Angina Severity, Depression, and Response to Percutaneous Revascularization in Patients With Chronic Total Occlusion of Coronary Arteries

Abstract: Objectives. This study sought to quantify depression rates in patients referred for percutaneous coronary intervention (PCI) for chronic total occlusion (CTO), assess its relationship to baseline angina symptoms, and compare angina improvement after CTO-PCI between depressed and non-depressed patients. Background. Depression is common among patients with chronic angina, and portends poor prognosis. CTOs are a common cause of angina. The relationships between angina, depression, and CTO intervention are unknown. Methods. We collected baseline and 30-day post-PCI data on angina (Seattle Angina Questionnaire [SAQ7]), dyspnea (Rose Dyspnea Scale [RDS]), and depression status (Patient Health Questionnaire [PHQ-2]) on 45 consecutive patients referred for CTO-PCI between October 2013 and October 2014. Results. Depression (PHQ-2 score ≥3) was present in 18/45 patients (40%) at baseline. Baseline SAQ7 Summary and SAQ7 Angina Frequency scores for depressed patients were 35.4 (range, 28.4-42.4) and 54.4 (range, 43.0-65.8), compared with 67.3 (range, 57.5-77.1) and 77.8 (range, 68.5-87.1) for non-depressed patients (P<.001 and P=.01, respectively). Following CTO-PCI, the mean improvement in SAQ7 Summary and SAQ7 Angina Frequency scores was 48.5 (range, 35.4-61.5) and 32.8 (range, 21.0-44.5) for patients with depression, compared with 16.5 (range, 5.87-27.2) and 12.6 (range, 3.0-22.2) for patients without depression (P<.001 and P=.01, respectively). Following PCI, the presence of depression was reduced (72% relative reduction vs baseline; P=.01). Conclusions. Depression identifies patients more limited by angina and more likely to respond to CTO-PCI compared with non-depressed patients. Depression screening may be indicated for patients with CTO, as 67% of CTO patients were not receiving treatment for depression.

J INVASIVE CARDIOL 2016;28(2):44-51. Epub 2015 October 15. 

Key words: coronary disease, stents, percutaneous coronary intervention, depression

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Chronic total occlusions (CTOs) of epicardial coronary arteries are a common angiographic finding among patients with angina and coronary artery disease (CAD). Recent studies have reported the prevalence of CTOs among patients with CAD to be between 18% and 31% among patients without prior coronary artery bypass grafting (CABG), and between 54% and 89% among patients with prior CABG.^1-4 With the development of more reliable methods for crossing CTO lesions (antegrade dissection/reentry and retrograde techniques), the rate of percutaneous coronary intervention (PCI) for CTO is growing, and procedural success is improving.^5-9 As these techniques are further developed, it will become increasingly important to identify clinical characteristics that prospectively identify CTO patients likely to derive the greatest symptom benefit from the procedure.

Multiple previous studies have established a strong relationship between symptoms of depression and CAD. Newly diagnosed depression has been linked to the risk of coronary events, and is more common among patients with refractory angina than patients with chronic stable angina in general.^10,11 Depression symptoms after CABG have been shown to predict a 65% greater risk of long-term mortality, and a 50% higher risk of atherosclerosis progression.^12,13 Moreover, in the PCI population, moderate to severe depression confers substantial risk for recurrent cardiac events (hazard ratio, 4.32; 95% confidence interval [CI], 1.35-13.88).¹⁴ Depression also relates to self-reported angina severity, with depressed patients reporting more angina and lower treatment satisfaction than non-depressed patients.¹⁵

However, the prevalence of depression and the relationship between depression and angina in CTO patients remains incompletely understood. In addition, little is known about the response in angina severity and depression symptoms to CTO-PCI. This study investigated the depression rate in CTO patients, the association between angina severity and depression prior to treatment, and the impact of PCI on self-reported angina and dyspnea symptoms and quality of life in patients with and without depression.

