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Topics: The Impact of Sirolimus-Eluting Stents on Patients at High Risk for Restenosis with Bare Metal Stenting

Faculty/Credentials: Atul Sharma, MD and S.Chiu Wong, MD, Maurice R. and Corinne P. Greenberg, Division of Cardiology, Department of Medicine, The New York Presbyterian Hospital-Weill Cornell Medical College, New York, New York

Learning Objectives. On completion of this activity, participants will be able to: 1. Identify the subgroups of patients at increased risk for in-stent restenosis with bare metal stents; 2. Describe the major trials demonstrating improved efficacy in treating these high risk populations with sirolimus-eluting stents.

Activity instructions. Successful completion of this activity entails reading the article, answering the test questions and obtaining a score of over 70%, and submitting the test and completed evaluation form to the address listed on the form. Tests will be accepted until the expiration date listed below. A certificate of completion will be mailed to you within 60 days. Estimated time to complete this activity: 1 hour

Initial release date: June 31, 2004 Expiration date: June 31, 2005.

Target audience. This educational activity is designed for physicians, nurses and cardiology technologists who treat patients with coronary artery disease.

Accreditation statements. This activity is sponsored by the North American Center for Continuing Medical Education (NACCME).
Physicians: The North American Center for Continuing Medical Education is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The American Medical Association has determined that non-US licensed physicians who participate in this CME activity are eligible for AMA PRA category1 credit.
The North American Center for Continuing Medical Education designates this continuing medical education activity for a maximum of 1 category 1 credit toward the AMA Physician™s Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity.
This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.

Nurses: The North American Center for Continuing Medical Education is an approved provider of continuing nursing education by the Pennsylvania State Nurses Association, an accredited approver by the American Nurses Credentialing Center™s Commission on Accreditation. This continuing nursing education activity was approved for 1 contact hour(s).
Provider approved by the California Board of Registered Nursing, Provider Number 13255 for 1 contact hour.

Radiologic Technologists: Activities approved by the American Medical Association (AMA Category 1) are eligible for ARRT Category B credit as long as they are relevant to the radiologic sciences. Radiologic Technologists, registered by the ARRT, may claim up to 12 Category B credits per biennium.

SICP: Society of Invasive Cardiovascular Professionals (SICP) approved for 1 CEU.

Commercial support disclosure. This educational activity has been supported by an educational grant from Cordis Corporation.

Faculty disclosure information. All faculty participating in Continuing Education programs presented by the North American Center for Continuing Medical Education are expected to disclose to the meeting audience any real or apparent conflict(s) of interest related to the content of their presentation.
Dr. Sharma has nothing to disclose. Dr. Wong discloses he is a consultant and advisory board member for Cordis Corporation, a Johnson & Johnson company.

In 1964, Dotter and Judkins proposed the concept of implanting intravascular stents to support the arterial wall following coronary angioplasty.1 Since that time, predictable angiographic results, improved safety, and proven reductions in target lesion revascularization compared with balloon angioplasty have led to explosive growth in the field of percutaneous coronary stenting. In 1994, less than 1% of the 270,000 angioplasty procedures performed in the US utilized stents.2 Since its approval in 1995 by the FDA for elective procedures, the use of stents has increased dramatically. Coronary stenting provides a mechanical solution to control coronary dissections, prevent acute elastic recoil, and reduce restenosis by routinely increasing target-lesion lumens.3 Initial results of randomized controlled trials demonstrated 25 to 30% reductions in binary restenosis compared with balloon angioplasty.4“5 Subsequent improvements in stent design, flexibility, and deliverability have led to a further decrease in restenosis rates as low as 20% in some studies.6 However, the success of coronary stenting has led to its widespread application in more challenging coronary lesions, and with that, a resultant rise in restenosis rates. Sirolimus-eluting stents (SES) were developed to combat the process of neointimal hyperplasia that ultimately leads to in-stent restenosis, and data from multiple trials have demonstrated large, marked reductions in the rates of target vessel revascularization and angiographic binary restenosis. This review focuses on the impact of sirolimus-eluting stent placement in patients and lesions with traditionally high rates of restenosis with bare metal stenting: patients with diabetes mellitus, small coronary vessels, and long lesions.

