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Comparative efficacy of 2 zotarolimus-eluting stent generations: Resolute versus endeavor stents in patients with coronary artery disease
Comparative efficacy of 2 zotarolimus-eluting stent generations: Resolute versus endeavor stents in patients with coronary artery disease Tomohisa Tada, MD, Robert A. Byrne, MB, BCh, PhD, Salvatore Cassese, MD, Lamin King, MS, Stefanie Schulz, MD, Julinda Mehilli, MD, Albert Schömig, MD, and Adnan Kastrati, MD Munich, Germany
Background The Resolute zotarolimus-eluting stent (R-ZES) utilizes the same metallic platform and anti-restenotic drug as the Endeavor zotarolimus-eluting stent (E-ZES) but is coated with a more biocompatible polymer with enhanced drug-release kinetics. The aim of this study was to compare the long-term clinical outcomes of 2 zotarolimus-eluting stent generations. Methods
In two randomized trials with broad inclusion criteria (ISAR-TEST 2 and ISAR-TEST 5), 1,000 patients were treated with R-ZES and 339 patients treated with E-ZES. In both trials follow-up angiography was scheduled at 6 to 8 months. The efficacy endpoint of interest was target lesion revascularization and the safety endpoints were the combined incidence of cardiac death or myocardial infarction related to target vessel as well as the incidence of definite stent thrombosis at 2-year follow-up.
Results
The incidence of target lesion revascularization at 2 years was 12.0% in the R-ZES group and 16.0% in the E-ZES (HR 0.72 [95% CI: 0.52-1.00], P = .052). The incidence of cardiac death or myocardial infarction was 5.5% vs. 4.8% (HR 1.15, [95% CI: 0.66-2.02], P = .62) and of definite stent thrombosis was 0.4% vs. 0.6% (HR 0.68, [95% CI: 0.12-3.72], P = .66), respectively. All measures of angiographic restenosis were in favor of the R-ZES; in-stent late lumen loss was 0.29 ± 0.56 with the R-ZES versus 0.58 ± 0.55 with the E-ZES (P b .0001).
Conclusions Comparison of the 2 Food and Drug Administration–approved zotarolimus-eluting stents suggested that the R-ZES as compared to the E-ZES displayed overall superior antirestenotic efficacy. Both devices were associated with a similar low risk of adverse safety events through 2 years. (Am Heart J 2013;165:80-6.)
The new generation Endeavor Resolute zotarolimuseluting stent (R-ZES) (Medtronic, Santa Rosa, CA) is based on the same stent backbone as the preceding Endeavor zotarolimus-eluting stent (E-ZES) (Medtronic) and is coated with the same dose of zotarolimus. The key difference between the R-ZES in comparison with the EZES is its polymer coating which is composed of 3 different hydrophilic and hydrophobic polymeric elements (BioLinx). 1 Initial non-randomized single arm studies of the R-ZES demonstrated high antirestenotic efficacy with a favorable safety profile among relatively low-risk patients out to 3 years 2-4 and a recent all-comers randomized clinical trial demonstrated comparable clin-
ical outcomes to the everolimus-eluting stent up to 2 years. 5,6 To date however long-term comparative efficacy studies between the R-ZES and the preceding E-ZES remain a significant scientific gap. Indeed in view of the wealth of trial data and clinical experience accumulated with the E-ZES, this stent represents an important benchmark against which to evaluate the performance of the new generation R-ZES. Against this background we sought to compare the long-term efficacy and safety of the 2 zotarolimus-eluting stent generations out to 2 years using the combined data from the ISAR-TEST 2 and the ISAR-TEST 5 randomized trials. 7-9
Methods From the Deutsches Herzzentrum, Technische Universität, Munich, Germany. Submitted May 31, 2012; accepted October 3, 2012. Reprint requests: Adnan Kastrati, MD, ISAR Center, Deutsches Herzzentrum, Lazarettstrasse 36, 80636 Munich, Germany. E-mail: [email protected] 0002-8703/$ - see front matter © 2013, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2012.10.019
Study population and protocol The study design, methods, and the primary results of the ISAR-TEST 2 and ISAR-TEST 5 clinical trials have been described previously. 7-9 The combined data from these two randomized trials comprised 1,000 patients treated with the R-ZES in ISARTEST 5 and 339 patients treated with the E-ZES in ISAR-TEST 2 (Figure 1).
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Figure 1
Patient flow and follow-up. SES, sirolimus-eluting stent; Dual-DES, polymer-free rapamycin- and probucol-eluting stent; ZES, zotarolimuseluting stent.
Inclusion criteria were identical in both studies. Enrolled patients were older than 18 years with chronic stable angina, or acute coronary syndromes or evidence of myocardial ischemia (inducible or spontaneous) in the presence of ≥50% de novo stenosis located in native coronary vessels. Written, informed consent for participation in the study was obtained from the patient or her/his legally-authorized representative. Patients with a target lesion located in the left main stem, cardiogenic shock, malignancies or other co-morbid condition with life expectancy less than 12 months or that may result in protocol non-compliance, known allergy to the study medications (zotarolimus) or pregnancy (present, suspected or planned) were considered ineligible for the study. Full details of treatment allocation, study devices, and adjunctive antithrombotic therapy have been previously reported. 7-9 An oral loading dose of 600 mg clopidogrel was administered to all patients prior to coronary intervention. During the procedure, patients were given intravenous aspirin, heparin or bivalirudin; glycoprotein IIb/IIIa inhibitor usage was at the discretion of the operators. After the intervention all patients, irrespective of treatment allocation, were prescribed 200 mg/day aspirin indefinitely, clopidogrel 150 mg for the first 3 days (or until discharge) followed by 75 mg/day for at least 6 months. Other cardiac medications were prescribed according to the judgment of patient's physician (e.g. β-blockers, ACEinhibitors, statins etc.).
