Abstract
The XIENCE V SPIRIT WOMEN study will focus on specific aspects of women's health in relation to coronary artery disease, such as menopausal status, use of hormonal contraceptives or their surrogates, and the referral path and symptoms at presentation. The study is a prospective, open-label, single-arm, multicenter study designed to evaluate the performance of the XIENCE V™ Everolimus-Eluting Coronary Stent System in the treatment of female patients with coronary artery lesions. It also includes a prospective, single-blind, double-arm, randomized, multicenter substudy, in which patients will be randomized in a 2:1 ratio between the XIENCE V stent and the CYPHER SELECT™ Plus. In total, approximately 2000 female patients, derived from the general interventional cardiology population, will be enrolled from up to 130 sites outside of the USA.
Keywords
Coronary artery disease is the most common form of heart disease and has been shown to be the leading cause of death in Western countries, with an approximately equal incidence in men and women [1]. As a result of increased life expectancy, particularly in women, the burden of the disease has been increasing. Unfortunately, the risk of heart disease in women is underestimated owing to the perception that women are ‘protected’ against ischemic heart disease [1,2].
Symptoms in women are often different from those in men. Classic symptoms such as chest pain and pain radiating down the left arm and up the left side of the jaw, do not always occur in women. Furthermore, indications in women may be vaguer than in men, such as feeling generally unwell, tired or flu-like symptoms. Pain, if it does occur, may be dull in women as opposed to the sharp pain that is observed in men. A feeling of breathlessness or anxiety may also be present. Therefore, these vague symptoms can frequently result in a misdiagnosis in women and, since general awareness of heart disease in women is poor, they are likely to be diagnosed less often and at a later stage than men [2,3].
Stenting of de novo lesions in native coronary arteries has been shown to be a safe and effective treatment of occlusion due to atherosclerosis [4,5]. The application of antiproliferative drugs to the stent is believed to decrease the need for patients to undergo repeat percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG). Drug-eluting stents (DES) are currently used in approximately 50% of procedures in Europe and the USA.
Many of the assumptions that have been made concerning cardiovascular disease in women are from studies where women have been under-represented. This is best demonstrated by the smaller representation of women in clinical studies [2], where the majority of percutaneous coronary intervention (PCI) trials to date have enrolled only 15–35% women. Given this under-representation, a recommendation by the Policy Conference on Cardiovascular Diseases in women of the European Society of Cardiology was made to conduct some clinical trials that would enroll exclusively female patients [1].
To address this unmet medical need, Abbot Cardiovascular Systems, Inc. (Santa-Clara, CA, USA) has recently designed a new DES named the XIENCE V™, and the first large interventional study to focus on how cardiovascular disease differs in women from men has been initiated. This study, known as XIENCE V SPIRIT WOMEN, will focus on specific aspects of women's health in relation to coronary artery disease, such as menopausal status, use of hormonal contraceptives or their surrogates, and the referral path and symptoms at presentation. None of which have been recorded in previously conducted studies. While not intended to solve all questions surrounding PCI in women, XIENCE V SPIRIT WOMEN has been designed to address the most critical aspects of this clinical question. The results of this study will allow better characterization of the female population undergoing DES implantation and, in addition, will further the evaluation of the safety and performance of Abbott Vascular's XIENCE V Everolimus-Eluting Coronary Stent System (EECSS; hereafter known as the XIENCE V stent) in real-world use in this specific population.
Study design
The XIENCE V SPIRIT WOMEN clinical evaluation is a prospective, open-label, single-arm, multicenter study designed to evaluate the performance of the XIENCE V stent, in the treatment of female patients with coronary artery lesions. In addition, this study includes a prospective, single-blind, double-arm, randomized, multicenter substudy.
Approximately 2000 female patients, derived from the general interventional cardiology population, will be enrolled from up to 130 sites outside of the USA. Of these, 1550 patients from approximately 100 sites will be enrolled in the SPIRIT WOMEN single-arm study (SAS) and up to 450 patients from up to 30 sites will be randomized in a 2:1 ratio (XIENCE V stent vs CYPHER SELECT™ Plus) in the randomized substudy (RSS).
Device details
The study device, the XIENCE V stent, (Abbott Cardiovascular Systems, Inc., CA, USA, an affiliate of Abbott Vascular Inc.) is comprised of the ML VISION stent or the ML MINI VISION stent on a delivery system with a drug-eluting coating. The drug coating is composed of two polymers and the antiproliferative drug everolimus. Everolimus is blended in a nonerodable polymer, coated over another nonerodable polymer primer layer. The coating comprises acrylic and fluorinated copolymers, both approved for use in blood-contacting applications. Everolimus (Certican®, Novartis Pharmaceuticals Corporation) is a drug that has been evaluated in clinical studies in the USA and Europe for use in conjunction with other medications to prevent heart and renal transplant rejection. Everolimus has received market approval in the EU and the XIENCE V stent received CE mark approval on 30 January 2006 and US FDA approval on 2 July 2008.
