Depression Screening RCT in ACS Patients: Quality of Life and Cost Outcomes
Phase: NA
Conditions: Acute Coronary Syndrome, Depressive Symptoms
Sponsor: Columbia University

 
 
 
Comparison of Depression Identification  
after Acute Coronary Syndrome:  
Quality of Life and Cost Outcomes 
ClinicalTrials.gov: NCT01993017 
 
 
 
 
 
 
 
 
Study Protocol 
 
 
 
 
 
 
 
 
 
 
Version 6 
Last updated 7/20/2021 
 

 
 
2 
Table of Contents 
 
Protocol Amendments………………………………………………………………………..…4 
Administrative Information ................................................................................................ 5 
Title Registration Data ................................................................................................... 5 
Roles and Responsibilities ............................................................................................... 7 
Project PI: ...................................................................................................................... 7 
Site PIs: ......................................................................................................................... 7 
Co-Investigators: ........................................................................................................... 8 
Site Personnel ............................................................................................................. 11 
Committees ................................................................................................................. 11 
Introduction ..................................................................................................................... 13 
Background and Rationale .......................................................................................... 13 
Objectives/Hypothesis ................................................................................................. 13 
Trial Design ................................................................................................................. 14 
Methods .......................................................................................................................... 15 
Participant, Interventions and Outcomes .................................................................... 15 
Study Setting: Coordinating Center ......................................................................... 15 
Study Setting: Recruitment Sites ............................................................................. 15 
Detailed Eligibility Criteria ........................................................................................ 17 
Interventions ............................................................................................................ 18 
Outcomes ................................................................................................................. 19 
Participant Timeline ................................................................................................. 21 
Sample Size ............................................................................................................. 21 
Recruitment .............................................................................................................. 22 
Assignment of Interventions ........................................................................................ 23 
Sequence generation ............................................................................................... 23 
Concealment Mechanism ........................................................................................ 23 
Implementation ........................................................................................................ 23 
Blinding .................................................................................................................... 23 
Data Collection, Management and Analysis ............................................................... 24 
Data Collection Methods .......................................................................................... 24 
Data Management ................................................................................................... 24 
Statistical Methods ................................................................................................... 25 
Data Monitoring ........................................................................................................... 28 

 
 
3 
Harms ...................................................................................................................... 28 
Auditing .................................................................................................................... 30 
Ethics and Dissemination ............................................................................................... 31 
Research Ethics Approval ........................................................................................... 31 
Protocol Amendments ................................................................................................. 31 
Informed Consent ........................................................................................................ 31 
Confidentiality .............................................................................................................. 32 
Declaration of Interests ............................................................................................... 32 
Access to data ............................................................................................................. 32 
Post-trial care .............................................................................................................. 32 
Dissemination policy ................................................................................................... 32 
 
 
 
 
 
 
 
 
 
 
   

4 
 
Protocol Amendments 
Summary of changes  
Affected section 
Summary of Revisions 
Made 
Rationale 
Study setting: 
recruitment sites 
Duke University ended 
recruitment June 2015  
• Insufficient patients were 
being enrolled from the Duke 
site 
Study setting: 
recruitment sites 
Columbia University Irving 
Medical Center was added as 
a recruitment site and 
Nathalie Moise assumed the 
role of Site PI for Columbia, 
July 2016  
• To achieve study accrual 
milestones 
• To increase the diversity of 
the study population to be 
inclusive of a greater 
proportion of ethnically 
diverse patients. 
Eligibility 
Spanish speakers became 
eligible for inclusion at the 
Columbia site, July 2016 
• There were substantial 
numbers of Spanish-speaking 
Hispanic patients at the 
Columbia site, necessitating 
their inclusion and 
broadening generalizability of 
study findings. 
Sponsor/collaborators Ian Kronish assumed the role 
of Principal Investigator from 
Karina Davidson, July 2017. 
• Dr. Davidson had assumed 
other responsibilities  
Eligibility 
Eligibility criteria were 
clarified to state that patients 
were eligible if they had an 
acute coronary syndrome 
from 2-12 months, July 2017 
• This was erroneously entered 
as 2-6 months on initial 
clinicaltrials.gov submission.  
Outcome measures 
Cost of health care utilization 
was moved from being listed 
as a co-primary outcome to a 
secondary outcome on 
Clinicaltrials.gov, October 
2017. 
• Cost of health care utilization 
was erroneously listed as a 
co-primary outcome from the 
outset. This was verified 
based upon review of the 
study protocol and grant 
submission. The DSMB 
approved this change, and 
the change was made while 
study data was still blinded. 
 
 
 

5 
 
Administrative Information 
Title Registration Data 
 
Scientific Title:  
Depression Screening RCT in ACS patients: Quality of Life 
and Cost Outcomes (Acronym: CODIACS QoL) 
 
Public Title:     
Comparison of Depression Identification after Acute 
Coronary Syndrome 
 
Trial Registration:   
ClinicalTrials.gov: NCT01993017 
 
Secondary Identifiers:  
Columbia University: IRB AAAK9253  
 
 
                
Duke Clinical Research Institute 
 
 
 
 
Health Partners Institute for Education and Research 
 
 
 
Kaiser Permanente Northwest – Center for Health Research 
 
 
   
 
 
 
 
Funding Agency:       
NHLBI  
Application Number: 1 R01 HL114924-01A1 
 
Primary Sponsor:  
Columbia University 
 
Collaborators: 
 
Duke Clinical Research Institute  
                                           Health Partners Institute for Education and Research 
 
 
 
 
Kaiser Permanente Northwest – Center for Health Research  
 
 
Contact for Public Queries: 
 
Joan Duer-Hefele, RN, MA, CCRC 
 
 
 
 
jd2171@cumc.columbia.edu 
 
 
 
 
Center for Behavioral Cardiovascular Health 
 
 
 
 
Columbia University Irving Medical Center 
 
 
 
 
622 West 168th Street, PH9-316 
 
 
 
 
New York, NY 10032 
 
 
 
 
212.342.4507 
 
Contact for Scientific Queries: 
Dr. Ian M. Kronish, Principal Investigator 
Florence Irving Associate Professor of Medicine 
Associate Director, Center for Behavioral Cardiovascular 
Health 
Department of Medicine 
 
 
 
 
Columbia University Irving Medical Center 
 
 
 
 
622 West 168th Street, PH9-311 
 
 
 
 
New York, NY 10032 
212.342.4486 
 
 
 
 
ik2293@columbia.edu 
 

6 
 
Countries of Recruitment: USA only 
 
Health Condition(s) or problem(s) studied: Acute Coronary Syndrome 
 
 
 
 
 
                   Depressive symptoms 
 
 
 
 
 
 
        Health care utilization 
 
Interventions: Randomization to no depressive symptom screening (No Screen), 
depressive symptom screening with physician notification of elevated depressive 
symptoms (Screen & Notify), or depressive symptom screening and participant-selected 
treatment for those with elevated depressive symptom levels: pharmacologic 
(sertraline), behavioral (Cognitive Behavioral Therapy), a combination of both treatment 
modalities or neither (Screen, Notify & Treat). 
 
Key Inclusion and Exclusion Criteria*:   
 
Inclusion criteria: 
English or Spanish†-speaking participants  
Documented ACS within the past 2-12 months   
Age 21 and older 
Has access to phone or computer 
 
Exclusion Criteria: 
Unable to speak English  
Less than 21 years of age 
Terminal illness (life expectancy <1 year as determined by physician/medical record)  
Psychiatric exclusions: dementia, history of bipolar disorder, psychosis, major 
depression,  
  suicide attempt or self-inflicted injuries, current alcohol or substance abuse, and/or 
currently    
  receiving depression treatment.  
 
*fully defined in the ‘Eligibility Criteria Section’ 
†Spanish-speaking participants recruited from Columbia-site,only 
 
Study Type: 3-arm parallel group Randomized Controlled Trial 
 
Date of First Enrollment:    February 6, 2014 (Kaiser site) 
Target Sample Size:  1500 enrollees 
 
Recruitment Status:  Completed recruitment  
Primary Outcomes: To examine the benefits and costs of the AHA’s advisory for 
depression screen and treatment of post-ACS patients.    
 
