Trajectories of Anxiety and Depression are Predictive of Physical Health-Related Quality of Life, Mortality, and Hospital Admission at 1-Year among Patients with Heart Failure Lynn P. Roser, PhD candidate, MSN, RN1,, Abdullah S. Alhurani, PhD candidate, MSN, MBA, RN1,2, Christopher S. Lee, PhD, RN, FAHA, FAAN3, Terry A. Lennie, PhD, RN, FAHA, FAAN1, Martha Biddle, PhD, RN, APRN, CCNS 1,Susan Frazier, PhD, RN, FAHA1, Stephen Fleming, PhD4, Debra A. Moser, PhD, FAAN1 1. University of Kentucky, College of Nursing, Lexington, KY 2. University of Jordan, Amman, Jordan 3. Oregon Health & Science University, School of Nursing Portland Campus, Portland, OR 4. University of Kentucky, College of Public Health, Lexington, KY

Acknowledgements: This work was supported by: The National Institutes of Health and the National Heart Lung and Blood Institute, 1R01HL083176 The National Institutes of Health and the National Institute of Nursing Research, R01 NR008567 The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, the National Heart Lung and Blood Institute, or the National Institute of Nursing Research. Financial sponsors played no role in the design, execution, analysis, and interpretation of data or writing of the study.

Background and Objective: Depression and anxiety symptoms influence health outcomes such as quality of life, hospital readmission, and mortality in patients with HF. However, little is known about the trajectories of these negative emotional states and how they may change and influence health outcomes over time. The primary aim of this study was to describe unique trajectories of depression and anxiety symptoms from baseline to 12-months and determine whether these trajectories were predictive of subsequent physical health-related quality of life (P-HRQOL) and event-free survival over the course of one-year among patients with HF.

Methods: Secondary analyses of 597 patients enrolled the Heart Failure Quality of Life Trialists Collaborative from eight sites in the United States with complete data on variables of interest. Settings for recruitment of participants included community hospitals, tertiary care centers, a federal health care system, and outpatient clinics that included both specialty and general practice clinics. Inclusion criteria were similar at all sites: 1) diagnosis of HF documented in the medical record by a physician provider; 2) community-dwelling; 3) free of major cognitive impairment; 4) free of major life-threatening comorbidities expected to result in death within 12 months; and 5) not on a cardiac transplant waiting list. The study was conducted based on the principles outlined in the Declaration of Helsinki and Institutional Review Board approval was obtained from all participating research sites.

Measures: Variable Instrument Description Score Range *Depression Patient Health Questionnaire-9 (PHQ-9) Questionnaire; 9 items: patients asked to rate how often they have been bothered by the identified symptoms over the previous two weeks on a scale from 0 (not at all) to 3 (nearly every day). 0-27; higher scores = higher level of symptoms of depression *Anxiety Brief Symptom Inventory Anxiety Subscale Questionnaire; 6 items; patients asked to rate each item describing anxiety symptoms on a 5-point scale from 0 (not at all) to 4 (extremely); 0-4, higher scores indicating higher levels of anxiety. *Physical Health-Related Quality of Life (P-HRQOL) Minnesota Living with HF Physical Subscale Questionnaire; 8-item subscale; patients asked to rank how HF has impacted the physical aspects of their lives such as activities of daily living, ability to work, ability to sleep and rest, enjoyment of leisure time. 0 to 45; higher scores indicate worse perception of physical related quality of life. *Well documented reliability and validity among patients with HF; collected at baseline, 3-months, and 12 -months

Measures (cont’d): Variable Description How Information Collected Event-Free Survival Time to first cardiac related hospitalization or all cause death Interview with patient and family, review of medical records Demographic Age, sex, race/ethnicity, marital status, whether the patient lives alone, educational level, and time since diagnosis of HF. Questionnaire at baseline Clinical New York Heart Association (NYHA) functional classification, most recent ejection fraction, body mass index (BMI), and prescribed medications (beta-blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blocker Patient questionnaire and interview at baseline

Analysis: Data were analyzed using SPSS software, version 22.0 (SPSS Inc., Chicago, IL) and Mplus v. 6.0 (Muthén & Muthén, Los Angeles, CA). Descriptive statistics, including mean, standard deviation and frequency distribution, and proportions were used to describe sample characteristics. Latent growth mixture modeling (GMM) was used to identify distinct trajectories of change in depression and anxiety. GMM is an approach to modeling that identifies distinct trajectories of change that vary around different means, have unique estimates of variance and homogenous within-trajectory growth. Based on conditional probabilities and not absolute certainty, cases are assigned to the “most likely” trajectory or pattern of change over time.

Results: The mean age (n=597) was 64 years. Approximately 62% were male and 55% had Class II heart failure. Three trajectories of depression and three trajectories of anxiety were identified (entropy = 0.919) based on baseline, 3-month, and 12-month scores. Changes in depressive symptoms were categorized as getting better (81.1%), bad and getting slightly worse (13.9%), and bad and getting much worse (5.0%). Changes in anxiety symptoms over 12 months were categorized as getting better (66.7%), stable with slight decline (22.1%), and getting much worse (11.2%).

Results: Linear Regression of Depression Trajectories Associated with P-HRQOL Trajectory 2 (β 11.6, 95% CI: 9.10-14.10; p<0.001 Trajectory 3 (B 15.6; 95% CI: 11.60-19.70; p<0.001) Overall Model (Adjusted R2 = 0.17, F= 63.6; P<0.001)

Results: Linear Regression of Anxiety Trajectories Associated with P-HRQOL Trajectory 2 (β 12.0±.0.9; 95% CI: 10.14-13.95; p<0.001) Trajectory 3 (β 18.7;±1.3; 95% CI: 16.16-21.16; p<0.001) Overall Model (Adjusted R2 = 0.34, F= 155; P<0.001)

Results: Depression Trajectories Associated with Event-Free Survival

Results: Anxiety Trajectories Associated with Event-Free Survival

Results: Adjusted Cox Proportional Hazards Regression Model of Depression and Anxiety Trajectories Associated with Event-Free Survival Predictor Variable Hazard Ratio 95% CI p Depression Trajectories Trajectory II compared to Trajectory I 2.17 1.45 – 3.26 <0.001 Trajectory III compared to Trajectory I 1.83 0.91 – 3.68 0.088 Anxiety Trajectories 1.12 0.74 – 1.69 0.581 2.18 1.38 – 3.45 0.001 Final Depression Model Overall Model (χ2 = 57.31, df. = 14; p <0.001) Final Model Overall Model (χ2 = 53.43, df. = 14; p <0.001) After controlling for age, gender, marital status , NYHA, LVEF, use of ACE Inhibitors , BMI, total comorbidities

Conclusion: We identified three distinct trajectories of changes in depression and three distinct trajectories of changes in anxiety, some of which were predictive of 1-year cardiac event-free survival and P-HRQOL. Research is needed to determine if targeting depression and anxiety improves these health outcomes.