Data management, end points, and definitions Patients were followed-up either by physician office visit or by telephone at 1, 12, and 24 months. Repeat coronary angiography was scheduled at 6 to 8 months. Relevant data were collected and entered into a computer database by specialized personnel of the Clinical Data Management Centre (ISAR Center,
Munich, Germany). All events were adjudicated and classified by an event adjudication committee blinded to the treatment groups. All events were reported to the Data Safety and Monitoring Board, which monitored the overall rate of events in the study. Baseline, post procedural, and follow-up coronary angiograms were digitally recorded and assessed off-line in the quantitative angiographic (QCA) core laboratory (ISAR Center, Munich, Germany) with an automated edge-detection system (CMS version 7.1, Medis Medical Imaging Systems) by two independent experienced operators blinded to treatment allocation. Measurements were performed on cineangiograms recorded after the intracoronary administration of nitro-glycerine using the same single worst-view projection at all times. The contrast-filled non-tapered catheter tip was used for calibration. Quantitative analysis was performed on both the “in-stent” and “in-segment” area (including the stented segment, as well as both 5-mm margins proximal and distal to the stent). Qualitative morphological lesion characteristics were characterized by standard criteria. The principal efficacy endpoint of interest was target lesion revascularization (TLR) at 2 years post index intervention. The principal safety endpoints of interest were the device-oriented composite of cardiac death and myocardial infarction (MI) related to the target vessel, and the incidence of definite stent thrombosis (according to Academic Research Consortium definition) at 2 years. Cardiac death was defined as death due to any of the following: acute myocardial infarction; cardiac perforation/pericardial tamponade; arrhythmia or conduction abnormality; stroke within 30 days of the procedure or stroke suspected of being related to the procedure; death due to complication of the procedure, including bleeding, vascular repair, transfusion reaction, or bypass surgery; or any death in which a cardiac cause cannot be excluded. Spontaneous MI was defined as any creatine kinase–MB or troponin increase with or
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without the development of Q-waves on electrocardiogram. Details relating to the adjudication of MI related to percutaneous coronary intervention or to bypass surgery are as reported previously. 10 TLR was defined as any ischemia-driven repeat percutaneous coronary intervention of the target lesion or bypass surgery of the target vessel. Ischemia-driven was defined by: diameter stenosis ≥50% (on “in-segment” QCA-analysis) at follow-up angiography and positive functional study corresponding to the area served by the target lesion or ischemic symptoms and electrocardiogram changes at rest referable to the target lesion; or diameter stenosis ≥70% at follow-up angiography in absence of documented clinical or functional ischemia. In patients with multilesion intervention, target lesion revascularization was defined as a reintervention in at least one of the lesions treated during the index procedure. Subgroup analysis among the patients with or without diabetes mellitus was also performed.
Statistical analysis This observational analysis is exploratory in nature. Baseline descriptive statistics are presented as frequencies and percentages for categorical variables and mean ± standard deviation (SD) or median [25th-75th percentiles] for continuous variables. Two-year clinical outcomes at patient-level and 6– 8 month angiographic outcomes at lesion-level were analyzed. Survival and event-free status were assessed using the methods of Kaplan-Meier. Differences across groups were checked for significance (depending on the distribution of the data) with analysis of variance or Kruskal-Wallis test (continuous data), or log-rank test (survival analysis). Intergroup outcome comparisons were assessed using the Student t test (continuous data), chi-square or Fisher exact test (categorical variables), or logrank test (survival analysis). The hazard ratio with 95% CI and P value of clinical outcomes were estimated using Cox proportional hazard regression methods. Statistical software S-PLUS, version 4.5 (Insightful Corp., Seattle, Washington) was used for all analysis. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Results Patients A total of 1,339 enrolled patients were assessed in this study: 1,000 patients received the R-ZES in ISAR-TEST 5 and 339 patients received the E-ZES in ISAR-TEST 2 ( Figure 1). Baseline clinical, angiographic, and procedural characteristics are shown in Tables I and II. Baseline demographic and clinical data were similar across the study arm of each trial except for more patients with insulin-dependent diabetes mellitus in the R-ZES group as compared to the E-ZES group (10.9% vs. 5.9%, P = .007, respectively). Regarding baseline lesion and procedural characteristics, patients receiving the R-ZES as compared with patients received the E-ZES more often had significantly smaller reference vessel size, longer lesion length, and longer total implanted stent length.
Table I. Baseline patient characteristics
Age (years) Female Diabetes mellitus insulin-dependent Hypertension Hyperlipidemia Current smoker Prior myocardial infarction Prior bypass surgery Multivessel disease Clinical presentation acute myocardial infarction unstable angina stable angina Multilesion intervention Ejection fraction (%)⁎
R-ZES (n = 1000)
E-ZES (n = 339)
68.1 ± 10.8 237 (23.7) 295 (29.5) 109 (10.9) 666 (66.6) 650 (65.0) 166 (16.6) 299 (29.9) 96 (9.6) 855 (85.5)
67.2 ± 10.9 83 (24.5) 89 (26.3) 20 (5.9) 229 (67.6) 222 (65.5) 61 (18.0) 88 (26.0) 29 (8.6) 280 (82.6)
221 (22.1) 200 (20.0) 579 (57.9) 378 (37.8) 52.4 ± 11.4
49 (14.5) 101 (29.8) 189 (55.8) 78 (23.0) 54.5 ± 10.4
P .30 .77 .25 .007 .75 .87 .55 .17 .57 .22 .0001
b.0001 .74
Data shown as means ± SD or number (percentage). R-ZES = Resolute zotarolimus-eluting stent; E-ZES = Endeavor zotarolimus stent. ⁎ Data available for 1159 patients (86.6%).
Table II. Angiographic and procedural characteristics
Target vessel left anterior descending left circumflex right coronary artery Chronic total occlusion Complex morphology (B2/C) Lesion length (mm) Vessel size (mm) Minimal lumen diameter, pre (mm) Balloon diameter (mm) Minimal lumen diameter, post (mm) Stented length (mm)
R-ZES (n = 1479)
E-ZES (n = 418)
666 (45.0) 386 (26.1) 427 (28.9) 76 (5.1) 1088 (73.6) 16.9 ± 10.0 2.80 ± 0.50 0.90 ± 0.50
172 (41.0) 128 (30.5) 120 (28.6) 16 (3.8) 315 (75.0) 14.7 ± 8.0 2.71 ± 0.48 1.00 ± 0.49
.26 .55 .0005 .0002 b.0001
3.08 ± 0.53 2.58 ± 0.49
2.99 ± 0.53 2.54 ± 0.48
.54 .04
26.8 ± 12.4
23.8 ± 11.0
b.0001
P
.17
Data shown as means ± SD or number (percentage). R-ZES = Resolute zotarolimus-eluting stent; E-ZES = Endeavor zotarolimus stent.
