ADVERTISEMENT
Prospective Native Coronary Artery Stenosis Treated with Sirolimus-Eluting Stent (ONASSIS) Registry — Acute Results and Mid-Term
August 2005
Percutaneous coronary intervention is an established method of nonsurgical coronary revascularization, accounting for more than 1,500,000 annual procedures worldwide.1 Despite technical advancements in recent years, with coronary stenting being the most important, restenosis remains the major problem that hampers the procedure’s efficacy. Angiographic restenosis rates following stent implantation is reported to be 15–20% in ideal lesions (BENESTENT I), but may occur in over 30–60% of patients with diabetes or with complex lesion anatomy (small vessels, long or bifurcation lesions).2–5
The introduction of the drug-eluting stents (DES) represents the third revolution in interventional cardiology following balloon angioplasty and stent implantation. Recent years have seen the emergence of stents coated with antirestenotic drugs capable of modulating smooth muscle cell proliferation and limiting the restenotic process. Several recently published multi-center trials (RAVEL,6 US-SIRIUS,7 E-SIRIUS,8 C-SIRIUS,9 TAXUS II10 and TAXUS IV11) and a single-center experience (RESEARCH Registry12), have shown that compared to bare metal stents (BMS), DES are safe and effective in reducing both repeat revascularization (angiographically- or clinically-driven) and major adverse cardiac events at long-term follow-up.
The purpose of this study was to investigate the impact of sirolimus-eluting stents (SES) on acute and mid-term outcomes of patients with coronary artery disease treated in everyday clinical practice, as compared with a strategy using bare metal stents.
Methods
Study patients. Between June 1, 2002 and August 15, 2003, 530 consecutive patients had been treated with SES in our department and were included in the present report; these patients represent 73% of the 726 patients treated with stents during this period. Patients treated only with bare metal stents in this period were not included in the present report. Unavailability was the main reason for nonutilization of SES (76% of cases); in the remaining patients, a SES was not implanted due to one of the following reasons: 1) a very tortuous and sometimes very calcified proximal segment was present, making it difficult to implant a SES (9%); 2) there was difficulty in locating the stenosis in a small vessel 4.0 mm lumen diameter proximal to the lesion (5%). These patients were compared with a group of 398 consecutive patients (75% of all patients treated with stents during that period) treated with BMS in the same time period before the utilization of SES. Excluded from this study were the following: 1) patients who received a stent in a very tortuous and calcified segment; 2) patients with a stent in a saphenous vein graft with a lumen diameter > 4.0 mm in the proximal segment; 3) patients with a stent in a small vessel; 4) patients with a stent in a bifurcation lesion involving the main vessel and the side branch. All procedures were performed after written informed consent was obtained. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki, as reflected in a priori approval by the institution’s human research committee.
Baseline clinical characteristics and in-hospital complications were confirmed by independent chart review. All patients underwent a pre- and post-intervention 12-lead electrocardiogram to detect ischemic changes, appearance of new pathologic Q-waves, or both. Blood samples were routinely obtained from all patients every 6 hours for the first 12 hours following the procedure for muscle-brain fraction of creatine kinase enzyme determination (normal values up to 6 ng/ml), and if elevated, daily until discharge. All patients undergoing coronary artery stenting in our hospital are included in a systematic prospective clinical follow-up protocol. Our institution regularly conducts patient follow-up at 1 and 5–6 months after percutaneous coronary intervention. Clinical outcomes after 6 months were obtained by telephone interviews conducted by research fellows. Late major clinical events including death, nonfatal myocardial infarction (MI), cerebrovascular accident, re-angioplasty or surgical revascularization for target lesion restenosis (TLR), and any revascularization for target and nontarget lesions were adjudicated by accompanying source documentation.
