Patients with chronic total occlusions (CTOs) of a coronary artery represent a complex, yet common, clinical conundrum among patients with ischemic heart disease. CTOs are identified in 18.4% of patients with significant coronary artery disease who undergo nonemergent coronary angiography 1 and in 9% of patients presenting with acute myocardial infarction (MI) 2. When untreated, the presence of a single CTO is associated with significant cardiovascular morbidity and mortality 3,4 and successful treatment has been shown to improve patients’ symptoms, function, and quality of life 5. Despite their symptomatic and prognostic impact, however, there is considerable variability in treatment for patients with CTOs. For example, a recent report from three Canadian hospitals showed that the percutaneous coronary intervention (PCI) attempt rates for CTOs varied between 1 and 16% between hospitals 1. There are a number of reasons for this variability including concerns over lower success rates, higher procedural risks, benefits that are incompletely characterized by randomized trials, and increased costs compared with non-CTO-PCI. Currently, the American College of Cardiology Foundation’s appropriateness use criteria ratings for CTO revascularization are systematically downgraded compared with similar non-CTO anatomy 6.
Notwithstanding these issues, there has been a renewed and intense interest in the field of CTO-PCI in recent years that has been driven, in large part, by the dissemination of advanced CTO-PCI techniques such as the hybrid approach 7 that have improved the likelihood for technical success 8,9. Although these technical advances have contributed toward increased enthusiasm for CTO-PCI among the interventional cardiology community, robust data on the safety, efficacy, benefits, and costs of the procedure are lacking.
To address these gaps in knowledge, we designed the Outcomes, Patient Health Status, and Efficiency IN Chronic Total Occlusion Hybrid Procedures (OPEN CTO) study. There are three specific aims of OPEN CTO that will be investigated according to the conceptual framework for the study shown in Fig. 1: (a) to describe the technical and procedural success and safety of the hybrid approach in consecutive patients selected for CTO-PCI (procedural outcomes); (b) to characterize health status before and after CTO-PCI (patient-centered benefits); and (c) to quantify the costs associated with the procedures. Providing an accurate assessment of the outcomes, benefits, and costs of treatment will serve as a foundation for reducing the variability in care and will support a definitive randomized trial of CTO-PCI.
Participating centers and patient population
OPEN CTO is an investigator-initiated multicenter, single-arm registry including 12 centers with an enrollment of 1000 patients. The operators had to have a minimum of 2 years of experience in CTO-PCI and had to have performed at least 100 CTO-PCI procedures before participating in OPEN CTO. All patients scheduled for a CTO-PCI by a designated hybrid CTO operator at the each hospital were screened for possible inclusion. Once a patient was identified, a brief screening form was completed that documented that the patient provided informed consent, was more than or equal to 18 years of age, was not of child-bearing potential (or had a negative pregnancy test), and agreed to participate in telephone follow-up. Informed consent was obtained from every patient. Each institution’s own Institutional Review Board approved the protocol, consenting process, and informed consent document. For the purposes of this study, CTO was defined as a 100% occlusion with antegrade intraluminal thrombolysis in myocardial infarction (TIMI) flow of 0 and clinical or angiographic evidence of occlusion duration more than or equal to 3 months. These angiographic features of a CTO, typically assessed using a diagnostic angiogram, were confirmed at the time of the intervention and any patient not meeting the definition at that time was excluded.
Because the detailed health status and clinical follow-up interviews (see below) were to be performed by a centralized call center without the capacity to translate, non-English-speaking patients and those unable or unwilling to participate in the interview (e.g. those incarcerated, too ill, demented, or deaf) were excluded.
Because the generalizability of all observational studies can be affected by selective enrollment of some patients (e.g. those with successful vs. unsuccessful procedures), it is critically important to ensure complete enrollment of consecutive patients. To address this, a unique feature of OPEN CTO is its ability to link to the National Cardiovascular Disease Registry’s (NCDR) Cath/PCI registry for auditing enrollment. All of the OPEN CTO investigators and institutions participated in the NCDR and agreed to release their NCDR data to the analytic center. The NCDR Cath/PCI registry, which collects data on all consecutive PCI procedures, was used to audit enrollment and ensure a truly a consecutive cohort or account for any under-reporting of failed or complicated procedures.
The clinical indication for CTO-PCI was determined by the operator, but in general included ischemic symptoms, moderate-risk or high-risk ischemia on noninvasive imaging studies, left ventricular dysfunction with evidence of viability, complete revascularization after acute coronary syndrome or elective PCI, arrhythmia, and avoidance of transplant or devices such as defibrillators. All of these were explicitly captured and will be used to determine the appropriateness of the procedures according to published appropriateness use criteria for PCI 10 in future analyses.