Angiographic surveillance Follow-up angiography at 6 to 8 months was performed in 78% of patients. All measures for angiographic restenosis favored the R-ZES as compared to the E-ZES ( Table III). There were significant differences between the R-ZES and the E-ZES in terms of in-segment binary angiographic restenosis (13.4% versus 19.3% respectively; P = .006), in-stent minimum lumen diameter (2.28 ± 0.68 mm vs 1.95 ± 0.72 mm respectively; P b .0001) and in-stent late luminal loss (0.29 ± 0.56 mm vs 0.58 ± 0.55 mm respectively; P b .0001; Figure 2).
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Table III. Angiographic results at 6–8 months
Minimal lumen diameter, in stent (mm) % Diameter stenosis, in stent Minimal lumen diameter, in segment (mm) % Diameter stenosis, in segment Late loss, in stent Binary restenosis, in segment
Table IV. Clinical results at 2 year
R-ZES (n = 1131)
E-ZES (n = 358)
P
2.28 ± 0.68
1.95 ± 0.72
b.0001
21.6 ± 19.2 2.02 ± 0.63
30.0 ± 21.2 1.79 ± 0.66
b.0001 b.0001
30.7 ± 19.4 0.29 ± 0.56 151 (13.4)
35.3 ± 17.7 0.58 ± 0.55 69 (19.3)
b.0001 b.0001 .006
Data shown as means ± SD or number (percentage).
Figure 2
R-ZES E-ZES (n = 1000) (n = 339) All-cause death Cardiac death Myocardial infarction Target lesion revascularization Definite Stent thrombosis Cardiac death or myocardial infarction
Hazard ratio (95% CI)
P
81 (8.3) 27 (2.8) 32 (3.3)
21 (6.2) 6 (1.8) 13 (3.9)
1.34 (0.83-2.17) .23 1.56 (0.64-3.78) .32 0.84 (0.44-1.59) .58
114 (12.0)
53 (16.0)
0.72 (0.52-1.00) .052
4 (0.4)
2 (0.6)
0.68 (0.12-3.72) .66
54 (5.5)
16 (4.8)
1.15 (0.66-2.02) .62
Data shown as number (percentage) by Kaplan-Meier analysis; hazard ratios and P values were calculated from Cox proportional hazard methods.
Figure 3
Cumulative distribution curves for late luminal loss. Hazard ratios and P values are derived from Cox proportional hazard methods.
Two-year clinical outcomes The results of 2-year follow-up are shown in Table IV. Two-year follow-up was complete on all but 59 patients (4.4%), with no significant difference in non-completion between the 2 study groups (14 patient [1.4%] at 1 year and 48 patients [4.8%] at 2 years in the R-ZES group and no patients at 1 year and 11 patients [3.2%] at 2 years in the E-ZES group, P = .36). In patients with incomplete follow-up, median duration of follow-up was 13.7 [8.220.8] months. Regarding efficacy outcomes, TLR was performed in 114 patients (12.0%) in the R-ZES group and 53 patients (16.0%) in the E-ZES group (P = .052) at 2 years (Figure 3). Regarding safety outcomes, the composite of cardiac death and myocardial infarction at 2 years occurred in 54 cases (5.5%) in the R-ZES group and 16 cases (4.8%) in the E-ZES (P = .72) (Figure 4). Definite stent thrombosis occurred in 4 patients (0.4%) in the R-ZES group and 2 patients (0.6%) in the E-ZES group (P = .71). In subgroup analysis use of the R-ZES was associated with significant risk reduction of TLR in patients with diabetes mellitus (13.9% vs. 23.6%, HR 0.56 [95% CI: 0.33-
Time to event curve for incidence of target lesion revascularization. Hazard ratios and P values are derived from Cox proportional hazard methods.
0.95], P = .03), whereas in patients without diabetes mellitus no difference was seen (10.4% vs 12.8%, HR 0.80 [95%CI: 0.53-1.22], P = .30). The interaction between stent type and presence of diabetes was significant (Pinteraction = .003).
Discussion The results of the current study demonstrate that in the setting of 2 randomized trials with broad inclusion criteria new-generation Resolute zotarolimus-eluting stents compared with earlier generation Endeavor zotarolimuseluting stents showed (1) a significant reduction in angiographic measures of restenosis at 6–8 months as well as numerically lower rates of target lesion
84 Tada et al
Figure 4
Time to event curve for incidence of composite endpoint of cardiac death, myocardial infarction. Hazard ratios and P values are derived from Cox proportional hazard methods.
