Comparison of Everolimus-Eluting and Paclitaxel- Eluting Coronary Stents in Patients Undergoing Multilesion and Multivessel Intervention

Transcription

1 JACC: CARDIOVASCULAR INTERVENTIONS VOL. 3, NO. 12, BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN /$36.00 PUBLISHED BY ELSEVIER INC. DOI: /j.jcin Comparison of Everolimus-Eluting and Paclitaxel- Eluting Coronary Stents in Patients Undergoing Multilesion and Multivessel Intervention The SPIRIT III (A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) and SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) Randomized Trials Dean J. Kereiakes, MD,* Krishnankutty Sudhir, MD, PHD, James B. Hermiller, MD, Paul C. Gordon, MD, Joanne Ferguson, RN, Manejeh Yaqub, MD, Poornima Sood, MD, MBA, Xiaolu Su, MS, Steven Yakubov, MD, Alexandra J. Lansky, MD, Gregg W. Stone, MD Cincinnati and Columbus, Ohio; Santa Clara, California; Indianapolis, Indiana; Providence, Rhode Island; and New York, New York Objectives We evaluated outcomes following XIENCE V everolimus-eluting stent (EES) compared with the Taxus Express 2 paclitaxel-eluting stent (PES) in patients undergoing multilesion and multivessel intervention. Background The optimal revascularization strategy for patients with multivessel disease is unknown. Methods The SPIRIT III (A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) (n 1,002) and SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) (n 3,690) trials enrolled patients with de novo lesions 28 mm in length and reference vessel diameter of 2.5 to 3.75 mm. The SPIRIT III trial enrolled patients with a single lesion in 1 or 2 coronary arteries, and the SPIRIT IV trial enrolled patients with up to 2 lesions in 3 different vessels (maximum 2 lesions per vessel). In both trials, patients were randomized 2:1 to EES vs. PES. Clinical outcomes to 1 year were analyzed in patients with single (n 3,823) versus multiple (n 765) treated vessels, and in those with single (n 3,536) versus multiple (n 1,052) treated lesions. Results Among patients with multivessel disease, EES compared with PES resulted in reduced rates of target vessel myocardial infarction (2.2% vs. 6.1%, p 0.007) and ischemia-driven target lesion revascularization (4.2% vs. 8.0%, p 0.04). Among patients undergoing multilesion stenting, EES compared with PES resulted in reduced rates of target vessel myocardial infarction (2.1% vs. 5.4%, p 0.008) and ischemia-driven target lesion revascularization (3.7% vs. 7.4%, p 0.01). The absolute benefits of EES versus PES in patients undergoing multivessel or multilesion intervention were greater than in those undergoing single-lesion, single-vessel intervention. Conclusions The EES compared with PES provided significant improvements in clinical safety and efficacy outcomes. The absolute benefit provided by EES versus PES appears to be proportional to the complexity of coronary disease. (SPIRIT III: A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With De Novo Native Coronary Artery Lesions [SPIRIT III]; NCT ) (SPIRIT IV Clinical Trial: Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With De Novo Native Coronary Artery Lesions [SPIRIT IV]; NCT ) (J Am Coll Cardiol Intv 2010;3: ) 2010 by the American College of Cardiology Foundation

2 1230 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010 Abbreviations and Acronyms BMS bare-metal stent(s) CABG coronary artery bypass graft DES drug-eluting stent(s) EES everolimus-eluting stent(s) ID-TLR ischemia-driven target lesion revascularization MACE major adverse cardiac events MI myocardial infarction PCI percutaneous coronary intervention PES paclitaxel-eluting stent(s) TLF target lesion failure Compared with bare-metal stent (BMS) deployment, drug-eluting stents (DES) reduce clinical and angiographic restenosis(1,2). The benefits of DES versus BMS are most apparent in patients with the highest absolute risk for restenosis (3,4). Despite rapid uptake and utilization of first-generation DES, specific issues related to their use have prompted iterative next-generation designs. Relatively thick stent struts and high metal content of first-generation DES impair deliverability and conformability, increase stent-mediated endoluminal injury, and serve as a barrier to endothelialization. In addition, the risk of late stent thrombosis is increased following first-generation DES compared with BMS, necessitating prolonged dual antiplatelet therapy (5-7). Finally, although first-generation DES are superior to BMS in reducing restenosis, the requirement for repeat revascularization remains problematic and proportional to the complexity of the coronary disease (3,8 