective, single centre registry. Setting: Tertiary referral centre. Patients: 44 consecutive patients (53 lesions) without previous brachytherapy who were treated with SES for in-stent restenosis were evaluated. Routine angiographic follow up was obtained at six months and the incidence of major adverse cardiovascular events was evaluated. Results: At baseline, 42% of the lesions were focal, 21% diffuse, 26% proliferative, and 11% total occlusions. Small vessel size (reference diameter ⩽ 2.5 mm) was present in 49%, long lesions (> 20 mm) in 30%, treatment of bypass grafts in 13%, and bifurcation stenting in 18%. At follow up, post-SES restenosis was observed in 14.6%. No restenosis was observed in focal lesions. For more complex lesions, restenosis rates ranged from 20–25%. At the one year follow up, the incidence of death was 0, myocardial infarction 4.7% (n  =  2), and target lesion revascularisation 16.3% (n  =  7). The target lesion was revascularised because of restenosis in 11.6% (n  =  5). Conclusions: Routine SES implantation is highly effective for focal in-stent restenosis and appears to be a promising strategy for more complex patterns of restenosis.

Effectiveness of sirolimus-eluting stent implantation for recurrent in-stent restenosis after brachytherapy

C vascular brachytherapy is, to date, the only effective treatment available for complex instent restenosis (ISR).1 However, its efficacy is hampered by late restenosis,2 late thrombosis,3,4 edge effect,5 geographic miss,6 and delayed healing.3 Moreover, the fate of the patients after “failed” brachytherapy is uncertain, as well as the result of the various percutaneous treatments employed thereafter. Sirolimus is a macrolide antibiotic produced by Streptomyces hygroscopicus with immunosuppressive effects; it is approved for the prevention of renal transplant rejection.7 The main effect of sirolimus is the interruption of G1 to S cell cycle progression mediated by its binding to a cytosolic receptor (FK506 protein binding protein 12) and a cascade of subsequent actions. Importantly, sirolimus inhibits proliferation and migration of vascular smooth muscle cells, a key element in the development of restenosis after percutaneous coronary interventions (PCIs). Recently, stent-based local sirolimus delivery has been shown to strongly suppress neointimal hyperplasia and prevent restenosis in de novo lesions followed up for 2 years.8,9 The revolutionary results obtained with drugeluting stents have encouraged the assessment of their efficacy in more complex clinical and morphologic subsets. The first human experience evaluating the sirolimus-eluting stent (SES) for the treatment of ISR has been recently reported; it showed this strategy to be highly effective.10 We describe here the first series of patients treated with SESs for recurrent ISR after brachytherapy. • • • The patients described in this report consist of 2 cohorts treated during separate time periods. The first cohort was treated between March 2001 and June 2001, as part of a pilot study on SESs for treatment of ISR. Since April 2002, shortly after European Community market approval, SES implantation has been adopted as the default strategy in all patients treated with PCI at our institution, irrespective of clinical presentation and coronary morphology. These latter patients have been included in the RESEARCH Registry (Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospitals) and will be followed up for 1 year.11 The only exclusion criteria were unavailability of an adequately sized SES at the time of the procedure and enrollment in another revascularization protocol (SESs were available in diameters from 2.25 to 3.0 mm and lengths of 8, 18, and 33 mm). All patients treated with SES after “failed” brachytherapy were scheduled for 6-month angiography. ISR was defined as 50% diameter stenosis by quantitative coronary angiography within a previously stented vessel segment and classified as proposed by Mehran et al.12 Treatment strategy and device utilization other than stenting was left to the physician’s discretion. The procedure was considered successful when residual stenosis 30% by quantitative coronary angiography was achieved together with Thrombolysis In Myocardial Infarction (TIMI) flow grade 2 to 3. The study stent utilized was the sirolimus-eluting Cypher (Cordis Europa NV, Johnson & Johnson, Roden, The Netherlands), which contains a 140 g sirolimus/cm metal surface area in a slow release formulation ( 28 days). Pretreatment with clopidogrel for 48 hours or a 300-mg loading dose was required. During the procedure, intravenous heparin was given to maintain an activated clotting time 300 seconds. After the procedure, all patients received aspirin indefinitely ( 75 mg/day) and clopidogrel (75 mg/day) for at least 2 months. Clinical status information was collected at follow-up visits or by telephone contact with the patient or referring physician. Data are presented as number and relative percentage or mean SD. Median and range have been reported when deemed necessary for a better description. From the beginning of the study until August 15, 2002, 12 consecutive patients (both cohorts) underwent PCI with SES implantation for recurrent ISR after local radiation therapy. All of them presented with angina pectoris and/or myocardial ischemia as documented by stress test or thallium scan. Coronary brachytherapy had been previously performed in 11 patients with catheter-based local irradiation (10 beta, 1 gamma) and in 1 patient with phosphorus-32 radioactive stent implantation. Baseline clinical and angiographic characteristics are listed in Tables 1 and 2, respectively. Nine patients (75%) had had more than 1 previous episode of restenosis. Average time from the preceding percutaneous reintervention was 24 months (range 111 to 1,678 days, median 719). Remarkably, 9 patients (75%) presented with a From Erasmus MC, Thoraxcenter, Rotterdam, The Netherlands. Dr. Serruys’ address is: Erasmus MC, Thoraxcenter, Bd404, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. E-mail: p.w.j. c.serruys@erasmusmc.nl. Manuscript received January 16, 2003; revised manuscript received and accepted April 14, 2003.