The control device used in the RSS is the CYPHER SELECT Plus. The CYPHER SELECT Plus uses sirolimus as an antiproliferative drug and obtained FDA approval in 2003. It is commercially available throughout Europe and international markets, including the USA.
Recruitment
Recruitment will include ‘real world’ female patients derived from the general interventional cardiology population who have been admitted for a PCI procedure. Female patients are eligible for the study who are over 18 years of age with evidence of myocardial ischemia, either stable or unstable angina, positive functional study or a reversible change in the ECG consistent with ischemia. Patients must also be acceptable for CABG surgery and must agree to undergo all protocol-required follow-up examinations. As the product has not been tested in pregnancy, patients of childbearing potential must have had a negative pregnancy test within 7 days before treatment and must not be nursing at the time of treatment. Patients are not eligible if they have participated in another device or drug study or have completed the follow-up phase of another study within 30 days prior to enrolment. Also excluded will be patients who have had a previous stent implant, either a bare metal stent or DES within the target vessel(s).
Following screening for general eligibility, patients are asked to provide informed consent, as approved by the appropriate medical ethics committee of the respective clinical site. Basic baseline data is collected for all patients, which will include the evaluation of specific female demographics such as menopausal, hysterectomy and oophorectomy status, past and current use of hormonal contraceptives, use of weak estrogens, symptoms at presentation and referral path.
Procedural information
Once the patient has entered the catheterization laboratory, the study angiographic inclusion criteria is confirmed. Patients with de novo target lesions measuring less than or equal to 28 mm in length and between 2.25 and 4.0 mm diameter by visual estimation are eligible. Stent implantation may be performed in one, two or three vessels. Patients may receive up to four planned study stents depending on the number of vessels treated and their respective lesion lengths. Overlapping stents must overlap with a minimum of 1 mm and a maximum of 4 mm. All target lesions should be treated using standard interventional techniques with mandatory predilation and stent implantation at a pressure not exceeding the rated burst pressure. Postdilatation is left to the discretion of the investigator, however, if performed, it is only to be done with balloons sized to fit within the boundaries of the stent. Brachytherapy in any lesion or vessel or any other non-study percutaneous procedure is not allowed at the time of the study procedure.
Following the confirmation of angiographic inclusion criteria, but prior to implantation of the first stent, registration for the SAS or randomization for the RSS is performed via an interactive voice response system (ICON Clinical Research) for all patients. Once randomized/registered, the patient is considered enrolled in the study as part of the intention-to-treat population, and should remain in the study until completion of the required follow-up period. The process of randomization/registration is designed to reduce investigator bias with regards to enrolment and/or withdrawal of patients in the study.
For patients in the SAS, the target lesion(s) should be treated by stenting with the XIENCE V stent according to the instructions for use and, in the event of bailout, the XIENCE V stent should be used. For patients in the RSS, all target lesion(s) should be treated according to the treatment allocated at randomization and, in the event of bailout, the stent used should be the same as allocated at randomization.
Periprocedural pharmaceutical treatment should be administered according to standard hospital practice. Either unfractionated heparin or bivalirudin may be used for procedural anticoagulation. The use of GpIIb/IIIa inhibitors is left to the discretion of the investigator. All patients enrolled in the study should be pretreated with a loading dose of clopidogrel 300 mg or higher and aspirin 75 mg or higher. Postprocedure, the protocol recommends that patients in the SAS receive clopidogrel 75 mg daily for a minimum of 6 months with aspirin 75 mg or higher for a minimum of 5 years. For the RSS, the protocol states that all patients must receive clopidogrel 75 mg daily for a minimum of 6 months with 75 mg or higher of aspirin for a minimum of 5 years.
Follow-up
Assessment of anginal status, collection of data regarding adverse events, details of any subsequent coronary interventions, clinical investigational plan medications and use and changes in concomitant medications, will be collected at 30 days, 240 days and 1, 2, 3, 4 and 5 years postprocedure for all patients. Additionally, angiographic follow-up at 270 days will be carried out for patients in the RSS. Prior to performing the follow-up angiogram or with any unanticipated revascularization, the investigator must record prospectively whether the revascularization is clinically indicated.
End points
The primary end point is the adjudicated composite rate of all death, all myocardial infarction (MI) and target vessel revascularization at 1 year [6]. In-stent late loss at 270 days is the main secondary end point for the randomized substudy. All study end point events will be adjudicated by an independent Clinical Event Committee according to the Academic Research Consortium Definitions (Table 1). All adverse events will be reported to an independent Data and Safety Monitoring Board and will be reviewed on a regular basis.
Myocardial infarction classification and criteria for diagnosis as defined by the Academic Research Consortium.
Baseline biomarker value required before study procedure and presumes a typical rise and fall.