10). In this regard, repeat revascularization rates are still higher with first-generation DES than with surgical coronary revascularization in patients with complex multivessel disease (9,10). To further improve the safety and efficacy of DES, the Xience V everolimus-eluting stent (EES) was developed, and it incorporates a thin (7.8 m), durable, biocompatible fluorocopolymer onto a thin strut ( in.) cobalt chromium platform. The SPIRIT (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions) II and III (11,12) trials demonstrated a significant reduction in quantitative angiographic late lumen loss as well as noninferior rates of target vessel failure following EES when compared with the Taxus Express 2 paclitaxel-eluting stent (PES). Although these trials were underpowered to detect From the *Christ Hospital, Heart and Vascular Center/The Lindner Research Center, Cincinnati, Ohio; Department of Cardiology, Ohio Health Research Institute, Riverside Methodist Hospital, Columbus, Ohio; Department of Clinical Research, Abbott Vascular, Santa Clara, California; The Care Group, Heart Center of Indiana, Indianapolis, Indiana; Cardiac Catheterization Laboratory, The Miriam Hospital, Providence, Rhode Island; and Center for Interventional Vascular Therapy, Columbia University Medical Center, The Cardiovascular Research Foundation, New York, New York. Dr. Kereiakes received grant and/or research support from Abbott Vascular, Cordis/Johnson & Johnson, Boston Scientific, Medtronic, and Daiichi Sankyo, Inc., and he received consulting fees from Abbott Vascular, Boston Scientific, Cordis/Johnson & Johnson, Eli Lilly, Medpace, REVA Medical Inc., and is on the Speakers Bureau for Eli Lilly & Co. Dr. Hermiller reports serving as a clinical superiority of EES, the absolute clinical benefits of EES versus PES through 3-year follow-up have continued to spread (13,14). Recently, larger, randomized controlled trials, which enrolled more complex patient cohorts, have demonstrated superior clinical benefits of EES when compared with either the Taxus Express 2 (15) or the second-generation Taxus Liberté (16) PES. To evaluate whether the improved safety and efficacy of the EES might translate into superior outcomes in patients with multivessel disease, we examined the pooled SPIRIT III and IV trials. Methods Study design. The design of the SPIRIT III and IV trials, which were both prospective, multicenter, randomized, single-blind, active-controlled studies, have previously been described (12,17). In brief, SPIRIT III randomized 1,002 patients with either 1 or 2 de novo native coronary artery lesions (maximum, 1 lesion per epicardial coronary artery) in a 2:1 ratio to receive either EES (Xience V, Abbott Vascular, Santa Clara, California) or PES (Taxus Express 2, Boston Scientific, Natick, Massachusetts), respectively. The SPIRIT IV trial randomized 3,690 patients with 1, 2, or 3 previously untreated native coronary artery lesions (maximum 2 lesions per epicardial vessel) in a 2:1 ratio to EES versus PES. Clinical and angiographic inclusion criteria were similar between studies and included study lesion diameter stenosis of 50% and 100%, reference vessel diameter 2.5 and 3.75 mm, and lesion length 28 mm. In SPIRIT III, bifurcation lesions were only enrolled if the side branch stenosis was 50% and the side branch diameter 2.0 mm. Conversely, in SPIRIT IV, bifurcation lesions with side branch stenosis 50% or 2.0-mm diameter were enrolled. In addition, ostial right coronary stenoses were eligible for enrollment in SPIRIT IV but not SPIRIT III. The most substantial difference between trial designs was the performance of protocol-specified routine angiographic follow-up in 564 patients at 8 months after the index percutaneous coronary intervention (PCI) in SPIRIT III, whereas SPIRIT IV had no routine angiographic follow-up. For both trials, EES were available in diameters of 2.5 to 4.0 mm and lengths of 8, 18, and 28 mm, whereas the full range of commercially available PES diameters of 2.5 to 3.5 mm and consultant for Abbott Vascular. Dr. Gordon reports having received research support from Abbott Vascular and Boston Scientific Corp. Dr. Sudhir, Ms. Ferguson, Dr. Yaqub, Dr. Sood, and Ms. Su are employees of Abbott Vascular. Dr. Yakubov reports serving on the advisory board of Abbott Vascular. Dr. Lansky reports having received research support from Abbott Vascular. Dr. Stone reports serving on the scientific advisory boards for and received honoraria from Abbott Vascular and Boston Scientific Corp. Manuscript received May 28, 2010; revised manuscript received August 26, 2010, accepted September 3, 2010.

