Randomized comparison of Zotarolimus-Eluting Endeavor Sprint versus bare-metal stent implantation in uncertain drug-eluting stent candidates: Rationale, design, and characterization of the patient population for the Zotarolimus-eluting Endeavor Sprint stent in Uncertain DES Candidates study Marco Valgimigli, MD, PhD, a,b Athanasios Patialiakas, MD, a Attila Thury, MD, PhD, c Salvatore Colangelo, MD, d Gianluca Campo, MD, a Matteo Tebaldi, MD, a Imre Ungi, MD, PhD, c Stefano Tondi, MD, e Marco Roffi, MD, f Alberto Menozzi, MD, PhD, g Nicoletta de Cesare, MD, h Roberto Garbo, MD, d Emanuele Meliga, MD, i Luca Testa, MD, PhD, j Henrique M. Gabriel, MD, k Flavio Airoldi, MD, l Marco Ferlini, MD, m Francesco Liistro, MD, n Antonio Dellavalle, MD, o Pascal Vranckx, MD, p and Carlo Briguori, MD, PhD q Ferrara, Torino, Modena, Baggiovara, Parma, Bergamo, Milan, Pavia, Arezzo, Savigliano, and Naples, Italy; Rotterdam, The Netherlands; Szeged, Hungary; Geneva, Switzerland; Lisbon, Portugal; and Hasselt, Belgium
Background The use of drug-eluting stent (DES) instead of bare-metal stent (BMS) in patients at high stent thrombosis or bleeding risk as well as in those at low restenosis risk (ie, uncertain DES candidates) remains a matter of debate. ZotarolimusEluting Endeavor Sprint stent (E-ZES) (Santa Rosa, CA) is a hydrophilic polymer-based second-generation device with unique drug fast-release profile, which may allow for a shorter dual antiplatelet therapy (DAPT) duration without safety concerns. Hypothesis The primary objective is to assess whether E-ZES implantation followed by a shorter than currently recommended course of DAPT will decrease the incidence of 12-month major adverse cardiovascular events as compared with BMS in undefined DES recipients. Actual duration of DAPT regimen will be dictated by patients' characteristics and not by stent type and, as such, can be as short as 30 days after intervention in both stent groups. Study Design The ZEUS study is an open-label randomized clinical trial conducted at 20 clinical sites in Italy, Switzerland, Portugal, and Hungary. With 1,600 individuals, this study will have 85% power to detect a 33% difference in the primary end point consisting of the composite of death, nonfatal myocardial infarction, or target vessel revascularization. Summary The ZEUS trial aims to assess whether the use of E-ZES, followed by a DAPT duration regimen based on patients' characteristics and not by stent type, is superior to conventional BMS implantation in undefined DES recipients who qualify for the presence of high thrombosis, bleeding, or low restenosis risk criteria. (Am Heart J 2013;166:831-8.)
Randomized controlled trials, 1 meta-analysis, 2 and observational studies 3 have consistently shown reduced rates of angiographic restenosis and ischemia-driven target vessel revascularization with drug-eluting stents
(DES) compared with bare-metal stents (BMS). However, the higher rates of very late stent thrombosis (ST) and the concern for a higher risk of late ST after early discontinuation of dual antiplatelet therapy (DAPT) with
From the aInterventional Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy, bThoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands, c Cardiology Center, Szeged, Hungary, dPoliclinico, San Giovanni Bosco, Torino, Italy, e Azienda Unità Sanitaria Locale di Modena–Ospedale Baggiovara, Modena, Italy, fDivision of Cardiology, University Hospital, Geneva, Switzerland, gInterventional Cardiology Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy, hPoliclinico S. Marco Zingonia,
San Donato Hospital, Arezzo, Italy, oOspedali Riuniti ASL 17, Savigliano, Italy, pVirga Jesse ziekenhuis, Hasselt, Belgium, and qClinica Mediterranea di Napoli, Naples, Italy. Clinical trial registration: ClinicalTrials.gov no. NCT01385319. Submitted February 10, 2013; accepted July 16, 2013. Reprint requests: Marco Valgimigli, MD, PhD, University of Ferrara, Via Aldo Moro, 8; 44124 Loc. Cona (FE), Italy. E-mail: [email protected]
Bergamo, Italy, iAzienda Ospedaliera Ordine Mauriziano, Torino, Italy, jInterventional Cardiology, Ist. Clinico S. Ambrogio, IRCCS San Donato, Milan, Italy, kHospital de Santa Cruz Carnaxide, Lisbon, Portugal, lIRCCS Multimedica Sesto San Giovanni, Milan, Italy, m Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, nCardiovascular Departments of
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first-generation DES have raised safety concerns. 4 As a consequence, the use of DES instead of BMS in patients at high thrombosis risk, whose risk for coronary events may be higher after DES; those at high bleeding risk, in whom long-term DAPT exposure poses safety concerns; or those at low risk for in-stent restenosis, whose long-term risk for adverse events after DES implantation may outweigh their benefit in terms of low reintervention rates, remains a matter of ongoing debate. Zotarolimus-Eluting Endeavor Sprint stent (E-ZES) is a hydrophilic polymer-based second-generation device with unique drug fast-release profile. Although this distinctive feature predisposes to less powerful inhibition of intimal hyperplasia compared with other DESs, it may allow for a shorter DAPT duration without safety concerns.
Technical characteristics of the E-ZES The Endeavor stent is a cobalt-based alloy stent with a phosphorylcholine polymer loaded with zotarolimus at dose concentration of 10 μg/mm stent length. It has been shown in preclinical studies that approximately 95% of zotarolimus is eluted from the stent within 15 days of implantation, although drug concentrations within surrounding vascular tissue may be detected at 30 days after stent deployment. 5 Zotarolimus is equivalent to sirolimus in terms of antiproliferative power (half maximal inhibitory concentration at 0.3 nM) but is more lipophilic with a distribution coefficient (logD) N4.5, as compared with 3.6 for sirolimus. Phosphorylcholine is a durable polymer primarily composed of hydrophilic monomers that mimic the chemical structure of phospholipid head groups, similar to the outer membrane of red blood cells (90% of phospholipids in the outer membrane of a red blood cell contain the phosphorylcholine head group). This polymer has a broad history of use in medical devices including coronary stents.