Methods

Study population and data sources. This study prospectively enrolled consecutive patients undergoing PCI of a native-vessel CTO at Massachusetts General Hospital (MGH) over a 1-year period from October 2013 to October 2014. Patients were eligible for CTO-PCI if they had symptoms refractory to medical therapy and ischemia was present on imaging. Patients were enrolled in the cohort prior to their procedure, and were followed regardless of procedural success. Data are presented for both the overall cohort and for those who had a successful PCI in a sensitivity analysis. Ethical approval from the Partners HealthCare institutional review board was given to collect data and complete this analysis.

This study utilized three primary sources of data. Patient demographics, comorbidities, cardiovascular medications, and procedural characteristics were obtained from an institutional database that collects detailed information on all patients undergoing cardiovascular procedures. Patient symptom data are routinely collected for patients undergoing pre- and postprocedure coronary angiography using a tablet-computer interface and are included in the electronic medical record. Antidepressant use at the time of CTO-PCI was also collected from the electronic medical record. 

Patient-reported outcomes. We collected several patient-reported outcomes based on validated survey instruments at baseline prior to PCI and 30 days after PCI. Depression was screened using the Patient Health Questionnaire 2 (PHQ-2). We used a cut-off of ≥3 to define depression in this population. Using this definition, this screening tool has been previously shown to predict the diagnosis of major depression with 74% sensitivity and 91% specificity in the primary care population.¹⁶ In the CAD population, this screening tool has a sensitivity of 39% and specificity of 92%.¹⁷ 

We also assessed angina using the summary scale and angina frequency scales of the short-form Seattle Angina Questionnaire (SAQ7-SS and SAQ7-AF, respectively).^18,19 The SAQ-7 is a seven-question instrument with three subscales and a summary scale. The scales are reported from 0 to 100, with 0 indicating the most severe symptoms and 100 indicating no symptoms. This measure has previously been shown to have high predictive and convergent validity, as well as excellent responsiveness to treatment with PCI, with a change in score of ≥10 points signifying a clinically meaningful change in angina status.^18,20 

Additional secondary outcome measures included the physical limitation and quality of life (SAQ7-PL, SAQ7-QOL) subscales of the short-form Seattle Angina Questionnaire, and the Rose Dyspnea Scale (RDS).^21-23 The RDS is a four-question instrument, with scores reported from 0 to 4 (with 0 indicating the most severe symptoms).

This project was part of a broader initiative to routinely collect patient-reported symptom severity in patients undergoing cardiac catheterization. In order to improve patient compliance and response rate, and to reduce administrative burden, short-form instruments were used. The short-form instruments correlate highly with the full-version instruments.^16,18,19

Additional data and potential confounders. Patient demographics collected include age, gender, race, and ethnicity. Multiple patient risk factors were also collected (Table 1). Preprocedure Canadian Cardiovascular Society (CCS) classification of angina severity and New York Heart Association (NYHA) classification of dyspnea severity were assessed by the treating cardiologists at the time of the procedure. If available, findings from stress echocardiography or stress myocardial perfusion imaging were recorded and characterized by the extent of ischemia into low-, medium-, and high-risk categories based on expected mortality of <1%, 1%-3%, and >3% per year, respectively.^24,25 Antianginal and antidepressant use before and after the procedure was also recorded. Coronary anatomy and details of the procedure were recorded (vessel and vessel diameter, occlusion length, primary crossing approach, number of stents, total stent length, and J-CTO score).^26,27

Statistical analysis. All analyses were performed with an intention-to-treat approach, with secondary analyses performed on the subset of patients who had successful PCI. Preprocedure and postprocedure values for all patient-reported outcomes were compared using paired t-tests for the entire cohort. Univariate comparisons of patient characteristics were made between depressed and non-depressed patients using contingency tables and Fisher’s exact tests or χ² tests for categorical variables and means and Student’s t-tests for continuous variables. 

In order to assess the relationship between baseline depression and baseline angina, we compared mean symptom scores of depressed vs non-depressed patients using t-tests. In addition, we assessed the correlation between baseline depression score (0-6) with symptom scores. 