CABG: Coronary artery bypass graft; CK: Creatine kinase; LBBB: Left bundle-branch block; PCI: Percutaneous coronary intervention; URL: Upper reference limit (defined 99th percentile of normal reference range).
Definition of MI
According to the study protocol, diagnosis of MI is made on the basis of total creatine kinase (CK) concentration of more than twice the upper limit of normal. If total CK is not available, then CK-MB of more than three-times the upper limit of normal is considered evidence of MI. If neither CK nor CK-MB are available, troponin elevation of more than five-times the 99th percentile or diagnostic value for the specific institution is considered to be evident of MI.
Sample size
The overall sample size for the study is based on the primary end point of adjudicated composite rate of all death, all MI and target vessel revascularization at 1 year and on the following assumptions: a sample size of 1550 patients enrolled in the SAS will produce a narrow two-sided 95% confidence interval around the clinical end point estimates. The half width of the two-sided confidence interval around the 1-year primary end point estimate will be between 1.5 and 1.7%. In addition, the pooled analysis, including patients from the SAS and patients from the RSS who were randomized to XIENCE V, will report on approximately 1850 patients. According to the study protocol, the event rate is expected to range between 10 and 14%.
The overall sample size for the RSS is based on the main secondary end point of in-stent late loss at 270 days and on the following assumptions: one-tailed noninferiority test, α equals 0.05, power equals 90%, where the randomization ratio is 2:1 (XIENCE V stent:CYPHER SELECT Plus stent, respectively). The true mean in-stent late loss is assumed to be equal for both treatment arms, the standard deviation is assumed to be 0.53 mm in both the XIENCE V arm and CYPHER arm, and the noninferiority margin δ of 0.17 mm. Given these assumptions, 252 subjects in the XIENCE V arm and 126 subjects in the CYPHER arm will be required. In order to account for dropout and to ensure adequate angiographic data, 450 subjects will be enrolled, of which approximately 300 will be in the XIENCE V stent arm and 150 in the CYPHER SELECT Plus stent arm.
Analysis
All analyses for SAS and RSS will be performed on the intent-to-treat population. In addition, for the RSS, the primary and secondary end points will be analyzed on the per-treatment evaluable population. This will consist of patients who have received the study device at the target lesion(s), who have no major procedural protocol deviations other than those relating to treatment arm (randomized versus actually received) and for whom follow-up data is available. Patients receiving a nonstudy stent on one or more of the target lesions or receiving several types of stents at target vessels will be excluded from this population.
Results
The first patient was enrolled in the study on the 5 July 2007. As of 11 July 2008, 567 patients have been enrolled. Study enrolment is planned to be completed by the end of 2008.
Significance
While a large amount of data is available regarding the general interventional cardiology population undergoing PCI, XIENCE V SPIRIT WOMEN is the first major study to focus entirely on the female population.
The findings of this study will provide information on specific aspects of women's health in relation to coronary artery disease. Through this type of initiative, Abbott Vascular aims to increase awareness among physicians and patients with regard to cardiovascular disease in women.
Conclusion
The findings of XIENCE V SPIRIT WOMEN will have important implications for the management of female patients undergoing PCI with DES implantation. In addition, the study will increase the understanding of the relationship between cardiovascular disease and hormonal status in this patient population and provide further efficacy data about the XIENCE V stent in the female population.
Future perspective
XIENCE V SPIRIT WOMEN is the only major DES study to solely enroll female patients. This highlights the need for additional clinical trials dedicated to this specific population, which will be essential to the provision of evidence-based treatment for the female population.
It is the aim that the results of this study will not only provide essential information to physicians treating female patients, but also provide the female population with the information necessary to make them aware of their risks of cardiovascular disease to enable them to better embrace preventative measures.
Executive summary
The risk of heart disease in women is underestimated because of the perception that women are ‘protected’ against ischemic heart disease.
Symptoms of heart disease are often different in women.
Women are under-represented in clinical studies.
A clinical evaluation of the XIENCE V™ Everolimus-Eluting Coronary Stent System in the treatment of women with de novo coronary artery lesions (XIENCE V SPIRIT WOMEN) is a prospective, open-label, single-arm, multicenter study designed to evaluate the performance of the XIENCE V stent in the treatment of female patients with coronary artery lesions.
The study includes a prospective, single-blind, double-arm, randomized, multicenter substudy. Patients will be randomized in a 2:1 ratio (XIENCE V stent vs CYPHER SELECT™ Plus).
First patient enrolled on 5 July 2007.
567 patients enrolled as of 11 July 2008.
Enrollment completion planned for the third quarter of 2008.
This study will increase awareness among physicians and patients with regard to cardiovascular disease in women.
This is the first major study to focus solely on the female patient undergoing percutaneous coronary intervention with drug-eluting stent implantation.
This study will increase the understanding of the relationship between cardiovascular disease and hormonal status in the female population.
Footnotes
Acknowledgement
The author would like to thank Marrianne Stuteville (Abbott Vascular) for her help in the preparation of this manuscript.
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.