revascularization out to 2 years; and (2) similar low risk of cardiac death and myocardial infarction, and stent thrombosis, through 2 years. The Resolute zotarolimus-eluting stent is the latest drugeluting stent to receive approval for clinical use in the United States by the Food and Drug Administration. 11 The device itself shares many design features with its forerunner —the Endeavor zotarolimus-eluting stent — including similar stent backbone with the same drug loading dosages. However, the R-ZES contains a novel durable polymer coating, which results in improved drugrelease kinetics (BioLinx). In view of this iterative improvement, as well as the wealth of evidence collected with the E-ZES, a benchmark comparison between the 2 devices may be considered clinically important. In this respect, the present report represents the first comparative analysis of angiographic and clinical outcomes in a broadly inclusive patient population. The results from our report clearly demonstrate that the more favorable drug-release kinetics achieved by the novel polymer coating employed on the R-ZES result in improved suppression of neointimal hyperplasia and significant reduction in terms of angiographic markers of antirestenotic efficacy. Indeed in-stent late lumen loss at 6 to 8 months was significantly lower in patients treated with R-ZES as compared with E-ZES (0.29 ± 0.56 mm vs 0.58 ± 0.55 mm respectively; P b .0001).This result is concordant with previous studies. The RESOLUTE first-inhuman study reported that the 9-month in-stent late lumen loss was 0.22 ± 0.27 mm, which was significantly less than 0.62 ± 0.46 mm seen in the matched E-ZES cohort of the ENDEAVOR II study. 3,12 In the setting of socalled “All comers” designed trials, including our data, the in-stent late loss was reported somewhat greater than the
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result from RESOLUTE first-in-human trial reflecting their broad inclusion criteria. RESOLUTE US trial reported 0.30 ± 0.54 mm at 8 months and RESOLUTE All Comers trial reported 0.27 ± 0.43 mm at 13 months. 5,13 According to these data, the R-ZES consistently halves the neointimal hyperplasia in comparison with the E-ZES up to 13 months. Furthermore, a non-randomized comparison of optical coherence tomography (OCT) findings also reported the better suppression of neointimal hyperplasia in selected patients treated with R-ZES as compared to EZES, (median neointimal thickness 0.11 mm vs 0.31 mm, respectively, at 6 months). 14 Regarding clinical outcomes, the rate of TLR was 12.0 % in R-ZES group and 16.0% in E-ZES group (P = .052).The clinical advantage was most pronounced in patients with diabetes mellitus who are considered to be at high risk for restenosis and may be thought to represent an enrichedrisk patient population in which differences in device efficacy are more readily observed. In contrast to our data, the percentage of TLR at 2 years in R-ZES group from Resolute All Comers trial was only 5.7%. Such differences between studies may be accounted for two reasons. First, angiographic follow-up was scheduled at 6–8 months for all patients in our study and its rate was approximately 80%, while in Resolute All Comers trial, 20% of patients were selected for an angiographic substudy at 13 months. Differences in timing and proportion of angiographic follow-up between studies may affect 2-year clinical outcomes and the high proportion of angiographic follow-up may have increased the absolute number of the patients receiving repeat revascularization in our study. Second, although both studies enrolled patients with broad inclusion criteria, the population enrolled in our study as compared with the Resolute All Comers trial might be considered higher risk, with higher mean age (68.1 years vs 64.4 years) as well as a higher proportion of patients with diabetes mellitus (29.5% vs 23.5%). In fact, the incidence of all-cause death at 2 years in our study was numerically considerably higher than that of Resolute All Comers trial (8.3% vs 3.2%). 6 The principal difference between the R-ZES and the preceding E-ZES is its durable polymer coating. The novel 3-component polymer combines hydrophilic surface elements with a hydrophobic core and offers potentially improved biocompatibility with enhanced drug-release kinetics. 1 The key advantage of this polymer coating is that the R-ZES has a more delayed drug release (50% and 85% drug release at 7 and 60 days after stent implantation, respectively) in comparison to the E-ZES stent (75% drug release at 2 days). 1 Indeed the current dataset highlights that when other factors (such as stent backbone and drug load) are equal, drug-release kinetics over the first 28 days is the critical determinant of device efficacy. This is in line with earlier studies comparing devices differing only in terms of drug-release kinetics. For example, we previously reported that the polymer-free sirolimus-eluting
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stent with rapid initial drug-release (~75% in the first 10 days) was associated with higher initial late loss at 6 to 8 months as compared to an identical biodegradable polymer-based sirolimus-eluting stents with slower drugrelease kinetics. 15 Similarly, It has been reported that a long release-kinetic (30 days) paclitaxel-eluting stent demonstrated greater efficacy at inhibiting neointimal hyperplasia than a shorter release-kinetic (10 days) stent with identical drug loading doses. 16 These findings agree with molecular biology studies demonstrating the critical role of pro-restenotic gene activation in the first 3 weeks after stent implantation. 17 Interestingly, the intracoronary assessment with OCT also revealed a higher proportion of uncovered and malapposed stent struts at 6 months in the R-ZES in comparison to the E-ZES. 14 However the clinical relevance of such OCT evidence of delayed arterial healing with R-ZES is not supported by recent clinical trials. In particular, the RESOLUTE US trial reported a very low rate (0.1 %) of definite or probable stent thrombosis in 1402 patients treated with the R-ZES at 12 months. 13 Furthermore low rates of stent thrombosis with the R-ZES were also reported in the RESOLUTE All Comers trial 5,6 and the TWENTE trial. 18 Indeed our data further support the high safety profile of the both the R-ZES and the E-ZES with a very low incidence of definite stent thrombosis in both studies groups at 2 years (0.4% in the R-ZES vs. 0.6% in the E-ZES, P = .66).
Study limitations The current study has a number of important limitations. First, the current report is based on a post hoc analysis from a pooled dataset including 2 randomized clinical trials. Accordingly, the findings should be considered exploratory and hypothesis generating in nature. However, because a direct randomized comparison between these 2 devices is not expected to be performed in the future, our findings provide unique information regarding the relative merits of the 2 devices. Second, although we applied the same eligibility criteria and protocol procedures in the 2 included randomized trials (ISAR-TEST 2 and ISAR-TEST 5), the trials did not run concurrently. Indeed differences in baseline characteristics and improvements in clinical management over time may have influenced the observed outcomes. In line with this patients treated with R-ZES clearly had more complex disease patterns—with higher rates of insulin-dependent diabetes mellitus, more multi-lesion interventions, and longer lesion length. Third, angiographic surveillance was scheduled for all patients in the original trial protocols. While this feature may increase the absolute differences between comparator devices the relative differences across study groups are likely to be unaffected. 19 Moreover, the angiographic follow-up rate was different between 2 groups (23.7% in R-ZES group and
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17.8% in E-ZES group, P = .001), a fact that may limit the accuracy of final results. Fourth, in our study, clopidogrel therapy was maintained for at least 6 months, in line with current European Society of Cardiology guidelines. 20 It should be acknowledged that the optimal duration of such therapy after drug-eluting stent implantation remains a matter of some debate 21and is the subject of a number of ongoing large randomized trials.
Conclusions Comparison of the two Food and Drug Administration–approved zotarolimus-eluting stents suggested that the R-ZES as compared to the E-ZES displayed overall superior antirestenotic efficacy. Both devices were associated with a similar low risk of adverse safety events through 2 years.
Funding sources There was no extramural funding used for this work.
Disclosures Dr Kastrati reports having received lecture fees from Abbott, Biotronik, Cordis, and Medtronic. The remaining authors report no conflicts of interest.