To assess whether symptom changes after CTO-PCI were influenced by baseline depression, we calculated the change in SAQ-7 measures and RDS between baseline and 30 days after PCI, and compared these changes for depressed vs non-depressed patients using t-tests. We further performed multivariable linear regression to examine the association of depression with the change in symptom score for each outcome, adjusted for patient characteristics with univariate association with depression at P<.20. Baseline depression (primary predictor), age, gender, Caucasian race, number of antianginals, and history of diabetes were included in the final multivariate regression models. Statistical significance was determined at the P<.05 level with two-sided tests. Statistical analysis was performed using the JMP 11 Pro platform (SAS Institute) and SAS 9.3 x64 platform (SAS Institute).

Results

A total of 55 eligible patients were referred during the study period. Of these, 49 patients (89.1%) had a successful PCI procedure (defined as technical success with successful reperfusion of the target vessel with TIMI-3 flow).²⁸ One patient experienced a periprocedural myocardial infarction. Ten patients (18.2%) did not have responses captured (1 at the time of procedure, and 9 at follow-up), leaving a total of 45 patients in the analysis cohort (42 with successful PCI; the success rate in this cohort was 93.3%). Eighteen of these 45 patients (40.0%) screened positive for depression with PHQ-2 ≥3, indicating an impaired psychological state. In contrast, in a healthy population, the proportion of subjects with PHQ-2 diagnosis of depression is 4.7%.²⁹ The mean overall PHQ-2 score was 2.29 (95% CI, 1.64-2.93). 

Demographics and risk factors. There were few differences in patient demographics, comorbidities, clinical presentation, and preprocedural medical therapy (including antidepressant therapy) between depressed and non-depressed patients (Table 1). Depressed patients were younger (mean age 62.8 years [95% CI, 58.1-67.5 years] in the depressed group vs 68.0 years [95% CI, 64.2-71.8 years] in the non-depressed group; P=.04) and had higher CCS class (CCS III or IV in 94.4% of the depressed group vs 55.6% of the non-depressed group; P=.01). Overall, 71.1% of patients were on at least two antianginal medications (77.8% in the depressed group vs 66.7% in the non-depressed group; P=.51).

CTO procedural details. There were no significant differences between the depressed and non-depressed groups in terms of procedural characteristics. The right coronary artery (RCA) was the most frequent anatomic site for intervention in both groups, with a larger proportion of depressed patients undergoing RCA intervention (83.3% vs 50.0%; P=.07). The most common CTO-PCI approaches were antegrade wiring (39.1%) and retrograde PCI (37.0%), with similar proportions in both groups. J-CTO scores were similar in both groups (1.89 [95% CI, 1.37-2.41] in the depressed group vs 2.07 [95% CI, 1.65-2.50] in the non-depressed group; P=.58) (Table 2).

Baseline measures. Patients with depression reported significantly more severe symptoms across all measures than patients without depression. The mean baseline SAQ7-SS in the total cohort for patients with depression was 35.4 (95% CI, 28.4-42.4) compared with 67.3 (95% CI, 57.5-77.1) in patients without depression (P<.001). Depressed patients also reported more frequent angina symptoms at baseline, with mean SAQ7-AF of 54.4 (95% CI, 43.0-65.8) compared with 77.8 (95% CI, 68.5-87.10) in non-depressed patients (P=.01). Other baseline measures are reported in Supplementary Table 1.

There was a linear correlation between baseline PHQ-2 scores and all symptom severity measures at baseline. Among the SAQ7 scales, PHQ-2 was most highly correlated with the SAQ7-SS with R² of 0.279 (P<.001) and SAQ7-PL with R² of 0.264 (P<.001) (Figure 1). PHQ-2 was also correlated with RDS, with R² of 0.289 (P<.001). There was no correlation between extent of ischemia and baseline SAQ7 or RDS scores (P>.25 for all scales).