Key Secondary Outcomes: Cost/Health Care Utilization 
 
MOP Version:  6 (Last updated  
 
Funding:  NHLBI R01 HL114924-01A1 

7 
 
Roles and Responsibilities 
Project PI: 
Dr. Ian M. Kronish, Associate Professor of Medicine, and the Associate Director of the 
Center for Behavioral Cardiovascular Health at Columbia University assumed the role of 
sole-PI in 2017. The project was initially led by Dr. Karina Davidson. Dr. Kronish had 
been the Columbia site-PI since 2015, became MPI with Dr. Davidson in 2016 prior to 
becoming sole-PI. Dr. Kronish’s main role in this project will be to lead this 
interdisciplinary team in the operational conduct of this trial, including supervision and 
quality control for all staff, ensuring timelines are met, and problem-solving barriers to 
successful study management. He will also contribute to the dissemination of all results, 
and ensure that co investigators and collaborators have the opportunity to contribute to 
these dissemination efforts.  Dr. Kronish’s responsibilities include: 
• Overseeing and coordinating all clinical components and training for the trial, 
including 
implementation, administration, supervision of research staff, communication 
and coordination with the three sites and all budgetary expenditures 
• Chairing telephone meetings of the Steering Committee, which will plan and 
implement all study policies and procedures, including interfacing with the Data 
Safety and Monitoring Board 
• Supervising the clinical coordinating Center personnel 
• Coordinating the preparation of all reports, data sharing documents, meeting 
abstracts, presentations and manuscripts for publication, and the release of the 
final data set (in collaboration with Dr. Ken Cheung and Site Investigators). 
• Serving as the liaison to the National Heart, Lung and Blood Institute. 
 
Dr. Kronish is trained in internal medicine, is past director of a primary care-based 
mental health collaborative care depression program, and is experienced at leading 
RCTs relevant to behavioral medicine, and thus is well-qualified to direct this multi-site 
RCT.  
Site PIs: 
 
Karen Margolis, MD from HealthPartners has participated for many years in large, 
multi-center randomized trials studying cardiovascular disease, including landmark 
studies such as ALLHAT, ACCORD, and the Women’s Health Initiative. She has 
intimate knowledge of the methods for recruitment and retention of a trial cohort, as well 
as how to maintain scrupulous attention to carrying out pharmacological and behavioral 
interventions according to a study protocol. Dr. Margolis has considerable experience 
with using electronic data to appropriately target and cost effectively recruit participants 
for a wide variety of clinical trials. In her role as site PI, Dr. Margolis will oversee all 
aspects of the successful implementation of the study. 
 
Rowena Dolor, MD has been the Director of the Duke Primary Care Research 
Network (PCRN) since 1997, and has participated in over 70 trials and studies on 
hypertension, diabetes, depression, anticoagulation, hyperlipidemia, obesity, asthma, 
otitis media, and vaccines. She works closely with her sites to ensure that proposed 
trials (a) answer an important question aimed towards improving patient care and 
clinical outcomes (b) are designed to minimize the burden on practice staff to participate 

8 
 
in the research study and does not interfere with clinic workflow, and (c) results are 
disseminated back to the practices at the end of the project. PCRC was involved in 
ARTIST, an RCT to investigate the effectiveness and outcomes of primary care patients 
who were randomized to one of three SSRIs, and her system enrolled 248 patients in a 
6-month period (results published in JAMA). Dr. Dolor also has expertise in 
cardiovascular disease; she co-authored the AHA Preventive Cardiology guidelines in 
women published in 2007 and 2011. Dr. Dolor’s role includes practice and patient 
recruitment, advising the investigative team on how to implement the study within a 
busy primary care environment, dissemination and implementation of the study findings, 
as well as collaborating on all aspects of study procedures.- 
 
Gregory N. Clarke, PhD is a Senior Investigator and Assistant Program Director at 
Kaiser-Permanente’s Center for Health Research (KP-CHR). Dr. Clarke has been 
conducting mental health research for 20 years and his areas of interest include 
depression treatment/prevention, child and adolescent mental health and treatments, 
and treatment of substance abuse comorbid with mental disorders. Dr. Clarke has been 
the principal investigator and co-investigator of several grants funded by the National 
Institute of Mental Health, conducting controlled outcomes trials of depression treatment 
and prevention in at-risk populations. Some of his most recent controlled trials examine 
the costs and clinical outcomes of preventing and treating depression in adolescent 
offspring of depressed parents enrolled in an HMO; the medication and psychotherapy 
treatment of depression in adolescents who have failed to respond to an initial course of 
SSRI anti-depressant medication; treatment of depression in adults also receiving 
outpatient treatment for alcohol addiction; simultaneous psychotherapy and medication 
for depressed adolescents treated in primary care; and Internet self-care programs for 
depressed adults and adolescents. In his role as site PI, Dr. Clarke will oversee all 
aspects of the successful implementation of the study at KP-CHR. 
 
Nathalie Moise, MD, MS 
Dr. Moise is an Assistant Professor of Medicine at Columbia University and a board-
certified internist. Her program of research involves developing and testing strategies to 
increase the implementation of cardiovascular and behavioral guidelines relevant to 
primary care. She also conducts research to increase the understanding of the impact 
of psychosocial factors on cardiovascular disease outcomes. She has served as a co-I 
on multiple federally-funded trials testing behavioral interventions for cardiovascular 
disease. She also actively treats patients with acute coronary syndromes and 
depression on the inpatient and outpatient setting. Dr. Moise assumed the role of site-PI 
of the Columbia University site from Dr. Kronish in 2016. 
Co-Investigators: 
 
Karina Davidson, PhD 
Dr. Davidson is Dean of Academic Affairs  Senior Vice President of Research for 
Northwell Health. Dr. Davidson was the sole PI of this trial from 2013-2015, became 
MPI with Dr. Kronish in 2016, and has been a co-I since 2017. Her current role is to 
facilitate dissemination of the trial results to the scientific community and the public.  
 
 
 

9 
 
Peter A. Shapiro, MD 
Dr. Shapiro is a Professor of Clinical Psychiatry at Columbia University College of 
Physicians and Surgeons, and Director of the Psychosomatic Medicine Fellowship 
Program and Associate Director of the Consultation-Liaison Psychiatry Service at 
New York Presbyterian Hospital-Columbia University Medical Center. The focus of 
Dr. Shapiro’s academic work has been on the treatment of depression in coronary 
artery disease and heart failure patients. He was a co-investigator for the SADHART 
studies of sertraline treatment after acute coronary syndromes as well as the COPES 
and CODIACS intervention trials. 
Dr. Shapiro’s background in clinical evaluation and treatment of depression in heart 
disease patients, use of quality of life measures in heart disease clinical trials, and 
collaboration in randomized clinical trials of depression treatment in heart disease make 
him highly qualified to serve as study psychiatrist. As in the COPES and CODIACS 
trials, Dr. Shapiro’s primary operational roles will be advising on treatment decisions in 
stepped care reviews of participants randomized to the Depression Screen and 
Intervention arm of the trial and serving as a consultant for the site medication 
prescribers.  
 
Daichi Shimbo, MD, MS 
Dr. Shimbo is an Associate Professor of Medicine at Columbia University and a board-
certified cardiologist. Dr. Shimbo has been involved in all of the depression—ACS 
studies conducted at the Center for Behavioral Cardiovascular Health. He will bring his 
expertise on ACS diagnosis and electronic medical record coding to ensure that 
sensitive and specific algorithms are used at each site for ACS patient selection. He will 
also ensure that the eligibility criteria are appropriately implemented, as he has done for 
previous trials. He will oversee the conduct of random site audits on approximately on 
5% of all randomized participants to verify the appropriate classification of qualifying 
ACS events and provide feedback where discrepancies are found. Importantly, he will 
take the lead as the Medical monitor who will review all AEs and UAPs, and provide 
consultation to site staff in the collection and timely reporting of these events as needed. 
He will create a twice yearly report on these events for the DSMB. Drs. Davidson and 
Shimbo will jointly ensure adherence to established federal and institutional patient 
safety and protection guidelines. Dr. Shimbo will also advise on analyses of the data 
and will ensure that cost and medical decision-making information relevant to cardiology 
is presented within the disseminated manuscripts. 
Ken Cheung, PhD    
Dr. Cheung is Interim Chair and Professor of Biostatistics, in the Mailman School of 
Public Health at Columbia University. He has extensive experience conducting data 
analyses relevant to RCTs in the area of cardiovascular disease. Dr. Cheung will 
receive reports from Faith Parsons, the CBCH Data Manager (see below), regarding the 
data operations. He will also lead the primary outcome analyses relevant to this trial.   
 
Consultants: 
 
Joseph Ladapo, MD, PhD 
Dr. Ladapo is Associate Professor of Medicine in the David Geffen School of Medicine 
at UCLA. He has expertise in conducting cost-effective analyses using data from large 
health systems. He has previously collaborated with CBCH investigators on cost-

10 
 
effectiveness analyses relevant to the COPES and CODIACS RCTs which evaluated 
enhanced depression treatment interventions in post-ACS patients.  
 
Coordinating Center Personnel: 
 
Vivian Medina,  MA, LCSW    
Vivian Medina is a full-time, licensed clinical social worker with the Center for Behavioral 
Cardiovascular Health at Columbia University and is the Cognitive Behavioral Therapy 
Treatment Specialist for the trial. She has provided cognitive behavioral therapy and 
problem solving therapy for a number of trials for the past eight years, and she has 
done so in-person, by webcasting, and by telephone. Ms. Medina received training in 
PST from Dr. Mark Hegel, Professor of Psychiatry, Community & Family Medicine, and 
The Dartmouth Institute at the Geisel School of Medicine at Dartmouth and has always 
met therapy fidelity standards in all past trials. She will conduct cognitive behavioral 
therapy sessions for all sites for this study. In addition to extensive experience in the 
delivery of telephone-delivered therapy to study participants with cardiovascular 
diseases, Ms. Medina is fully bilingual and has successfully conducted cognitive 
behavioral therapy with both English and Spanish-speaking subjects. She will also 
attend the bi-weekly participant progress/safety meetings, and will consult Dr. Shapiro 
when needed.  
 