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in patients with long coronary stenoses: The LongOCT study (Optical Coherence Tomography in Long Lesions). JACC Cardiovasc Interv 2011;4:778-85. Mehilli J, Byrne RA, Wieczorek A, et al. Randomized trial of three rapamycin-eluting stents with different coating strategies for the reduction of coronary restenosis. Eur Heart J 2008;29:1975-82. Serruys PW, Sianos G, Abizaid A, et al. The effect of variable dose and release kinetics on neointimal hyperplasia using a novel paclitaxel-eluting stent platform: The paclitaxel in-stent controlled elution study (PISCES). J Am Coll Cardiol 2005;46:253-60. Tanner FC, Yang ZY, Duckers E, et al. Expression of cyclindependent kinase inhibitors in vascular disease. Circ Res 1998;82: 396-403. von Birgelen C, Basalus MW, Tandjung K, et al. A randomized controlled trial in second-generation zotarolimus-eluting Resolute stents versus everolimus-eluting Xience V stents in real-world patients: The TWENTE trial. J Am Coll Cardiol 2012;59:1350-61. Uchida T, Popma J, Stone GW, et al. The clinical impact of routine angiographic follow-up in randomized trials of drug-eluting stents: A critical assessment of “oculostenotic” reintervention in patients with intermediate lesions. JACC Cardiovasc Interv 2010;3:403-11. Wijns W, Kolh P, Danchin N, et al. Guidelines on myocardial revascularization. Eur Heart J 2010;31:2501-55. Cassese S, Byrne R, Tada T, et al. Clinical impact of extended dual antiplatelet therapy after percutaneous coronary interventions in the drug-eluting stent era: a meta-analysis of randomized trials Eur Heart J. [in press].
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Background The Resolute zotarolimus-eluting stent (R-ZES) utilizes the same metallic platform and anti-restenotic drug as the Endeavor zotarolimus-eluting stent (E-ZES) but is coated with a more biocompatible polymer with enhanced drug-release kinetics. The aim of this study was to compare the long-term clinical outcomes of 2 zotarolimus-eluting stent generations. Methods
In two randomized trials with broad inclusion criteria (ISAR-TEST 2 and ISAR-TEST 5), 1,000 patients were treated with R-ZES and 339 patients treated with E-ZES. In both trials follow-up angiography was scheduled at 6 to 8 months. The efficacy endpoint of interest was target lesion revascularization and the safety endpoints were the combined incidence of cardiac death or myocardial infarction related to target vessel as well as the incidence of definite stent thrombosis at 2-year follow-up.
Results
The incidence of target lesion revascularization at 2 years was 12.0% in the R-ZES group and 16.0% in the E-ZES (HR 0.72 [95% CI: 0.52-1.00], P = .052). The incidence of cardiac death or myocardial infarction was 5.5% vs. 4.8% (HR 1.15, [95% CI: 0.66-2.02], P = .62) and of definite stent thrombosis was 0.4% vs. 0.6% (HR 0.68, [95% CI: 0.12-3.72], P = .66), respectively. All measures of angiographic restenosis were in favor of the R-ZES; in-stent late lumen loss was 0.29 ± 0.56 with the R-ZES versus 0.58 ± 0.55 with the E-ZES (P b .0001).
Conclusions Comparison of the 2 Food and Drug Administration–approved zotarolimus-eluting stents suggested that the R-ZES as compared to the E-ZES displayed overall superior antirestenotic efficacy. Both devices were associated with a similar low risk of adverse safety events through 2 years. (Am Heart J 2013;165:80-6.)
The new generation Endeavor Resolute zotarolimuseluting stent (R-ZES) (Medtronic, Santa Rosa, CA) is based on the same stent backbone as the preceding Endeavor zotarolimus-eluting stent (E-ZES) (Medtronic) and is coated with the same dose of zotarolimus. The key difference between the R-ZES in comparison with the EZES is its polymer coating which is composed of 3 different hydrophilic and hydrophobic polymeric elements (BioLinx). 1 Initial non-randomized single arm studies of the R-ZES demonstrated high antirestenotic efficacy with a favorable safety profile among relatively low-risk patients out to 3 years 2-4 and a recent all-comers randomized clinical trial demonstrated comparable clin-
ical outcomes to the everolimus-eluting stent up to 2 years. 5,6 To date however long-term comparative efficacy studies between the R-ZES and the preceding E-ZES remain a significant scientific gap. Indeed in view of the wealth of trial data and clinical experience accumulated with the E-ZES, this stent represents an important benchmark against which to evaluate the performance of the new generation R-ZES. Against this background we sought to compare the long-term efficacy and safety of the 2 zotarolimus-eluting stent generations out to 2 years using the combined data from the ISAR-TEST 2 and the ISAR-TEST 5 randomized trials. 7-9
Methods From the Deutsches Herzzentrum, Technische Universität, Munich, Germany. Submitted May 31, 2012; accepted October 3, 2012. Reprint requests: Adnan Kastrati, MD, ISAR Center, Deutsches Herzzentrum, Lazarettstrasse 36, 80636 Munich, Germany. E-mail: [email protected] 0002-8703/$ - see front matter © 2013, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2012.10.019
Study population and protocol The study design, methods, and the primary results of the ISAR-TEST 2 and ISAR-TEST 5 clinical trials have been described previously. 7-9 The combined data from these two randomized trials comprised 1,000 patients treated with the R-ZES in ISARTEST 5 and 339 patients treated with the E-ZES in ISAR-TEST 2 (Figure 1).
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Figure 1
Patient flow and follow-up. SES, sirolimus-eluting stent; Dual-DES, polymer-free rapamycin- and probucol-eluting stent; ZES, zotarolimuseluting stent.
Inclusion criteria were identical in both studies. Enrolled patients were older than 18 years with chronic stable angina, or acute coronary syndromes or evidence of myocardial ischemia (inducible or spontaneous) in the presence of ≥50% de novo stenosis located in native coronary vessels. Written, informed consent for participation in the study was obtained from the patient or her/his legally-authorized representative. Patients with a target lesion located in the left main stem, cardiogenic shock, malignancies or other co-morbid condition with life expectancy less than 12 months or that may result in protocol non-compliance, known allergy to the study medications (zotarolimus) or pregnancy (present, suspected or planned) were considered ineligible for the study. Full details of treatment allocation, study devices, and adjunctive antithrombotic therapy have been previously reported. 7-9 An oral loading dose of 600 mg clopidogrel was administered to all patients prior to coronary intervention. During the procedure, patients were given intravenous aspirin, heparin or bivalirudin; glycoprotein IIb/IIIa inhibitor usage was at the discretion of the operators. After the intervention all patients, irrespective of treatment allocation, were prescribed 200 mg/day aspirin indefinitely, clopidogrel 150 mg for the first 3 days (or until discharge) followed by 75 mg/day for at least 6 months. Other cardiac medications were prescribed according to the judgment of patient's physician (e.g. β-blockers, ACEinhibitors, statins etc.).