Protocol. Angioplasty was performed using standard technique. A bolus of 70 units of heparin per kilogram of body weight was given after sheath insertion; thereafter, heparin boluses were administered during the procedure as needed according to the activated clotting time values (200–280 seconds). Before the procedure, all patients received aspirin 100 mg per day. A minimum of 1-month ticlopidine (250 mg b.i.d.) or clopidogrel (loading dose of 300 mg followed by 75 mg daily per day) was administered to patients receiving BMS and at least 6-months for patients treated with SES. All patients were advised to continue aspirin indefinitely. Periprocedural glycoprotein (GP) IIb/IIIa inhibitors were used at the operator’s discretion.
The femoral approach was selected in all patients using 6 French (Fr) or 7 Fr guiding catheters. Pre- and post-procedural intracoronary nitroglycerin (100–200 mg) was routinely administered. The lesion was pre-dilated with an appropriate-sized balloon and the stent was delivered using pre-mounted systems. Reference vessel and lesion measurements were obtained using off-line computerized quantitative analysis systems. Several slotted-tube, and corrugated stents were used in the bare metal stent patient group depending on lesion length, location, proximal tortuosity and operator preferences. After stent deployment, further dilatations were performed as needed using high-pressure inflations (> 16 atmospheres) or larger balloons. The arterial sheath was removed after the procedure using a closure device (collagen or suture), or 4 to 6 hours later, depending on the activated clotting time level achieved with manual compression.
Definitions. Unstable angina was defined as recent ( 20 minutes). Coronary artery stenosis morphology was characterized according to the modified American College of Cardiology/American Heart Association classification.13 Non-Q-wave MI post-procedure was defined as muscle-brain fraction of creatine kinase elevation > 3 times normal values, in the absence of new pathologic Q-waves. Multivessel disease was defined as the presence of significant narrowing (> 50% diameter stenosis) in more than one major coronary artery. Multilesion stenting was considered when stent placement was performed in at least two lesions in separate segments (> 5 mm apart) on the same coronary artery. Multivessel stenting was defined as percutaneous coronary intervention with stent implantation in at least two lesions in separate coronary vessels. Clinical success was defined as angiographic success ( 50% in any major coronary artery or their large branches, unless a bypass graft fed the territory distal to a diseased segment. Event-free survival was defined as freedom from death (considered cardiac unless a non-cardiac cause could be documented), nonfatal MI, cerebrovascular accident, re-angioplasty or CABG (in the target or nontarget sites). All re-interventions were clinically driven (> 50% diameter stenosis in the presence of angina and/or proven myocardial ischemia in the target vessel by noninvasive testing).
Statistical analysis. Data included baseline patient characteristics, information on coronary artery lesion characteristics, in-hospital results and out-patient clinical follow-up. The primary clinical analysis consisted of a comparison between the two groups that were divided by the type of stent used. Categorical variables are presented as absolute numbers (percent) and were compared by the chi-square test or Fisher’s exact test, as appropriate. Continuous data, expressed as mean ± standard deviation, were compared with the Student’s t-test. The Kaplan-Meier method was used to generate a survival curve. A log-rank test was used to detect differences between the two groups for the Kaplan-Meier estimations. Statistical significance was considered at a p-value 2 stents (6% versus 3%; p In-hospital results and complications. The clinical success rate was 99.6% in patients treated with SES and 98.5% in those who received BMS (p = 0.08). There was only one death (0.3%) in the BMS group and no patient in either group required CABG before hospital discharge (Table 3). One patient in the SES group (0.2%) and 3 in the BMS group (0.8%) underwent repeat angioplasty before hospital discharge as a result of stent thrombosis (p = 0.3). The incidence of Q-wave MI was 0% in the SES group and 1% in the BMS group (p = 0.03), and non-Q-wave MI occurred in 5.7% and 4.0% of the patient groups, respectively (p = 0.3). Vascular and/or major bleeding complications (need for vascular operation and/or blood transfusion) did not differ between the two groups.
