Author + information
- Received September 17, 2018
- Revision received December 18, 2018
- Accepted December 26, 2018
- Published online April 1, 2019.
- Robert W. Yeh, MD, MSca,∗ (, )
- Hector Tamez, MD, MPHa,
- Eric A. Secemsky, MD, MSca,
- J. Aaron Grantham, MDb,
- James Sapontis, MBBChc,
- John A. Spertus, MD, MPHb,
- David J. Cohen, MD, MScb,
- William J. Nicholson, MDd,
- Kensey Gosch, MSb,
- Philip G. Jones, MSb,
- Linda R. Valsdottir, MSa,
- Jeffrey Bruckel, MD, MPHe,
- William L. Lombardi, MDf and
- Farouc A. Jaffer, MD, PhDg
- aRichard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Division of Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- bSaint Luke’s Mid America Heart Institute/UMKC, Kansas City, Missouri
- cMonashHeart, Melbourne, Victoria, Australia
- dYork Hospital, York, Pennsylvania
- eDivision of Cardiology, University of Rochester, Rochester, New York
- fDivision of Cardiology, University of Washington, Seattle, Washington
- gDivision of Cardiology, Massachusetts General Hospital, Boston, Massachusetts
- ↵∗Address for correspondence:
Dr. Robert W. Yeh, Richard A. and Susan F. Smith Center for Outcomes Research in Cardiology, Beth Israel Deaconess Medical Center, 375 Longwood Avenue, 4th floor, Boston, Massachusetts 02215.
Objectives This study sought to examine depression prevalence among chronic total occlusion (CTO) patients and compared symptom improvement among depressed and nondepressed patients after percutaneous coronary intervention (PCI).
Background Depression in cardiovascular patients is common, but its prevalence among CTO patients and its association with PCI response is understudied.
Methods Among 811 patients from the OPEN-CTO (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures) registry, we evaluated change in health status between baseline and 1-year post-PCI, as measured by the Seattle Angina Questionnaire (SAQ) and the Rose Dyspnea Score. Depression was defined using the Personal Health Questionnaire-8. The independent association between health status and depression following PCI was assessed using multivariable regression.
Results Among the 811 patients, 190 (23%) screened positive for major depression, of whom 6.3% were on antidepressant therapy at intervention. Depressed patients experienced more baseline angina, but by 1-year post-PCI they experienced greater improvements than nondepressed patients (change in SAQ Summary: 31.4 ± 22.4 vs. 24.2 ± 20.0; p < 0.001). After adjustment, baseline depressed patients had more improvement in health status (adjusted difference in SAQ Summary improvement, depressed vs. nondepressed: 5.48 ± 1.81; p = 0.003).
Conclusions Depression is common among CTO PCI patients, but few were treated with antidepressants at baseline. Depressed patients had more severe baseline angina and significant improvement in health status after PCI. (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion [OPEN-CTO]; NCT02026466)
Chronic total occlusion (CTO) of a coronary artery can cause debilitating symptoms, including refractory angina, dyspnea, and poorer quality of life. Although CTOs are technically more challenging to treat with percutaneous coronary intervention (PCI), recent improvements in dedicated services and algorithms have resulted in improved safety and technical success rates of CTO PCI (1). In observational studies, successful CTO PCI has been associated with sustained health status improvement, including reduction in symptoms of angina and dyspnea (2).
Depression is frequent in patients with both acute and chronic manifestations of ischemic heart disease and has a strong association with refractory angina (3–6). In addition, the presence of depression is related to recurrent cardiac events among those undergoing PCI (7). However, few studies have systematically characterized the prevalence of depression among patients undergoing elective PCI, including those undergoing complex procedures for CTO. Similarly, it is not known whether depression influences patient-reported symptoms and their improvement following CTO PCI revascularization. Given the often long-standing angina experienced by CTO patients and the technical difficulties and risks associated with CTO PCI, it is particularly important to identify how factors such as depression may impact outcomes following these procedures.
The OPEN-CTO (Outcomes, Patient Health Status, and Efficiency in Chronic Total Occlusion Hybrid Procedures) Registry is a multicenter registry that enrolled 1,000 consecutive patients undergoing CTO PCI and collected detailed patient-reported outcomes at baseline and follow-up. For this analysis, we aimed to determine: 1) the prevalence of depression among patients undergoing CTO PCI; 2) its association with angina-related health status before PCI; and 3) the change in angina after CTO PCI among those with and without significant depressive symptoms.
