Author + information
- Received February 15, 2018
- Revision received July 2, 2018
- Accepted July 24, 2018
- Published online November 19, 2018.
- Yevgeniy Khariton, MDa,
- Sophia Airhart, MDb,
- Adam C. Salisbury, MD, MSca,
- John A. Spertus, MD, MPHa,
- Kensey L. Gosch, MSa,
- J. Aaron Grantham, MDa,
- Dimitrios Karmpaliotis, MDc,
- Jeffrey W. Moses, MDc,
- William J. Nicholson, MDd,
- David J. Cohen, MD, MSca,
- William Lombardi, MDe,
- James Sapontis, MDf and
- James M. McCabe, MDe,∗ ()
- aSaint Luke’s Mid America Heart Institute and University of Missouri-Kansas City, Kansas City, Missouri
- bUniversity of Arizona Medical Center, Tucson, Arizona
- cColumbia University Medical Center, New York Presbyterian Hospital, New York, New York
- dYork Hospital, York, Pennsylvania
- eUniversity of Washington, Seattle, Washington
- fThe Avenue Hospital and Monash Medical Center, Windsor, Victoria, Australia
- ↵∗Address for correspondence:
Dr. James M. McCabe, University of Washington, Seattle, 1959 NE Pacific Street, Box 356422, Seattle, Washington.
Objectives This study sought to describe the association between chronic total occlusion (CTO) revascularization (CTO percutaneous coronary intervention [PCI]) and health status in patients with and without cardiomyopathy.
Background Prior PCI trials for cardiomyopathy have excluded CTO patients. Whether patients with reduced left ventricular ejection fraction (LVEF) receive similar health status benefit from CTO-PCI compared with patients with normal LVEF is unclear.
Methods We assessed health status change, using the Seattle Angina Questionnaire (SAQ) Summary, SAQ Angina Frequency, and Rose Dyspnea Scale scores, among patients undergoing successful CTO PCI in the OPEN-CTO (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion) Registry. Participants were classified by LVEF (normal, ≥50%; mild-moderate, 30% to 49%; and severe, <30%), with higher SAQ and lower Rose Dyspnea Scale scores indicating better health status. Differences in 1-year outcomes were compared using hierarchical multivariable regression.
Results Of 762 patients, 506 (66.4%), 193 (25.3%), and 63 (8.3%) had normal, mild-moderate, and severely reduced LVEF. SAQ Summary score improvements were observed in each group (27.1 ± 20.4, 26.7 ± 21.2, and 20.3 ± 18.1, respectively). Compared with patients with LVEF ≥50%, those with LVEF <30% had less improvement in SAQ Summary Score (−5.2 points; 95% confidence interval: −9.0 to −1.5; p = 0.01) and Rose Dyspnea Scale (+0.5 points; 95% confidence interval: 0.1 to 0.8; p = 0.01), with no difference in odds of angina (odds ratio: 1.3; 95% confidence interval: 0.6 to 3.0; p = 0.48). Health status improvement was similar between patients with LVEF ≥50% and LVEF 30% to 49%.
Conclusions Although health status improvement was less in patients with severely reduced LVEF compared with those with normal LVEF, each group experienced large health status improvements after CTO-PCI.
Chronic total occlusions (CTO) of the coronary arteries are detected in roughly 1 in 5 patients undergoing coronary angiography (1) and are frequent among those with ischemic cardiomyopathy (2). Although studies have suggested that patients who undergo successful recanalization of a CTO experience improved left ventricular function and survival when compared with those who have unsuccessful procedures (3,4), the impact of successful CTO recanalization on angina burden and quality of life (QoL) remains unclear.
CTO revascularization has been assigned a class IIa recommendation for reduction of angina relief in patients with medically refractory angina (5). However, patients with CTOs have traditionally been excluded from or underrepresented in trials of percutaneous revascularization in the setting of left ventricular dysfunction (6,7), and the impact of CTO percutaneous coronary intervention (PCI) on patients’ symptoms, function, and QoL is not well defined. To address this gap in knowledge, we used data from the OPEN-CTO (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures) registry to examine whether patients who underwent CTO-PCI experienced health status benefits independent of left ventricular ejection fraction (LVEF).
