TWENTE Study: The Real-World Endeavor Resolute Versus Xience V Drug-Eluting Stent Study in Twente: study design, rationale and objectives

Abstract

Background. New-generation drug-eluting stents (DES) may solve several problems encountered with first-generation DES, but there is a lack of prospective head-to-head comparisons between new-generation DES. In addition, the outcome of regulatory trials may not perfectly reflect the outcome in ‘real world’ patients.

Objectives. To compare the efficacy and safety of two new-generation DES in a ‘real world’ patient population.

Methods. A prospective, randomised, single-blinded clinical trial to evaluate clinical outcome after Endeavor Resolute vs. Xience V stent implantation. The primary endpoint is target vessel failure at one-year follow-up. In addition, the study comprises a two-year and an open-label five-year follow-up. (Neth Heart J 2010;18:360–4.)

The positive results of early drug-eluting stent (DES) trials led to widespread DES use.^1-3 However, meta-analyses^4,5 and long-term follow-up data^6,7 demonstrated that DES improved morbidity but did not reduce mortality (compared with bare metal stents; BMS). Newer generation DES may solve the problems encountered with first-generation DES. In the present article, we describe the design of the TWENTE study (The real-World Endeavor Resolute versus Xience V drug-eluting steNt study in TwentE) that compares two newer generation DES, we comment on the rationale of the study, and briefly discuss several key issues of this trial.

Rationale of the study

Endeavor Resolute and Xience V are two new-generation DES. Pivotal clinical trials have demonstrated the safety and efficacy of both stents.^8-12 The positive clinical results may reflect superior drug characteristics, polymer morphology,^13,14 and biocompatibility,^15-17 which may account for a better endothelialisation compared with older-generation DES.¹⁸ When we started the present study no data from prospective randomised head-to-head comparisons between these two DES in a real-world scenario were available.

Accordingly, the TWENTE study was designed to evaluate the clinical outcome of randomised use of Endeavor Resolute versus Xience V stents in a non-selected patient population.

Study design

General design

TWENTE is an ongoing, physician-initiated clinical trial. This study has a prospective, two arm, randomised, single-blinded design. The aim of the TWENTE study is to compare efficacy and safety of Endeavor Resolute versus Xience V DES in a real-world patient population with:

• Single or multiple lesions to be treated in any stage of coronary artery disease, ranging from single vessel to complex three-vessel disease;

• De-novo coronary lesions, restenoses following previous PCI, and/or lesions in venous or arterial coronary artery bypass grafts (CABG);

• Various clinical syndromes, including stable angina pectoris, unstable angina pectoris with or without cardiac marker rise, non-ST-elevation myocardial infarction (non-STEMI), and status following recent STEMI (except during the initial 48 hours).

Patients will be monitored throughout the two-year study period for the occurrence of death, myocardial infarction (MI), re-intervention (re-PCI or CABG), stent thrombosis, and new-onset angina pectoris or worsening of symptoms. Then, an additional open-label follow-up (duration of three years) will be performed to evaluate the efficacy and safety of the study devices until five-year follow-up. Between 18 June 2008 and 18 May 2010, a total of 1196 patients were included in the TWENTE trial, which corresponds with an inclusion rate of 624 patients per year.

Study hypothesis

The hypothesis to be tested in this trial is that the zotarolimus-eluting stent (Endeavor-Resolute; Medtronic Vascular, Santa Rosa, CA, USA) is non-inferior to the everolimus-eluting stent (Xience V; Abbott Vascular, Santa Clara, CA, USA) as assessed by the primary endpoint target vessel failure (TVF) after one year (non-inferiority hypothesis), as outlined below.

Study population

Enrolment is planned in 1380 patients with symptomatic coronary artery disease and coronary (or graft) lesions >50%, in whom PCI with DES implantation is indicated. Patients are enrolled at the Thoraxcentrum Twente in Enschede, the Netherlands. Details of the inclusion and exclusion criteria are presented in table 1.

Table 1.

Inclusion and exclusion criteria.