Postprocedure measures. The median duration of follow-up was 33 days (95% CI, 31-35 days), with a maximum of 63 days. There were significant improvements in all measures between the baseline and postprocedure measures overall (P<.001 for all pre-post comparisons). Postprocedure CTO-PCI measures and differences are noted in Supplementary Table 1. SAQ7-SS had a mean change of 29.3 (95% CI, 19.9-38.8), and SAQ7-AF had a mean change of 20.7 (95% CI, 12.7-28.6). The largest change was for the SAQ-QOL, with a mean difference of 33.0 (95% CI, 19.7-46.3). There were no significant differences between depressed and non-depressed patient measures at the time of follow-up, despite depressed patients having significantly worse baseline scores. 

Consistent with this observation, patients with depression had larger mean improvement in all angina measures than patients without depression (Supplementary Table 1). Depressed patients had mean improvements of 48.5 (95% CI, 35.4-61.5) and 32.8 (95% CI, 21.0-44.5) compared with 16.5 (95% CI, 5.87-27.2) and 12.6 (95% CI, 3.0-22.2) for non-depressed patients in the SAQ7-SS and SAQ7-AF, respectively (P<.001 and P=.01) (Figure 2), exceeding the accepted clinically significant SAQ7 score difference of 10 points. After adjustment for age, gender, Caucasian race, diabetes, and the number of antianginals, the effect of depression on improvement in symptoms remained statistically significant (P<.05 for all SAQ7 scales) (Supplementary Table 2). Improvement in RDS was non-significantly greater in depressed pateints compared with non-depressed patients, with scores of 1.83 (95% CI, 1.25-2.41) and 1.15 (95% CI, 0.68-1.62), respectively (P=.07). After adjustment in the same multivariate model, improvement in RDS was not significantly associated with depression.

Pre-PCI and post-PCI depression. There was a significant difference in the PHQ-2 based presence of depression before and after PCI. Five patients (11.1%) reported post-PCI depression in the overall cohort, compared with 18 patients (40%) before PCI (P=.01). This represents a 72% reduction in depression in this group of patients depressed at baseline. Only 1 patient who was not depressed at baseline reported depression at follow-up; interestingly, this patient did not have a successful procedure. Mean PHQ2 decreased from 2.23 (95% CI, 1.64-2.93) at baseline to 0.71 (95% CI, 0.28-1.14) post PCI (P=.04). 

Sensitivity analysis. A sensitivity analysis was also performed, limiting the analysis to the cohort of patients with successful CTO-PCI. Baseline measures in the successful PCI cohort were similar to the total cohort, with no significant differences at baseline between the successful and unsuccessful PCI cohorts (P>.40 for all SAQ7 and RDS scales). When limiting the analysis to only those patients who underwent successful PCI, depressed patients had mean improvements of 51.5 (95% CI, 42.2-60.8) and 34.7 (95% CI, 22.6-46.9) compared with 17.4 (95% CI, 4.4-30.5) and 13.2 (95% CI, 3.2-23.2) for non-depressed patients in the SAQ7-SS and SAQ7-AF, respectively (P<.001 and P=.01). The successful PCI group also had significantly more improvement in RDS in depressed vs non-depressed groups, with mean improvements of 2.0 (95% CI, 1.44-2.56) and 1.24 (95% CI, 0.78-1.70), respectively (P=.04). Rates in the successful PCI cohort showed a larger treatment effect on depression, with 17 patients (40.5%) depressed before the procedure, and 3 patients (7.1%) depressed after the procedure (P<.001). All patients who reported post-PCI depression were depressed at baseline. Mean PHQ2 scores in the successful PCI cohort decreased from 2.33 (95% CI, 1.81-2.85) at baseline to 0.52 (95% CI, 0.003-1.04) post PCI (P<.001). 