Data management, end points, and definitions Patients were followed-up either by physician office visit or by telephone at 1, 12, and 24 months. Repeat coronary angiography was scheduled at 6 to 8 months. Relevant data were collected and entered into a computer database by specialized personnel of the Clinical Data Management Centre (ISAR Center,
Munich, Germany). All events were adjudicated and classified by an event adjudication committee blinded to the treatment groups. All events were reported to the Data Safety and Monitoring Board, which monitored the overall rate of events in the study. Baseline, post procedural, and follow-up coronary angiograms were digitally recorded and assessed off-line in the quantitative angiographic (QCA) core laboratory (ISAR Center, Munich, Germany) with an automated edge-detection system (CMS version 7.1, Medis Medical Imaging Systems) by two independent experienced operators blinded to treatment allocation. Measurements were performed on cineangiograms recorded after the intracoronary administration of nitro-glycerine using the same single worst-view projection at all times. The contrast-filled non-tapered catheter tip was used for calibration. Quantitative analysis was performed on both the “in-stent” and “in-segment” area (including the stented segment, as well as both 5-mm margins proximal and distal to the stent). Qualitative morphological lesion characteristics were characterized by standard criteria. The principal efficacy endpoint of interest was target lesion revascularization (TLR) at 2 years post index intervention. The principal safety endpoints of interest were the device-oriented composite of cardiac death and myocardial infarction (MI) related to the target vessel, and the incidence of definite stent thrombosis (according to Academic Research Consortium definition) at 2 years. Cardiac death was defined as death due to any of the following: acute myocardial infarction; cardiac perforation/pericardial tamponade; arrhythmia or conduction abnormality; stroke within 30 days of the procedure or stroke suspected of being related to the procedure; death due to complication of the procedure, including bleeding, vascular repair, transfusion reaction, or bypass surgery; or any death in which a cardiac cause cannot be excluded. Spontaneous MI was defined as any creatine kinase–MB or troponin increase with or
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without the development of Q-waves on electrocardiogram. Details relating to the adjudication of MI related to percutaneous coronary intervention or to bypass surgery are as reported previously. 10 TLR was defined as any ischemia-driven repeat percutaneous coronary intervention of the target lesion or bypass surgery of the target vessel. Ischemia-driven was defined by: diameter stenosis ≥50% (on “in-segment” QCA-analysis) at follow-up angiography and positive functional study corresponding to the area served by the target lesion or ischemic symptoms and electrocardiogram changes at rest referable to the target lesion; or diameter stenosis ≥70% at follow-up angiography in absence of documented clinical or functional ischemia. In patients with multilesion intervention, target lesion revascularization was defined as a reintervention in at least one of the lesions treated during the index procedure. Subgroup analysis among the patients with or without diabetes mellitus was also performed.
Statistical analysis This observational analysis is exploratory in nature. Baseline descriptive statistics are presented as frequencies and percentages for categorical variables and mean ± standard deviation (SD) or median [25th-75th percentiles] for continuous variables. Two-year clinical outcomes at patient-level and 6– 8 month angiographic outcomes at lesion-level were analyzed. Survival and event-free status were assessed using the methods of Kaplan-Meier. Differences across groups were checked for significance (depending on the distribution of the data) with analysis of variance or Kruskal-Wallis test (continuous data), or log-rank test (survival analysis). Intergroup outcome comparisons were assessed using the Student t test (continuous data), chi-square or Fisher exact test (categorical variables), or logrank test (survival analysis). The hazard ratio with 95% CI and P value of clinical outcomes were estimated using Cox proportional hazard regression methods. Statistical software S-PLUS, version 4.5 (Insightful Corp., Seattle, Washington) was used for all analysis. No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.
Results Patients A total of 1,339 enrolled patients were assessed in this study: 1,000 patients received the R-ZES in ISAR-TEST 5 and 339 patients received the E-ZES in ISAR-TEST 2 ( Figure 1). Baseline clinical, angiographic, and procedural characteristics are shown in Tables I and II. Baseline demographic and clinical data were similar across the study arm of each trial except for more patients with insulin-dependent diabetes mellitus in the R-ZES group as compared to the E-ZES group (10.9% vs. 5.9%, P = .007, respectively). Regarding baseline lesion and procedural characteristics, patients receiving the R-ZES as compared with patients received the E-ZES more often had significantly smaller reference vessel size, longer lesion length, and longer total implanted stent length.
Table I. Baseline patient characteristics
Age (years) Female Diabetes mellitus insulin-dependent Hypertension Hyperlipidemia Current smoker Prior myocardial infarction Prior bypass surgery Multivessel disease Clinical presentation acute myocardial infarction unstable angina stable angina Multilesion intervention Ejection fraction (%)⁎
R-ZES (n = 1000)
E-ZES (n = 339)
68.1 ± 10.8 237 (23.7) 295 (29.5) 109 (10.9) 666 (66.6) 650 (65.0) 166 (16.6) 299 (29.9) 96 (9.6) 855 (85.5)
67.2 ± 10.9 83 (24.5) 89 (26.3) 20 (5.9) 229 (67.6) 222 (65.5) 61 (18.0) 88 (26.0) 29 (8.6) 280 (82.6)
221 (22.1) 200 (20.0) 579 (57.9) 378 (37.8) 52.4 ± 11.4
49 (14.5) 101 (29.8) 189 (55.8) 78 (23.0) 54.5 ± 10.4
P .30 .77 .25 .007 .75 .87 .55 .17 .57 .22 .0001
b.0001 .74
Data shown as means ± SD or number (percentage). R-ZES = Resolute zotarolimus-eluting stent; E-ZES = Endeavor zotarolimus stent. ⁎ Data available for 1159 patients (86.6%).