Inclusion criteria Indication for use of DES based on NVVC and ESC guidelines and/or clinical judgment of interventional cardiologist Age ≥18 years and mentally capable to provide informed consent Signed informed consent

Exclusion criteria ST-elevation myocardial infarction (STEMI) or STEMI-equivalent requiring primary PCI or rescue PCI during past 48 hours Planned staged revascularisation procedure Renal failure requiring haemodialysis Current participation in investigational drug or device study Comorbidity or condition that could - in the investigators opinion - limit the patient’s ability to participate in the study, to comply with follow-up requirements or could impact the scientific integrity of the study Life expectancy <1 year If the choice of DES type is dictated by logistic reasons (e.g., if a DES with the required dimensions is provided by only one manufacturer)

NVVC=Netherlands Society of Cardiology, ESC=European Society of Cardiology, DES=drug-eluting stents.

Study devices

Endeavor Resolute (figures 1A and C) is based on the Driver cobalt chromium platform with a strut thickness of 91 μm, coated with a mixture of zotarolimus as the antiproliferative drug plus Biolinx polymer;¹² the coating thickness is 5.6 μm. Xience V stents (figures 1B and D) consist of the Vision multi-link cobalt-chromium platform with a strut thickness of 81 μm, covered by a 7.8 μm thick layer of a mixture of fluoropolymer and everolimus as the antiproliferative drug.¹⁹

Figure 1.

Geometry and surface morphology of Endeavor Resolute and Xience V. Micro-computed tomography images of Endeavor Resolute (A) and Xience V (B). Scanning electron microscopic images of Endeavor Resolute (C) and Xience V (D) (images from ongoing bench side studies in DES, performed by C. von Birgelen and co-workers, University of Twente, Enschede, the Netherlands.

Ethics, informed consent, and randomisation

The study is conducted according to the principles of the Declaration of Helsinki (1964) and in accordance with the Medical Research Involving Human Subjects Act. The local medical ethics committee has approved the study protocol. Before participating, patients are informed about the purpose, and possible risks/benefits of the study. Written informed consent is obtained in all patients. Patients who meet the inclusion criteria and give informed consent are randomised between implantation of Endeavor Resolute vs. Xience V stents in a proportion of 1:1. Allocation to treatment is stratified by gender and performed by means of sealed envelopes, containing a computer-generated sequence that was produced with random block size. The two treatment groups are studied concurrently.

Treatment of patients

Patients who are not on oral aspirin therapy receive a loading dose of at least 300 mg prior to PCI. In elective PCI patients, clopidogrel therapy of 75 mg daily is started one week before the PCI. In urgent PCI, a loading dose of 600 mg clopidogrel is given as soon as possible, either before PCI or (at least) directly after the PCI is performed. The PCI procedure is performed according to routine clinical standards via the femoral or radial route, using 6 French guiding catheters. Prior to PCI, unfractionated heparin is administered intravenously, and an intracoronary bolus of nitroglycerin is given and repeated if necessary. Glycoprotein IIb/IIIa inhibitor use is left to the operator’s discretion. Following the index PCI procedure, patients are generally maintained on aspirin ≥80 mg daily during the entire trial (and preferably lifelong). If patients require oral anticoagulation therapy (e.g., for atrial fibrillation), aspirin ≥80 mg daily is prescribed for at least one to three months after PCI. Clopidogrel 75 mg daily is recommended and prescribed for a period of 12 months. Further medical treatment is performed according to current medical guidelines, clinical standards, and the judgment of the referring physicians.

Follow-up

Following the index PCI procedure, patients are contacted by telephone or seen in the outpatient clinic after 30 days and after 3, 12, and 24 months. In addition, there will be a five-year open-label follow-up. Data are collected on clinical endpoints (see below) and on (dis)continuation of the dual antiplatelet therapy.

Primary study endpoints

The primary endpoint of this study is defined as the composite (TVF) after one-year follow-up. Target vessel failure is defined as (in hierarchical order): target vessel related death, myocardial infarction, or clinically driven target vessel revascularisation by means of re-PCI or CABG. All clinical endpoints are defined according to the Academic Research Consortium (ARC) definitions and addendum.^20,21

Secondary study endpoints

Secondary endpoints include clinical, laboratory, angiographic, and intravascular ultrasound (IVUS) endpoints. Secondary clinical endpoints comprise:

• Death due to cardiac, vascular, non-cardiovascular, and all-cause mortality at 1, 3, 12, and 24 month follow-up;

• Myocardial infarction (all; related to target vessel; related to non-target vessel);

• Re-PCI or CABG (all; related to target vessel; related to non-target vessel);

• New onset of angina pectoris (or increase in angina class according to the Canadian Cardiovascular Society classification);

• Stent thrombosis according to the ARC definitions.