Joan Duer-Hefele, RN, MA, CCRC   
Ms. Duer-Hefele is the Center for Behavioral Cardiovascular Health’s Nurse Manager 
and will function as Project Manager for this trial. In addition to the oversight of study 
operations and personnel, participant recruitment, and retention, Ms. Duer-Hefele will 
manage all quality assurance activities in consultation with study investigators. 
Ms. Duer-Hefele is both a credentialed nursing administrator and certified clinical 
research coordinator. She has extensive training in human subjects protections and 
privacy practices. She has more than 25 years personnel management experience, the 
last 15 of which directly relate to the implementation of clinical research projects, 
including regulatory oversight and quality monitoring activities. In this project, Ms. Duer-
Hefele’s role will be to assume responsibility for the development of metrics related to 
study implementation and the continuous assessment of achievement to ensure timely 
progress toward study objectives. She will assume responsibility for facilitating the 
training and management of all study personnel, compliance with regulatory mandates, 
data integrity, quality assurance activities, and ensuring participant safety. She will 
report directly to Dr. Davidson, the Principal Investigator 
 
Faith Parsons, BS 
Ms. Parsons has three years of experience as the Data Manager for the CODIACS-I 
RCT Study, thus she is well acquainted with the study protocol. She will coordinate with 
Ms. MacMillan  and the KP-CHR team in the creation of the centralized, web-based 
tracking and data entry system. She will also be responsible, under the direction of Dr. 
Muntner, for the management of the overall project data, and will prepare data reports 
for regular study team and DSMB meetings. Further, she will monitor the overall 
integrity of the study data by generating missing data and other relevant reports, and if 
necessary, work closely with study site personnel to resolve missing or inconsistent 
data. In the later years of the project, she will be responsible for preparing the data 
dictionary and dataset for data analysis activities. 

11 
 
 
Tara St. Onge, BS, RN 
Ms. St. Onge is a research assistant at the Center for Behavioral Cardiovascular Health. 
She will assist Ms. Duer-Hefele in project management activities such as organizing 
communications amongst sites and coordinating the bi-weekly treatment and operations 
meetings. 
 
Site Personnel: 
 
This section can be customized for each site’s coordinators and medication treatment 
prescribers.  
 
Committees: 
Data Safety and Monitoring Board 
The Data Safety Monitoring Board (DSMB) is composed of four members as well as an 
ex officio representative from NHLBI.  
 
Walter T. Ambrosius, PhD  (Chairperson) 
Professor, Department of Biostatistics 
Director, Design and Analysis Unit 
Wake Forest  University School of Medicine 
 
Richard C. Veith, M.D.    
Richard D. and Bernice E. Tutt Endowed Professor in the Neurosciences  
Chair, Department of Psychiatry and Behavioral Sciences 
University of Washington School of Medicine 
 
Stephen Lepore, Ph.D 
Professor, Department of Health 
Director, Social and Behavioral Health Interventions Laboratory 
Temple University 
 
Joseph A. Diamond, M.D 
Cardiologist 
Director, Nuclear Cardiology at Long Island Jewish Medical Center 
North Shore, Long Island Jewish Medical Center 
 
Catherine Stoney, Ph.D. 
NHLBI Project Officer (Ex Officio) 
 
Ms. St. Onge also serves as an executive secretary to the DSMB. The composition of 
the board includes individuals with expertise important to the present study and their 
appointments were made in consultation with NHLBI staff. The CODIACS-QOL DSMB 
follows NHLBI rules of formation and operation. All data concerning adverse outcomes 
will be reviewed by the Data Safety Monitoring Board on the schedule set by the DSMB.   
Serious events will be evaluated during a conference call any serious adverse effects 
will be reported to the IRB. 

12 
 
 
Steering Committee 
The Steering Committee is the decision-making body for this study. It consists of the 
Principal Investigators for the study. The Steering Committee will develop policies and 
procedures under the direction of the Data Safety and Monitoring Board. The Steering 
Committee will direct the efforts of the Columbia coordinating center and the recruitment 
and successful retention of participants at each of the four sites HealthPartners 
Research foundation (Margolis, site PI), Duke University Primary care-based Research 
Network (Dolor, site PI), Kaiser Northwest (Clarke, site PI), and Columbia University 
Irving Medical Center (Moise, site PI). The NHLBI R01 funding is to CUIMC, and 
subcontracts will be established with each of the three sites. There will be no subject 
recruitment at CUIMC.  
 
Operations Committee 
The Operations Committee will help in addressing any operational issues that arise from 
each site during the duration of the study. This committee will be comprised of Joan 
Duer-Hefele, Faith Parsons, Tara St. Onge, and each of the sites’ project managers and 
coordinators. They will meet bi-weekly with each site via telephone to discuss any 
protocol, operational, or data base issues. If major issues arise they will be brought to 
the attention of the PIs.  
 
Treatment Committee 
The Treatment Committee will be in charge of handling any treatment related issues 
from each of the three sites. The Treatment Committee will be comprised of Dr. Peter 
Shapiro and Vivian Medina LCSW, and the medication treatment specialist at each site. 
This committee will meet bi-weekly via phone to discuss any active cases.  
 
Publications and Disseminations Committee  
The Steering Committee will create a Publications and Dissemination Committee, led by 
PI Dr. Kronish, to facilitate the creation, publication, and dissemination of potential 
manuscripts that use study data.  
 
 

13 
 
Introduction 
Background and Rationale 
 
Patients with an acute coronary syndrome (ACS) and comorbid depression have a 2-
fold higher risk for recurrent ACS and mortality, worse quality of life, and higher costs of 
care than non-depressed ACS patients. The strength of these observational findings 
prompted the American Heart Association (AHA) to advise that routine depression 
screening for ACS patients and referral for depression diagnosis and treatment as 
indicated occur. Unfortunately, there are no randomized controlled trials (RCT) to inform 
this large, potentially expensive screening recommendation. And, screening 
guidelines/advisories in the absence of RCT evidence have recently been extensively 
criticized (and withdrawn). This poses a serious dilemma for clinicians, health care 
systems, and for health care policy leaders. An RCT is urgently needed to provide 
evidence for these different constituents about the costs and benefits of the AHA 
depression screen and treat algorithm. Two critical gaps in knowledge must be filled to 
determine if public health would be improved by the AHA strategy for depression 
screening in post-ACS patients: 1) Does this strategy improve quality-adjusted life years 
for patients with a recent ACS (primary outcome)?  and 2) Is the cost of providing 
depression screening and any type of depression treatment within the acceptable and 
typical amounts reimbursed for health care services? 
 
Our specific aim is to determine the quality-adjusted life year benefits (primary 
outcome) and health care costs of following the AHA’s advisory for depression 
screening and then referral for further diagnosis and treatment in post-ACS patients, if 
elevated depressive symptoms are found. To accomplish this aim, we will randomize 
patients from four different, geographically diverse health systems to three different 
groups: 1) to the AHA depression screen, notify, and treat if elevated depressive 
symptoms are found algorithm (intervention group) or: 2) to receive no depression 
screening (strong control group) or: 3) to be screened and a primary care provider 
notified of elevated depressive symptoms (minimally enhanced control group). Health-
related quality of life, depressive symptoms, and costs will be obtained from all patients, 
so that the benefits and the costs of these three different depression screening 
strategies can be compared. 
 
Depression and acute coronary syndromes (ACS) carry large world-wide public health 
burden, and their comorbidity is common. Multitudes of observational studies have 
convinced leading authorities to advise that ACS patients should be screened for 
depression, and then treated if it is detected. No randomized controlled trial exists to 
directly test if this strategy improves any outcome. This research is significant because 
it will provide vital randomized controlled trial (RCT) data from four different health care 
systems on cost-effectiveness and quality of life to inform national screening guidelines 
about the usefulness of depression screening and treatment in ACS patients 
 
 
 
 
 
 
 
 
Objectives/Hypothesis 
 
The overarching goal of this research is to conduct a state-of-the-art RCT that will 
rigorously evaluate the benefits and costs of AHA’s depression advisory for modern 
post-ACS patients. 

14 
 
 
To examine in a randomized controlled trial the benefits and costs of the AHA’s 
advisory for depression screen and treatment of post-ACS patients. 
 
Hypothesis 1:    Screen, notify, & treat intervention group will gain significantly more 
quality-adjusted life years (primary outcome) across 18 months when compared to No 
Depression screen control group, and also when compared to the Depression screen & 
notify control group. 
 