A critical step in generalizing findings from OPEN CTO is to have a clear, reproducible treatment strategy for CTO-PCI. The hybrid approach to CTO-PCI was initially developed and tested by a group of 17 CTO operators from the USA, Canada, and Europe at the Bellingham CTO summit in February 2011. The concepts developed during that course, including the hybrid algorithm (Fig. 2) and the hybrid philosophy of procedural planning and execution, were subsequently published in 2012 7,11.
Use of the hybrid algorithm requires the assessment of four angiographic features including the proximal cap anatomy, target vessel quality, presence of traversable collaterals, and the occlusion length. The operators used the algorithm to map out and execute the procedure using the strategy most likely to be successful first, while limiting the amount of time, contrast, and radiation by rapidly switching from a failing approach to alternative strategies in a logical prespecified sequence. The hybrid approach to CTO-PCI has been reported previously to be associated with high success rates and adequate safety 12 in a multicenter, unaudited registry. In the present study, extensive procedural details were captured to allow an in-depth look at the success and efficiency of the hybrid approach.
Data collection and management at baseline and follow-up
To obtain a robust assessment of the care and patient outcomes, detailed baseline data collection and telephone follow-up at 1, 6, and 12 months were performed (currently, 1-year follow-up is 80% complete). Baseline data were collected from the medical record by the onsite research nurses who were trained by the project coordinator. The data were entered into Velos (Freemont, California, USA), an electronic data-capturing software system, which has a robust data query engine and system validations for data quality. These data were supplemented with a detailed patient interview conducted by a trained interviewer before treatment.
Given that a primary indication for CTO-PCI is to improve patients’ health status, the OPEN CTO registry was designed to carefully collect patients’ perceptions of their disease. Comprehensive patient-reported health status was captured using a broad range of validated instruments including the Seattle Angina Questionnaire (SAQ) 13, the Rose Dyspnea Scale (RDS) 14, the Veterans RAND 12-Item Health Survey (VR12) 15, the EuroQOL-5D (EQ5D) 16, and the Patient Health Questionnaire (PHQ) 8 17 at baseline, 1, 6, and 12 months. The SAQ is a validated, disease-specific, and prognostically sensitive 19-item questionnaire with three primary domains; Angina Frequency, Physical Limitation, and Quality of Life, as well as a summary score 18. Scores range from 0 to 100, with 100 representing the absence of angina and optimal physical function and quality of life related to angina 13. As dyspnea is an important, although less specific symptom of coronary artery disease, we also collected the RDS, a four-item questionnaire designed to assess breathlessness with a range of 0–4, with lower scores representing less dyspnea. Originally developed for patients with pulmonary disease 14, the RDS was later validated in patients with ischemic heart disease 19. These disease-specific measures were supplemented with more generic, overall assessments of patients’ health status. The VR12 is an abbreviated, updated, and validated generic health status instrument 20 used to reproduce the physical and mental component summary scales of the VR36 health status survey 15. The EQ5D is a five-item, preference-based health status measure for describing and valuing health 16 that has been validated in a USA population 21 and will be used in the determination of health utilities and quality-adjusted life years, which are critical outcomes for the planned cost-effectiveness analyses after follow-up is complete. Finally, the PHQ-8, derived from the PRIME-MD survey for common mental disorders on which the diagnosis of Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) depressive disorders is based, was used to quantify depressive symptoms 17.
All procedural angiograms in OPEN CTO were reviewed by an angiographic core laboratory (Saint Luke’s Mid America Heart Institute, Kansas City, Missouri, USA) using QAngio XA 7.3 (Medis Medical Imaging Systems, Leiden, the Netherlands) software. This provided an objective and reproducible assessment of technical success, complications (e.g. occlusion of a significant side branch), and lesion complexity. In addition, the core lab quantified the Japanese Chronic Total Occlusion 22 score and the SYNergy between PCI with the TAXUS and Cardiac Surgery score 23 of the CTO vessel. Comprehensive SYNergy between PCI with the TAXUS and Cardiac Surgery scoring could not be performed as complete diagnostic angiograms were not scanned by the core lab.
To ensure unbiased follow-up, we employed an experienced centralized call center with staff trained in health status interviewing techniques for all follow-up at 1, 6, and 12 months. In addition to a detailed health status assessment at each time point, the call center staff asked patients about current medication, medication discontinuance and reason, rehospitalization and cause, repeat cardiac catheterization, cardiovascular testing, and signs of radiation skin injury. Patients who reported signs of radiation skin injury were referred to the interventional cardiologist who performed the procedure.