Table II. Angiographic and procedural characteristics
Target vessel left anterior descending left circumflex right coronary artery Chronic total occlusion Complex morphology (B2/C) Lesion length (mm) Vessel size (mm) Minimal lumen diameter, pre (mm) Balloon diameter (mm) Minimal lumen diameter, post (mm) Stented length (mm)
R-ZES (n = 1479)
E-ZES (n = 418)
666 (45.0) 386 (26.1) 427 (28.9) 76 (5.1) 1088 (73.6) 16.9 ± 10.0 2.80 ± 0.50 0.90 ± 0.50
172 (41.0) 128 (30.5) 120 (28.6) 16 (3.8) 315 (75.0) 14.7 ± 8.0 2.71 ± 0.48 1.00 ± 0.49
.26 .55 .0005 .0002 b.0001
3.08 ± 0.53 2.58 ± 0.49
2.99 ± 0.53 2.54 ± 0.48
.54 .04
26.8 ± 12.4
23.8 ± 11.0
b.0001
P
.17
Data shown as means ± SD or number (percentage). R-ZES = Resolute zotarolimus-eluting stent; E-ZES = Endeavor zotarolimus stent.
Angiographic surveillance Follow-up angiography at 6 to 8 months was performed in 78% of patients. All measures for angiographic restenosis favored the R-ZES as compared to the E-ZES ( Table III). There were significant differences between the R-ZES and the E-ZES in terms of in-segment binary angiographic restenosis (13.4% versus 19.3% respectively; P = .006), in-stent minimum lumen diameter (2.28 ± 0.68 mm vs 1.95 ± 0.72 mm respectively; P b .0001) and in-stent late luminal loss (0.29 ± 0.56 mm vs 0.58 ± 0.55 mm respectively; P b .0001; Figure 2).
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Table III. Angiographic results at 6–8 months
Minimal lumen diameter, in stent (mm) % Diameter stenosis, in stent Minimal lumen diameter, in segment (mm) % Diameter stenosis, in segment Late loss, in stent Binary restenosis, in segment
Table IV. Clinical results at 2 year
R-ZES (n = 1131)
E-ZES (n = 358)
P
2.28 ± 0.68
1.95 ± 0.72
b.0001
21.6 ± 19.2 2.02 ± 0.63
30.0 ± 21.2 1.79 ± 0.66
b.0001 b.0001
30.7 ± 19.4 0.29 ± 0.56 151 (13.4)
35.3 ± 17.7 0.58 ± 0.55 69 (19.3)
b.0001 b.0001 .006
Data shown as means ± SD or number (percentage).
Figure 2
R-ZES E-ZES (n = 1000) (n = 339) All-cause death Cardiac death Myocardial infarction Target lesion revascularization Definite Stent thrombosis Cardiac death or myocardial infarction
Hazard ratio (95% CI)
P
81 (8.3) 27 (2.8) 32 (3.3)
21 (6.2) 6 (1.8) 13 (3.9)
1.34 (0.83-2.17) .23 1.56 (0.64-3.78) .32 0.84 (0.44-1.59) .58
114 (12.0)
53 (16.0)
0.72 (0.52-1.00) .052
4 (0.4)
2 (0.6)
0.68 (0.12-3.72) .66
54 (5.5)
16 (4.8)
1.15 (0.66-2.02) .62
Data shown as number (percentage) by Kaplan-Meier analysis; hazard ratios and P values were calculated from Cox proportional hazard methods.
Figure 3
Cumulative distribution curves for late luminal loss. Hazard ratios and P values are derived from Cox proportional hazard methods.
Two-year clinical outcomes The results of 2-year follow-up are shown in Table IV. Two-year follow-up was complete on all but 59 patients (4.4%), with no significant difference in non-completion between the 2 study groups (14 patient [1.4%] at 1 year and 48 patients [4.8%] at 2 years in the R-ZES group and no patients at 1 year and 11 patients [3.2%] at 2 years in the E-ZES group, P = .36). In patients with incomplete follow-up, median duration of follow-up was 13.7 [8.220.8] months. Regarding efficacy outcomes, TLR was performed in 114 patients (12.0%) in the R-ZES group and 53 patients (16.0%) in the E-ZES group (P = .052) at 2 years (Figure 3). Regarding safety outcomes, the composite of cardiac death and myocardial infarction at 2 years occurred in 54 cases (5.5%) in the R-ZES group and 16 cases (4.8%) in the E-ZES (P = .72) (Figure 4). Definite stent thrombosis occurred in 4 patients (0.4%) in the R-ZES group and 2 patients (0.6%) in the E-ZES group (P = .71). In subgroup analysis use of the R-ZES was associated with significant risk reduction of TLR in patients with diabetes mellitus (13.9% vs. 23.6%, HR 0.56 [95% CI: 0.33-
Time to event curve for incidence of target lesion revascularization. Hazard ratios and P values are derived from Cox proportional hazard methods.
0.95], P = .03), whereas in patients without diabetes mellitus no difference was seen (10.4% vs 12.8%, HR 0.80 [95%CI: 0.53-1.22], P = .30). The interaction between stent type and presence of diabetes was significant (Pinteraction = .003).
Discussion The results of the current study demonstrate that in the setting of 2 randomized trials with broad inclusion criteria new-generation Resolute zotarolimus-eluting stents compared with earlier generation Endeavor zotarolimuseluting stents showed (1) a significant reduction in angiographic measures of restenosis at 6–8 months as well as numerically lower rates of target lesion
84 Tada et al
Figure 4
Time to event curve for incidence of composite endpoint of cardiac death, myocardial infarction. Hazard ratios and P values are derived from Cox proportional hazard methods.