Hypothesis 2: Those randomized to AHA’s Depression screen & treat intervention 
group will have a favorable incremental cost-effectiveness ratio when compared to No 
Depression screen control and also when compared to the Depression screen & notify 
control group. 
 
Trial Design 
 
To accomplish these aims, we will randomize patients from four different, geographically 
diverse health systems to three different groups: 1) to the AHA depressive symptom 
screen and treat if elevated depressive symptoms are found (Screen, Notify & Treat 
intervention group) or: 2) to receive no depressive symptom screen (No Screen strong 
control group) or: 3) to be screened and a primary care provider notified of elevated 
depressive symptoms (Screen & Notify minimally enhanced control group). Health-
related quality of life, depressive symptoms, and costs will be obtained from all 
participants, so that the benefits and the costs of these three different screening 
strategies can be compared. 
 
 

15 
 
Methods 
Participant, Interventions and Outcomes 
 
Study Setting: Coordinating Center 
 
The Center for Behavioral Cardiovascular Health at Columbia University (CBCH) 
is a clinical research center in the Department of Medicine, Division of General Medicine 
at the Columbia University Irving Medical Center The Center currently has a staff and 
faculty of over 40 highly skilled interdisciplinary professionals (internists, cardiologists, 
psychologists, and quantitative faculty) engaged in more than 20 different 
interdisciplinary research studies investigating the behavioral and biological factors that 
explain the relationship between depression and heart disease, ways to treat 
depression in those with established heart disease, the psychosocial factors and 
biological mechanisms that contribute to hypertension, and alternative approaches to 
diagnosing and treating hypertension. CBCH serves as the Coordinating Center for this 
trial. 
Study Setting: Recruitment Sites 
 
Kaiser Permanente (KP-CHR), founded in 1946, was the country’s first HMO. 
Currently, national Kaiser membership exceeds 9,000,000. KP-CHR is a professional 
autonomous multi-disciplinary research organization housed within one of eight semi-
autonomous regions of the country’s first and largest not-for-profit HMO and services 
approximately 475,000 members in northwest Oregon and southwest Washington. 
Clinical outpatient facilities include approximately 30 comprehensive ambulatory clinics 
located across this metro area. A large proportion of the hundreds of RCTs that have 
been conducted at CHR during its 48 years in operation are those focused on 
depression, cardiovascular diseases and other chronic conditions, many of which 
included cost effectiveness analyses. 
 
HealthPartners is the largest consumer-governed nonprofit health care organization in 
the country, providing care, coverage, research, and education to improve health and 
well-being in partnership with its members, patients and community. Included under 
HealthPartners’ umbrella are Regions Hospital (a tertiary-care hospital in St. Paul, MN), 
Park Nicollet HealthPartners Care Group, HealthPartners Center for Memory & Aging, 
Park Nicollet Methodist Hospital (a 426-bed facility with more than 960 physicians in St. 
Louis Park, MN) and HealthPartners Institute for Education and Research. 
HealthPartners has formal relationships with hospitals and clinics throughout Minnesota 
and western Wisconsin, including Westfields Hospital (New Richmond, WI), Lakeview 
Hospital (Stillwater, MN), Hudson Hospitals and Clinics (Hudson, WI) and Physicians 
Neck and Back Clinic (Roseville, MN). 
Founded in 1957, the HealthPartners family of care serves more than 1.5 million 
medical and dental health plan members and more than1 million patients. In 2013, 
HealthPartners and Park Nicollet Health Services combined under the name 
HealthPartners and a single consumer-governed board of directors. The new 
organization includes a multispecialty group practice of more than 1,700 physicians; 
seven hospitals; 47 primary care clinics; 22 urgent care locations; 22 dental clinics; and 
numerous specialty practices in Minnesota and western Wisconsin. HealthPartners is 

16 
 
the top-ranked commercial health plan in Minnesota and is also ranked among the top 
30 plans in the nation, according to the National Committee for Quality Assurance’s 
Health Insurance Plan Rankings 2012-2013. For more information, visit 
www.healthpartners.com.  
Park Nicollet HealthPartners Care Group has physicians practicing in more than 35 
medical and surgical specialties. Access to data from the primary care clinics, hospitals 
and the International Health Center and specialty centers allows HealthPartners 
Institute for Education and Research to conduct research on large patient populations 
and subpopulations. 
Regions Hospital, the site of the Institute’s IRB and other committees, serves a 
culturally, economically and ethnically diverse population. The hospital is the state’s 
second largest provider of charity care. Regions features the Center for Undergraduate 
and Graduate Clinical Education, a full medical library, a psychiatric unit associated with 
the emergency department, an HIV/AIDS program, digestive care center, birth center 
and same-day surgery. The 54,000-square-foot emergency department has 53 beds 
and an 11-bed mental health crisis unit and onsite radiology and lab services.  
The Duke Clinical Research Institute (DCRI), a multidisciplinary group of faculty and 
staff from the Departments of Medicine, Surgery, Anesthesiology, Pediatrics, 
Community and Family Medicine, and the Heart Center at Duke University Medical 
Center is fully committed to this project and will supplement as needed the resources 
that are described in the proposal. The Duke Primary Care Research Consortium 
(PCRC) is a primary care research network composed of academic and community 
practices within the Duke University Health System (DUHS) and surrounding 
communities. The PCRC is organizationally placed within the Duke Clinical Research 
Institute (DCRI). For the proposed study, we will work with 15 primary care practices 
that are part of the network. The PCRC has participated in over 70 studies on 
hypertension, diabetes, depression, anticoagulation, hyperlipidemia, obesity, asthma, 
otitis media, and vaccines, and is often the lead recruiting sites on these national trials. 
 
 
Columbia University Irving Medical Center-New York Presbyterian is comprised of 
an academic medical center (CUIMC) that forms the largest campus of the New York 
Presbyterian (NYP) health system. The four major divisions of NYP are the 
aforementioned hospital, the NYP Regional Hospital Network, NYP Physician Services, 
and NYP Community and Population Health. With more than 1,800 physicians, 
surgeons, dentists, and nurses in locations throughout the New York City metro area, 
CUIMC-NYP provides comprehensive patient care and offers a range of general and 
specialized medical, dental, and nursing services.  
 
 
 

17 
 
Detailed Eligibility Criteria 
 
Inclusion Criteria 
 
Criteria 
EMR Verification and ICD-9 Codes 
English or Spanish*-
speaking participants 
*Spanish-speaking 
participants eligible at 
Columbia-site, only 
 
Primary language designation in EMR (if available) 
Participant attestation  
Documented ACS within 
the past 2-12 months 
Evidence of one or more of the following within the past 2-
12 months: 
(1) Diagnosis of acute myocardial infarction (410) 
during an inpatient hospitalization 
(2) Diagnosis of unstable angina (411) during an 
inpatient hospitalization with a history of coronary 
artery disease (414) 
 
 
410.00-410.92   Acute Myocardial Infarction 
411.00-411.89   Other acute and sub-acute forms of    
                           ischemic heart disease 
414.00-414.9     Other forms ischemic heart disease 
 
Over the age of 21 years 
 
DOB  
Has access to a phone 
and/or computer 
 
Participant confirmation of phone number listed in EMR 
 
ICD 9 discharge codes of 410 (acute myocardial infarction) through EMR searches have 
excellent positive predictive value when clinical data are abstracted and checked by two 
coders blinded to discharge code. Thus, we will use this discharge code for ACS 
eligibility. We will furthermore select potential participants with ICD 9 code hospital 
discharge codes of 411 (unstable angina), who also have established coronary artery 
disease (ICD 9 code of 414) to ensure that participants meet the definition of an ACS, 
as described in ACS case definitions by numerous cardiology societies. This approach 
– having broad eligibility – provides for a high degree of generalizability. 
 
Medical Exclusion Criteria 
Terminal illness defined as, but not limited to: 
 
NYHA class IV, ACC class D CHF requiring inotropes or mechanical assist devices 
or critical aortic stenosis without plan for correction 
End-stage COPD/emphysema 
Advanced cirrhosis with encephalopathy, varices, severe ascites 

18 
 
Severe rheumatologic diseases requiring frequent hospitalizations, and multiple 
cytotoxic agents and/or disease modifying drugs 
Metastatic pancreatic, esophageal, colorectal or stomach cancer 
Metastatic sarcoma, ovarian, melanoma or renal cell cancer 
Metastatic breast cancer with multiple recurrences despite treatment 
Advanced CNS malignancies  
Recurrent hematologic malignancies with multiple recurrences despite treatment 
Persistent AIDS, untreated or treated 
Currently pregnant 
 
Participant Reported Screening Exclusions 
 
Potential participants will complete a brief screening questionnaire to confirm that they 
have none of the above conditions, that they speak English and that they are interested 
in being enrolled in the study 
 
Interventions 
The 1500 participants who meet eligibility and indicate a willingness to participate and 
potentially receive treatment will then be randomized. Those randomized to the AHA 
Depression Screen, Notify & Treat or Depression Screen & Notify groups will then 
complete assessment of depressive symptom severity, while those randomized to No 
Depression Screen group will not. All participants will be followed according to the same 
schedule of assessments. 
 