Secondary laboratory endpoints include the extent of biomarkers elevation post-PCI and secondary angiographic (QCA) endpoints comprise established quantitative coronary angiographic parameters. In the subpopulation of patients referred for angiographic re-evaluation with or without subsequent re-PCI (i.e., patients with clinically indicated angiographic re-evaluation), a QCA substudy will be performed. Another angiographic secondary endpoint is the angiographic evidence of stent thrombosis as outlined in the ARC definitions.²⁰ In the subpopulation of patients with clinically indicated IVUS examinations, the IVUS recordings will be analysed as previously described.²²

Power calculation and statistics

The main outcome parameter is the difference in time to TVF between the two DES after one year, analysed by log-rank test and Cox regression. Statistical significance is set at 5% and power at 80%. Assuming a median time to TVF of 48 months, based on the Endeavor III trial,²³ a hazard ratio of 1.35, an accrual time of two years, and an additional follow-up of one year for TVF, 690 patients per group are needed. Eighteen months after the start of the study, an interim analysis for the incidence of TVF on the pooled data will be performed and, if required, a new power analysis will be performed.

Data management

Data entry is performed by the cardiology research team of the Thoraxcentrum Twente. QCA and IVUS analyses are performed in the core lab in Enschede (analysts blinded to clinical information). An independent Clinical Events Committee will adjudicate all events. In patients with clinically driven repeat invasive procedures, all angiograms and IVUS recordings will be evaluated.

Discussion

Endeavor Resolute and Xience V are two examples of newer-generation DES which may overcome the shortcomings of first-generation DES.²⁵ These two DES differ in stent platform, which could have consequences for device flexibility and side branch access.²⁴ In addition, the DES use different coatings, which is reflected in their microscopic appearance.¹³ Finally, both DES deliver different antiproliferative drugs. Despite marked differences in several DES key components, both stents are commonly expected to further improve the clinical outcome of PCI.²⁵ In the TWENTE study the parameter ‘target vessel failure’ - a clinical endpoint - was chosen to be the primary endpoint. This endpoint reflects both effectiveness and safety aspects of the stents investigated.²⁶

Do we need randomised post-marketing studies in a ‘real world’ scenario?

Obviously, each of the two DES that are compared in the TWENTE study has previously been examined in regulatory trials.^8-12 But the study populations of most regulatory trials differ substantially from the patients treated in a ‘real world scenario’. This discrepancy is underlined by the different rates of stent thrombosis in low-risk patients (as included in many regulatory trials) vs. high-risk patients and/or patients treated with DES in off-label scenarios.²⁷ The aforementioned limitations of regulatory trials and the inherent limitations of non-randomised ‘real world’ studies (i.e. registries without control group) recently motivated some ‘real world’ trials.^28,29 In the TWENTE study, we adopted very few exclusion criteria in order to reflect the everyday ‘real world’ practice. As part of this practice, patients treated by primary PCI for acute STEMI were not included in the study because this setting is not considered as a standard indication for DES use.

Expected scientific evidence and limitations of the study

To evaluate the weight of the expected scientific evidence of a trial, a scoring system as proposed by Silber et al. can be used.³⁰ According to that scoring system, the TWENTE study may achieve a relatively good score of up to eight. The maximum score of ten points of this scoring system is reserved for double-blinded and multicentre trials.³⁰ The outcome of any single-centre trial is usually received with some reservation, inherent in this study design, because generalisation of the study results is considered to be somewhat limited. Nevertheless, the example of the recently published COMPARE trial shows that single-centre trials can provide very interesting and clinically relevant data.²⁹

Trial registration number

NCT01066650 (www.clinicaltrials.gov); NTR 1256 (www.trialregister.nl)

Acknowledgements

This study is supported in equal shares by research grants from Abbot Vascular and Medtronic Inc., the Netherlands.