Evidence from clinical trials with E-ZES Unlike evidence provided by first-generation DES, there was no increased risk of death, myocardial infarction (MI), or ST, and there was a benefit to the prevention of repeat revascularization procedures in E-ZES compared with BMS in a combined patient level data from 6 prospective randomized single-arm multicenter trials involving 2,132 patients treated with zotarolimus-eluting stent (ZES) and 596 patients treated with a BMS control. 6 The hypothesis that E-ZES would lead to fewer ST events than sirolimus-eluting stent (SES) through a 3-year follow-up has been tested in the PROTECT trial. 7 At 3 years, rates of definite or probable ST did not differ between groups. This finding has been tentatively explained by the lower than anticipated rate of ST in
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the SES arm and by the long-term DAPT duration, which was mandated by the protocol. Dual antiplatelet therapy was used in 8,402 patients (96%) at discharge, 7,456 (88%) at 1 year, 3,041 (37%) at 2 years, and 2,364 (30%) at 3 years. Interestingly, the pattern of events over time was distributed differentially, with both devices having the same incidence of early ST, but SES having fewer late, but more very late, ST (definite or probable) than E-ZES. The higher incidence of late ST in the E-ZES was driven by an increased rate of probable ST. In the SES group, the higher incidence of very late ST events than that in the EZES group was driven by an increased incidence of definite ST. It remains speculative whether a different mechanism of MI (ie, occlusive restenosis in the E-ZES group vs noncovered stent struts in the SES group) contributed to this result. Hence, the results of the PROTECT trial might support the favorable long-term safety profile of E-ZES as compared with SES with respect to the risk of very late ST, but they question the use of this device in patients at high restenosis risk who would tolerate a long course of DAPT after stenting. Major randomized controlled trials comparing E-ZES to BMS or to first or other secondgeneration DES are summarized in Table I.
Optimal duration of DAPT after Endeavor Sprint implantation Kandzari et al 20 analyzed outcomes in 2,032 patients undergoing coronary revascularization with E-ZES in 5 trials who for various reasons discontinued DAPT at 6 months and found that outcomes did not differ compared with patients who received longer clopidogrel therapy (up to 12 or 24 months). In the RESET trial of 2,148 patients randomized to the EZES stent and 3 months of DAPT and 1,058 patients treated with standard 12-month DAPT and other DES, the combined end point of any death, MI, and ST occurred in 1.3% in the standard therapy arm versus 0.8% in the 3month group (P = .48). 17 Interestingly, prospective studies undertaken to evaluate the degree of E-ZES stent coverage have consistently showed a very low rate of uncovered/ malapposed struts at 6- or even 3-month optical coherence tomography evaluation, which favorably compared with both first-generation DES or even BMS. 21 The results of the PRODIGY trial showed no increase in the rate of fatal or ischemic events in patients receiving 6month DAPT as compared with 24-month therapy duration after everolimus-eluting stent (EES), paclitaxeleluting stent (PES), E-ZES, or BMS. 19 The composite of death, MI, or cerebrovascular accident did not differ in patients receiving BMS, PES, or EES implantation across DAPT groups, whereas it was significantly lower in E-ZES patients undergoing short- as
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Table I. Dual anti-platelet therapy recommendations and stent thrombosis rates in randomized controlled trials of zotarolimus-eluting Endeavor Sprint stent
Study ENDEAVOR II 8 ENDEAVOR III 9 ENDEAVOR IV 10 Pilgrim et al. 11 PROTECT 12 SORT OUT III 13 ZEST 14 ZEST-AMI15 ISAR-TEST 2 16 RESET 17 KOMER 18 PRODIGY 19
Follow-up (y)
Control group (CoG)
DAPT duration (m)
ST at 1 y
No. of patients 1,197 436 1,548 302 8,791 2,332 2,645 328 1,007 2,117 611 2,013
5 5 5 1 3 3 1 1 2 1 1.5 2
Driver BMS SES PES TiNO BMS SES SES SES/PES SES/PES SES/DUAL-DES SES SES/PES BMS/PES/EES
3 ≥3 ≥6 3 3 to 12 12 ≥12 ≥12 12 3/12 ≥12 6-24
0.7/1.4⁎ 0.3/0 0.7/0.1 0/0.7 1.1/0.7 1.1/0.3 0.5/0/0.7 0/3.6/2.7 0.6/0.90.9 0.2/0.3 2.0/2.0/2.1 0.6/2.0/1.6/0.6
VLST
E-ZES/CoG (%) 0.2/0.2⁎ 0.3/0.9 0.4/1.1 NA 0.3/1.1 0/1.1 NA 0/0/0 0/0/0 NA 0/0/0 0.2/0/0.6/0.2
DUAL-DES, Sirolimus- and probucol-eluting stent; TiNO, titanium-nitride-oxide BMS; ST, definite ST; VLST, definite very late ST; SES, sirolimus-eluting Cypher stent; PES, paclitaxeleluting Taxus stent. ⁎ Definite or probable ST.