Overview of Visit Schedule & Measures. The overall guiding rationale for all visit and 
measure choices was to be cost-effective, brief, and convenient to the participant. The 
three participating health care organizations have different methods of recruiting 
however; they will all utilize an electronic medical record (EMR) algorithm to identify 
medically eligible patients. At the EMR eligibility stage, electronic medical records will 
be screened for documented ACS, age, language preference, and all other medical and 
psychiatric eligibility criteria. Patients identified as potentially eligible through this 
process may be contacted by mail, postcard, or email and offered either an email 
address or telephone number to contact if interested in study participation. This initial 
contact may include a study brochure, letter on behalf of their primary care provider, 
and/or a copy of the Informed Consent Form. Patients who express interest can either 
be screened and introduced to the consenting process over the phone, or scheduled for 
an in-person study screening and consent visit depending upon local practices and IRB 
approval.   
 
In general, those who do respond by email or phone within approximately 2 weeks after 
the date of initial contact will be telephoned by the recruitment staff. We will carefully 
document who did not complete screening, who was ineligible (and for what reason) 
and who refused. Patients who consented and are eligible after screening will then be 
randomized during either the initial telephone call, a follow-up phone call or at an in-
person visit. Participants who are randomized to Depression Screen & Notify arm will 
complete a PHQ-8 assessment, and those with clinically significant scores (≥ 10) will 
have a letter or electronic message sent to their PCP and/or cardiologist. Participants 

19 
 
who are randomized to the AHA Depression Screen, Notify & Treat arm will also 
complete a PHQ-8 assessment, and those with clinically significant scores (≥ 10) will be 
offered the option of receiving treatment for their depressive symptoms. Participants will 
be presented with the option of receiving medication therapy (sertraline or bupropion), 
Cognitive Behavioral Therapy (delivered via phone), a combination of both therapies or 
neither therapy. Depending on their treatment choice, they will be scheduled for their 
initial treatment visit, ideally within two weeks of randomization. Their PCP and/or 
cardiologists will also be notified if they have clinically significant scores (≥ 10) on the 
PHQ-8 assessment. Those randomized to No Depression Screen group will not receive 
the depression screen PHQ-8 at baseline. 
 
All participants, regardless of randomization assignment, will complete the CES-D10, 
SF-12 health-related quality of life measure, symptoms checklist and lost productivity at 
enrollment and after 6-, 12-, and 18-months of study participation. All participants will 
also complete the PHQ-8 assessment at 18-months, with referral to treatment for those 
with scores ≥ 10. Participants will be contacted by telephone, or have an in-person visit 
scheduled, as they prefer. These administration methods have been compared in past 
studies and found to be equivalent. These follow-up contacts will be brief, and 
scheduled at the participant’s convenience wherever possible. 
All participants will report their health service utilization at 6-, 12- and 18-months. 
Additionally, all will have EMR searches of health care utilization extracted for the 18-
month duration of the trial.  
 
Outcomes 
Quality-adjusted Life Year Assessment (Primary). Following the precedent set by 
RCTs with other depressed medical populations, we chose the Short Form Health 
Survey (SF-12) questionnaire to assess health related quality of life for the economic 
analysis. The SF-12 uses Likert scales to assess health-related quality of life aspects 
that are most directly relevant to depressed post-ACS patients: mobility and physical 
activities, ability to self-care, ability to perform usual activities, pain, and anxiety/ 
depression. Extensive validation, including construct validity, published normative data, 
and sensitivity to change have all been published for this scale. It has been used 
extensively the cost-effectiveness of a screening or intervention practice, and has 
successfully been used in depression interventions with other patients, allowing 
comparability with other data and settings. It is ideal for using in mail or web surveys, 
and takes less than 5 minutes. The NICE group in Britain recommends its use for 
providing cost and QALY data. We will collect deaths/dates of death from the national 
death index & EMR. 
 
Depression Symptom Assessment. The AHA advisory suggests using the PHQ-2 
(yes-no version) first, and then the full PHQ-8 for the assessment of depression 
symptom severity. In CODIACS QoL we will not utilize the PHQ-2, and instead ask all 8 
items of the PHQ-8. The PHQ-8 has excellent psychometric properties, including 
sensitivity to successful change from treatment, good test-retest reliability when no 
treatment is offered, construct validity, reasonable correlations with health-related 
quality of life measures, and the ability to approximate likelihood of a major depressive 

20 
 
disorder. Scores on the PHQ-8 range from 0- 24 and a score of ≥10 is used for 
detecting likely depressive disorder, and clinically significant depression levels.  
 
CES-D10. The Center for Epidemiologic Studies Depression Scale (CESD) is a 
screening measure (NOT a diagnostic tool) developed to identify current depressive 
symptomatology related to major or clinical depression in adults and adolescents. The 
CES-D10 is a short version of the original 20-item scale. The scores range from 0 to 30, 
and a score of 10 or greater is considered significant. 
 
Depression-free Days. These will be calculated by using linear interpolation to 
estimate daily depression severity from the CES-D10 obtained at each of the four 
assessment points for all groups.   
 
Health Service Utilization. A participant self-report tool used in documenting visits to 
health care providers, medications taken for anxiety and depression, emergency room 
visits and hospitalizations. 
 
Loss of Productivity.  A participant self-report tool used to document the nature of 
employment and absences due to health problems. 
 
Overview of Cost/Health Care Utilization Data.   
 
Costs to be collected 
for the trial 
 
From electric medical 
record 
From patient report 
Antidepressant cost, 
therapy cost, other 
mental health visits 
X 
X 
Depression-free days 
 
X 
Primary care visits, 
ED/urgent care, other 
medical visits, 
diagnostic services, 
inpatient services other 
outpatient services 
X 
 
Days able to 
work/impact on work 
and leisure productivity 
 
X 
 
We will generate cost data using a combination of EMR extraction and patient surveys 
as detailed in the table above. We will calculate the cost of all possible depression care 
used (antidepressant cost and therapy cost. We will also collect data on all non-study 
delivery of depression treatment utilization from patient report and EMR. To derive other 
healthcare costs, we will use the EMR to collect data on all episodes of non-depression 
related healthcare utilization during the 18-month trial period: outpatient visits, 
ED/urgent care, as well as all in-patient care and any diagnostic tests or services. 
Average Medicare reimbursement rates according to diagnosis-related groups will be 
applied to inpatient visits to estimate hospitalization costs, and the Medicare fee 
schedule will be applied to outpatient and ED resource use according to current 

21 
 
procedural terminology codes. Finally, to calculate costs and potential cost-offsets from 
a societal perspective, we will collect participant report data on time lost from work. Lost 
productivity is believed by many experts to be assessed in our measure of health-
related QoL instrument, the SF12. However, a sensitivity analysis will be conducted to 
test this assumption. 
 
Participant Timeline 
Table 1. Schedule of screening, baseline and follow-up forms 
Form Name 
Screening Base,ine 
6 
Months 
12 
Months 
18 
Months 
Screening Questionnaire 
X 
  
  
  
  
Subject Contact rnformation 
  
X 
  
  
  
Subject Contact rnformation 
Update Form (if indicated) 
  
  
X 
X 
X 
Demographics 
  
X 
  
  
  
PHQ-8 
  
X* 
 
 
X 
CES-D10 
 
X 
X 
X 
X 
SF-12 
  
X 
X 
X 
X 
Heasth Service Use 
Questionnaire 
  
  
X 
X 
X 
Symptoms Checksist 
  
X 
X 
X 
X 
Lost Productivity Questionnaire 
  
X 
X 
X 
X 
Unanticipated Event Report 
  
  
^ 
^ 
^ 
Quasity Assurance Form** 
 
 
X 
X 
X 
*Participants randomized to the No Depression Screen arm will NOT complete PHQ-8 
at baseline 
** For blinded coordinator only 
^Only completed if necessary 
Sample Size 
For the primary outcome in Aim 1, we will be making two primary comparisons: 
Difference in QALYs comparing AHA’s Screen, Notify & Treat group vs. Screen & Notify 
and then separately to No Screen group. For choosing a sample size, we assumed a 
standard deviation for QALYs in the conservative control group (e.g., no depression 
screen) of 0.17. Additionally, based on a prior study of management of depression for 
patients with cancer, we assumed a net improvement in QALYs of 0.155 over 18 
months of follow-up for individuals receiving the AHA’s screen & treat intervention would 
be reasonable to expect. We assumed a 0.055 gain in QALYs for all participants not 
receiving treatment (i.e., those in the No Screen group, the Screen & Notify group and 
those without depression in the AHA’s Screen, Notify & Treat group). An important 
consideration for this trial is that only 20% of patients randomized to the AHA’s Screen, 
Notify & Treat group will meet criteria for depression and thus will receive the treatment 
part of intervention. Therefore, assuming an improvement in QALYs of 0.21 (0.055 
background improvement + net improvement of 0.155) over the 18-month follow-up 
period for the 20% of participants with diagnosed depression and a 0.055 improvement 
in QALYs for the 80% of participants in this randomization group without depression, an 
overall gain in QALYs of 0.086 over the 18-month follow-up period can be anticipated in 