The OPEN-CTO Registry has been previously described (8). Briefly, this was an investigator-initiated, multicenter, single-arm registry including 12 high-volume CTO PCI centers in the United States. All patients scheduled for CTO PCI by a designated PCI operator were screened, and those patients ≥18 years of age, nonpregnant, and who agreed to participate in telephone follow-up were included. CTO was defined as a coronary artery lesion of 100% severity known to be occluded ≥3 months with a Thrombolysis In Myocardial Infarction flow of 0. The “hybrid approach” to CTO PCI was used for all procedures, involving a targeted combination of antegrade, retrograde, true luminal, and subintimal techniques to optimize procedural success (9). Written informed consent was obtained from every subject and the protocol was approved by the institutional review board of each participating site.
Study outcomes and variables
The primary exposure for this study was patient-reported depression status at the time of the index procedure, defined as a Personal Health Questionnaire Depression Scale (PHQ-8) score of ≥10 points. The PHQ-8 is a well-validated screening tool for depression comprised of 8 questions, with a score ranging from 0 to 24 (10).
The primary outcome for this analysis was the difference in change in angina-related health status as measured by 3 domains of the Seattle Angina Questionnaire (SAQ) (11) and the Rose Dyspnea Scale (RDS) (12) between baseline and 1 year post-PCI. We used an “intention-to-treat” analysis instead of success versus failure to minimize confounding by unmeasured variables related to failure. The outcomes are validated measures of angina and dyspnea, the principal manifestations of coronary CTO, and have been previously used to assess symptoms in the CTO population (2,13). The SAQ is a 19-item questionnaire assessing angina in multiple domains. For this study, we report: angina frequency, which quantifies the frequency of angina over the previous month; physical limitation, which assesses how activities of daily living are limited because of angina; and quality of life, which measures the extent to which a patient believes that angina limits his/her quality of life (11). The scores range from 0 to 100, with 100 representing perfect health status. The RDS is a 4-item questionnaire that assesses patient-reported shortness of breath, with scores ranging from 0 to 4 and lower scores representing less shortness of breath. These measures were assessed at baseline before PCI, and through telephone interviews by trained staff 1, 6, and 12 months after the procedure.
Sociodemographic and clinical characteristics were obtained from patients at baseline, and coronary angiography and procedural factors were collected by each participating site. Procedural angiograms were reviewed by a central angiographic core laboratory (Saint Luke’s Mid America Heart Institute, Kansas City, Missouri).
Clinical and procedural characteristics as well as health status scores were compared between patients with and without major depressive symptoms at baseline using chi-square or Student's t-tests as appropriate. The primary analysis compared the difference in the change in health status scores from baseline to 1 year post-PCI between depressed and nondepressed patients, using Student's t-tests to compare SAQ and RDS scores. Student's t-tests were also used to compare the difference in SAQ, RDS, and PHQ-8 scores between depressed and nondepressed patients at baseline and at 1 year, respectively. Unadjusted scores at baseline, 1 month, 6 months, and 1 year were plotted for both depressed and nondepressed patients to evaluate changes in health status over time.
To adjust for the differences in baseline characteristics between depressed and nondepressed patients, we proceeded to perform linear multivariable regression adjusting for demographics and comorbidities selected on the basis of clinical importance, which included: age, race, sex, body mass index, smoking status, significant untreated lesions, history of diabetes mellitus, myocardial infarction, coronary artery bypass grafting, PCI, chronic kidney disease, stroke/transient ischemic attack, and lung disease. Sensitivity analyses were performed using a repeated measures model including patients with missing 12-month SAQ and RDS scores to account for possible bias introduced by missing data (14).
Analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina). A p value <0.05 was considered statistically significant. This study was supported by an unrestricted grant from Boston Scientific Corporation to the study sponsor, Saint Luke’s Hospital of Kansas City. Boston Scientific relinquished all rights to serve on the steering committee or to approve the publication of any analyses.
Among 1,000 patients enrolled in the OPEN-CTO Registry, 965 had PHQ-8, SAQ, and RDS evaluations at baseline, and 811 had these scores available at 1 year follow-up. These 811 patients comprised the cohort for this study. Patients excluded due to missing scores were more likely to have diabetes mellitus (51.9% vs. 38.7%; p < 0.001), chronic kidney disease (20.6% vs. 11.8%; p = 0.001), congestive heart failure (29.1% vs. 21.5%; p = 0.024), and differences in baseline systolic function (p = 0.38) (Online Table 1).
Of 811 patients, 190 (23%) screened positive for major depression. Depressed patients were younger, more often women, and had a higher rate of most comorbidities including diabetes, chronic kidney disease, congestive heart failure, and lung disease (Table 1). Lesion complexity, as measured by the J-CTO Score (15), was similar for patients with and without depression (mean: 2.4 ± 1.3 vs. 2.3 ± 1.3; p = 0.47), as was the rate of procedural success (82.6% vs. 82.1%; p = 0.87). Notably, only 6.3% of depressed patients were on an antidepressant medication at the time of CTO PCI. At baseline, depressed patients had significantly greater angina than those without depression, with lower values on every domain of the SAQ (Table 2). Symptoms of dyspnea were also more severe among depressed patients, with higher scores on the RDS (3.0 ± 1.2 vs. 1.9 ± 1.5; p < 0.001).