compared with long-term DAPT therapy, with positive interaction testing. 22
Study design and population ZEUS is a multinational randomized trial conducted at 20 sites in Europe, designed to evaluate the combined efficacy and safety of E-ZES as compared with BMS in uncertain DES candidates. Eligible patients are those at high risk for thrombotic or bleeding events—either for inherent patients characteristics or need for or contraindications to concomitant medications—or individuals at perceived low restenosis risk in whom DES implantation followed by long-term DAPT duration has been questioned due to risk/benefit and cost-effectiveness considerations. Patients at high bleeding risk do not qualify for being good DES candidates based on the concern that currently recommended at least 12-month DAPT duration after stent placement exposes them to an unacceptable bleeding profile. Patients at high thrombotic risk may experience a worse safety profile after DES implantation as compared with BMS despite long-term DAPT duration. Finally, in patients at low restenosis risk, the bleeding hazard as well as the extra direct and indirect (ie, related to bleeding management) costs driven by long-term DAPT duration may overshadow the relatively low absolute risk reduction in Target Vessel Revascularization after DES as compared with BMS. Unique to this study, DAPT duration will be driven exclusively by patients' clinical profile (eg, indication to the stent procedure or perceived bleeding risk) and not by the type of implanted stent (BMS vs E-ZES), thus allowing for 30-day DAPT duration or monotherapy with a P2Y12 blocker or aspirin in patients who are intolerant to aspirin or P2Y12 inhibitors, respectively. The protocol mandates 30-day DAPT duration in patients who qualify at least 1 bleeding
risk criterion, irrespective of the concomitant fulfillment of other high thrombotic risk of low restenosis risk criteria. A shorter than 30 days of DAPT duration is only allowed in patients who cannot tolerate this regimen, including those who experienced bleeding episode(s) before the completion of the 30-day DAPT therapy. Patients recruited for high thrombotic or low restenosis risk criteria had to be treated with a DAPT duration regimen, which is consistent with the presenting clinical scenario, irrespective of the implanted stent type. Thus, patients with unstable presentation or those showing at least 1 high thrombotic risk criterion should undergo up to 6-month DAPT duration. On the other hand, stable patients who are not satisfying any high bleeding or thrombotic risk criteria will undergo 1-month DAPT regimen in both stent groups (Table II). Patients undergoing elective, urgent, or emergent percutaneous coronary intervention (PCI) with intended stent implantation were randomly assigned in a 1:1 fashion to third-generation thin-strut BMS or E-ZES. Although all commercially available thin-strut BMS (ie, strut thickness b100 μm) are allowed, Tsunami (Terumo, Ann Arbor, MI), Skylor (Medotrinic), Integrity (Medtronic, Santa Rosa, CA), Vision (Abbott, Santa Rosa, CA), and Avant-Garde (CID Vascular, Saluggia, Torino, Italy) were the 5 most commonly used devices in this stent group. Individuals eligible for enrollment were patients aged 18 years or older with chronic stable coronary artery disease (CAD) or acute coronary syndromes, including non–STelevation and ST-elevation MI. They are eligible if they have at least 1 lesion with a diameter stenosis of ≥50% that is suitable for coronary stent implantation in a vessel with a reference vessel diameter of at least 2.25 mm, provided they qualify for being undefined DES recipients based on criteria outlined in Table II. We set no limit for the number of treated lesions, vessels, or lesion length
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Table II. Inclusion criteria and protocol-mandated instructions for DAPT duration Predefined criteria-qualifying uncertain DES candidates
DAPT duration after stenting
High bleeding risk criteria Clinical indication to treatment with oral anticoagulant, including use of warfarin other oral anticoagulant agents Recent (within previous 12 m) bleeding episode(s), which required medical attention Previous bleeding episode(s), which required hospitalization if the bleeding diathesis has not been completely resolved (ie, surgical removal of the bleeding source) Age N80 y Systemic conditions associated to increased bleeding risk (eg, hematologic disorders or any known coagulopathy determining bleeding diathesis, including history of or current thrombocytopenia defined as platelet count b100000/mm3 (b100 × 109/L). Known anemia defined as repeatedly documented hemoglobin b10 g/dL, which is not due to an acute and documented blood loss Need for chronic treatment with steroids or NSAID
DAPT duration for 30 d DAPT duration for 30 d DAPT duration for 30 d DAPT duration for 30 d DAPT duration for 30 d
DAPT duration for 30 d DAPT duration for 30 d
High thrombotic risk criteria Intolerance to aspirin
Indefinite monotherapy with one of the available P2Y12 inhibitor, including clopidogrel or prasugrel Intolerance to any available P2Y12 inhibitor Indefinite monotherapy with aspirin Planned surgery (other than skin) within 12 m of PCI DAPT duration up to surgical intervention Diagnosed malignancy (other than skin) and life expectancy N1 y DAPT duration up to 6 m Systemic conditions associated with thrombosis diathesis (eg, hematologic disorders and any DAPT duration up to 6 m known systemic conditions determining a prothrombotic state including immunological disorders)
Low restenosis risk criteria No stent b3.0 mm in diameter is intended for implantation, irrespective of lesion length or presence of diabetes. Left main intervention, saphenous vein graft stenting, or treatment for in-stent restenosis is excluded from recruitment unless patients satisfy at least one of the high bleeding or thrombotic risk criteria. DAPT duration in this category depends on the indication to the procedure as detailed below Stable CAD DAPT duration for 30 d⁎ Unstable CAD DAPT duration for up to 6 m⁎ NSAID, Nonsteroidal anti-inflammatory drugs. ⁎ In patients presenting concomitant high bleeding or thrombotic risk features, DAPT duration will be adapted as follows: bleeding risk status dominates thrombotic risk, which, in turn, dominates restenosis risk.
and excluded no patients based on comorbid disorders or age. We, therefore, targeted a patient population who has been almost systematically excluded from previous pivotal DES trials and allowed for the shortest DAPT duration ever permitted in the context of a DES trial (ie, as short as 30 days).
Randomization and staged procedures Allocation of study treatment was performed via a Web-based interactive randomization system available at www.cardiostudy.it/zeus. Randomization was achieved with computer-generated random sequence with a random block size stratified according to the clinical site and the predefined criterion qualifying the eligible patient as uncertain DES candidate. In case of multiple qualifying inclusion criteria, high bleeding risk features were prespecified to dominate on high thrombotic risk characteristics, which, in turn, dominate on low restenosis risk criteria. Protocol-mandated DAPT duration followed the same hierarchy, as outlined in Table II. Staging was allowed by the protocol, and DAPT duration had to be counted starting from the day of the last implanted stent.
Treatment protocol and follow-up procedures All patients received aspirin (160-325 mg orally or 500 mg intravenously as a loading dose [LD] and then 80-160 mg orally) and clopidogrel (300 or 600 mg orally as an LD to be given preferably before PCI but not later than at the time the patient leaves the catheterization laboratory followed by 75 mg/d) or prasugrel (60-mg LD followed by 10 or 5 mg/d). Patients who were not eligible to DAPT were treated with either aspirin or clopidogrel (or prasugrel) monotherapy. At the time of DAPT discontinuation, patients were left free to continue either of the 2 antiplatelet agents (ie, aspirin or clopidogrel/prasugrel) at discretion of the treating physician.
Follow-up Patients return for study visits at 30 days and then every 6 months up to 1 year (last study visit). During follow-up visits, patients are assessed for adverse events and 12-lead electrocardiographic (ECG) recordings and questioned on their compliance with the study medication. Any interruption or termination as well as the reason for this is documented.
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Figure 1
Primary Inclusion Criterion High Bleeding Risk
24% High Thrombosis Risk
52% 12%
12%
Low Restenosis Risk-Stable
Low Restenosis Risk-Unstable
Distribution of the primary inclusion criterion-qualifying patients for recruitment in the study.
Blinding This study was conceived as a single-blinded study. Yet, no specific procedure has been adopted to ensure patients' blindness beyond formal recommendations into the protocol, and no information will be available at the end of the study regarding the proportion of patients who became aware of the actually implanted stent type. Thus, our study should be regarded as an open-label study, which carries its obvious and wellknown limitations.