Mid-term clinical outcome. Clinical follow-up data (Table 4) were obtained in 524 of 530 (99%) of the patients treated with SES and 398 of 398 (100%) in the BMS group (mean time 11.22 ± 3.4 and 11.41 ± 3.12 months, respectively, range 5–19 months). The incidence of death was similar (1.1% in the SES patients, 1.3% in the BMS patients; p = 1.0), and MI occurred in 0.8% and 1.8% of the patient groups, respectively (p = 0.22). Two of the 6 deaths in the SES group were cardiac in origin (as a result of acute MI), 3 were due to cancer, and 1 was the result of a car accident. Of the 5 patients treated with BMS, 2 died suddenly, 1 following CABG, 1 following a cerebrovascular accident, and the last one after a non-cardiac operation (possible pulmonary embolism). Two additional patients in the SES group experienced a non-fatal cerebrovascular accident, with permanent disability in 1 of them. Noninvasive tests for ischemia detection were performed in 287 of 530 (54%) patients in the SES group, and in 223 of 398 (56%) patients in the BMS group. A revascularization procedure (re-angioplasty or CABG) for target lesion restenosis was required in 2.1% of patients treated with SES, compared to 10.1% in the BMS patients (p Discussion
In the present study, we found that consecutive unselected patients with coronary artery disease treated with SES implantation had better mid-term clinical outcomes compared to patients treated with BMS. The incidence of death or non-fatal MI were not significantly different between the two groups of patients, but the need for clinically-driven target vessel revascularization was significantly lower in the patients treated with SES. Patients treated with SES had more risk factors for coronary artery disease, as well as a higher incidence of multivessel disease, type C lesions, number of lesions treated, and stents implanted. These changes in clinical practice are based on the excellent acute and mid-term results reported in the selected patients enrolled in the multi-center trials using DES. Although both study groups differed in some baseline clinical and procedural characteristics which may influence an unbiased comparison between them, it is generally accepted that most differences would be expected to increase the risk of restenosis and major adverse cardiac events (MACE) at follow-up. These favorable results were accomplished without any increase in unexpected sudden events; the stent thrombosis rate before hospital discharge in our SES group (0.2%) was comparable to that reported in previous studies with BMS. A lower percentage of patients treated with SES received peri-procedural GP IIb/IIIa inhibitors, but clopidogrel therapy was prescribed for a longer period (6–12 months).
Stent implantation and restenosis rate. Stent implantation has been the primary method of percutaneous coronary revascularization over the last 5 to 10 years. This practice pattern has been the result of documented improved clinical outcomes compared to conventional balloon angioplasty due to a significant reduction in restenosis (angiographically- and clinically-driven) at long-term follow-up, and the need for emergency CABG due to occlusive dissection during the procedure.14,15 Stent restenosis rates are reported to be 30–60% in patients with diabetes, end-stage renal disease or complex lesions (small vessels, long lesions, or bifurcation lesions).16 In the U.S. alone, approximately 200,000 repeat revascularizations were performed in 2001, at an annual cost of $1.5 billion.
Restenosis following DES implantation. The development of DES offers the potential to take advantage of the positive attributes of stenting, while it further reduces the need for target vessel revascularization (TVR). Several single- and multi-center trials conducted in Europe and Latin America (FIM and RAVEL)16,17 and in the U.S. (SIRIUS)7 have shown a dramatic reduction in the restenosis rate in patients treated with SES, compared to those treated with BMS. At 2-year follow-up in a subgroup of patients, the beneficial impact of neointimal growth inhibition was persistent.18 Results from two other multi-center trials have also been recently published: the E-SIRIUS and C-SIRIUS studies confirmed the favorable results of SES in reducing restenosis, despite the fact that patients treated with these stents had longer lesions and smaller vessels.8,9 In these trials, there was little difference in the relative reduction of in-stent and in-segment late loss. Similar and very promising results were reported using the paclitaxel-eluting stent for coronary lesions in the TAXUS I and II trials.10,19 The results of the TAXUS IV trial were very recently reported.11 The incidence of TVR, the primary endpoint in this trial, was 3% in the TAXUS trial, and 11.3% in the BMS group (p 12 Both studies included consecutive unselected patients treated with percutaneous coronary intervention in everyday clinical practice and compared a strategy of SES implantation with conventional approaches using BMS. Although we had a higher number of diabetic patients in the SES group (30% versus 18%), in both studies, patients were treated with a more aggressive interventional approach, which included an increased number and length of stents implanted, a high frequency of multivessel disease patients, and dilation of more complex lesions (type C). These changes in clinical practice may reflect the realization by interventional cardiologists that the excellent acute and mid-term results reported in the selected patients enrolled in the multi-center trials may also extend to patients and lesions at high risk for restenosis.