Diabetic Patients
Diabetes mellitus has been shown to be an important risk factor for poor outcomes following percutaneous transluminal coronary angioplasty.7 Coronary stents have attenuated both the risk of acute vessel closure and of restenosis compared to balloon angioplasty8 however, the presence of diabetes remains a strong independent risk factor for in-stent restenosis.9 A retrospective observational study by Elezi and colleagues, comparing 715 diabetic patients with 2839 nondiabetic patients, demonstrated increased rates of restenosis (diabetics 37.5% versus nondiabetics 28.3%, p<0.001) and higher rates of death, myocardial infarction (MI), or target vessel revascularization (TVR) at 30 days (diabetics 6.7% versus nondiabetics 3.8%, p<0.0001).10 A greater degree of neointimal hyperplasia is thought to be the mechanism behind the increased restenosis rates, as evidenced by increased late loss and smaller minimum luminal diameter documented on angiographic and intravascular ultrasound follow-up.11 The routine use of abciximab in diabetic patients undergoing percutaneous coronary revascularization with a stent in the EPISTENT trial resulted in a greater than 50% reduction in the need for TVR compared with patients receiving a stent without abciximab (6-month TVR rate of 16.6% in the stent-placebo group versus 8.1% in the stent-abciximab group).12 However, restenosis rates have remained high in other studies involving glycoprotein IIb/IIIa inhibitors and patients with diabetes.13 In a recent trial of 11,500 patients, angiographic restenosis was seen in approximately 33% of all patients treated with bare-metal stents.14 Given that SES aggressively inhibits neointimal hyperplasia,15 there is great optimism that these devices will dramatically impact the rate of restenosis in this high-risk patient subgroup.

The RAVEL (Randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization) trial, published in June of 2002, was a double-blind, placebo-controlled trial comparing the two types of stents for revascularization of single, primary lesions in native coronary arteries.16 The study enrolled 238 patients, and the primary end point was in-stent late lumen loss at 6 months. The percentage of in-stent stenosis of the luminal diameter, rare of binary restenosis, and a composite clinical end point of death, MI, and revascularization (either percutaneous or surgical) was also evaluated. Patients were eligible for the study if they had a single primary lesion 2.5-3.5mm in diameter that could be covered with an 18mm stent. Average lesion length was 9.6mm, with mean vessel size noted as 2.6mm. The SES treatment group demonstrated essentially no late-lumen loss (-0.01±0.33mm) and no episodes of binary restenosis at 6 months. In comparison, the standard-stent group had a late-lumen loss of 0.80±0.53mm and 26.6% restenosis both highly significant reductions. One-year MACE rates were 5.8% in the SES group compared to 28.8% in the bare-metal stent group (p<0.0001), with the difference in events was almost entirely due to a higher TVR rate in the standard-stent group. A sub-group analysis of the 44 diabetic patients in this study, 19 of whom received SES and 25 of whom received bare-metal stents, was recently published.17 In this study, 6 month in-stent late-lumen loss was low for diabetic patients treated with SES, (0.07±0.2mm) in comparison to the bare-metal stent group (0.82±0.5mm, p<0.001), and similar to non-diabetic patients treated with SES (-0.03±0.27mm). There were no episodes of binary restenosis in the diabetic subgroup receiving SES, compared to 42% in diabetics receiving standard stents. Twelve-month clinical MACE rates also favored diabetics receiving SES (90% event-free survival in the SES cohort compared with 52% in the bare-metal group, p<0.01), with the large difference in repeat TVR (0% for SES versus 36% for standard-stent groups, p=0.007) driving the results.

The SIRIUS (Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery) study followed RAVEL and was a larger, (1058 patient) randomized, double-blind trial. SIRIUS again compared SES to bare-metal stents in single, de novo lesions in native coronary arteries.18 In comparison to RAVEL, patients in SIRIUS were:

 Older (mean age 62.3 in SIRIUS versus 60.7 in RAVEL, p=0.04),
 More likely to have had prior revascularization (24.7% previous CABG, 9.5% previous PCI in SIRIUS compared to 18.1% and 1.7% in RAVEL, p<0.001),
 Diabetes mellitus (26.4% versus 18.5%, p=0.10),
 Hyperlipidemia and hypertension (73.6% and 67.7% respectively for patients in SIRIUS in comparison to 51.5% and 49.2% respectively for patients in RAVEL, p<0.001).
 Patients enrolled in SIRIUS also had more frequent multivessel coronary disease (41.6% versus 29.6%, p<0.001)
 and had longer lesions (14.4mm compared with 9.6mm, p<0.001), therefore representing a patient population with more complex coronary disease.