3 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, lengths of 8, 12, 16, 20, 24, 28, and 32 mm were used. Both studies were approved by the institutional review boards at participating centers, and consecutive eligible patients signed informed consent. Medication administration and clinical follow-up. In both trials, aspirin 300 mg was administered before catheterization and an oral clopidogrel load of 300 mg was recommended before the procedure and required within 1 h after stent implantation. In both trials, aspirin 80 mg was administered daily indefinitely, and clopidogrel 75 mg daily was prescribed for 6 months (SPIRIT III) or for 12 months (SPIRIT IV). In both trials, clinical follow-up was scheduled at 3, 180, 240, 270, and 365 days and then yearly through 5 years. Clinical end points and definitions. End point definitions have been described previously and were similar in both trials (12,17). Target lesion failure (TLF at 1 year was defined as the composite of cardiac death, target vessel myocardial infarction (MI), or ischemia-driven target lesion revascularization (ID-TLR) by either PCI or coronary artery bypass graft (CABG) surgery. The individual components of TLF have been defined previously (17). Additional end points for analysis included the composite of cardiac death or target vessel MI; ID-TLR; major adverse cardiac events (MACE), defined as the composite of cardiac death, MI, or ID-TLR; target vessel failure, defined as the composite of cardiac death, MI, or ID-target vessel revascularization; and stent thrombosis, which was adjudicated using the Academic Research Consortium definite or probable criteria (18). Statistical analysis. Because the examination of subgroup data is inherently underpowered, the SPIRIT III and IV databases were pooled, which was justified by similar inclusion/exclusion criteria, randomization ratios, end point definitions, and clinical follow-up schedules. Pooling of patient-level data from both trials yielded 4,692 randomized patients. Binary variables are presented as percentages and were compared by Fisher exact test. Continuous variables are presented as mean SD and were compared by t test. All data are presented in the intent-to-treat population, consisting of all patients randomized, regardless of the treatment actually received. However, patients lost to follow-up in whom no event had occurred were not included in the denominator for calculations of binary end points. Survival curves using all available follow-up data were also constructed for time-to-event variables using Kaplan-Meier estimates and compared by log-rank test. A 2-sided alpha 0.05 was used for all superiority testing. All p values are displayed for descriptive (hypothesis-generating) purposes. All statistical analyses were performed by SAS (version 9.1.3, SAS Institute, Cary, North Carolina). Results Study population. The study populations from both SPIRIT III (n 1,002) and SPIRIT IV (n 3,690) have been described previously (12,17). One patient from SPIRIT III was excluded from the final analysis, and 3 patients were excluded from SPIRIT IV who were randomized in error and not treated. The combined study population included 4,689 patients who were randomly assigned 2:1 to receive EES (n 3,127) or PES (n 1,562). Single-vessel PCI was performed in 3,903 patients (83%), Figure 1. SPIRIT III/IV Pooled Analysis Study Flow Diagram Subjects are stratified by randomly assigned stent type (EES vs. PES) as well as number of vessels and lesions treated (single vs. multiple). *One PES patient in SPIRIT III trial was excluded from this analysis. EES everolimus-eluting stent; LL lesion length; lsns lesions; PES paclitaxel-eluting stent(s); pts patients; RVD reference vessel diameter; SPIRIT III Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with De Novo Native Coronary Artery Lesions III trial.