Study end points The primary objective of this study is to assess whether E-ZES implantation, followed by a duration of DAPT therapy reflecting patient's and not stent's characteristics, will decrease the incidence of 12-month major adverse cardiovascular events including all-cause death, nonfatal MI, or any target vessel revascularization as compared with BMS in uncertain DES recipients. Secondary end points include each component of the primary end point; cardiac death; the composite primary end point evaluated from the moment of DAPT discontinuation; the incidence of ST according to the Academic Research Consortium definition, evaluated cumulatively or after the landmark time point of DAPT discontinuation; total and ischemic stroke; the need for recurrent target lesion revascularization; and bleeding outcomes.
Prespecified analysis of the primary and secondary end points will be performed according to the predefined 3 major criteria qualifying patients for inclusion (ie, high thrombosis or bleeding and low restenosis risk category), age, gender, presence of diabetes, clinical presentation at time of randomization, complexity and number of treated lesions, renal function, and DAPT duration. The development of an MI within 48 hours after completion of PCI is defined as creatine kinase–MB (CKMB) ≥3 times the upper limit of normal, whether accompanied by chest pain and/or ECG changes, or new pathologic Q waves (≥0.04 seconds in duration in ≥2 contiguous leads). An MI in patients with CK-MB elevation prior PCI is defined by at least a 25% decrease in CK-MB from a prior peak level, followed by a new increase of at least 50% above the preceding valley and ≥3 times the upper limit of normal. The development of a new (nonprocedure related) MI after PCI/stent placement is defined as new pathologic Q waves or CK-MB or troponin I/T elevation above the upper limit of normal, accompanied by ischemic symptoms and/or ECG changes. Safety end points will include the rate of bleeding according to the BARC, TIMI, and GUSTO criteria. 19
Statistical considerations The null hypothesis (H0) for this study is that the incidence of the primary end point in patients who are
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Figure 2
16, 2%
A
46, 6% Clinical indication to treatment with oral anticoagulation
48, 6%
54, 6%
Age > 80
307, 37% 54, 6%
Recent bleeding episode(s) Previous bleeding episode(s) Systematic conditions associated to increased bleeding risk Known Anemia Need for chronic treatment with steroids or NSAID
303, 37%
B
8, 4%
1, 0%
Planned Surgery
45, 24%
Intolerance to ASA
90, 47%
Cancer Systemic conditions associated with thrombosis diathesis
47, 25%
Intolerance to any available P2Y12 inhibitor
Breakdown of the individual features identifying patients at high bleeding risk (A) or at high thrombosis risk (B) in the study.
allocated to treatment with the E-ZES (πEND) will be equal to the incidence of the primary end point in patients allocated to treatment with the BMS (πBMS). The alternative hypothesis (H1) is that the incidence of the primary end point will be different in patients allocated to treatment with the E-ZES or BMS. Thus, H0: πEND = πBMS and H1: πEND ≠ πBMS. Based on a conservative interpretation of previous findings, 6,8,19,23 πEND and πBMS are estimated at 10% and 15%, respectively. Hence, the relative treatment effect in favor of the Endeavor stent is estimated at 33%,
corresponding with a hazard ratio of 0.67. If α and β are fixed at 5% and 15%, then a total of at least 1,556 (2 × 778) patients have to be randomized. The maximum percentage of patients who will be lost to follow-up for the primary end point is estimated at 2% to 3%. The chosen sample size is, therefore, 1,600. The monitoring plan of the study required that independent study monitors, employed by University of Ferrara, verify 100% of the data in the case report forms. The data for all patients with end point events will be reviewed by an independent adjudication committee
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whose members were blinded to treatment assignments. Three formal interim analyses were performed when 25%, 50%, and 75% of the suspected number of primary end point events in patients allocated to treatment with the BMS have occurred (ie, after 32, 63, and 95 events, respectively). The Data safety Monitoring Board applied a modified version of the Haybittle-Peto rule and considered πBMS − πEND significance in favor of the Endeavor stent if this difference was positive and exceeded 4 (first and second interim analysis; α = .0001) or 3 (third interim analysis; α = .00047) SDs. The α level for the final analysis will be the conventional level of .05, which is appropriate because of the low α levels that are applied in the interim analyses. The Data safety Monitoring Board also considered the consistency of the main secondary end point and consistently suggested the continuation of the study as planned. Categorical outcomes for the primary or secondary objectives of the study will be compared by means of the χ 2 test or Fisher exact test, which is consistent with the use of binomial proportions test to determine the sample size of the study. In addition, time-to-event outcomes, determined with Kaplan-Meier methods, will be compared by means of the log-rank test.
Study organization The ZEUS trial is being conducted at 20 investigative sites in Italy, Switzerland, Portugal, and Hungary. The study is an investigator-driven clinical trial supported by a research grant from Medtronic. The authors are solely responsible for the design and conduct of this study, all study analyses, and drafting and editing of the manuscript. Data are being coordinated and analyzed by an Academic Research Unit, Ferrara, Italy. The trial registration number is NCT01385319 available at http://clinicaltrials.gov/ct2/ show/NCT01385319?term=ZEUS&rank=1. Recruitment in the study began in June 2011. The enrollment phase was completed in September 2012 with 1,606 patients, and follow-up will last until September 2013 so as to reach the 1year clinical surveillance.
Characterization of the study population according to the qualifying criteria for inclusion Figure 1 shows the distribution of the primary (ie, the key qualifying criterion according to the prespecified hierarchy—bleeding risk dominates thrombosis risk, which, in turn, dominates restenosis risk) condition, which qualified patients for recruitment. The most prevalent category was high bleeding risk status, encompassing 828 patients (51.6%), followed by low restenosis risk status with unstable presentation (388 [24.2%] patients), low restenosis risk with stable presentation (199 [12.4%] patients), and finally high thrombosis risk
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group (191 [11.9%] patients). Altogether, 524 patients (32.6%) satisfiedN1 prespecified criterion qualifying for inclusion. Figure 2 shows the individual features identifying patients at high bleeding risk (panel A) or at high thrombosis risk (panel B).
Disclosures Dr. Athanasios Patialiakas received grants from HCS (Hellenic Cardiology Society) and from EL.I.KAR (Hellenic Heart Institute).