Outcomes at 1 year after CTO PCI
One-year post-CTO PCI, patients diagnosed with depression at baseline experienced significantly greater improvements in all domains of the SAQ than patients without depression (Table 2). However, there remained a statistically significant difference in angina and dyspnea between depressed and nondepressed patients, with depressed patients exhibiting consistently worse health status than nondepressed patients (Table 2). Changes in RDS scores were similar between groups.
After adjustment for baseline demographics and comorbidities, baseline depression remained independently associated with greater improvement in all measures of the SAQ 1 year after PCI (Table 3). There was no association between baseline depression and change in RDS score.
Among the 190 patients with depression at baseline, 157 (82.6%) reverted to a nondepressed state 1 year following PCI, whereas 19 of 621 (2.3%) of patients without depression at baseline had new depression at 1 year of follow-up.
Among patients who had a successful CTO PCI procedure (n = 667; 82%), depressed patients experienced worse health status than nondepressed patients at baseline and 1 year post-procedure. Similar to the intention-to-treat primary analysis, this success versus failure analysis demonstrated that depressed patients had significantly greater improvement in health status than nondepressed patients on all domains of the SAQ, but not the RDS (Online Table 2).
Change in patient-reported outcomes over time
The greatest change in health status was achieved by both groups at 1 month of follow-up and was sustained at 6 months and 1 year (Figure 1). Despite achieving greater gains in SAQ scores following CTO PCI, patients with significant baseline depressive symptoms had overall worse SAQ scores at all time points than nondepressed patients (Figure 1).
Repeated measures analysis showed an average difference in change of the SAQ physical limitation of 12.18 points (95% confidence interval [CI]: 8.14 to 16.22), quality of life of 6.73 points (95% CI: 2.71 to 10.74), angina frequency of 6.54 points (95% CI: 2.56 to 10.51), and summary scores of 7.47 points (95% CI: 4.36 to 10.57) from baseline to 12 months when comparing depressed versus nondepressed patients. The RDS average difference in change from baseline to 12 months was −0.11 points (95% CI: −0.26 to 0.13) between depressed and nondepressed patients at baseline. An adjusted repeated measures analysis showed similar findings (Online Table 3).
In this analysis of the OPEN-CTO Registry, more than 1 in 5 patients with CTOs undergoing PCI were classified as depressed based on their responses to the PHQ-8. This exceeds the rate of depression found in the general population (16), but is consistent with elevated depression rates observed in patients with stable coronary heart disease and acute myocardial infarction. Among patients with coronary artery disease, depression occurs in 20% to 40% (6,17–19) and corresponds with worse outcomes and increased mortality (20,21), although limited data have been published about the prevalence and impact of depression on outcomes in the CTO population. In our study, depressed patients were infrequently on antidepressant therapy (6.3%). Although 3.2% of patients classified as nondepressed were taking antidepressants, we cannot determine whether they were being treated for depression versus another indication for therapy.
The association between depressive symptoms and the presence of CTO may have several explanations. Patients with chronic pain may manifest adverse psychological effects of long-term angina and dyspnea, leading to higher rates of depression. Ischemia has been associated with depression and patients having higher awareness to their anginal symptoms (22,23). Major depression may also decrease a patient’s ability to adapt to chronic pain. Additionally, the progressive reductions in function associated with chronic illness may cause depression, which is itself associated with additive functional impairment (24). It has also been shown that depressed patients have lower rates of physical activity and medication compliance, which could help explain the more severe baseline angina symptoms in this group (18,25–30).
Patients with baseline depression had worse symptoms of angina and dyspnea compared with those without depression, and they showed significantly greater improvement in angina-related health status 1 year post-PCI. However, depressed patients continued to have lower quality of life scores at 1 year compared with those patients with normal depression scores. These results are not adjusted for baseline angina and dyspnea and thus we need to consider possible attenuation of the magnitude of angina improvement after adjustment for baseline angina. Not surprisingly, after a clinically relevant improvement in angina and dyspnea in patients with depressive symptoms at baseline, 83% of depressed patients had reverted to nondepressed status 1 year following CTO PCI.