4 1232 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010 Table 1. Baseline Demographics in Patients With Single- and Multivessel Treatment Single-Vessel Treatment Multivessel Treatment EES PES EES PES Demographic Features (n 2,616 Patients) (n 1,287 Patients) p Value (n 511 Patients) (n 274 Patients) p Value Age, yrs Male Current smoker Hypertension Hypercholesterolemia Diabetes mellitus Insulin requiring All prior cardiac interventions On target vessel Unstable angina Prior myocardial infarction Values are mean SD or %. EES everolimus-eluting stent(s); PES paclitaxel-eluting stent(s). whereas 785 patients (17%) underwent multivessel PCI. Study flow is illustrated in Figure 1. Patients were further stratified for analysis according to treatment of a single lesion (n 3,614; 77%) or multiple lesions (n 1,074; 23%). Both baseline clinical (Table 1) and angiographic (Table 2) features were similar between the randomly assigned stent cohorts in the various groups with the sole exception that lesion length was slightly longer in singlevessel patients treated with EES versus PES ( vs ; p 0.04). Procedural results. The number of lesions treated was similar by randomly assigned stent type for patients with singleor multivessel disease (Table 3). Because of the trial design s limitation of stent lengths available for EES (3 lengths) versus PES (7 lengths), the numbers of stents deployed per patient and per lesion were slightly greater in patients assigned to EES. Both total stent length per lesion treated and total stent length/lesion length ratios were significantly higher in EES versus PES treated subjects irrespective of the number of vessels treated. Antiplatelet agent use. Antiplatelet agent compliance was similar among patients in both single- and multivessel treatment groups and between EES and PES treatment arms. In the single-vessel treatment group, 88.1% of EES and 87.5% of PES patients (p 0.63) remained on dual (aspirin plus thienopyridine) therapy at 1 year. In the multivessel treatment group, 90.2% of EES and 91.8% of PES patients (p 0.51) remained on dual therapy at 1 year. Single- versus multivessel treatment. The cumulative incidence of TLF and its individual components are shown stratified by stent type and number of treated vessels in Table 2. Target Lesion Characteristics in Patients With Single- and Multivessel Treatment Single-Vessel Treatment Multivessel Treatment Target Lesion Characteristics EES PES EES PES (n 2,821 Lesions) (n 1,375 Lesions) p Value (n 1,093 Lesions) (n 593 Lesions) p Value Coronary artery location Left anterior descending Left circumflex Right ACC/AHA lesion class B2 and C Calcification (moderate or severe) Reference vessel diameter, mm Minimal luminal diameter, mm Diameter stenosis Lesion length, mm Values are % or mean SD. ACC American College of Cardiology; AHA American Heart Association; other abbreviations as in Table 1.

5 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, Table 3. Procedural Results in Patients With Single- and Multivessel Treatment Single-Vessel Treatment Multivessel Treatment EES PES EES PES Procedural Variables (n 2,616 Patients) (n 2,821 Lesions) (n 1,287 Patients) (n 1,375 Lesions) p Value (n 511 Patients) (n 1,093 Lesions) (n 274 Patients) (n 593 Lesions) p Value Patients with multiple lesions NA Number of lesions per patient Number of stents per patient Number of stents per lesion Total stent length per lesion Total stent lesion length ratio Values are % or mean SD. N/A nonapplicable; other abbreviations as in Tables 1 and 2. Table 4. The 1-year rate of TLF was reduced by EES compared with PES in both single- and multivessel treatment groups. Although the Kaplan-Meier curves for TLF event occurrence through 1 year demonstrate apparent numerically greater relative benefit of EES versus PES in the multivessel compared with single-vessel treatment group (52% vs. 36% reduction) (Figs. 2A and 2B), a statistically significant interaction was not present (p 0.30). Cardiac death rates at 1 year were similar by stent type for both single- and multivessel treatment groups. The rates of target vessel MI at 1 year were comparable by stent type for single- but not for multivessel treatment patients, in whom target vessel MI was significantly reduced by EES compared with PES (2.2% vs. 6.1%; p 0.007). This observation