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primary percutaneous coronary intervention in patients with STelevation myocardial infarction: results from the Korean Multicentre Endeavor (KOMER) acute myocardial infarction (AMI) trial. EuroIntervention: journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology 2011;7(8):936-43. Valgimigli M, Campo G, Monti M, et al. Short- versus long-term duration of dual-antiplatelet therapy after coronary stenting: a randomized multicenter trial. Circulation 2012;125(16): 2015-26. Kandzari DE, Barker CS, Leon MB, et al. Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimuseluting stents. JACC Cardiovasc Interv 2011;4(10):1119-28. Kim JS, Jang IK, Fan C, et al. Evaluation in 3 months duration of neointimal coverage after zotarolimus-eluting stent implantation by optical coherence tomography: the ENDEAVOR OCT trial. JACC Cardiovasc Interv 2009;2(12):1240-7. Valgimigli M, Borghesi M, Tebaldi M,, et al. Should duration of dual antiplatelet therapy depend on the type and/or potency of implanted stent? A pre-specified analysis from the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY). Eur Heart J; [Epub ahead of print]. Valgimigli M, Borghesi M, Tebaldi M, et al. Should duration of dual antiplatelet therapy depend on the type and/or potency of implanted stent? A pre-specified analysis from the PROlonging Dual antiplatelet treatment after Grading stent-induced Intimal hyperplasia studY (PRODIGY). Eur Heart J 2013;34(12):909-19.
Background The use of drug-eluting stent (DES) instead of bare-metal stent (BMS) in patients at high stent thrombosis or bleeding risk as well as in those at low restenosis risk (ie, uncertain DES candidates) remains a matter of debate. ZotarolimusEluting Endeavor Sprint stent (E-ZES) (Santa Rosa, CA) is a hydrophilic polymer-based second-generation device with unique drug fast-release profile, which may allow for a shorter dual antiplatelet therapy (DAPT) duration without safety concerns. Hypothesis The primary objective is to assess whether E-ZES implantation followed by a shorter than currently recommended course of DAPT will decrease the incidence of 12-month major adverse cardiovascular events as compared with BMS in undefined DES recipients. Actual duration of DAPT regimen will be dictated by patients' characteristics and not by stent type and, as such, can be as short as 30 days after intervention in both stent groups. Study Design The ZEUS study is an open-label randomized clinical trial conducted at 20 clinical sites in Italy, Switzerland, Portugal, and Hungary. With 1,600 individuals, this study will have 85% power to detect a 33% difference in the primary end point consisting of the composite of death, nonfatal myocardial infarction, or target vessel revascularization. Summary The ZEUS trial aims to assess whether the use of E-ZES, followed by a DAPT duration regimen based on patients' characteristics and not by stent type, is superior to conventional BMS implantation in undefined DES recipients who qualify for the presence of high thrombosis, bleeding, or low restenosis risk criteria. (Am Heart J 2013;166:831-8.)
Randomized controlled trials, 1 meta-analysis, 2 and observational studies 3 have consistently shown reduced rates of angiographic restenosis and ischemia-driven target vessel revascularization with drug-eluting stents
(DES) compared with bare-metal stents (BMS). However, the higher rates of very late stent thrombosis (ST) and the concern for a higher risk of late ST after early discontinuation of dual antiplatelet therapy (DAPT) with
From the aInterventional Cardiology Unit, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy, bThoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands, c Cardiology Center, Szeged, Hungary, dPoliclinico, San Giovanni Bosco, Torino, Italy, e Azienda Unità Sanitaria Locale di Modena–Ospedale Baggiovara, Modena, Italy, fDivision of Cardiology, University Hospital, Geneva, Switzerland, gInterventional Cardiology Unit, Azienda Ospedaliero-Universitaria di Parma, Parma, Italy, hPoliclinico S. Marco Zingonia,
San Donato Hospital, Arezzo, Italy, oOspedali Riuniti ASL 17, Savigliano, Italy, pVirga Jesse ziekenhuis, Hasselt, Belgium, and qClinica Mediterranea di Napoli, Naples, Italy. Clinical trial registration: ClinicalTrials.gov no. NCT01385319. Submitted February 10, 2013; accepted July 16, 2013. Reprint requests: Marco Valgimigli, MD, PhD, University of Ferrara, Via Aldo Moro, 8; 44124 Loc. Cona (FE), Italy. E-mail: [email protected]
Bergamo, Italy, iAzienda Ospedaliera Ordine Mauriziano, Torino, Italy, jInterventional Cardiology, Ist. Clinico S. Ambrogio, IRCCS San Donato, Milan, Italy, kHospital de Santa Cruz Carnaxide, Lisbon, Portugal, lIRCCS Multimedica Sesto San Giovanni, Milan, Italy, m Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, nCardiovascular Departments of
0002-8703/$ - see front matter © 2013, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2013.07.033
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first-generation DES have raised safety concerns. 4 As a consequence, the use of DES instead of BMS in patients at high thrombosis risk, whose risk for coronary events may be higher after DES; those at high bleeding risk, in whom long-term DAPT exposure poses safety concerns; or those at low risk for in-stent restenosis, whose long-term risk for adverse events after DES implantation may outweigh their benefit in terms of low reintervention rates, remains a matter of ongoing debate. Zotarolimus-Eluting Endeavor Sprint stent (E-ZES) is a hydrophilic polymer-based second-generation device with unique drug fast-release profile. Although this distinctive feature predisposes to less powerful inhibition of intimal hyperplasia compared with other DESs, it may allow for a shorter DAPT duration without safety concerns.
Technical characteristics of the E-ZES The Endeavor stent is a cobalt-based alloy stent with a phosphorylcholine polymer loaded with zotarolimus at dose concentration of 10 μg/mm stent length. It has been shown in preclinical studies that approximately 95% of zotarolimus is eluted from the stent within 15 days of implantation, although drug concentrations within surrounding vascular tissue may be detected at 30 days after stent deployment. 5 Zotarolimus is equivalent to sirolimus in terms of antiproliferative power (half maximal inhibitory concentration at 0.3 nM) but is more lipophilic with a distribution coefficient (logD) N4.5, as compared with 3.6 for sirolimus. Phosphorylcholine is a durable polymer primarily composed of hydrophilic monomers that mimic the chemical structure of phospholipid head groups, similar to the outer membrane of red blood cells (90% of phospholipids in the outer membrane of a red blood cell contain the phosphorylcholine head group). This polymer has a broad history of use in medical devices including coronary stents.