The primary endpoint of the study was target vessel failure at 270 days. The SES treatment group demonstrated a 59% reduction in the primary end point. Target vessel failure occurred in 8.6% of patients treated with SES compared to 21.0% in patients treated with standard stents (p<0.001), with a decrease in TVR again driving the composite end point (4.1% in the SES group versus 16.6% in the bare-metal stent group). In-stent late-lumen loss at 8-month follow-up was 0.17±0.45mm in the SES group in comparison to 1.00±0.70 in the standard stent group, a highly statistically significant difference (p<0.001). Likewise, binary restenosis rates were also markedly different between the two cohorts 3.2% in patients receiving SES versus 35.4% in traditional stent patients. As in RAVEL, there were no significant differences in death, MI, or stent thrombosis between the two groups at 270 days follow-up.

Among the 279 patients with diabetes (26.4% of the total cohort), there was a statistically significant reduction in the rate of target lesion revascularization among patients treated with SES compared to bare-metal stents (6.9% SES versus 22.3% bare-metal stents, p<0.001). A recent paper analyzing 1-year clinical outcomes data from the SIRIUS trial demonstrated that diabetics treated with SES had an approximate 70% reduction in target lesion revascularization rates (8.4% for diabetics treated with SES versus 26.4% for diabetics treated with standard stents), independent of reference vessel diameter and lesion length.19

The above data demonstrate that SES inhibition of neointimal proliferation has a significant impact on the rate of restenosis among diabetics who fulfill enrollment criteria delineated for these two studies. But what about diabetics with even more complex disease real world diabetics? A recently published, non-randomized, consecutive series of patients comprising the RESEARCH registry (Rapamycin-eluting stent evaluated at Rotterdam Cardiology Hospital) sheds some light on this question. In this registry, 508 consecutive patients at Rotterdam hospital received SES as the default stent strategy and were compared to 450 patients receiving bare-metal stents in the time period prior to SES availability. Of these patients, 18% of the SES treatment group, or 91 patients, had diabetes, and were compared to 68 diabetic patients (15%) in the pre-SES group. In this small treatment population, there was a trend towards less TVR at 1 year in the diabetic cohort receiving SES (hazard ratio 0.72, 95% CI 0.30“1.77) which did not reach statistical significance (p=0.50). Diabetes mellitus itself remained a strong predictor of both MACE (hazard ratio 1.62, 95% CI 1.02“2.43, p=0.02) and of TVR itself (hazard ratio 1.81, 95% CI 1.10“2.99, p=0.02).20 These results have been corroborated in other registry data.21

In the future, the FREEDOM trial will compare clinical outcomes of diabetic patients with multi-vessel coronary artery disease, following treatment with either percutaneous coronary intervention using SES or coronary artery bypass surgery. The study is a multi-center, prospective, randomized trial with the primary endpoint of all-cause mortality at 5 years. Enrollment of some 2300 patients is scheduled to begin in the fall of 2004.

Small Vessels and Long Lesions
Numerous studies have documented the impact of vessel size on short- and long-term outcomes following coronary stenting.22,23 Smaller stent volumes are associated with increased neointimal proliferation24 as well as a lower degree of acute gain with comparable amounts of late loss.25 As a result, vessel size (as measured by the surrogate of in-stent minimal area) has been shown to be inversely related to in-stent restenosis.26 In one study among 2602 patients undergoing successful stent implantation, angiographic restenosis was significantly higher in the group of patients with vessel diameter of <2.8mm (38.6% at 1 year) in comparison to both patients with vessel diameters ranging from 2.8 to 3.2mm (28.4% at 1 year) and vessels greater than 3.2mm in diameter (20.4% at 1 year, p<0.001). Randomized, controlled trials have documented restenosis rates of up to 35% at 1 year, with even higher rates for patients with concomitant diabetes mellitus or those with long lesions.23,27

The combination of vessel size and lesion length is a powerful predictor of neointimal hyperplasia for bare-metal stents.26 Both lesion length and stent length have been shown to be independent predictors of in-stent restenosis, with rates as high as 70% for patients with small vessels and very long (>60mm) total stent length.26,28,29 This increased risk is independent of the number of stents used, though there is some suggestion that different stent designs may contribute to an increased risk of abrupt vessel closure.30