Discussion

This study demonstrates several important findings related to depressed patients undergoing CTO-PCI. First, the 40% rate of depression among patients with CTO in this study is similar to that reported among those with chronic stable angina in general, and is five-times higher than reported in the general population.^15,30 Second, depression in CTO patients is associated with significantly increased baseline angina severity compared with non-depressed patients, with a difference in SAQ7 scores of 30 points (where a clinically meaningful difference is 10 points). This SAQ7 score difference is two-three times more severe than prior studies of patients with chronic stable angina that investigated depressed and non-depressed patients.¹⁵ Third, and most importantly, after CTO-PCI, depressed patients derived a greater improvement in self-reported angina severity, physical limitation, and quality of life compared with non-depressed patients. Moreover, patients undergoing CTO-PCI reported fewer depression symptoms after PCI, and overall 72% reduction in the diagnosis of depression by the PHQ-2 instrument. Although extent of ischemia can impact angina severity, we did not observe an association between extent of ischemia on stress testing and symptom severity at baseline.

These findings have not been previously described and raise a number of important issues. The presence of significant depressive symptoms appears to demarcate more severe anginal symptoms and the greater potential for response to CTO-PCI treatment. It is unclear whether patients report more severe angina symptoms due to preexisting depression, or whether the depression symptoms are a reflection of chronic pain and disability. Patients with depression have also been found to have poorer rates of medication compliance, which could also contribute to the more severe baseline symptoms in the depressed group.^31-36 Our data suggest that depression symptoms may be, at least in part, a consequence of chronic angina and ischemia, given the significant improvement in rates of depression symptoms observed after CTO-PCI. As depression is linked to increased mortality in patients with cardiovascular disease, patients with CTO may be a population that requires greater effort to identify depressive symptoms, and initiate appropriate treatment for depression.^12,37 Only 33% of patients who screened positive for depression were on active pharmacological treatment for their depression (we were unable to assess the use of psychotherapeutic treatment).

Study limitations. Our study has several limitations. First, this is an observational study without randomization to treatment and non-treatment groups. It is therefore difficult to completely control for confounders, although based on the previously reported performance of the SAQ, we anticipate SAQ measurement stability over a 1-month period in the absence of intervention. We conducted all analyses on all patients referred for CTO-PCI, not only those with successful procedures, in order to mitigate selection bias. It is possible that improvement in symptoms may have been partially due to placebo effect or may have been achieved throughout intensification of medical therapy, although the effect of these factors would likely be present in both depressed and non-depressed patients and does not explain the greater improvement we observed in depressed patients. In addition, the improvements in angina we observed were very large, and 100% of patients were taking at least 1 antianginal medication at the time of PCI, with 71.1% on 2 or more. Second, the follow-up period of 30 days was relatively short, and it is unclear how durable the improvement in angina and depression will be after a longer follow-up period. Third, this represents the experience of only a single center with a limited number of patients. However, the study was sufficiently powered to detect the differences observed in patient-reported outcomes. Fourth, we used short-form instruments rather than the full instruments, which may perform differently.

Conclusion

Despite its limitations, our study highlights an important dimension of care for patients with angina and CTO. We believe it to be the first describing the high prevalence of depression in the CTO population, the linkage of depression with angina severity, and the observation that CTO patients experience significant improvement in angina and depression metrics after CTO-PCI. These data suggest a need for depression screening in CTO patients, and that depression may be associated with favorable response to treatment. Future multicenter studies are warranted to further validate these results.

Acknowledgments. The study authors thank the MGH Cardiac Catheterization Laboratory staff for assistance in administering the questionnaire. 

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From ¹Massachusetts General Hospital, ¹Edward P. Lawrence Center for Quality and Safety and ²Cardiology Division, Corrigan-Minehan Heart Center, Boston, Massachusetts.

Funding: The collection of patient-reported outcomes was funded by Partners Healthcare. The study was also supported by the Hassenfeld Scholars Program.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Jaffer reports personal fees from Boston Scientific and Abbott Vascular. Dr Yeh reports personal fees from Abbott Vascular, Gilead Sciences, and Boston Scientific. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted July 2, 2015, provisional acceptance given July 23, 2015, final version accepted July 30, 2015.

Address for correspondence: Robert W. Yeh, MD, MSc, GRB800, Cardiology Division, Massachusetts General Hospital, 55 Fruit St, Boston MA 02114. Email: ryeh@mgh.harvard.edu