All of our patients in the SES group received clopidogrel therapy for 6–12 months. Though prolonged clopidogrel use is consistent with recent studies showing an incremental benefit of extended thienopyridine therapy,21 it is not known if this strategy is necessary to prevent subacute thrombosis after implantation of a DES. The frequency of GP IIb /IIIa inhibitor infusion in our patients treated with SES was 19%. Despite the low incidence of administration of these medications, the incidence of non-Q-wave MI was 5.7%. In a recent study22 of patients undergoing multivessel stenting with SES where more liberal use of GP IIb/IIIa inhibitors was applied (59%), the incidence of non-Q-wave MI was 12.8% in patients with two-vessel disease, and 32.1% in patients with three-vessel disease.
Multivessel stenting was performed at a similar rate (28%) in patients with multivessel disease treated with SES or BMS. Most of our patients with incomplete revascularization had totally occluded vessels supplying non-viable myocardium. There is only one published study22 reporting the results of SES implantation in patients with multivessel disease (complete revascularization was achieved in 70%). The cumulative MACE rate was 22.3%, and the TLR was 14.3%/patient and 6.7%/lesion. The multi-center ARTS II trial, which has already completed the enrollment phase, will clarify the long-term effectiveness of SES in patients with multivessel disease. In the present study, we have included a small percentage of patients with in-stent restenosis (7%) and lesions located in bypass grafts (3%) treated with SES. Despite the excellent long-term results, the small number of patients precludes any definitive conclusions. However, restenotic lesions have been shown to be amenable to treatment with SES.23Study limitations. This is not a randomized clinical trial designed to assess the efficacy of SES compared to BMS in patients with coronary artery disease, and therefore inherently contains all the disadvantages of such a comparative analysis. Offsetting this limitation, the data were collected prospectively and were entered into a dedicated database with almost complete follow–up. Angiographic follow-up was performed in a small number of patients (11%) for several reasons, thus the angiographic restenosis rate cannot be determined. However, the incidence of clinically-driven revascularization and event-free survival are two widely-used and validated parameters. Moreover, this study represents conditions of real-world experience rather than the conditions typically included in randomized trials.
Conclusions
This study confirms that, compared to BMS, the implantation of SES in everyday practice in a broad range of clinical presentations for coronary artery disease is associated with excellent in-hospital and mid-term results, mainly because of the dramatic reduction in the need for repeat revascularization. These favorable results were obtained despite a higher risk factor profile (diabetics), or more complex lesion characteristics (longer lesions, more stents implanted). SES implantation is associated with a low incidence of stent thrombosis in the era of combined long-term antiplatelet treatment.
E-mail: vvoudris@otenet.gr
1. American Heart Association, 2002 heart and stroke statistical update. Dallas: American Heart Association, 2001.
2. Serruys PW, de Jaegere P, Kiemeneij F, et al. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med 1994; 331:489–49
3. Serruys PW, Kay P, Disco C, Deshpande NV, de Feyter PJ. Periprocedural quantitative coronary angiography after Palmaz-Schatz stent implantation predicts the restenosis rate at six months: results of meta-analysis of the Belgian Netherlands Stent Study (BENESTENT) I; BENESTENT II and MUSIC trials. J Am Coll Cardiol 1999;34:1067–1074.
4. Moer R, Myreng Y, Molstald P, et al. Stenting in small coronary arteries (SISCA) trial: A randomized comparison between balloon angioplasty and the heparin coated stent. J Am Coll Cardiol 2001;38:1598–1603.