22 
 
this randomization group (0.21 * 0.2 + 0.055 *0.8 = 0.086). Thus, we anticipate a 
relative difference in QALYs of 0.031 (0.086 change in the AHA’s screen & treat group 
minus 0.055 in the no screen group). We will have 80% statistical power to detect this 
difference of 0.031 with a sample size of n=475 participants in each group. We chose to 
determine sample size based on a pairwise comparison at 80% power in the two-step 
procedure, as a conservative approach relative to powering based on the F-test (See 
Statistical Analysis section, below, for further details).  Specifically, under the scenario 
where one group has higher QALY than the other two by an effect size 0.18, the F-test 
will yield 84% power. Adding in 5% loss to follow-up, we selected an overall sample size 
of n=500 in each randomization group for an overall sample size of n=1500. Power 
analyses are typically based on the primary clinical outcome. We selected the QALY as 
our primary outcome and did not have specific economic hypotheses that required 
statistically tests. Therefore, we chose to follow this tradition, and do not present power 
calculations for our incremental cost-effectiveness ratios. 
Recruitment 
The four participating health care organizations have different methods of recruiting 
however, they will all utilize an electronic medical record (EMR) algorithm to identify 
medically eligible patients. At the EMR eligibility stage, electronic medical records will 
be screened for documented ACS, age, language preference, and all other medical and 
psychiatric eligibility criteria. Patients identified as potentially eligible through this 
process may be contacted by mail, postcard, or email and offered either an email 
address or telephone number to contact if interested in study participation. This initial 
contact may include a study brochure, letter on behalf of their primary care provider, 
and/or a copy of the Informed Consent Form. Patients who express interest may either 
be screened and introduced to the consenting process over the phone, or scheduled for 
an in-person study screening and consent visit depending upon local practices and IRB 
approval.   
In general, those who do respond by email or phone within approximately 2 weeks after 
the date of initial contact will be telephoned by the recruitment staff. We will carefully 
document who did not complete screening, who was ineligible (and for what reason) 
and who refused. Patients who consented and are eligible after screening will then be 
randomized during the either the initial telephone call, a follow-up phone call or at an in-
person visit. Participants who are randomized to Depression Screen & Notify arm will 
complete a PHQ-8 assessment, and those with clinically significant scores (≥ 10) will 
have a letter sent to their PCP and/or cardiologist. Participants who are randomized to 
the AHA Depression Screen, Notify & Treat arm will also complete a PHQ-8 
assessment, and those with clinically significant scores (≥ 10) will be offered the option 
of receiving treatment for their depressive symptoms. Participants will be presented with 
the option of receiving medication therapy (sertraline), Cognitive Behavioral Therapy 
(delivered via phone), a combination of both therapies or neither therapy. Depending on 
their treatment choice, they will be scheduled for their initial treatment visit, ideally within 
two weeks of randomization, depending on their treatment choice. Those with clinically 
significant scores (≥ 10) in the Depression Screen, Notify, & Treat group will also have a 
letter sent to their PCP and/or cardiologist in the same manner as patients in the Screen 
& Notify group. Those randomized to the No Depression Screen group will not receive 
the depression screen (PHQ-8) at baseline. 

23 
 
Assignment of Interventions 
Sequence generation 
Participants will be randomly assigned to one of three groups:  No Depression Screen, 
Depression Screen and Notify, or AHA Depression Screen, Notify and Treat. The 
randomization algorithm will be embedded in the web-based tracking system, using 
randomly assigned block sizes of 3, 6 and 9.  
Concealment Mechanism 
Participants will be randomized using the web-based tracking system. “User-roles” are 
assigned to study personnel, and the randomization tool is only available to unblinded 
coordinators at each site. Concealment will be ensured as the randomization algorithm 
will run in the backend, and only the randomization assignment will be visible to the 
unblinded coordinator after all necessary information about the participant has been 
entered.  
Implementation 
All eligible participants who give consent will be randomized by the unblinded 
coordinator after completion of all baseline assessments. The randomization tool is only 
available to designated unblinded coordinators (UC) at each site. The UC will enter the 
required information in the tracking system, after which the participant’s group 
assignment will be immediately available. 
 
If the participant is randomized to the No Depression Screen arm, the UC will inform the 
participant that no further assessments are required.  
 
If the participant is randomized to the Depression Screen and Notify arm, the UC will 
administer the PHQ-8. If the PHQ score is ≥ 10, the UC will notify the participant’s 
primary care provider and/or cardiologist either through the tracking system, by email, or 
mail in accordance with their IRB requirements.  
 
If the participant is randomized to the AHA Depression Screen, Notify, and Treat arm, 
the UC will administer the PHQ-8. IF the PHQ score is ≥ 10, the UC will inform the 
patient of the available treatment options. Depending on the participant’s choice of 
treatment, the UC will facilitate the initial contact with the relevant treatment 
specialist(s), ideally within two weeks of randomization and will work closely with the 
treatment specialist(s) to monitor the participant’s treatment progress. The participant’s 
PCP and/or cardiologist will also be notified of the positive depression screen. 
Blinding 
The blinded coordinator (BC) will administer all study regular assessments at 6-, 12- 
and 18-months, and will not be allowed to know the participants’ group allocation, and 
this is ensured by the “user-role” designation in the tracking system. In addition to the 
UC, and due to the nature of the study treatment, participants, site PIs, and other 
personnel not designated as BC, cannot be blinded to the group allocation, but are 
encouraged not to disclose the allocation either at or when assisting the BC in 
scheduling follow up assessments. After each study visit, the BC will complete a 1-item 
questionnaire asking if the participant disclosed if they were in treatment. This 
information will be tracked, however no intervention will occur if the BC becomes 
unblinded.  

24 
 
Data Collection, Management and Analysis 
Data Collection Methods 
 
Screening 
Screening will be accomplished in two stages. First, an EMR search of ICD-9 codes 
matched against the study eligibility and exclusion criteria will be used to identify eligible 
participants. The following ICD-9 discharge codes will be used to match eligibility 
criteria, 410 (acute myocardial infarction), 411 (unstable angina), 413.9 (angina pectoris 
NEC/NOS), 414 (coronary artery disease). Codes were updated for ICD-10 in later 
years of recruitment. Then, those who express interest will complete a short Screening 
Questionnaire to verify that none of the exclusion criteria apply to them.  
 
Baseline and Follow-Up Assessments 
Research data for the study include: 
• Participants’ responses to self-report assessments and measures including, 
demographics, CES-D10, quality of life (SF-12), symptoms checklist, health 
service use, and lost productivity, and unanticipated events 
• Electronic medical record (EMR) data extraction 
 
There will be four study visits/interviews: baseline, and three follow-up visits/interviews, 
at 6-, 12, and 18-months after enrollment. The list of forms and the schedule of 
collection is found in Table 1 above. Personally identifiable information (PII) and 
protected health information (PHI) will be collected, and will be used to contact 
participants for follow-up visits, treatment delivery (if applicable), and to conduct a 
National Death Index search within 5 years after the study ends. Only authorized 
personnel, who have official status as part of the authorized research team, will have 
access to any records containing PII and PHI. 
 
Treatment-Related Information 
Study forms/guidelines are available to study treatment specialists to aid them in 
monitoring depressive symptoms, and tracking the progress of participants undergoing 
treatment. These forms are provided for the treatment specialists’ convenience, and not 
for data analysis, and are included in the intervention manual. 
 
Healthcare Utilization Data  
Healthcare utilization data from date of enrollment to 18-months after will be 
downloaded from the integrated medical record systems at each site and delivered to 
Columbia University via secure electronic file transfer.  
 
Data Management 
Data Entry, Security and Storage 
A dedicated, HIPAA-compliant, web-based tracking and data entry system created by 
KP-CHR will be used for this study. Baseline and follow-up self-report data will be 
collected in one of two ways: (1) the BC will complete the assessments with the 
participant over the phone or in-person, and will directly enter the responses on the 
web-based system, or (2) the blinded assessor completes the assessment using pen 
and paper forms, and either the BC or other research personnel will enter the data at a 

25 
 
later time. All data are stored in a secure server at Kaiser Permanente, and 
automatically backed up according to an established regular schedule. 
 
Tracking Screened Subjects 
Local study sites will manage the tracking of all participants approached for the study, 
and will document who completed screening, who was ineligible (including reasons for 
exclusion), and who refused. An aggregated report of the screening outcome will be 
sent to Columbia University for the biweekly operations meetings. 
Tracking Enrolled Participants 
Tracking of enrolled participants will be managed through the web-based tracking 
system using a ‘to-do-list’ mechanism. When a participant comes in window for a follow-
up visit, his/her ID number will appear in the ‘to-do list’ section of the study personnel’s 
page on the tracking system. All contacts and communication attempts with the 
participant, including study payments, will also be logged in the tracking system.  
 