Healthcare resource utilization from the index hospitalization and any subsequent coronary revascularization procedures were collected and will be analyzed to support the health economic aims of the study. These data, in conjunction with hospital billing data, were collected by the Health Economics Core Laboratory and will be used to assess the initial and long-term costs for percutaneous coronary revascularization of patients with CTOs using a standard methodology 24 after follow-up is complete.
To further ensure the accuracy of adverse events' ascertainment, OPEN CTO is supported by a clinical events committee that will adjudicate all postdischarge events once follow-up is complete. Patient-reported postdischarge events are being captured and adjudicated as shown in Fig. 3.
Events including rehospitalization, death, and cardiac procedures that are reported by a site, a patient, or were planned triggered a request for records from the relevant hospital or clinic by the analytical center. These records are being reviewed by a trained research nurse and categorized into those in need of adjudication and those clearly not cardiovascular or index procedure related. Two clinical events committee members are in the process of reviewing the records; a third adjudicator is used in the event of a discordant review by the first two. Data from these reports are abstracted and entered into a follow-up case report form.
Whenever possible, definitions were adopted on the basis of the American College of Cardiology key data elements and definitions for measuring the clinical management and outcomes of patients with acute coronary syndromes 25. Periprocedural MI was defined according to the European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Health Federation task force for the redefinition of myocardial infarction, specifically types 4a and 5 (PCI-related and coronary artery bypass grafting-related MI, respectively) 26. Acute kidney injury was defined according to the Acute Kidney Injury Network definition 27 and bleeding was defined according to the NCDR definition 28.
Technical success for the index PCI procedure was determined by the angiographic core laboratory and defined as the positioning of a guidewire in the distal true lumen, deployment of a balloon or stent with restoration of TIMI antegrade flow of II or III, and residual stenosis less than or equal to 50% by angiographic core lab analysis, without occlusion of a significant side branch. A significant side branch was defined as a branch supplying the left ventricle (including diagonal, posterolateral, posterior descending, obtuse marginal, and septal branches) that is 1.5 mm or more in diameter by core lab analysis. An exploratory analysis of other commonly used definitions of success in CTO-PCI will be carried out, for example, final TIMI flow equal to 3 and residual stenosis less than or equal to 30% by core lab analysis and final TIMI flow equal to 3 and residual stenosis less than or equal to 30% as determined by the operator. Procedural success was defined as technical success and no major adverse cardiac or cerebrovascular events. Procedural major adverse cardiac or cerebrovascular events included in-hospital death, procedure-related MI, emergent coronary artery bypass grafting, stroke, or clinical perforation. Clinical perforation was defined as any perforation requiring treatment. Those treatments included pericardiocentesis, covered stent implantation, prolonged balloon inflation, and intentional thrombotic occlusion (coil implantation, thrombus, thrombin, fat, microsphere, or gelfoam injection). Long-term major adverse coronary events (MACE) were defined as death, MI, target vessel revascularization, or target vessel reocclusion. Rehospitalization was ascertained by patient report at 30 days, 6 months, and 1 year. After follow-up is complete (1 year), all rehospitalization and MACE events will be adjudicated as procedure related (up to 30 days) and cardiovascular or noncardiac.
Descriptive statistics were summarized as means and SDs for continuous variables, and counts and percentages for categorical variables. Baseline characteristics were compared between groups (e.g. successful vs. failed procedures, male vs. female, symptomatic vs. asymptomatic, complicated vs. uncomplicated procedures) using the Student’s t-test for continuous variables and Pearson’s χ 2-test for categorical variables.
Although Aim 1 is merely a descriptive analysis of periprocedural outcomes, the power calculations were driven by Aim 2. To conduct Aim 2, we plan to compare the health status outcomes of successful versus failed procedures. Assuming an 85% procedural success rate, we will have 90% power to detect a 6.5-point difference in the mean scores between successful and failed CTO-PCI for the Angina Frequency, Physical Limitation, and Quality of Life domains of the SAQ.
For a more complete description of the health status outcomes of CTO patients treated with PCI, the SAQ, VF12, PHQ-8, and EuroQol-5D endpoints will be analyzed using an adjusted repeated-measures mixed model with 1-, 6-, and 12-month responses serving as outcome variables once follow-up is complete.
Independence of investigators
The OPEN CTO trial is supported by a grant from Boston Scientific Corporation to the study sponsor, Saint Luke’s Hospital of Kansas City. The design, execution, oversight, and analyses of OPEN CTO were overseen by an independent six-member steering committee and eight-member publications committee each comprised of experts in interventional cardiology, CTO-PCI, cardiovascular outcomes, and health economics and translational research. The sponsor relinquished all rights to approve the publication of any analyses.