Study population and data collection
Details of the OPEN-CTO registry and its design have been published previously (8). Briefly, 1,000 patients were consecutively enrolled at 12 experienced CTO-PCI centers across the United States. All operators were required to have had at least 2 years’ experience in CTO revascularization. At each center, all patients scheduled for CTO-PCI by a designated hybrid CTO operator were consecutively screened. Of those screened, all patients ≥18 years of age that consented to participate with serial telephone interviews and had at least 1 CTO, as defined by Thrombolysis In Myocardial Infarction Score (9) antegrade flow of zero with a lesion that had been present for at 3 months, were enrolled. Non-English-speaking patients or those otherwise unable to participate in follow-up health assessments were excluded. For purposes of this analysis, patients with undocumented LVEF or missing baseline or 12-month health status information were excluded from the analytic cohort. Finally, only participants with successful CTO-PCI were analyzed, to better understand the relative merits of revascularization in this understudied scenario. After patients who did not have a successful procedure (n = 137), were missing LVEF (n = 77), or were missing health status data on enrollment or at 12 months (n = 24) were excluded, the final cohort was comprised of 762 patients (Figure 1).
QoL assessment was performed at 1, 6, and 12-month follow-up using disease-specific instruments (8). Baseline patient QoL information was collected on enrollment and subsequent assessments were acquired through telephone interviews performed by trained study personnel. Clinical information (sociodemographic and medical history) and the most recent LVEF assessment was abstracted from patients’ medical records using standardized case record forms at the time of enrollment. OPEN-CTO received local institutional review board approval from all participating centers, and informed consent was obtained from each patient.
Primary health status outcomes
We used the Seattle Angina Questionnaire (SAQ), a 19-item disease-specific health status measure, to assess coronary disease specific health status (10). The SAQ includes 5 domains: angina frequency, angina stability, physical limitation, QoL, and treatment satisfaction and the angina frequency, physical limitation, and QoL domains can be combined into an overall summary score (11). For this study, we focused on the Summary Score (SAQ-SS) and the Angina Frequency score (SAQ-AF), which were believed to provide the most complete capture of angina-specific health status. The SAQ-SS ranges from 0 to 100, with higher scores indicating less angina, better physical function, and higher QoL. The Angina Frequency score can also be categorized into daily (0 to 30), weekly (31 to 60), monthly (61 to 99), and no angina (100) symptoms (12). To explicitly measure dyspnea, we used the Rose Dyspnea Scale (RDS) that captures the level of activity with which patients report shortness of breath and ranges from 0 to 4 (where lower RDS scores indicate less dyspnea). It has also been shown to be sensitive to change in patients with ischemic heart disease (13).
Technical procedural success was defined as the positioning of a guidewire in the distal true lumen of the CTO, followed by angioplasty with residual Thrombolysis in Myocardial Infarction Score II or III flow, residual stenosis of 50% or less, and no significant occlusion of visualized side branches. Procedural adjudication was performed at a designated core laboratory.
Before angiography, assessment of LVEF was performed using 1 of several modalities, including echocardiography (41.6%), nuclear imaging (32.8%), angiography (23.0%), and magnetic resonance imaging (1.5%). Patients with documented LVEF were then categorized, using their most recent LVEF, into groups consistent with prior publications (14) as normal (≥50%), mild-moderate (30% to 49%), and severely reduced (<30%).
Baseline patient characteristics were compared across strata of LVEF using the linear trend test for continuous variables and the Mantel-Haenszel trend test for categorical variables. All results were reported as a mean ± standard deviation or frequencies and percentages for continuous and categorical data, respectively.