Two recent randomized, controlled trials have been performed evaluating the use of SES in patients with small (<3.0mm) coronary vessels and long (15“32mm) lesions. The European multi-center, randomized, double-blind study of the sirolimus-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo coronary artery lesions (E-SIRIUS) tested the efficacy of SES in preventing restenosis in patients with small arteries and long lesions potentially requiring more than one stent.31 A total of 352 patients were enrolled, and a single coronary lesion in a vessel 2.5“3.0mm in diameter with a lesion length of 15“32mm was required for entry. Exclusion criteria included an evolving MI, ostial or calcified lesions, bifurcation lesions, and ejection fraction <25%. The primary endpoint was 8-month changes in minimum luminal diameter and the frequency of angiographic binary restenosis. Nine-month MACE was also noted. In the SES treatment group, mean reference vessel diameter was 2.6mm and mean lesion length was 14.9mm. In addition, 49% of patients were treated with more than one stent, with a mean stent length of 23.0mm and a stent:lesion ratio of 1.7:1. Eight-month minimum luminal diameter was greater in the SES cohort compared with the traditional stent cohort (2.22mm versus 1.33mm, p<0.00001). In-stent late-lumen loss was 0.20mm in the SES treatment group compared with 1.05mm in the bare-metal stent group (p<0.00001). The rate of binary restenosis was significantly less in the SES treatment arm compared to control stents (5.9% compared to 42.3%, p<0.0001). The overall MACE rate at 9 months also favored the SES group (8.0% compared with 22.6%, p=0.0002), due mainly to a reduction in TVR (4.0 versus 20.9%, p<0.0001).

The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small coronary arteries (C-SIRIUS) was a study with a design almost identical to E-SIRIUS (the evaluation of SES in patients with small coronary vessels and long lesions).32 Inclusion and exclusion criteria were similar to E-SIRIUS. Primary and secondary endpoints were similar. Average reference vessel diameter was 2.65±0.30mm and mean lesion length was 14.5±6.3mm. One hundred total patients were enrolled. Again, there was a statistically significant increase in minimum luminal diameter comparing patients treated with SES and those treated with bare-metal stents (2.46mm versus 1.49mm, p<0.001). Angiographic restenosis occurred in 2.3% of the SES cohort compared with 52.3% of patients treated with traditional stents (p<0.001). A reduction in TLR again was primarily responsible for the overall difference in freedom from MACE at 9 months between the two groups (96% for SES patients and 81.7% for standard stent patients, p=0.029).

Additionally, 1-year follow-up from the SIRIUS trial continues to demonstrate 70 to 80% reductions in TLR between patients who received SES and those who were treated with bare-metal stenting, even in patients with reference vessel diameters of <2.5 as well as those with lesion lengths longer than 15mm.19 Furthermore, data from the RESEARCH registry on 96 patients with long lesions (>36mm stented segments) treated with SES demonstrated an 11.9% binary restenosis rate at 6-month angiographic follow-up (available in 71% of patients), with an in-stent late loss of 0.13±0.47mm.33 MACE rates at 6 months remained low (8.3%), and the authors conclude that in a real world population of patients requiring multiple stents over very long vessel segments, SES implantation appears safe and effective.

Recently published RESEARCH registry data evaluated the use of 2.25mm SES in real world patients. SES were placed in 91 patients with a total of 112 lesions, and continued minimal late-lumen loss (0.07±0.48mm) at an average follow-up of 7.1±1.3 months was demonstrated.34 Binary restenosis rates in these vessels are approximately 10.7%, with 12-month TLR of 5.5%, demonstrating low rates of clinical and angiographic restenosis/ complications. Finally, preliminary 8-month results from the SES-SMART, a multi-center, non-randomized trial designed to assess the efficacy of 2.25mm SES in de novo coronary lesions, reveal a 9.3% in-segment binary restenosis for the SES treatment group compared with 53.1% for the bare metal stent group (p<0.01). Secondary outcome MACE rates also favored the SES cohort (9.3% versus 31.3%, p<0.01), with benefits noted across all subgroups.35

Conclusions
Sirolimus-eluting stents inhibit neointimal proliferation and thereby dramatically reduce rates of in-stent restenosis, even in patients previously considered high risk for such events. Randomized, controlled trials demonstrate a 70-80% reduction in restenosis rates among patients with diabetes mellitus, patients with small coronary arteries, and those with long lesions. The results of ongoing and planned studies will serve to further clarify the role of sirolimus-eluting stents in coronary revascularization.