This study may provide additional motivation to screen for depression in patients who have a CTO, because untreated depression is associated with poorer health outcomes including reduced quality of life (5,6,31), recurrent events, and death (7,20). Furthermore, depression screening and treatment is likely to be of greater impact in CTO patients not undergoing PCI, because most depressed patients became nondepressed after CTO PCI. Depressed patients achieved greater benefit than nondepressed patients after adjustment for differences in baseline characteristics; and sustained 1-year improvements after CTO PCI with improvements in SAQ scores of 27 to 39, where gains of >10 points are considered clinically significant (11). This finding may indicate that CTO patients should be a target for more concerted depression screening and treatment along with interventional treatment to optimize their care and help them achieve greater symptom benefit. Whether more aggressive antidepression intervention and therapy may attenuate some of the differences observed between groups and their response to treatment needs further investigation.
First, the OPEN-CTO Registry is an observational study of patients who were scheduled to undergo PCI. As such, these findings may not be representative of all CTO patients, particularly for those who had CTO PCI was not performed. In addition, the observed associations between depression and health status may be related to unmeasured variables confounding the analysis. Furthermore, we did not penalize our results for multiple hypothesis testing, and all results should be considered exploratory in nature. A small subset of OPEN-CTO registry patients did not have SAQ data at 1 year and thus were not included in the primary analysis, which can introduce selection bias. However, the sensitivity analysis showed similar results suggesting that the bias was either very small or not present. Next, it is possible that improvement in symptoms could have in part been caused by placebo effect; regression to the mean; intensification of medical therapy; or in the case of improvement following failed PCI procedures, by improvements in coronary flow that did not result in complete revascularization. However, we would not expect these factors to differentially affect depressed and nondepressed patients. Lastly, the study was conducted at experienced CTO PCI centers with high rates of procedural success. As such, the improvements in symptoms observed for depressed and nondepressed patients after CTO PCI may be of greater magnitude compared with patients treated at centers with less experience.
Depression is common among patients undergoing CTO PCI, yet may be undertreated. These results indicate that patients with a CTO could benefit from enhanced screening for depression, because many patients may not be receiving appropriate diagnosis and treatment. Following CTO PCI, depressed patients experienced significant improvements in both health status and depressive symptoms. Depressed patients with CTO should be recognized as a group that may derive substantial benefit from PCI but may additionally require other therapies to achieve optimal health status.
WHAT IS KNOWN? Depression is known to impact patients with cardiovascular disease.
WHAT IS NEW? This study demonstrated that depression is common among patients with CTO, and that patients with depressive symptoms had more severe baseline angina and experienced significant improvement in health status after PCI.
WHAT IS NEXT? This study may indicate that CTO patients should be a target for more concerted depression screening and treatment along with interventional treatment to optimize their care and help them achieve greater symptom benefit. Whether more aggressive antidepression intervention and therapy may attenuate some of the differences observed between groups and their response to treatment needs further investigation.
This study was an investigator-initiated registry funded by Boston Scientific. Dr. Yeh has received research grant support from Abiomed, AstraZeneca, and Boston Scientific; has Scientific Advisory Board membership for Abbott Vascular, Boston Scientific, and Medtronic; and received consulting honoraria from Abbott Vascular, Asahi Intecc, Boston Scientific, and Teleflex. Dr. Grantham has received speaking fees and honoraria from Boston Scientific, Abbott Vascular, and Asahi Intecc; has received institutional research grant support from Boston Scientific; institutional educational grant support from Abbott Vascular, Vascular Solutions, Boston Scientific, and Asahi Intecc; and is a part-time employee of Corindus Vascular Robotics. Dr. Sapontis has received speaking fees and honoraria from Boston Scientific. Dr. Spertus has received research grants from Lilly, Novartis, and Abbott Vascular; served as a consultant for Novartis, Amgen, Bayer, and United Healthcare; owns the copyright to the Seattle Angina Questionnaire; and has an equity interest in Health Outcomes Sciences. Dr. Cohen has received institutional research grant support from Boston Scientific, Abbott Vascular, and Medtronic; and consulting fees from Medtronic. Dr. Nicholson has performed consulting/proctoring for Abbott Vascular, Boston Scientific, and Medtronic; and is on the Advisory Board of Abbott Vascular, Boston Scientific, and Medtronic. Dr. Bruckel has a consulting role with AvantGarde Health. Dr. Lombardi has received speaking fees and honoraria from Boston Scientific, Abbott Vascular, and Abiomed; consulted 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. Jaffer has received consulting fees from Abbott Vascular, Boston Scientific, Philips, and Siemens; and research grant funding from Siemens and Canon. 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
- percutaneous coronary intervention
- Personal Health Questionnaire Depression Scale
- Rose Dyspnea Scale
- Seattle Angina Questionnaire
- Received September 17, 2018.
- Revision received December 18, 2018.
- Accepted December 26, 2018.
- 2019 American College of Cardiology Foundation
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