To quantify between-group differences in QoL benefits following CTO-PCI, we performed hierarchical multivariable linear or logistic regression, as appropriate, with LVEF as a categorical variable and with normal LVEF as the reference category. Health status scores for each domain, at 1 year, were the primary outcome. We adjusted for potential confounders based on prior literature (15–17), including baseline health status score, age, sex, body mass index, smoking status, history of diabetes mellitus, history of chronic obstructive lung disease, history of peripheral arterial disease, history of chronic kidney disease, history of coronary artery bypass grafting, and physiologically complete revascularization at the time of the baseline CTO-PCI procedure. An interaction between baseline health status and left ventricular function was also analyzed. Both SAQ-SS and RDS scores were treated as continuous variables, and SAQ-AF was defined as either no (100) or any (<100) reported angina.
We performed 2 sensitivity analyses, where we examined only those patients with single-vessel disease undergoing CTO-PCI, and patients with both successful and unsuccessful procedures. These were done to provide a clearer understanding of the role of the CTO when assessing health status change following CTO-PCI and overall procedure effectiveness in real-world practice, respectively. Similarly, an interaction between baseline health status and left ventricular function was also assessed.
Few patients were missing data for baseline covariates (<2%). Of 762 patients, 699 (91.7%) had LVEF documented within 12 months of CTO-PCI and 63 (8.3%) had documentation at ≥12 months or were missing the date at which LVEF was assessed. Because of low rates of missing data, no data imputation methods were used. A pre-set alpha level of 0.05 was considered statistically significant and a 5-point change in the SAQ-SS and SAQ-AF score was considered clinically meaningful. All statistical analyses were performed using SAS version 9.4 software (SAS Institute, Inc., Cary, North Carolina). Analyses were performed at Saint Luke’s Mid-America Heart Institute, and the lead authors take responsibility for guiding data analysis and the interpretation of the results.
Baseline patient characteristics, angiographic characteristics, and health status
The baseline characteristics of the primary analytic cohort are described in Table 1. Of the analysis sample, 506 (66.4%), 193 (25.3%), and 63 (8.3%) patients had normal, mild-moderate, and severely reduced LVEF, respectively. Patients with normal cardiac function were less likely to have had a documented history of myocardial infarction (p < 0.001), non-CTO revascularization (p = 0.002), chronic kidney disease (p = 0.001), and heart failure (p < 0.001) than those with mild-moderate and severely reduced function. There were no statistically significant differences in baseline SAQ-SS (p = 0.30), SAQ-AF (p = 0.11), and RDS (p = 0.92) scores among groups.
There were also no significant differences in total number of CTO lesions among patients with normal, mild-moderate, and severely reduced LVEF groups as assessed during angiography (p = 0.839). However, patients with normal cardiac function were less likely to have had 2 or 3 angiographically significant lesions (CTO and non-CTO) compared with those with mild-moderate and severely reduced function (p < 0.001).
Change in health status after CTO PCI
All patients undergoing successful CTO-PCI demonstrated large, clinically meaningful improvements in QoL scores (Table 2). Patients with normal cardiac function, on average, reported an unadjusted mean improvement of 27.1 ± 20.4 points in SAQ-SS, improvement of 23.4 ± 25.3 points in SAQ-AF, and improvement of −1.1 ± 1.5 points in RDS. Patients with mild-moderately reduced cardiac function experienced a mean improvement of 26.7 ± 21.2 points in SAQ-SS score, improvement of 24.6 ± 26.2 points in SAQ-AF score, and improvement of −1.0 ± 1.7 points in RDS score. Finally, patients with severely reduced left ventricular function demonstrated an improvement of 20.3 ± 18.1 points in SAQ-SS, improvement of 17.2 ± 29.8 points in SAQ-AF, and improvement of −0.8 ± 1.5 points in RDS score. Change in score between baseline and 12 months was similar among patients with normal, mild-moderate, and severely reduced LVEF for SAQ-AF (0.10) and RDS (0.11), but not for SAQ-SS (0.02).