drove a numerically greater relative reduction in the composite occurrence of cardiac death or target vessel MI in favor of EES in patients undergoing multivessel PCI (57% reduction; p 0.02) compared with single-vessel PCI (18% reduction; p 0.36) (Figs. 3A and 3B), although the p value for interaction did not achieve statistical significance (p 0.12). Although ID-TLR was increased for both stent types in the multivessel compared with the singlevessel treatment group, the relative benefit of EES versus PES was comparable (49% vs. 43%, respectively) (Figs. 4A and 4B). Similarly, the rates of both MACE and stent thrombosis were increased in the multivessel PCI compared with the single-vessel PCI group. The relative reduction in MACE provided by EES versus PES was numerically greater in the multivessel group (50% vs. 34% single-vessel group), although the p value for interaction was not significant (p 0.28). For Academic Research Consortium defined definite/probable stent thrombosis, the relative reduction, EES versus PES, was similar between the single- and multivessel groups (50% single vs. 56% multivessel), with a nonsignificant p value for interaction (p 0.96). One-year nonhierarchical rates of cardiac death, Q-wave and non Q-wave MI, as well as TLR stratified by stent type and number of treated vessels are shown (Fig. 5). Single- versus multilesion treatment. Clinical outcomes stratified by stent type and number of treated lesions are Table 4. Clinical Outcomes at 1 Year in Patients With Single- and Multivessel Treatment Single-Vessel Treatment (n 3,903 Patients) Multivessel Treatment (n 785 Patients) EES PES EES PES (n 2,616 Patients) (n 1,287 Patients) p Value (n 511 Patients) (n 274 Patients) p Value Target lesion failure 4.1% (106 of 2,571) 6.4% (80 of 1,252) % (30 of 502) 12.2% (32 of 263) Cardiac death 0.4% (11 of 2,571) 0.4% (5 of 1,252) % (4 of 502) 1.1% (3 of 263) 0.70 Target vessel myocardial infarction 1.8% (47 of 2,571) 2.4% (30 of 1,252) % (11 of 502) 6.1% (16 of 263) Q-wave 0.2% (4 of 2,571) 0.2% (3 of 1,252) % (1 of 502) 1.1% (3 of 263) 0.12 Non Q-wave 1.7% (43 of 2,571) 2.2% (28 of 1,252) % (10 of 502) 4.9% (13 of 263) 0.04 Ischemia-driven target lesion revascularization 2.4% (62 of 2,571) 4.2% (52 of 1,252) % (21 of 502) 8.0% (21 of 263) 0.04 Major adverse cardiac events 4.3% (110 of 2,571) 6.5% (82 of 1,252) % (31 of 502) 12.5% (33 of 263) Stent thrombosis (ARC definite/probable) 0.3% (7 of 2,546) 0.6% (8 of 1,238) % (6 of 495) 2.7% (7 of 259) 0.15 ARC Academic Research Consortium; other abbreviations as in Table 1.

6 1234 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010 Figure 2. TLF to 1 Year Kaplan-Meier time-to-event curves showing target lesion failure rates through 1 year for EES vs. PES in: (A) patients with single-vessel treatment and (B) patients with multivessel treatment. CI confidence interval; HR hazard ratio; TLF target lesion failure; other abbreviations as in Figure 1. shown (Table 5). The relative magnitude of clinical benefit provided by EES (vs. PES) was again greater in patients treated with multilesion (vs. single-lesion) disease. Discussion The clinical prognosis for patients with multivessel disease following PCI is worse than for those with single-vessel disease (19,20). Although randomized trials have shown that DES reduce clinical and angiographic restenosis when compared with BMS (1,2), few trials have included patients with multivessel coronary artery disease (21 23). In contrast, multiple observational registries have demonstrated the benefits of DES compared with BMS in real-world patients with multivessel disease and/or those treated for off-label indications (1-3). However, these observational studies are often confounded by selection bias and covariate (both known and unknown) imbalances. Nonetheless, the use of DES for treatment of multivessel coronary disease has emerged as an alternative to CABG, which is the established gold standard for these patients. Whether this practice is justified remains controversial. In the recent SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery)