Between 21 January 2014 and 22 July 2015, 1000 patients were enrolled in OPEN CTO. A total of 28 patients either refused (N=26) or were missed by the screening process (N=2).
The NCDR Cath/PCI registry audit results are summarized in Table 1. There were 1096 CTO-PCI procedures that were performed by participating operators during the time they enrolled in OPEN CTO. Overall, 987 of those patients could be definitively matched to an OPEN CTO enrolled patient (enrolled group). The remaining 109 were considered to be not enrolled in OPEN CTO (not enrolled group). Compared with the enrolled group, the patients in the nonenrolled group were less frequently of White race and more frequently of Hispanic origin. Procedural outcomes including NCDR-defined technical and procedural success were numerically but not significantly lower among the nonenrolled group compared with the enrolled group. MACE and other complication rates were similar. Contrast volume and procedure times were lower among the nonenrolled group compared with the enrolled group.
In light of the considerable variability in the percutaneous treatment of CTO lesions and the ongoing controversy surrounding the risks and benefit of such procedures, we have designed a detailed registry to better describe the contemporary techniques, periprocedural risks, and outcomes of CTO-PCI. The OPEN CTO investigators successfully enrolled 1000 patients over 18 months at 12 centers and systematically collected detailed patient, procedural, health status, and cost data. To our knowledge, this is the most comprehensive consecutively enrolled registry with longitudinal follow-up of this emerging treatment strategy and, as such, will be able to support analyses providing unique insights into the success rates, safety, benefits, and costs of CTO-PCI using the hybrid approach.
Supporting our contention that OPEN is the most rigorous and comprehensive registry to date of CTO-PCI, several features of OPEN CTO that are not part of other recent large registries are worth highlighting and are summarized in Table 2. First, the ability to leverage the NCDR to audit the completeness of enrollment at each center will help to ensure that there is no important selection bias (cherry picking). By comparing the patients of each operator who were not enrolled with those enrolled, we were able to ensure that there was no systematic under-reporting of failed procedures or adverse events. Race and ethnicity differences were found between enrolled and not enrolled patients. This is likely a reflection of the requirement to speak English as the call center was not equipped with non-English translators. Nonetheless, success and MACE rates were similar between enrolled and nonenrolled patients, confirming that eligible patients were consecutively enrolled and these events are not under-reported. This is particularly important as a recent meta-analysis including 65 studies of CTO-PCI complications 34 suggested that CTO-PCI procedural MACE rates were lower than those reported for elective angioplasty in the NCDR 35. While under-reporting of MACE events in these 65 studies may not completely account for the low MACE rates, we intended to eliminate this possibility in OPEN CTO so that hybrid operators can more accurately inform their patients of the risks of the procedure.
Moreover, given the known variability in inter-physician assessments of coronary angiography 36, an angiographic core lab will review all angiograms to ensure consistent interpretation of lesion complexity, procedural success, and complications. To date, only one recent large registry of CTO-PCI procedural and clinical outcomes has included angiographic core lab analysis. Core lab validation of final TIMI flow and residual stenosis is critically important in accurately and reproducibly determining the success rate in CTO-PCI. We will also use an independent committee for clinical events adjudication to enhance the specificity of follow-up event characterization. We will perform follow-up through a centralized call center to ensure as complete a follow-up as possible of health status outcomes. To date, only one study has assessed 1-year health status outcomes using patient-reported outcome measures (PROMs). This study was limited by 30% loss to follow-up rates 29. Finally, we will utilize an experienced steering committee to carefully review and approve the scientific rigor of all analyses. Collectively, these steps will enable OPEN CTO to provide the most rigorously collected and contemporary information to date on CTO-PCI.
Defining the benefits of PCI has, in general, been limited by the predominant use of physician-ascertained angina with the Canadian Classification System of angina 30. Efforts to define the benefits of CTO-PCI using patient-reported health status instruments, such as the SAQ, have been scant, despite increasing advocacy for PROMs as a measure of cardiovascular health 37. The few studies that used PROMs have been limited by high loss to follow-up 29, a single-center design 29, and short-term follow-up 5. The OPEN CTO registry will include detailed assessments of angina (using SAQ), angina equivalents such as dyspnea (using the RDS), general physical health (using VR12), and the impact of CTO-PCI on patient outlook and depression (using the PHQ), all of which are potential benefits of CTO-PCI. Finally, the consistent use of the hybrid approach across these centers will enable more consistent translation of the OPEN CTO experience to other centers that seek to perform CTO-PCI.