Data Discrepancies and Resolutions 
Data discrepancies and missing data reports from baseline, follow-up visit, and 
treatment-related information will be generated either (1) automatically by the web-
based tracking system, or (2) by running program code(s) created by the data manager. 
The data manager will send a list of errors and detailed descriptions to the project 
managers for resolution. All sites are required to address all items in the report by 
checking available documentations to correct any inconsistency, or by declaring the 
item as permanently missing. The local sites’ study personnel will be responsible for 
updating and correcting the data entry in the web-based system within two weeks of 
receipt of the report.  
 
The data manager, will work with the study statistician and health economist, to check 
all variables from the EMR data extraction for outliers, consistency and completeness. A 
detailed report will then be sent to the site project managers to resolve any data 
inconsistencies and discrepancies. Resolutions to data queries from EMR data will be 
expected at the soonest possible time.  
Statistical Methods 
All analyses will use the principle of intention-to-treat. Baseline characteristics will be 
examined as means (standard deviation) or percentages by randomization assignment 
to confirm a balanced allocation. As randomization will be performed stratified by study 
site, we will also assess baseline characteristics further stratified by study site. Also, 
participant characteristics will be compared across study site 
 
Hypothesis 1:  
 Those randomized to AHA’s Depression Screen, Notify & Treat intervention group will 
gain significantly more quality-adjusted life years across 18 months when compared to 
No Depression Screen control group, and also when compared to the Depression 
Screen & Notify control group.  
We will compare outcomes for participants randomized to each of the three groups. 
Change in QALYs from baseline through 18 months post-randomization will serve as 
the primary outcome for this trial. First, quality of life utilities will be calculated using 
participants’ scores on the SF-12 at each visit (baseline [pre-randomization] and 6, 12, 

26 
 
and 18 months post-randomization). All participants who complete the SF-12 will be 
classified according to the SF-6D. The SF-6D describes 18,000 health states.  The 
average profile for each randomized group will be calculated. A multiple regression 
formula that applies weights will be used to assign quality of life utilities for each 
participant. Next, QALYs will be derived by multiplying the SF-6D derived quality of life 
utilities by 0.5 years for each 6 month-period, assuming linearity for changes in utility 
within each period. Any mortality events will be assigned zero QALYs from that point to 
the end of follow-up. With these scores calculated, we will calculate the average QALY 
gained (or lost) in each randomized group compared to assuming the utility calculated 
at baseline remained constant across 18-months.  
The goal of the primary analysis is to identify whether there is difference in QALYs 
among the three groups. We plan to perform a two-step gate-keeping test procedure: 
We will first perform an F-test using ANOVA, and then proceed to do all three pairwise 
comparisons using two-sided t-test at 5% nominal significance only if the F-test has a p-
value less than 0.05.  With three randomization groups and three pairwise comparisons, 
this two-step procedure has been shown to preserve the familywise error rate in the 
strong sense, that is, a false positive comparison will occur at most with 5% probability 
under all possible scenarios.46,47 This method is also generally more powerful than 
Bonferroni’s adjustments.  
In a secondary analysis, we will use a mixed model with a random intercept to assess 
the change in quality of life utilities over time comparing individuals in the AHA Screen, 
Notify & Treat group vs. the other two randomization groups. This model will incorporate 
main effects of time (i.e., baseline, and 6-, 12-, and 18-months post-randomization), 
treatment group, and the time by treatment group interaction. Using this model, we will 
be able to calculate the mean utility at each follow-up time period for the 3 groups and 
determine whether the response profile differs by time across groups. 
 
Hypothesis 2:  
Those randomized to AHA’s Depression Screen, Notify & Treat intervention group will 
have a favorable incremental cost-effectiveness ratio when compared to No Depression 
Screen control group and also when compared to the Depression Screen & Notify 
control group.  
 
For this hypothesis, we will judge the cost effectiveness of AHA Screen, Notify & Treat 
group compared to the Screen & Notify group, then we will compare the Screen & Notify 
group to the No Screen group on the basis of incremental cost-effectiveness ratios. The 
base case analysis will adopt a societal perspective with respect to costs and health 
benefits. Costs will include all healthcare costs and lost productivity cost related to use 
of website/staff time for depression screening, and the cost of all possible depression 
care used (antidepressant cost and therapy cost, including the cost for 
telephone/webcam use). Costs will be denominated in 2012 dollars and discounted at 
an annual rate of 3% as per the Panel on Cost-Effectiveness in Health and Medicine. 
For health benefits, we will convert SF-12 scores to QALYs, using the four (pre-
randomization, 6, 12, & 18 month) measured values. Incremental cost-effectiveness 
analyses for comparison of treatment groups will be calculated sequentially using the 
ratio of the difference in average cost per participant divided by the difference in 
average QALY gained.  

27 
 
 
Sensitivity Analysis  
We will perform sensitivity analyses by adopting a range of ‘best and worst case’ 
scenarios for resource costs (including actual costs from the three health care systems, 
or from estimates obtained using charge-to cost ratios), a range of initial depression 
prevalence, and depression treatment benefit (including considerations of recall bias for 
self-reported measures). We will also recalculate the incremental cost-effectiveness 
ratios separately by health care system, so that a range by site can be presented. 
Multivariate Monte Carlo simulation will be used to obtain 95% confidence intervals for 
estimates of cost and effectiveness, which will be used to produce a range of 
incremental cost-effectiveness ratios to determine the robustness of our results. In 
addition, we will repeat we will repeat our baseline analysis and sensitivity analysis after 
restricting cost accounting to the payer perspective only. 
 
 
 

28 
 
Data Monitoring 
 
Our procedures will follow the NHLBI guidelines on DSMBs that was released October 
2011 (http://www.nhlbi.nih.gov/funding/policies/dsmpolicy.htm). Specifically, in 
consultation with NHLBI, 4 DSMB members have been appointed. The Board includes a 
psychiatrist, cardiologist, psychologist and biostatistician with experience in prospective 
interventional trials and behavioral and/or psychosocial cardiology trials. The chair will 
have additional duties to review past minutes, conduct the meetings and review minutes 
prepared by the executive secretary. The DSMB developed an operational plan during 
the first six months of the study. The operational plan is similar to current plans the 
principal investigator has developed for ongoing trials funded by NHLBI and consistent 
with NHLBI’s Policy on Human Subjects Research: Data and Safety Monitoring Plans 
dated October 2011. The plan includes conflict of interest disclosure statements for 
each member, frequency and location of meetings, policies and procedures and 
dissemination of meeting materials, notification of NHLBI staff, data to be reviewed and 
procedures for evaluating data and reporting findings. The specific study functions and 
outcomes that the DSMB will review at each meeting include: dropout rate, baseline 
PHQ-8 scores, CES-D10 scores, and number receiving AHA diagnosis and treatment 
portions of the intervention protocol. The primary safety measures will be adverse 
events reports and 18-month PHQ-8 scores. Other items reviewed by the DSMB at 
each meeting will include: (a) data quality, completeness, and timeliness; (b)recruitment 
performance of each site; (c) adequacy of compliance with goals for recruitment and 
retention, including women and minorities; (d) protocol adherence; and (e) presence of 
factors that could adversely affect participant safety, study outcome or compromise data 
confidentiality. 
 
The Data Manager, under the direction of Dr. Cheung, will provide the DSMB with data 
reports on numbers of participants recruited into the trial, participant outcomes, and 
serious adverse reactions on a twice-yearly basis, or as determined by the DSMB. All 
investigators on this grant will be the decision-making body to implement policies and 
procedures and follow directives of the DSMB. The DSMB will determine if 
unanticipated events are related to the study, whether the study’s informed consent 
form and process needs to be modified, whether the study’s procedures need to be 
modified and whether the study should be discontinued due to serious adverse 
outcomes in either the control groups or in the intervention group. All data provided will 
be provided in a blinded fashion. The Steering Committee will serve as an additional 
oversight body to determine if the DSMB should be asked to meet sooner than 
anticipated based on the operational plan. 
 
Harms 
 
Since CODIACS-QOL is a screening trial, and not a treatment trial, the DSMB did not 
outline a list of reportable adverse events.  However, given the nature of our population, 
and that some trial arms will be receiving therapy(ies), we have listed unanticipated AEs 
that must be reported to the DSMB according to the following guidelines. 
 
The risk to participants will be minimal as the subjects will receive at least their usual 
medical care. We know of no study that has found that the type of intervention proposed 

29 
 
here has been associated adverse risk. Any adverse event (AE) or unanticipated 
problem will be identified, responded to, recorded by the site investigator, who will in 
turn ensure that the information is passed on (see Table below). If the AE or problem is 
unexpected, related to study involvement, and puts the participant at increased risk, it 
will be reported to the local IRB immediately, in accordance with local policies. These 
events will also be reported to Columbia University, which will collect and disseminate 
the information to the other sites and the DSMB. All other AEs and problems will be 
reported at the time of the biannual DSMB meetings. As this is a screening trial with a 
commonly used instrument, it is expected that no such events will occur. 
 