5. Farb A, Weber DK, Kolodgie FD, et al. Morphological predictors of restenosis after coronary stenting in humans. Circulation 2002;105:2974–2980.
6. Morice MC, Serruys PW, Sousa JE, et al. RAVEL Study Group. Randomized study with the sirolimus-coated Bx Velocity balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions. N Engl J Med 2002;346:1773–1780.
7. Moses JW, Leon MB, Pompa JJ, et al. for the SIRIUS Investigators. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349:1315–1323.
8. Schofer J, Schluter M, Gershlick AH, et al. for the E-SIRIUS Investigators. Sirolimus-eluting stents for treatment of patients with long atherosclerotic lesions in small coronary arteries: Double-blind, randomized controlled trial (E-SIRIUS). Lancet 2003;362:1093–1099.
9. Schampaert E, Cohen EA, Schluter M, et al. for the C-SIRIUS Investigators. The Canadian study of the sirolimus-eluting stent in the treatment of patients with long de novo lesions in small native coronary arteries (C-SIRIUS). J Am Coll Cardiol 2004;43:1110–1115.
10. Colombo A, Drzewiecki J, Banning A, et al. for the TAXUS II Study Group. Randomized study to assess the effectiveness of slow and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003;108:788–794.
11. Stone GW, Ellis SG, Cox DA, et al. for the TAXUS-IV Investigators. A polymer-based paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350:221–231.
12. Lemos PA, Serruys PW, van Domburg RT, et al. Unrestricted utilization of sirolimus-eluting stents compared with conventional bare stent implantation in the “real word”: The rapamycin-eluting stent evaluated at Rotterdam cardiology hospital (RESEARCH) registry. Circulation 2004;109:190–195.
13. Ryan TJ, Bauman WB, Kennedy JW, et al. Guidelines for percutaneous transluminal angioplasty. A report of the American Heart Association/American College of Cardiology Task Force on assessment of diagnostic and therapeutic cardiovascular procedures. Circulation 1993;88:2987–3007.
14. Brophy JM, Belisle P, Joseph L. Evidence for use of coronary stents: A hierarchical Bayesian meta-analysis. Ann Intern Med 2003;138:777–786.
15. Holmes DR Jr, Savage M, LaBlanch JM, et al. Results of Prevention of Restenosis with Tranilast and its Outcomes (PRESTO) trial. Circulation 2002;106:1243–1250.
16. Mercado N, Boersma E, Wijns W, et al. Clinical and quantitative coronary angiographic predictors of coronary restenosis. A comparative analysis from balloon to stent era. J Am Coll Cardiol 2001;38:645–652.
17. Sousa JE, Costa MA, Abizaid AC, et al. Sustained suppression of neointimal proliferation by sirolimus-eluting stents: One-year angiographic and intravascular ultrasound follow-up. Circulation 2001;104:2007–2011.
18. Degertekin M, Serruys PW, Foley DP, et al. Persistent inhibition in neointimal hyperplasia after sirolimus-eluting stent implantation: Long-term (up to 2 years) clinical, angiographic, and intravascular ultrasound follow-up. Circulation 2002;106:1610–1613.
19. 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 to de novo coronary lesions. Circulation 2003;107:38–42.
20. Holmes DR Jr, Leon MB, Moses JW, et al. Analysis of 1-year clinical outcome in the SIRIUS trial: A randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation 2004;109:634–640.
21. Steinhubl SR, Berger PB, Mann JT III, et al for the CREDO Investigators Clopidogrel for the Reduction of Events During Observation. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized control trial. JAMA 2002;288:2411–2420.
22. Orlic D, Bonizzoni E, Stankovic G, et al. Treatment of multivessel coronary artery disease with sirolimus-eluting stent implantation:immediate and mid-term results. J Am Coll Cardiol 2004;43:1154–1160.
23. Degertekin M, Regar E, Tanabe K, et al. Sirolimus-eluting stent for treatment of complex in-stent restenosis: The first clinical experience. J Am Coll Cardiol 2003;41:184–189.