In a final, parsimonious model, patients with mild-moderately reduced LVEF demonstrated similarly robust improvements in QoL compared with those with a normal LVEF following CTO-PCI. Accordingly, between the 2 cohorts, there were no statistically significant differences in SAQ-SS improvement (0.00-point higher; 95% confidence interval [CI]: −2.2 to 2.3; p = 0.99), odds of experiencing any angina (odds ratio: 0.8; 95% CI: 0.5 to 1.3; p = 0.37), and RDS improvement (0.1-point less improvement; 95% CI: −0.1 to 0.4; p = 0.22) (Figures 2 and 3⇓⇓).
Following adjustment, CTO-PCI still conveyed a clinically large improvement in QoL for patients with severely reduced LVEF, although the magnitude of the effect was slightly less robust for overall health status (SAQ-SS, −5.2; 95% CI: -9.0 to −1.5; p = 0.01) and dyspnea relief (RDS score, +0.5; 95% CI: 0.1 to 0.8; p = 0.01) compared with patients with a normal LVEF at baseline. However, there were no significant differences in presence of any angina (odds ratio: 1.3; 95% CI: 0.6 to 3.0; p = 0.48) between the best and worst LVEF cohorts (Figures 2 and 3). All interactions between baseline health status and LVEF categories were nonsignificant.
Health status benefit of CTO-PCI by LVEF in sensitivity analyses
Results of our sensitivity analyses were qualitatively consistent with our primary findings. When considering only those patients with CTOs (i.e., without other obstructive coronary disease), there were 448, 163, and 47 patients with normal, mild-moderately reduced, and severely reduced LVEF, respectively. Compared with patients with normal LVEF, those with severely reduced function had significantly less improvement in overall health status
(SAQ SS, −6.8; p = 0.001) and dyspnea resolution (RDS, +0.4; p = 0.04) without any difference in residual odds of angina presence (SAQ-AF odds ratio: 1.8; p = 0.17). However, those with mild-moderately reduced LVEF had no differences in score improvement when compared with patients with normal LVEF as measured by SAQ-SS (p = 0.55), SAQ-AF (p = 0.55), and RDS (p = 0.09) (Online Tables 1 to 3). Similar findings were observed across a combined cohort of patients with successful and unsuccessful CTO-PCI (Online Tables 4 to 6).
We studied change in patients’ health status from baseline to 12 months after successful CTO-PCI among patients with normal, mild-moderate, and severely reduced LVEF in the OPEN-CTO Registry. We found that regardless of baseline LVEF, there were large improvements in health status by 12 months after the index CTO-PCI; and patients with severely reduced LVEF had slightly less improvement in generic and disease-specific health status measures than those with normal cardiac function, despite similar improvements in angina relief. These findings were consistent across unadjusted and multivariable-adjusted analyses. This study of CTO-PCI among patients in a real-world setting represents an important contribution on the health status benefits of CTO-PCI and highlights the utility of this procedure.
The OPEN-CTO registry is the largest observational cohort of CTO revascularization to date that documents disease-specific health status before and after treatment, and its inclusion of patients with left ventricular systolic dysfunction (LVSD) contributes important insight to a literature comprised primarily of patients with normal cardiac function (18). Although the effects of CTO-PCI on change in LVEF and ventricular strain have been examined (19,20), the relationship between ventricular function and health status remains poorly defined (21,22). However, there is growing evidence describing the health status benefits of CTO-PCI among patients with reduced LVEF (18,19,23–27). Cardona et al. (19) prospectively studied the influence of CTO revascularization on health status outcomes in patients with evidence of CTO territorial viability and documented a beneficial reduction in angina. Although clinically significant, those conclusions were diminished by a small sample size, an unclear definition of “angina,” and lack of classification according to LVSD. Importantly, this complements the information obtained using the SAQ and RDS questionnaires in OPEN-CTO, which have proven to be responsive and sensitive to change in health status over time. Wijeysundera et al. (24) conducted a multicenter prospective analysis to compare the impact of PCI or surgical-guided CTO revascularization with standard-of-care medical treatment on change in SAQ-SS between baseline and 12 months. Patients treated with CTO revascularization, as compared with the medical therapy arm, experienced significant improvements in multiple SAQ domains at 12 months, but were not categorized by conventional gradations of cardiac dysfunction. Finally, the FACTOR trial investigators collected 1-month SAQ health status on patients referred for CTO-PCI and reported that the benefits of intervention applied primarily toward those with symptomatic angina (25). Although its results were limited by short-term data collection and exclusion of patients with LVEF <30%, our findings document 12-month health status benefits in patients with normal to severely reduced ventricular function.