By virtue of its systematic assessment of procedural complications and with the assurance of complete inclusion of patients and events through auditing, OPEN CTO will provide sufficient detail to allow a comprehensive description and analyses of predictors of adverse events. By comparing the observed adverse event rates in OPEN CTO with expected event rates for non-CTO-PCI, we should be poised to provide a clearer picture of the risks of CTO-PCI; in the future, these data can be used to fully inform potential patients of this therapeutic option. Finally, an accurate assessment of these outcomes and their causes is very important toward informing the sample size and treatment effect estimates of upcoming randomized-controlled trials in CTO-PCI.
An additional unique aspect of OPEN CTO is the prospective collection of economic data. Two previous reports have addressed the costs of CTO-PCI. One, done from a hospital perspective, described a positive contribution margin by a single, expert CTO-PCI program 38. Another, done from a societal perspective, used data from multiple registry sources, none of which included dedicated CTO operators using a single systematic approach, to develop a Markov model-based estimate of the incremental cost-effectiveness of CTO-PCI 39. A major goal of OPEN CTO is to accurately assess the costs of CTO-PCI using the contemporary hybrid approach. These data, together with the EQ5D-derived utility assessments, will support the development of an updated cost-effectiveness model based largely on empirical data.
OPEN CTO is a prospective real-world registry and not a randomized clinical trial. Any interpretation of the results of OPEN CTO must be made with the consideration that unaccounted confounding remains possible despite multiple statistical methods to minimize this possibility. In addition, as a real-world registry reflecting standard of care, we could not mandate the performance of noninvasive imaging studies, which limits our ability to evaluate ischemia and left ventricular function at baseline and follow-up. Although OPEN CTO will be performed by 12 operators with varying experience in CTO-PCI, these operators still represent a group of well-trained, high-volume operators. Thus, the results may not be generalizable to untrained and lower volume CTO operators
OPEN CTO will be the most comprehensive and rigorously collected dataset to date providing unique insights into the success, safety, a broad array of health status effects, and the costs of CTO-PCI using a reproducible technical approach to patients with these complex lesions.
Conflicts of interest
Dr Sapontis reports speaking fees and honoraria from Boston Scientific. Dr Marso reports speaking fees and honoraria from Boston Scientific and Abbott Vascular. Dr Cohen reports institutional research grant support from Boston Scientific, Abbott Vascular, and Medtronic and consulting fees from Medtronic and Abbott Vascular. Dr Lombardi reports speaking fees and honoraria from Boston Scientific, Abbott Vascular, and Abiomed, consultancy for Vascular Solutions, Abbott Vascular, Boston Scientific, Abiomed, and Roxwood Medical. He has Equity in Roxwood Medical and Bridgepoint Medical. His wife is an employee of Spectranetics. Dr Karmpaliotis reports speaking fees, honoraria, and consulting fees from Abbott Vascular, Boston Scientific, and Medtronic. Dr Nicholson reports speaking fees and honoraria from Boston Scientific and Abbott Vascular. Dr Pershad reports speaking fees and honoraria from Boston Scientific Medtronic, Asahi Intecc, Edwards Lifesciences, and Abiomed, and consultancy for Abiomed and Boston Scientific. Dr Wyman reports speaking fees, honoraria and consulting from Boston Scientific and Abbott Vascular. Dr Spaedy reports speaking fees and honoraria from Boston Scientific and Abbott Vascular. Dr Cook reports speaking fees and honoraria from Boston Scientific and Abbott Vascular. Dr Doshi reports speaking fees and consulting fees from Boston Scientific and Abbott Vascular, consulting fees from CSI, Medtronic, and Spectranetics, and research grants from Boston Scientific. Dr Federici reports honoraria from Boston Scientific. Dr Thompson is an employee of Boston Scientific, Inc. Dr Spertus reports research grants from Lilly, Gilead, and Abbott Vascular. He has served as a consultant for Novartis, Amgen, Regeneron, and United Healthcare. He owns the copyright to the SAQ, KCCQ, and PAQ, and has an equity interest in Health Outcomes Sciences. Dr Grantham reports speaking fees and honoraria from Boston Scientific, Abbott Vascular, and Asahi Intecc, institutional research grant support from Boston Scientific, institutional educational grant support from Abbott Vascular, Vascular Solutions, Boston Scientific, and Asahi Intecc, and part-time employment by Corindus Vascular Robotics. For the remaining authors there are no conflicts of interest.
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