Author + information
- Received February 23, 2011
- Revision received March 9, 2011
- Accepted March 10, 2011
- Published online April 26, 2011.
- Alan C. Yeung, MD⁎,
- Martin B. Leon, MD‡,
- Ash Jain, MD†,
- Thaddeus R. Tolleson, MD§,
- Douglas J. Spriggs, MD∥,
- Brent T. Mc Laurin, MD¶,
- Jeffrey J. Popma, MD#,
- Peter J. Fitzgerald, MD⁎,
- Donald E. Cutlip, MD⁎⁎,
- Joseph M. Massaro, PhD††,
- Laura Mauri, MD, MSc‡‡,⁎ (, )
- RESOLUTE US Investigators
- ↵⁎Reprint requests and correspondence:
Dr. Laura Mauri, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, Massachusetts 02115
Objectives The RESOLUTE US (R-US) trial is a prospective, observational study designed to evaluate the clinical effectiveness of the Resolute zotarolimus-eluting stent (R-ZES) in a U.S. population.
Background The R-ZES releases zotarolimus over a 6-month period in order to achieve optimal clinical effectiveness and safety.
Methods The R-US trial recruited patients with de novo native coronary lesions suitable for 1- or 2-vessel treatment with stents from 2.25 to 4.0 mm in diameter. In the main analysis cohort (2.5- to 3.5-mm stents and single-lesion treatment), the primary endpoint was 12-month target lesion failure (TLF) defined as the composite of cardiac death, myocardial infarction (MI), and clinically-driven target lesion revascularization (TLR), compared with data from Endeavor zotarolimus-eluting stent (E-ZES) trials, adjusting for baseline covariates through propensity scores.
Results Overall, 1,402 patients were enrolled with a mean reference vessel diameter of 2.59 ± 0.47 mm and diabetes prevalence of 34.4%. In the main analysis cohort, TLF was 3.7% at 12 months compared with historical E-ZES results (TLF = 6.5%). The R-ZES met the 3.3% margin of noninferiority (rate difference = −2.8%, upper 1-sided 95% confidence interval: −1.3%, p < 0.001). The overall TLF rate was 4.7%, and rates of cardiac death, MI, and TLR were 0.7%, 1.4%, and 2.8%, respectively. The 12-month rate of stent thrombosis was 0.1%.
Conclusions The R-ZES achieved a very low rate of clinical restenosis while maintaining low rates of important clinical safety events such as death, MI, and stent thrombosis at 1-year follow-up. (The Medtronic RESOLUTE US Clinical Trial [R-US]; NCT00726453)
Despite the success of drug-eluting stents (DES) in reducing repeat revascularization procedures via local delivery of potent antiproliferative drugs from the stent surface, about 5% of DES patients require repeat procedures within a year, with higher rates in patients with diabetes mellitus or smaller vessels (1–3). The long-term safety of DES remains an important area of clinical investigation, particularly the avoidance of late stent thrombosis (ST) (4).
The Resolute zotarolimus-eluting coronary stent (R-ZES) (Medtronic, Santa Rosa, California) is designed using the same cobalt chromium stent platform and drug as the U.S. Federal Drug Administration–approved Endeavor zotarolimus-eluting coronary stent (E-ZES) (Medtronic). The R-ZES utilizes a new hydrophilic biocompatible polymer that provides extended release of zotarolimus over approximately 180 days (5). This longer duration of drug release was designed to improve prevention of restenosis while maintaining low ST rates.
The RESOLUTE US (R-US) trial is a multicenter, prospective trial designed to compare the R-ZES to historical clinical trial data for the E-ZES, while also examining small vessel treatment and a U.S. population with a relatively high prevalence of diabetes mellitus.
Study overview and patient population
The R-US trial design and methods with device characteristics, study procedures, and prescribed medications have been previously described (6,7). The clinical outcomes of patients treated with R-ZES in lesions suitable for 2.25- to 4.0-mm stents in 1 or 2 vessels were evaluated. To avoid the confounding effect of angiography on clinical outcomes, subjects were either enrolled with prospective, clinical follow-up only (clinical cohort, n = 1,242), or with protocol-specified angiographic follow-up in a consecutive series of subjects at eligible sites (angiographic cohort, n = 160). A subset of the angiographic cohort also received intravascular ultrasound (IVUS) examination (n = 100). A 38-mm stent length substudy is still enrolling patients.
Institutional review boards at all sites approved the study protocol. Written informed consent was obtained from each patient. Major inclusion criteria included adults with clinical evidence of ischemic heart disease attributable to stenotic lesion(s) in de novo native coronary arteries and planned treatment of up to 2 lesions located in separate target vessels. Important exclusion criteria included evidence of acute myocardial infarction (MI) within 72 h of the procedure or previous treatment of the target vessels for restenosis.