Our finding that, despite a robust reduction in angina burden for all patients with CTO, patients with severely compromised cardiac function experienced less overall health status improvement at 1 year compared with those with normal cardiac function warrants further discussion. For one, it is clear that patients with LVSD and heart failure have other comorbidities that may impact QoL, such as anemia, atrial fibrillation, chronic kidney disease, chronic obstructive pulmonary disease, and depression (28–30). It is also possible that this difference in improvement reflects residual severe cardiomyopathy, and that residual cardiomyopathy results in ongoing dyspnea symptoms and reduced functional capacity that may be difficult to parse out from angina as a “dyspnea equivalent” when using generic health instruments, such as the RDS. To that end, this might explain why there were no significant differences in the magnitude of improvement in SAQ-AF domain scores across groups, as opposed to differences in overall health status benefit. Third, it is noteworthy that viability testing was performed in only 38.1% of patients with severely reduced LVEF and those patients had less viability (and, perhaps, less potential for health status improvement) in the CTO territory (87.5%) compared with those with mild-moderate (89.5%) and normal (100%) LVEF, albeit without a consistent viability testing strategy. Finally, it is important to emphasize that despite a smaller temporal health status benefit in patients with reduced, compared with normal, LVEF, this between-group difference is overwhelmed by large health status benefits observed across all LVEF groups.
Our findings are limited by the observational nature of this registry, and residual or unmeasured confounding cannot be excluded. Although there is always a possibility of confounding in observational studies, the finding of similar benefits across a range of LVEF categories suggests that successful CTO-PCI can improve health status regardless of patients’ baseline LVEF. Second, this study did not address major adverse cardiac events or mortality. Although improving patients’ health status is one of multiple primary goals of treatment with CTO-PCI, these important outcomes should be evaluated in future studies of the impact of CTO-PCI on outcomes in patients with LVSD. Third, OPEN-CTO was an observational study of patients selected for management with PCI. Without a comparison group of patients treated with surgery or medical therapy alone (and exclusion of those with an unsuccessful procedure), the incremental benefit of CTO-PCI compared with these alternative management strategies cannot be defined. Although this comparison is important and warrants further evaluation in future trials, given recent randomized trial observations of incremental SAQ improvement in patients treated with optimal medical therapy, alone (31), this was not a goal of the current analysis or the OPEN-CTO study. Fourth, although patients with both low-risk and intermediate-to-high-risk findings on stress testing may experience health status benefit from CTO-PCI (27), viability testing was performed in less than one-half of patients within each LVEF category. Finally, follow-up echocardiogram data were not collected in OPEN-CTO. Accordingly, we were unable to measure the incremental change in LVEF following CTO-PCI, and it is unknown whether there was greater symptomatic benefit in patients with improved ventricular function.
The incidence of a CTO in patients with angina poses a clinical treatment dilemma to physicians whose patients’ symptoms are refractory to medical therapy. Our findings suggest that, although patients with LVEF <30% have less overall health status improvement at 1 year compared with those with normal cardiac function, patients may experience large, sustained benefits in angina symptom burden, dyspnea, and overall QoL following CTO-PCI, regardless of LVEF.
WHAT IS KNOWN?: Prior studies have shown that patients undergoing successful CTO revascularization experience improved left ventricular function and survival, but the impact of successful CTO-PCI on long-term angina burden and quality of life in patients is unclear.
WHAT IS NEW?: We found that patients experience large, sustained improvements in angina symptom burden, dyspnea, and overall quality of life following CTO-PCI across the spectrum of baseline ventricular function.