Evidence from clinical trials with E-ZES Unlike evidence provided by first-generation DES, there was no increased risk of death, myocardial infarction (MI), or ST, and there was a benefit to the prevention of repeat revascularization procedures in E-ZES compared with BMS in a combined patient level data from 6 prospective randomized single-arm multicenter trials involving 2,132 patients treated with zotarolimus-eluting stent (ZES) and 596 patients treated with a BMS control. 6 The hypothesis that E-ZES would lead to fewer ST events than sirolimus-eluting stent (SES) through a 3-year follow-up has been tested in the PROTECT trial. 7 At 3 years, rates of definite or probable ST did not differ between groups. This finding has been tentatively explained by the lower than anticipated rate of ST in
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the SES arm and by the long-term DAPT duration, which was mandated by the protocol. Dual antiplatelet therapy was used in 8,402 patients (96%) at discharge, 7,456 (88%) at 1 year, 3,041 (37%) at 2 years, and 2,364 (30%) at 3 years. Interestingly, the pattern of events over time was distributed differentially, with both devices having the same incidence of early ST, but SES having fewer late, but more very late, ST (definite or probable) than E-ZES. The higher incidence of late ST in the E-ZES was driven by an increased rate of probable ST. In the SES group, the higher incidence of very late ST events than that in the EZES group was driven by an increased incidence of definite ST. It remains speculative whether a different mechanism of MI (ie, occlusive restenosis in the E-ZES group vs noncovered stent struts in the SES group) contributed to this result. Hence, the results of the PROTECT trial might support the favorable long-term safety profile of E-ZES as compared with SES with respect to the risk of very late ST, but they question the use of this device in patients at high restenosis risk who would tolerate a long course of DAPT after stenting. Major randomized controlled trials comparing E-ZES to BMS or to first or other secondgeneration DES are summarized in Table I.
Optimal duration of DAPT after Endeavor Sprint implantation Kandzari et al 20 analyzed outcomes in 2,032 patients undergoing coronary revascularization with E-ZES in 5 trials who for various reasons discontinued DAPT at 6 months and found that outcomes did not differ compared with patients who received longer clopidogrel therapy (up to 12 or 24 months). In the RESET trial of 2,148 patients randomized to the EZES stent and 3 months of DAPT and 1,058 patients treated with standard 12-month DAPT and other DES, the combined end point of any death, MI, and ST occurred in 1.3% in the standard therapy arm versus 0.8% in the 3month group (P = .48). 17 Interestingly, prospective studies undertaken to evaluate the degree of E-ZES stent coverage have consistently showed a very low rate of uncovered/ malapposed struts at 6- or even 3-month optical coherence tomography evaluation, which favorably compared with both first-generation DES or even BMS. 21 The results of the PRODIGY trial showed no increase in the rate of fatal or ischemic events in patients receiving 6month DAPT as compared with 24-month therapy duration after everolimus-eluting stent (EES), paclitaxeleluting stent (PES), E-ZES, or BMS. 19 The composite of death, MI, or cerebrovascular accident did not differ in patients receiving BMS, PES, or EES implantation across DAPT groups, whereas it was significantly lower in E-ZES patients undergoing short- as
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Table I. Dual anti-platelet therapy recommendations and stent thrombosis rates in randomized controlled trials of zotarolimus-eluting Endeavor Sprint stent
Study ENDEAVOR II 8 ENDEAVOR III 9 ENDEAVOR IV 10 Pilgrim et al. 11 PROTECT 12 SORT OUT III 13 ZEST 14 ZEST-AMI15 ISAR-TEST 2 16 RESET 17 KOMER 18 PRODIGY 19
Follow-up (y)
Control group (CoG)
DAPT duration (m)
ST at 1 y
No. of patients 1,197 436 1,548 302 8,791 2,332 2,645 328 1,007 2,117 611 2,013
5 5 5 1 3 3 1 1 2 1 1.5 2
Driver BMS SES PES TiNO BMS SES SES SES/PES SES/PES SES/DUAL-DES SES SES/PES BMS/PES/EES
3 ≥3 ≥6 3 3 to 12 12 ≥12 ≥12 12 3/12 ≥12 6-24
0.7/1.4⁎ 0.3/0 0.7/0.1 0/0.7 1.1/0.7 1.1/0.3 0.5/0/0.7 0/3.6/2.7 0.6/0.90.9 0.2/0.3 2.0/2.0/2.1 0.6/2.0/1.6/0.6
VLST
E-ZES/CoG (%) 0.2/0.2⁎ 0.3/0.9 0.4/1.1 NA 0.3/1.1 0/1.1 NA 0/0/0 0/0/0 NA 0/0/0 0.2/0/0.6/0.2
DUAL-DES, Sirolimus- and probucol-eluting stent; TiNO, titanium-nitride-oxide BMS; ST, definite ST; VLST, definite very late ST; SES, sirolimus-eluting Cypher stent; PES, paclitaxeleluting Taxus stent. ⁎ Definite or probable ST.