 
Adverse Events and Unanticipated Problems Reporting Timelines (modified from 
NHLBI guidelines on reporting SAEs and Ups) 
 
What Event is 
Reported 
When is Event 
Reported 
By Whom is 
Event Reported 
To Whom is Event 
Reported 
Fatal or life-
threatening 
unexpected, 
suspected serious 
adverse reactions 
Within 7 calendar 
days of initial 
receipt of 
information 
Investigator 
Local/internal 
IRBs/Institutional 
Officials 
 
Study coordinating 
center (who in turn 
report to DSMB) 
Non-fatal, non-life-
threatening 
unexpected, 
suspected serious 
adverse reactions 
Within 15 calendar 
days 
of initial receipt of 
information 
Investigator 
Local/internal 
IRBs/Institutional 
Officials 
 
Study coordinating 
center (who in turn 
report to DSMB) 
Unanticipated 
Problem that is not 
an SAE 
Within 14 days of 
the investigator 
becoming aware 
of the problem 
Investigator 
Local/internal 
IRBs/Institutional 
Officials 
 
Study coordinating 
center (who in turn 
report to DSMB 
 
Should a study-participation related, unexpected adverse event occur, the study 
cardiologist (Dr. Shimbo) and/or study psychiatrist (Dr. Shapiro) will review the 
circumstances of the event and report accordingly to the DSMB. Any serious adverse 
effects will be reported to the  CUIMC IRB. If any adverse outcomes might influence the 
continued participation of the participants, active participants will be informed. All 
participants will be provided contact information instructed to contact either the study 
coordinator or local PI in the event the participant would like to discuss any study-
related issue or adverse event that arises. 
 
 
 

30 
 
Procedures for Side Effects Due to Study Antidepressants: 
Participants will have all possible side-effects carefully described and explained before 
any course of anti-depressants is initiated. Site medication providers have undergone 
thorough training on the detection and management of side-effects with Dr. Shapiro, 
who remains available for consultation with the site medication prescribers. Below is an 
overview of what was taught, and will be followed for the trial: 
 
Strategies for Managing Antidepressant Side Effects 
General Strategies: 
1. Explore whether the side effects are ‘physical’ or ‘psychological’? 
2. Wait and support. Many side effects (i.e., GI depressive symptoms with SSRIs) will 
subside over 1-2 weeks of treatment. 
3. Lower the dose (temporarily). 
4. ‘Treat’ the side effects (see below). 
5. Change to a different antidepressant. 
6. Change to or add psychotherapy. 
 
Antidepressant Drug Interactions: 
All antidepressants are metabolized by the P450 isoenzyme system in the liver. Certain 
antidepressants inhibit specific subtypes of P450 enzymes and this may increase blood 
levels in participants who are taking other medications metabolized by the same 
isoenzyme systems. Care is advised in participants who are taking medications with a 
narrow therapeutic window such as digoxin, warfarin, anticonvulsants, or theophylline. It 
is advised to observe clinically for side effects from such medications and to 
recheck serum blood levels of such medications as the dose of the antidepressant is 
titrated upwards. 
 
Procedures for Discontinuation Syndrome:  
Abrupt discontinuation of short acting antidepressants can lead to an uncomfortable 
antidepressant withdrawal syndrome. All participants choosing anti-depressants 
will have this carefully explained, and will be monitored (by self-report) for continued 
adherence to their prescribed anti-depressant. Any participant reporting symptoms 
consistent with withdrawal syndrome will be reminded that their symptoms could be due 
to cessation of anti-depressant adherence, and will be urged to taper, rather than cease 
their medication use. Tapering will also be considered as appropriate when at stepped 
care decision points, an alternative medication is recommended 
 
Any AE or unanticipated problem will be identified, responded to, recorded by the site 
investigator, who will in turn ensure that the information is passed on. If the AE or 
problem is unexpected, related to study involvement, and puts the participant at 
increased risk, it will be reported to the local IRB immediately, in accordance with local 
policies. These events will also be reported to Columbia University, which will collect 
and disseminate the information to the other sites and the DSMB. All other AEs and 
problems will be reported at the time of the biannual DSMB meetings. 
 
Auditing 
Routine audits of data completion and timeliness will be overseen by the study data 
manager. 

31 
 
Ethics and Dissemination 
 
Research Ethics Approval 
This protocol and the template informed consent forms have been approved by 
Columbia University’s Institutional Review Board (IRB) with respect to scientific content 
and compliance with applicable research and human subjects regulations. The, 
participant education and recruitment materials, data collection forms, and Intervention 
manual have also been approved by the CUIMC IRB. Any subsequent modifications will 
also be reviewed and approved by the CUIMC IRB. Respective local site IRBs are 
required to approve protocol materials and a site-specific informed consent form. Each 
study site must submit verification of IRB approval to the Coordinating Center prior to 
the initiation of study activities. 
 
Subsequent to initial review and approval, Columbia University’s IRB, and the 
responsible local IRBs will review the protocol at least annually. The overall PI and site 
PIs will make safety and progress reports to the IRBs at least annually and within three 
months of completion of study visits. or completion at his/her site. These reports will 
include the total number of participants enrolled, reports to the DSMB, and any other 
requested reports. 
 
Protocol Amendments 
Any modifications to the protocol which may impact on the conduct of the study, 
potential benefit of the patient or may affect patient safety, including changes of study 
objectives, study design, patient population, sample sizes, study procedures, or 
significant administrative aspects will require a formal amendment to the protocol. Such 
amendment will be agreed upon by the overall PI, site PIs and co-investigators, and 
approved by the DSMB and responsible IRB prior to implementation and notified to the 
health authorities in accordance with local regulations. 
 
Administrative changes of the protocol are minor corrections and/or clarifications that 
have no effect on the way the study is to be conducted. These administrative changes 
will be agreed upon by the overall PI and site PIs, and will be documented in a 
memorandum. The responsible IRBs may be notified of administrative changes at the 
discretion of the PIs.  
Informed Consent 
The protocol and informed consent procedures will be approved by the Institutional 
Review Boards at each participating institution. Consent forms will be worded in 
language that a person with a 6th grade education can understand and will be available 
in English. At the time of enrollment, the staff member will give a complete description of 
the study to the participant in clear, easy-to-understand language. After reading and 
understanding the consent and the procedures, those who choose to participate will 
sign and date the consent. 
 
All staff involved in this study will have completed and passed GCP and HIPAA training, 
and will have been provided with materials and instruction in the proper and ethical 

32 
 
manner in which consent should be obtained. If a web-based or telephone consent is 
obtained, it will comply with all GCP and HIPAA regulations, and be IRB-approved. 
 
Confidentiality 
As part of the process involved in obtaining written informed consent, all participants will 
be reminded that their responses are confidential and that they may refuse to participate 
in the study or withdraw at any time without explanation, and further, that such an action 
will in no way affect their future interactions with their health care provider or the 
participating Medical Center.  
 
To ensure confidentiality, all study-related information will be stored securely at the 
study sites. When paper records are obtained, those containing names or other 
personal identifiers, such as locator forms, medical records, and informed consent 
forms, will be stored separately from study records identified by participant ID number. 
Forms, lists, logbooks, appointment books, and any other listings that link participant ID 
numbers to other identifying information will be stored in a separate, locked file in an 
area with limited access. All databases will be secured with password-protected access 
systems. Datasets for analysis will be associated with an individual participant only by 
an assigned identification number.  
 
All staff will have all relevant IRB and HIPAA training in the protection of human subject 
participants (Good Clinical Practice). 
Declaration of Interests 
All investigative staff has reported any conflicts of interest to their local IRB as part of 
the protocol approval process. 
Access to data 
Only authorized personnel, those who have official status as part of the authorized 
research team, will have access to any records containing identifiable participant data. 
Study personnel at local sites will only have access to their own site’s data, and will be 
limited by their “user-roles” (i.e. HealthPartners study personnel will only have access to 
HealthPartners participants, blinded coordinators will not have access to group 
allocation, or treatment information). 
 
The Clinical Coordinating Center will oversee the intra-study data sharing process.  
Post-trial care 
Participants found to have clinically significant depressive symptoms (PHQ 8 score ≥ 
10) at the 18-month visit/interview, will have their PCP and/or cardiologist notified. 
Dissemination policy 
Study results will be posted at ClinicalTrials.Gov within one year of study completion. 
Sites will be encouraged to send each participant a “Thank You” letter upon their 
completion of study participation. Additionally, it is suggested that, when data is 
analyzed, a brief lay person summary of the trial results be disseminated through 
patient communications at each respective site. A Publications and Disseminations 
Committee will be formed, and this committee will then create a policy/guideline for 

33 
 
authorship and review process of manuscripts and abstracts for publication or 
conference presentations.