WHAT IS NEXT?: Future studies are needed to confirm the effects of this procedure on long-term health status in patients with and without LVSD.
Funded by Saint Luke’s Hospital of Kansas City, with Investigator Initiated Research Grant from Boston Scientific Corporation. Dr. Khariton is supported by the National Heart, Lung, and Blood Institutes of Health under Aware Number T32HL110837; the content is solely the responsibility of the author and does not necessarily represent the official views of the National Institutes of Health. Dr. Salisbury has received institutional grant support from Boston Scientific and Gilead; speaking fees and honoraria from Boston Scientific and Abiomed; and consulting fees from Medtronic. Dr. Spertus has received research grants from Lilly, Gilead, and Abbott Vascular; served as a consultant for Novartis, Amgen, Regeneron, and United Healthcare; owns the copyright to the Seattle Angina Questionnaire, Kansas City Cardiomyopathy Questionnaire and Peripheral Artery Questionnaire; and has an equity interest in Health Outcomes Sciences. Dr. Grantham has received 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. Dr. Karmpaliotis has received speaking fees, honoraria, and consulting fees from Abbott Vascular, Boston Scientific, and Medtronic. Dr. Nicholson is a consultant and on the Advisory Board for Boston Scientific, Medtronic, and Abbott Vascular. Dr. Cohen has received institutional research grant support from Boston Scientific, Abbott Vascular, and Medtronic; and consulting fees from Medtronic and Abbott Vascular. Dr. Lombardi has received speaking fees and honoraria from Boston Scientific, Abbott Vascular, and Abiomed; consultancy for Vascular Solutions, Abbott Vascular, Boston Scientific, Abiomed, and Roxwood Medical; has equity in Roxwood Medical and Bridgepoint Medical; and his wife is an employee of Spectranetics. Dr. Sapontis has received speaking fees and honoraria from Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- confidence interval
- chronic total occlusion
- left ventricular ejection fraction
- left ventricular systolic dysfunction
- percutaneous coronary intervention
- quality of life
- Rose Dyspnea Scale
- Seattle Angina Questionnaire
- Seattle Angina Questionnaire Angina Frequency score
- Seattle Angina Questionnaire Summary Score
- Received February 15, 2018.
- Revision received July 2, 2018.
- Accepted July 24, 2018.
- Tajstra M.,
- Pyka L.,
- Gorol J.,
- et al.
- Jones D.A.,
- Weerackody R.,
- Rathod K.,
- et al.
- Olivari Z.,
- Rubartelli P.,
- Piscione F.,
- et al.
- Sapontis J.,
- Marso S.P.,
- Cohen D.J.,
- et al.
- Kern M.,
- Moore J.,
- Aguirre F.,
- et al.
- Spertus J.,
- Winder J.A.,
- Dewhurst T.A.,
- et al.
- Chan P.S.,
- Jones P.G.,
- Arnold S.A.,
- Spertus J.A.
- Arnold S.V.,
- Grodzinsky A.,
- Gosch K.L.,
- et al.
- Sajobi T.T.,
- Wang M.,
- Awosoga O.,
- et al.
- Norris C.M.,
- Spertus J.A.,
- Jensen L.,
- et al.
- Cardona M.,
- Martin V.,
- Prat-Gonzalez S.,
- et al.
- Staniute M.,
- Vaskelyte J.,
- Rumbinaite E.,
- et al.
- Grantham J.A.,
- Jones P.G.,
- Cannon L.,
- Spertus J.A.
- Qintar M.,
- Grantham J.A.,
- Sapontis J.,
- et al.
- Salisbury A.C.,
- Sapontis J.,
- Saxon J.T.,
- et al.
- Yancy C.W.,
- Jessup M.,
- Bozkurt B.,
- et al.
- RuDusky B.M.
- ↵Werner GS. A randomized multicentre trial to evaluate the utilization of revascularization or optimal medical therapy for the treatment of chronic total coronary occlusions (EUROCTO-Trial). Analysis presented at: EuroPCR 2017; May 18, 2017; Paris, France.