compared with long-term DAPT therapy, with positive interaction testing. 22
Study design and population ZEUS is a multinational randomized trial conducted at 20 sites in Europe, designed to evaluate the combined efficacy and safety of E-ZES as compared with BMS in uncertain DES candidates. Eligible patients are those at high risk for thrombotic or bleeding events—either for inherent patients characteristics or need for or contraindications to concomitant medications—or individuals at perceived low restenosis risk in whom DES implantation followed by long-term DAPT duration has been questioned due to risk/benefit and cost-effectiveness considerations. Patients at high bleeding risk do not qualify for being good DES candidates based on the concern that currently recommended at least 12-month DAPT duration after stent placement exposes them to an unacceptable bleeding profile. Patients at high thrombotic risk may experience a worse safety profile after DES implantation as compared with BMS despite long-term DAPT duration. Finally, in patients at low restenosis risk, the bleeding hazard as well as the extra direct and indirect (ie, related to bleeding management) costs driven by long-term DAPT duration may overshadow the relatively low absolute risk reduction in Target Vessel Revascularization after DES as compared with BMS. Unique to this study, DAPT duration will be driven exclusively by patients' clinical profile (eg, indication to the stent procedure or perceived bleeding risk) and not by the type of implanted stent (BMS vs E-ZES), thus allowing for 30-day DAPT duration or monotherapy with a P2Y12 blocker or aspirin in patients who are intolerant to aspirin or P2Y12 inhibitors, respectively. The protocol mandates 30-day DAPT duration in patients who qualify at least 1 bleeding
risk criterion, irrespective of the concomitant fulfillment of other high thrombotic risk of low restenosis risk criteria. A shorter than 30 days of DAPT duration is only allowed in patients who cannot tolerate this regimen, including those who experienced bleeding episode(s) before the completion of the 30-day DAPT therapy. Patients recruited for high thrombotic or low restenosis risk criteria had to be treated with a DAPT duration regimen, which is consistent with the presenting clinical scenario, irrespective of the implanted stent type. Thus, patients with unstable presentation or those showing at least 1 high thrombotic risk criterion should undergo up to 6-month DAPT duration. On the other hand, stable patients who are not satisfying any high bleeding or thrombotic risk criteria will undergo 1-month DAPT regimen in both stent groups (Table II). Patients undergoing elective, urgent, or emergent percutaneous coronary intervention (PCI) with intended stent implantation were randomly assigned in a 1:1 fashion to third-generation thin-strut BMS or E-ZES. Although all commercially available thin-strut BMS (ie, strut thickness b100 μm) are allowed, Tsunami (Terumo, Ann Arbor, MI), Skylor (Medotrinic), Integrity (Medtronic, Santa Rosa, CA), Vision (Abbott, Santa Rosa, CA), and Avant-Garde (CID Vascular, Saluggia, Torino, Italy) were the 5 most commonly used devices in this stent group. Individuals eligible for enrollment were patients aged 18 years or older with chronic stable coronary artery disease (CAD) or acute coronary syndromes, including non–STelevation and ST-elevation MI. They are eligible if they have at least 1 lesion with a diameter stenosis of ≥50% that is suitable for coronary stent implantation in a vessel with a reference vessel diameter of at least 2.25 mm, provided they qualify for being undefined DES recipients based on criteria outlined in Table II. We set no limit for the number of treated lesions, vessels, or lesion length
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Table II. Inclusion criteria and protocol-mandated instructions for DAPT duration Predefined criteria-qualifying uncertain DES candidates
DAPT duration after stenting
High bleeding risk criteria Clinical indication to treatment with oral anticoagulant, including use of warfarin other oral anticoagulant agents Recent (within previous 12 m) bleeding episode(s), which required medical attention Previous bleeding episode(s), which required hospitalization if the bleeding diathesis has not been completely resolved (ie, surgical removal of the bleeding source) Age N80 y Systemic conditions associated to increased bleeding risk (eg, hematologic disorders or any known coagulopathy determining bleeding diathesis, including history of or current thrombocytopenia defined as platelet count b100000/mm3 (b100 × 109/L). Known anemia defined as repeatedly documented hemoglobin b10 g/dL, which is not due to an acute and documented blood loss Need for chronic treatment with steroids or NSAID
DAPT duration for 30 d DAPT duration for 30 d DAPT duration for 30 d DAPT duration for 30 d DAPT duration for 30 d
DAPT duration for 30 d DAPT duration for 30 d
High thrombotic risk criteria Intolerance to aspirin
Indefinite monotherapy with one of the available P2Y12 inhibitor, including clopidogrel or prasugrel Intolerance to any available P2Y12 inhibitor Indefinite monotherapy with aspirin Planned surgery (other than skin) within 12 m of PCI DAPT duration up to surgical intervention Diagnosed malignancy (other than skin) and life expectancy N1 y DAPT duration up to 6 m Systemic conditions associated with thrombosis diathesis (eg, hematologic disorders and any DAPT duration up to 6 m known systemic conditions determining a prothrombotic state including immunological disorders)
Low restenosis risk criteria No stent b3.0 mm in diameter is intended for implantation, irrespective of lesion length or presence of diabetes. Left main intervention, saphenous vein graft stenting, or treatment for in-stent restenosis is excluded from recruitment unless patients satisfy at least one of the high bleeding or thrombotic risk criteria. DAPT duration in this category depends on the indication to the procedure as detailed below Stable CAD DAPT duration for 30 d⁎ Unstable CAD DAPT duration for up to 6 m⁎ NSAID, Nonsteroidal anti-inflammatory drugs. ⁎ In patients presenting concomitant high bleeding or thrombotic risk features, DAPT duration will be adapted as follows: bleeding risk status dominates thrombotic risk, which, in turn, dominates restenosis risk.
and excluded no patients based on comorbid disorders or age. We, therefore, targeted a patient population who has been almost systematically excluded from previous pivotal DES trials and allowed for the shortest DAPT duration ever permitted in the context of a DES trial (ie, as short as 30 days).
Randomization and staged procedures Allocation of study treatment was performed via a Web-based interactive randomization system available at www.cardiostudy.it/zeus. Randomization was achieved with computer-generated random sequence with a random block size stratified according to the clinical site and the predefined criterion qualifying the eligible patient as uncertain DES candidate. In case of multiple qualifying inclusion criteria, high bleeding risk features were prespecified to dominate on high thrombotic risk characteristics, which, in turn, dominate on low restenosis risk criteria. Protocol-mandated DAPT duration followed the same hierarchy, as outlined in Table II. Staging was allowed by the protocol, and DAPT duration had to be counted starting from the day of the last implanted stent.
Treatment protocol and follow-up procedures All patients received aspirin (160-325 mg orally or 500 mg intravenously as a loading dose [LD] and then 80-160 mg orally) and clopidogrel (300 or 600 mg orally as an LD to be given preferably before PCI but not later than at the time the patient leaves the catheterization laboratory followed by 75 mg/d) or prasugrel (60-mg LD followed by 10 or 5 mg/d). Patients who were not eligible to DAPT were treated with either aspirin or clopidogrel (or prasugrel) monotherapy. At the time of DAPT discontinuation, patients were left free to continue either of the 2 antiplatelet agents (ie, aspirin or clopidogrel/prasugrel) at discretion of the treating physician.
Follow-up Patients return for study visits at 30 days and then every 6 months up to 1 year (last study visit). During follow-up visits, patients are assessed for adverse events and 12-lead electrocardiographic (ECG) recordings and questioned on their compliance with the study medication. Any interruption or termination as well as the reason for this is documented.
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Figure 1
Primary Inclusion Criterion High Bleeding Risk
24% High Thrombosis Risk
52% 12%
12%
Low Restenosis Risk-Stable
Low Restenosis Risk-Unstable
Distribution of the primary inclusion criterion-qualifying patients for recruitment in the study.