The main analysis consisted of patients from the clinical cohort (n = 1,242) compared with historical controls derived from all trials of E-ZES patients with clinical follow-up only (ENDEAVOR II, ENDEAVOR IV, ENDEAVOR PK, and ENDEAVOR II Continued Access trials) (8–10). Because these E-ZES trials predominantly enrolled patients treated for a single lesion with 2.5- to 3.5-mm stents, the population for the main analysis of the R-US trial was further restricted to patients with 2.5- to 3.5-mm stents with single-lesion treatment (main analysis cohort, n = 1,001). Clinical outcomes were also analyzed for all enrolled patients.
The primary endpoint of the main analysis cohort was target lesion failure (TLF), defined as cardiac death, MI, or clinically-driven target lesion revascularization (TLR) by percutaneous or surgical methods at 12 months. The primary endpoint for the 2.25-mm stent group was also TLF at 12 months. The primary angiographic endpoint for the 4.0-mm stent group was in-segment late loss at 8 months. If multiple lesions qualifying were treated, an index lesion was selected as previously described (6).
For this trial, all deaths were considered cardiac unless an unequivocal noncardiac cause could be established. MI was defined as previously described (6). TLR was defined as clinically-driven repeat percutaneous coronary intervention (PCI) of the target lesion or coronary artery bypass grafting (CABG) including the target vessel. Target vessel revascularization (TVR) was defined as clinically-driven repeat PCI or CABG of the target vessel. All ST events were adjudicated according to Academic Research Consortium criteria (11).
Data management and core laboratories
All data were submitted to a central data coordinating facility (Harvard Clinical Research Institute [HCRI], Boston, Massachusetts). An independent clinical events committee (HCRI) and core laboratories (angiographic: Beth Israel Deaconess Medical Center, Boston, Massachusetts; IVUS: Cardiovascular Core Analysis Laboratory, Stanford University, Palo Alto, California) reviewed the relevant primary data.
The primary analysis was designed such that a total of 800 analyzable patients with single lesions in the main analysis cohort would yield 87% power to assess the noninferiority of the R-ZES compared with E-ZES using a noninferiority margin (delta) of 3.3% with respect to the primary endpoint of TLF. Baseline characteristics that could impact the primary endpoint were compared between treatment groups, and propensity score adjustment was used to address imbalances at baseline between the 2 groups. Variables used to generate the propensity score are shown in the Online Appendix. The c-index for the separation of groups is 0.663. A 1-sided upper 95% confidence interval of the treatment difference (R-ZES minus E-ZES) in TLF rates adjusted for propensity score quintile was calculated. All statistical analyses were performed by HCRI using PC SAS for Windows version 9.1 (SAS Institute, Cary, North Carolina).
From August 21, 2008, to December 16, 2009, 1,402 patients were enrolled at 116 centers in the United States (Fig. 1). Diabetes mellitus prevalence was 34% overall (Table 1). The main analysis cohort patients had shorter lesions, smaller mean reference vessel diameter (RVD), and a higher incidence of diabetes mellitus than E-ZES control patients (Online Table 1).
The 12-month rate of TLF for the main analysis cohort was 3.7% (36 of 982) compared with 6.5% (70 of 1,076) for historical control patients treated with the E-ZES (difference, −2.8%; adjusted 1-sided 95% confidence interval upper limit, −1.3%; pnoninferiority < 0.001; post-hoc psuperiority = 0.002). The Kaplan-Meier curve for TLF is displayed in Figure 2. The 12-month rates of cardiac death, MI, and TLR are shown in Figure 3.
Overall clinical outcomes
The 30-day and 12-month clinical outcomes for the overall study population are shown in Table 2. The cumulative incidence curves for TLF, cardiac death and MI, TLR, and definite and probable ST for the overall population are displayed in Figure 4.
The overall rate of ST was 0.1% (2 of 1,376), and dual antiplatelet use was 97.0% at 30 days and 93.3% at 12 months. Definite or probable ST was observed only among patients treated with 2.25-mm stents. This included 1 patient with definite ST who presented with MI and angiographically confirmed ST on day 32 despite dual antiplatelet therapy, and 1 patient with probable ST who was not discharged on aspirin and died of presumed cardiac causes on day 5.
Angiographic and IVUS outcomes
The 2.25- and 4.0-mm stent groups
Prespecified endpoints for the 2.25-mm stent group and 4.0-stent group were met (2.25-mm group: 12-month TLF, 4.8% (7 of 146); 1-sided 95% confidence interval upper limit, 8.8%; comparison with a preset performance goal of 20%, p < 0.001; 4.0-mm group: TLF, 6.8% (4 of 59); in-segment late loss, 0.14 ± 0.44 mm; psuperiority < 0.001 compared with 0.65 ± 0.62 mm from historical bare-metal stent control).