revascularization out to 2 years; and (2) similar low risk of cardiac death and myocardial infarction, and stent thrombosis, through 2 years. The Resolute zotarolimus-eluting stent is the latest drugeluting stent to receive approval for clinical use in the United States by the Food and Drug Administration. 11 The device itself shares many design features with its forerunner —the Endeavor zotarolimus-eluting stent — including similar stent backbone with the same drug loading dosages. However, the R-ZES contains a novel durable polymer coating, which results in improved drugrelease kinetics (BioLinx). In view of this iterative improvement, as well as the wealth of evidence collected with the E-ZES, a benchmark comparison between the 2 devices may be considered clinically important. In this respect, the present report represents the first comparative analysis of angiographic and clinical outcomes in a broadly inclusive patient population. The results from our report clearly demonstrate that the more favorable drug-release kinetics achieved by the novel polymer coating employed on the R-ZES result in improved suppression of neointimal hyperplasia and significant reduction in terms of angiographic markers of antirestenotic efficacy. Indeed in-stent late lumen loss at 6 to 8 months was significantly lower in patients treated with R-ZES as compared with E-ZES (0.29 ± 0.56 mm vs 0.58 ± 0.55 mm respectively; P b .0001).This result is concordant with previous studies. The RESOLUTE first-inhuman study reported that the 9-month in-stent late lumen loss was 0.22 ± 0.27 mm, which was significantly less than 0.62 ± 0.46 mm seen in the matched E-ZES cohort of the ENDEAVOR II study. 3,12 In the setting of socalled “All comers” designed trials, including our data, the in-stent late loss was reported somewhat greater than the
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result from RESOLUTE first-in-human trial reflecting their broad inclusion criteria. RESOLUTE US trial reported 0.30 ± 0.54 mm at 8 months and RESOLUTE All Comers trial reported 0.27 ± 0.43 mm at 13 months. 5,13 According to these data, the R-ZES consistently halves the neointimal hyperplasia in comparison with the E-ZES up to 13 months. Furthermore, a non-randomized comparison of optical coherence tomography (OCT) findings also reported the better suppression of neointimal hyperplasia in selected patients treated with R-ZES as compared to EZES, (median neointimal thickness 0.11 mm vs 0.31 mm, respectively, at 6 months). 14 Regarding clinical outcomes, the rate of TLR was 12.0 % in R-ZES group and 16.0% in E-ZES group (P = .052).The clinical advantage was most pronounced in patients with diabetes mellitus who are considered to be at high risk for restenosis and may be thought to represent an enrichedrisk patient population in which differences in device efficacy are more readily observed. In contrast to our data, the percentage of TLR at 2 years in R-ZES group from Resolute All Comers trial was only 5.7%. Such differences between studies may be accounted for two reasons. First, angiographic follow-up was scheduled at 6–8 months for all patients in our study and its rate was approximately 80%, while in Resolute All Comers trial, 20% of patients were selected for an angiographic substudy at 13 months. Differences in timing and proportion of angiographic follow-up between studies may affect 2-year clinical outcomes and the high proportion of angiographic follow-up may have increased the absolute number of the patients receiving repeat revascularization in our study. Second, although both studies enrolled patients with broad inclusion criteria, the population enrolled in our study as compared with the Resolute All Comers trial might be considered higher risk, with higher mean age (68.1 years vs 64.4 years) as well as a higher proportion of patients with diabetes mellitus (29.5% vs 23.5%). In fact, the incidence of all-cause death at 2 years in our study was numerically considerably higher than that of Resolute All Comers trial (8.3% vs 3.2%). 6 The principal difference between the R-ZES and the preceding E-ZES is its durable polymer coating. The novel 3-component polymer combines hydrophilic surface elements with a hydrophobic core and offers potentially improved biocompatibility with enhanced drug-release kinetics. 1 The key advantage of this polymer coating is that the R-ZES has a more delayed drug release (50% and 85% drug release at 7 and 60 days after stent implantation, respectively) in comparison to the E-ZES stent (75% drug release at 2 days). 1 Indeed the current dataset highlights that when other factors (such as stent backbone and drug load) are equal, drug-release kinetics over the first 28 days is the critical determinant of device efficacy. This is in line with earlier studies comparing devices differing only in terms of drug-release kinetics. For example, we previously reported that the polymer-free sirolimus-eluting
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stent with rapid initial drug-release (~75% in the first 10 days) was associated with higher initial late loss at 6 to 8 months as compared to an identical biodegradable polymer-based sirolimus-eluting stents with slower drugrelease kinetics. 15 Similarly, It has been reported that a long release-kinetic (30 days) paclitaxel-eluting stent demonstrated greater efficacy at inhibiting neointimal hyperplasia than a shorter release-kinetic (10 days) stent with identical drug loading doses. 16 These findings agree with molecular biology studies demonstrating the critical role of pro-restenotic gene activation in the first 3 weeks after stent implantation. 17 Interestingly, the intracoronary assessment with OCT also revealed a higher proportion of uncovered and malapposed stent struts at 6 months in the R-ZES in comparison to the E-ZES. 14 However the clinical relevance of such OCT evidence of delayed arterial healing with R-ZES is not supported by recent clinical trials. In particular, the RESOLUTE US trial reported a very low rate (0.1 %) of definite or probable stent thrombosis in 1402 patients treated with the R-ZES at 12 months. 13 Furthermore low rates of stent thrombosis with the R-ZES were also reported in the RESOLUTE All Comers trial 5,6 and the TWENTE trial. 18 Indeed our data further support the high safety profile of the both the R-ZES and the E-ZES with a very low incidence of definite stent thrombosis in both studies groups at 2 years (0.4% in the R-ZES vs. 0.6% in the E-ZES, P = .66).
Study limitations The current study has a number of important limitations. First, the current report is based on a post hoc analysis from a pooled dataset including 2 randomized clinical trials. Accordingly, the findings should be considered exploratory and hypothesis generating in nature. However, because a direct randomized comparison between these 2 devices is not expected to be performed in the future, our findings provide unique information regarding the relative merits of the 2 devices. Second, although we applied the same eligibility criteria and protocol procedures in the 2 included randomized trials (ISAR-TEST 2 and ISAR-TEST 5), the trials did not run concurrently. Indeed differences in baseline characteristics and improvements in clinical management over time may have influenced the observed outcomes. In line with this patients treated with R-ZES clearly had more complex disease patterns—with higher rates of insulin-dependent diabetes mellitus, more multi-lesion interventions, and longer lesion length. Third, angiographic surveillance was scheduled for all patients in the original trial protocols. While this feature may increase the absolute differences between comparator devices the relative differences across study groups are likely to be unaffected. 19 Moreover, the angiographic follow-up rate was different between 2 groups (23.7% in R-ZES group and
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17.8% in E-ZES group, P = .001), a fact that may limit the accuracy of final results. Fourth, in our study, clopidogrel therapy was maintained for at least 6 months, in line with current European Society of Cardiology guidelines. 20 It should be acknowledged that the optimal duration of such therapy after drug-eluting stent implantation remains a matter of some debate 21and is the subject of a number of ongoing large randomized trials.
Conclusions Comparison of the two Food and Drug Administration–approved zotarolimus-eluting stents suggested that the R-ZES as compared to the E-ZES displayed overall superior antirestenotic efficacy. Both devices were associated with a similar low risk of adverse safety events through 2 years.
Funding sources There was no extramural funding used for this work.
Disclosures Dr Kastrati reports having received lecture fees from Abbott, Biotronik, Cordis, and Medtronic. The remaining authors report no conflicts of interest.
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