Blinding This study was conceived as a single-blinded study. Yet, no specific procedure has been adopted to ensure patients' blindness beyond formal recommendations into the protocol, and no information will be available at the end of the study regarding the proportion of patients who became aware of the actually implanted stent type. Thus, our study should be regarded as an open-label study, which carries its obvious and wellknown limitations.
Study end points The primary objective of this study is to assess whether E-ZES implantation, followed by a duration of DAPT therapy reflecting patient's and not stent's characteristics, will decrease the incidence of 12-month major adverse cardiovascular events including all-cause death, nonfatal MI, or any target vessel revascularization as compared with BMS in uncertain DES recipients. Secondary end points include each component of the primary end point; cardiac death; the composite primary end point evaluated from the moment of DAPT discontinuation; the incidence of ST according to the Academic Research Consortium definition, evaluated cumulatively or after the landmark time point of DAPT discontinuation; total and ischemic stroke; the need for recurrent target lesion revascularization; and bleeding outcomes.
Prespecified analysis of the primary and secondary end points will be performed according to the predefined 3 major criteria qualifying patients for inclusion (ie, high thrombosis or bleeding and low restenosis risk category), age, gender, presence of diabetes, clinical presentation at time of randomization, complexity and number of treated lesions, renal function, and DAPT duration. The development of an MI within 48 hours after completion of PCI is defined as creatine kinase–MB (CKMB) ≥3 times the upper limit of normal, whether accompanied by chest pain and/or ECG changes, or new pathologic Q waves (≥0.04 seconds in duration in ≥2 contiguous leads). An MI in patients with CK-MB elevation prior PCI is defined by at least a 25% decrease in CK-MB from a prior peak level, followed by a new increase of at least 50% above the preceding valley and ≥3 times the upper limit of normal. The development of a new (nonprocedure related) MI after PCI/stent placement is defined as new pathologic Q waves or CK-MB or troponin I/T elevation above the upper limit of normal, accompanied by ischemic symptoms and/or ECG changes. Safety end points will include the rate of bleeding according to the BARC, TIMI, and GUSTO criteria. 19
Statistical considerations The null hypothesis (H0) for this study is that the incidence of the primary end point in patients who are
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Figure 2
16, 2%
A
46, 6% Clinical indication to treatment with oral anticoagulation
48, 6%
54, 6%
Age > 80
307, 37% 54, 6%
Recent bleeding episode(s) Previous bleeding episode(s) Systematic conditions associated to increased bleeding risk Known Anemia Need for chronic treatment with steroids or NSAID
303, 37%
B
8, 4%
1, 0%
Planned Surgery
45, 24%
Intolerance to ASA
90, 47%
Cancer Systemic conditions associated with thrombosis diathesis
47, 25%
Intolerance to any available P2Y12 inhibitor
Breakdown of the individual features identifying patients at high bleeding risk (A) or at high thrombosis risk (B) in the study.
allocated to treatment with the E-ZES (πEND) will be equal to the incidence of the primary end point in patients allocated to treatment with the BMS (πBMS). The alternative hypothesis (H1) is that the incidence of the primary end point will be different in patients allocated to treatment with the E-ZES or BMS. Thus, H0: πEND = πBMS and H1: πEND ≠ πBMS. Based on a conservative interpretation of previous findings, 6,8,19,23 πEND and πBMS are estimated at 10% and 15%, respectively. Hence, the relative treatment effect in favor of the Endeavor stent is estimated at 33%,
corresponding with a hazard ratio of 0.67. If α and β are fixed at 5% and 15%, then a total of at least 1,556 (2 × 778) patients have to be randomized. The maximum percentage of patients who will be lost to follow-up for the primary end point is estimated at 2% to 3%. The chosen sample size is, therefore, 1,600. The monitoring plan of the study required that independent study monitors, employed by University of Ferrara, verify 100% of the data in the case report forms. The data for all patients with end point events will be reviewed by an independent adjudication committee
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whose members were blinded to treatment assignments. Three formal interim analyses were performed when 25%, 50%, and 75% of the suspected number of primary end point events in patients allocated to treatment with the BMS have occurred (ie, after 32, 63, and 95 events, respectively). The Data safety Monitoring Board applied a modified version of the Haybittle-Peto rule and considered πBMS − πEND significance in favor of the Endeavor stent if this difference was positive and exceeded 4 (first and second interim analysis; α = .0001) or 3 (third interim analysis; α = .00047) SDs. The α level for the final analysis will be the conventional level of .05, which is appropriate because of the low α levels that are applied in the interim analyses. The Data safety Monitoring Board also considered the consistency of the main secondary end point and consistently suggested the continuation of the study as planned. Categorical outcomes for the primary or secondary objectives of the study will be compared by means of the χ 2 test or Fisher exact test, which is consistent with the use of binomial proportions test to determine the sample size of the study. In addition, time-to-event outcomes, determined with Kaplan-Meier methods, will be compared by means of the log-rank test.
Study organization The ZEUS trial is being conducted at 20 investigative sites in Italy, Switzerland, Portugal, and Hungary. The study is an investigator-driven clinical trial supported by a research grant from Medtronic. The authors are solely responsible for the design and conduct of this study, all study analyses, and drafting and editing of the manuscript. Data are being coordinated and analyzed by an Academic Research Unit, Ferrara, Italy. The trial registration number is NCT01385319 available at http://clinicaltrials.gov/ct2/ show/NCT01385319?term=ZEUS&rank=1. Recruitment in the study began in June 2011. The enrollment phase was completed in September 2012 with 1,606 patients, and follow-up will last until September 2013 so as to reach the 1year clinical surveillance.
Characterization of the study population according to the qualifying criteria for inclusion Figure 1 shows the distribution of the primary (ie, the key qualifying criterion according to the prespecified hierarchy—bleeding risk dominates thrombosis risk, which, in turn, dominates restenosis risk) condition, which qualified patients for recruitment. The most prevalent category was high bleeding risk status, encompassing 828 patients (51.6%), followed by low restenosis risk status with unstable presentation (388 [24.2%] patients), low restenosis risk with stable presentation (199 [12.4%] patients), and finally high thrombosis risk
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group (191 [11.9%] patients). Altogether, 524 patients (32.6%) satisfiedN1 prespecified criterion qualifying for inclusion. Figure 2 shows the individual features identifying patients at high bleeding risk (panel A) or at high thrombosis risk (panel B).
Disclosures Dr. Athanasios Patialiakas received grants from HCS (Hellenic Cardiology Society) and from EL.I.KAR (Hellenic Heart Institute).
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