Three hundred seventy-four patients with 2.5- to 3.5-mm stents and diabetes mellitus from the clinical cohort were included in a pre-specified diabetic analysis. The rate of 12-month TLF was 4.3% (cardiac death, 0.5%; MI, 0.8%; TLR, 3.0%).
This study met its primary endpoint of noninferiority of the R-ZES main analysis cohort compared with the E-ZES control group. In this cohort (2.5- to 3.5-mm stents in single lesions; 71% of overall patients), the R-ZES significantly lowered TLF by 43% (6.5% to 3.7%, psuperiority = 0.002), including a low rate of TLR (2.0%). These findings were consistent with the overall clinical outcomes when patients with 2.25-mm stents, 4.0-mm stents, and 2-vessel treatment were also included. This favorable result was achieved despite the higher proportion of diabetic patients (34%) than prior studies and the inclusion of patients receiving 2.25-mm stents (11%), wherein both of these high-risk subsets also had favorable clinical outcomes.
Compared with the 30-day ST rate of 0.8% observed in the RESOLUTE All Comers trial (12), the ST rate in this U.S. trial is 0.1% (2/1,376). Both of these events occurred in 2.25-mm stents, confirming published observations that small vessels may confer additional risk even with bare-metal stents (13). The absence of ST in patients with stents ≥2.5 mm is notable, though this is achieved with dual antiplatelet therapy (93.3% at 12 months), and longer-term follow-up is ongoing. Recent randomized and registry studies have extended the observations regarding the R-ZES to include some patient populations excluded from this trial, such as acute or recent MI, and more complex coronary anatomy (12,14).
Randomized studies are the gold standard for comparison of treatments, as these methods prevent important sources of potential bias. Although R-US uses a single-cohort observational design, care was taken to minimize bias and maintain the same standards for endpoint ascertainment as prior approval studies to which these data would be compared. Patients with identical inclusion criteria formed the comparator groups. Endpoint definition, ascertainment, and adjudication were performed with the same methods. Finally, because the study population was more complex than the comparative cohort, the primary study hypothesis testing was performed with propensity score adjustment. These methods allowed a high degree of reliability of the data and analysis to ensure prevention of potential bias.
Although not a randomized clinical study, the R-US trial shows the R-ZES to be highly efficacious even in challenging patients with diabetes mellitus and small-size stents, with a low incidence of stent thrombosis. This is the first study, to our knowledge, to evaluate the direct impact of drug elution characteristics on clinical outcomes, using identical drug-eluting stents except for a new polymer that extends drug elution.
The authors thank Manuela Negoita, MD, and Judith Jaeger, Medtronic, Inc., for contributions to study management, Minglei Liu, PhD, Medtronic, Inc., for statistical review, and Denise Jones, BSN, and Colleen Gilbert, PharmD, for editorial support.
For a supplemental table and an expanded Methods section, please see the online version of this article.
The RESOLUTE US Trial is funded by Medtronic, Inc., Santa Rosa, California. The Data Coordinating Center is Harvard Clinical Research Institute. Drs. Yeung and Leon are on a scientific advisory board for Medtronic. Dr. Jain has received lecture honoraria from Medtronic. Dr. Popma receives institutional research grants from Medtronic, Abbott, Boston Scientific, and Cordis; and he serves on the Advisory Boards of Boston Scientific, Cordis, and Abbott. Dr. Fitzgerald is a consultant and on a scientific advisory board for Medtronic. Dr. Cutlip is a Principal Investigator for Medtronic (paid to institution). Dr. Massaro is a paid consultant for Harvard Clinical Research Institute (HCRI) and, through his relationship with HCRI, received salary for statistical analysis and payment from Medtronic. Dr. Mauri receives institutional research support from Cordis, Medtronic, Abbott Vascular, Boston Scientific, Eli Lilly, Daiichi Sankyo, Bristol-Myers Squibb, and sanofi-aventis and is a consultant to Medtronic and Cordis. All other authors have reported that they have no relationships to disclose.
- Abbreviations and Acronyms
- coronary artery bypass grafting
- drug-eluting stent(s)
- Endeavor zotarolimus-eluting stent(s)
- Harvard Clinical Research Institute
- insulin-dependent diabetes mellitus
- intravascular ultrasound
- myocardial infarction
- minimum lumen diameter
- percutaneous coronary intervention
- reference vessel diameter
- Resolute zotarolimus-eluting stent(s)
- stent thrombosis
- Thrombolysis In Myocardial Infarction
- target lesion failure
- target lesion revascularization
- target vessel revascularization
- Received February 23, 2011.
- Revision received March 9, 2011.
- Accepted March 10, 2011.
- American College of Cardiology Foundation
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