7 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, Figure 3. Cardiac Death or Target Vessel MI to 1 Year Kaplan-Meier time-to-event curves showing the composite occurrence of cardiac death or target vessel MI through 1 year for EES vs. PES in: (A) patients with single-vessel treatment and (B) patients with multivessel treatment. MI myocardial infarction; other abbreviations as in Figures 1 and 2. trial, 1,800 patients with 3-vessel and/or left main coronary artery disease were randomly assigned to either PCI using PES or CABG (9). The primary end point of major adverse cardiovascular and cerebrovascular events (composite occurrence of all-cause death, stroke, MI, or repeat revascularization) was significantly increased to 12 months following PCI compared with CABG. Major adverse cardiovascular and cerebrovascular events were directly proportional to the complexity of underlying coronary disease as determined by tertile of SYNTAX score (measure of angiographic complexity) following PCI but not CABG. The increase in major adverse cardiovascular and cerebrovascular events following PCI was largely explained by an increased requirement for repeat revascularization (13.5% PCI vs. 5.9% CABG; p 0.001) that was not associated with a concomitant increase in the rate of death or MI. Indeed, CABG was associated with an increased incidence of stroke (2.2%) compared with PCI (0.6%; p 0.003). However, the SYNTAX trial was underpowered for these low-frequency safety events, and CABG remains the gold standard for most patients with left main and complex multivessel disease. The present large-scale randomized comparison of EES versus PES in patients with multivessel disease has relevance as to whether superior results might be obtained in patients with complex coronary artery disease undergoing PCI with an improved stent platform. The major results of note in the

8 1236 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010 Figure 4. ID-TLR to 1 Year Kaplan-Meier time-to-event curves showing ischemia-driven TLR rates through 1 year for EES vs. PES in: (A) patients with single-vessel treatment and (B) patients with multivessel treatment. ID ischemia-driven; TLR target lesion revascularization; other abbreviations as in Figures 1, 2, and 3. present study are that: 1) The incidences of target vessel MI and composite cardiac death or MI to 1 year were significantly reduced by EES compared with PES. 2) The incidence of ID-TLR to 1 year was reduced by EES versus PES, particularly in those subjects with multivessel/ multilesion treatment. 3) The absolute benefit afforded by EES compared with PES was proportional to the complexity of coronary disease as reflected by either the number of vessels or lesions treated. 4) The incremental benefit in both MI and ID-TLR with EES in complex coronary disease was also reflected by reductions in the composite safety and efficacy end points of TLF and MACE. These clinical end points have relevance to the results of the SYNTAX trial and suggest that EES may enhance both the relative safety (composite of death, MI, or stroke) and efficacy (repeat revascularization) of PCI compared with CABG. The observations in the present study regarding the relative safety and efficacy of EES versus PES are supported by data from recent randomized controlled trials and clinical registries. Applegate et al. (8) previously reported from the SPIRIT III trial that at 2-year follow-up, patients treated for 2-vessel disease with EES rather than PES had a relative reduction in target vessel failure (by 35%) and MACE (by 61%). More recently, in the COMPARE (Second- Generation Everolimus-Eluting and Paclitaxel-Eluting Stents in Real-Life Practice) trial (16), 1,800 real-world

9 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, Figure 5. Clinical Outcomes Stratified by Angiographic Complexity and Stent Type One-year nonhierarchical rates of cardiac death, target vessel Q-wave myocardial infarction (QMI) or non Q-wave myocardial infarction (NQMI) as well as target lesion revascularization for everolimus- versus paclitaxel-eluting stent(s) stratified by single- or multivessel treatment. Abbreviations as in Figures 1, 2, 3, and 4. patients (60% acute coronary syndrome, 25% ST-segment elevation MI, 27% multivessel treatment with an average lesions treated per patient) were randomly assigned to treatment with either EES or the Taxus Liberté PES. The absolute benefit of EES versus PES for reduction of MACE (composite of death, nonfatal MI, ID target vessel revascularization) was greater in multivessel (8.0% vs. 13.0%, respectively) compared with single-vessel (6.0% vs. 8%, respectively) disease patients. In the COMPARE trial, both ID-TLR (2% EES vs. 5% PES; p ) and stent thrombosis (Academic Research Consortium defined definite or probable definition) were reduced by EES (0.7% vs. 3.0% PES; p 0.002), which is similar to the SPIRIT III and IV trials. Thus, the cumulative experience in 4,689 patients undergoing both elective and nonelective PCI enrolled into the SPIRIT III (14), SPIRIT IV (15), or COMPARE trials (16) who were randomly assigned to treatment with EES or PES demonstrates substantial clinical benefit of EES with respect to measures of both safety and efficacy. Study limitations. Several limitations of this study should be acknowledged. First, despite the relatively large number of total patients in the present analysis, sample sizes in individual subgroups may still be insufficient to derive reliable estimates of stent thrombosis or other low frequency occurrence events. Second, the availability of only 3 stent lengths for EES versus 7 stent lengths for PES limited the ability to tailor stent length-to-target lesion length in EES-treated patients. As a result, the average stent length/lesion as well as the stent Table 5. Clinical Outcomes at 1 Year in Patients With Single- and Multilesion Treatment Single-Lesion Treatment (n 3,614 Patients) Multilesion Treatment (n 1,074 Patients) EES PES EES PES (n 2,415 Patients) (n 1,199 Patients) p Value (n 712 Patients) (n 362 Patients) p Value Target lesion failure 4.1% (98 of 2,371) 6.2% (72 of 1,165) % (38 of 702) 11.4% (40 of 350) Cardiac death 0.5% (11 of 2,371) 0.4% (5 of 1,165) % (4 of 702) 0.9% (3 of 350) 0.69 Target vessel myocardial infarction 1.8% (43 of 2,371) 2.3% (27 of 1,165) % (15 of 702) 5.4% (19 of 350) Q-wave 0.1% (3 of 2,371) 0.3% (3 of 1,165) % (2 of 702) 0.9% (3 of 350) 0.3 Non Q-wave 1.7% (40 of 2,371) 2.1% (25 of 1,165) % (13 of 702) 4.6% (16 of 350) 0.02 Ischemia-driven target lesion revascularization 2.4% (57 of 2,371) 4.0% (47 of 1,165) % (26 of 702) 7.4% (26 of 350) 0.01 Major adverse cardiac events 4.3% (102 of 2,371) 6.4% (74 of 1,165) % (39 of 702) 11.7% (41 of 350) Stent thrombosis (ARC definite/probable) 0.3% (6 of 2,346) 0.6% (7 of 1,151) % (7 of 695) 2.3% (8 of 346) 0.10 Abbreviations as in Tables 1, 2, 3, and 4.

10 1238 JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 3, NO. 12, 2010 length-to-lesion length ratios were greater with EES than PES. As longer DES stent lengths have directly been correlated with the risk for stent thrombosis, MI and ID-TLR (5,21,24-26), the relative benefit provided by EES versus PES might even be further improved by the available wide range of EES stent lengths and diameters. In addition, it should be noted that in the SYNTAX trial, the average number of target lesions treated per patient was 3.6 compared with either the single- (1.08 lesions) or multivessel (2.15 lesions) treatment groups in the present analysis. The small numbers of patients undergoing PCI in all 3 vessels (n 24) or of 3 lesions (n 120) in the present study precludes meaningful separate analysis. Thus, randomized trials of PCI with EES versus CABG are required to determine if the outcomes with EES are sufficiently improved to supplant surgery in patients with the most coronary anatomy. Finally, although the benefit attributable to EES versus PES appears to be directly proportional to the complexity of coronary disease being treated, a statistical interaction by stent type was not demonstrated, and even the pooled analysis remains underpowered to allow definitive conclusions regarding relative efficacy. Conclusions The limitations notwithstanding, in the present pooled analyses of 4,689 patients enrolled into the SPIRIT III and IV trials who were randomized to treatment with EES or PES, EES provided substantial clinical safety and efficacy benefits compared with PES. Furthermore, the absolute benefit of EES versus PES was directly proportional to the complexity of coronary artery disease as reflected by either the number of target vessels or lesions treated. These observations may have significant implications with respect to the optimal choice of revascularization strategy (PCI vs. CABG) in patients with multivessel coronary disease. 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