Secondary Event Prevention Using Population Risk Management After PCI
Phase: NA
Conditions: Myocardial Ischemia, Rheumatic Diseases
Sponsor: VA Office of Research and Development

1 
CIRB 16-02 
Secondary Event Prevention using Population Risk Management After PCI and for Anti-
Rheumatic Medications (SEPPRMACI-ARM) 
Funding Agency: Department of Veterans Affairs 
(Note that the primary study is funded by VA HSR&D (95% of total budget) with a small 
supplementary grant from the University of Colorado Division of Rheumatology (5%)  
Principal Investigator/Study Chair: Dr. Caplan 
Ver.12 
March 6, 2019

2 
 
Abstract 
Optimal treatment of veterans requires the consistent use of a number of medications. 
The failure to adhere to prescribed medication regimen results in higher health care costs and 
poor outcomes, including greater rates of hospitalization across a wide spectrum of health 
conditions.1 
In the case of ischemic heart disease (IHD), for example, optimal treatment can require 
a number of medications to maintain or improve cardiovascular health. These medications 
include 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (“statins”), beta adrenergic 
receptor antagonists (“beta-blockers”), aspirin, and thienopyridines (“platelet inhibitors”) such as 
clopidogrel. Non-adherence to medications, however, is common2 and increases the risk of 
subsequent adverse cardiovascular events (CVE; i.e., cardiac death, myocardial infarction [MI], 
unstable angina).3 Our pilot data demonstrate that gaps in statin refills (i.e., an indicator of 
medication non-adherence) occur frequently in the year following percutaneous coronary 
intervention (PCI). Similarly, for the rheumatic diseases, optimal treatment requires the use of 
Disease Modifying Anti-Rheumatic Drugs (DMARDs), which are often used in combination. 
Non-adherence to DMARDs is also associated with poor outcomes in the rheumatic diseases.4 
To improve medication adherence rates, we propose to test a multi-faceted, targeted, 
patient-centered medication adherence intervention using a novel, modified stepped-wedge 
study design in two common and clinically important scenarios:  1) for patients with IHD 
following PCI and 2) for patients with chronic rheumatic diseases requiring DMARD therapy. By 
testing in two unrelated conditions, we hope to demonstrate the generalizability of our findings.  
This intervention will consist of: proactive real-time adherence monitoring of patients and 
targeting of individuals only when they have exhibited non-adherence behavior (i.e., if patients 
have not refilled their medication more than 4 or 7 days after it was due to be refilled). The 
intervention will employ a tailored, escalating-intensity approach which begins with some 
combination of personalized short messaging service (SMS) text messages and interactive 
voice response (IVR) telephone technology, depending on patient preference. Patients failing 
SMS and then IVR by not refilling their medication (or declining SMS and failing IVR) escalate to 
a trained research interventionalist (typically, a clinical pharmacist). The interventionalist will 
contact the patient and address adherence barriers based on the dimensions outlined by the 
World Health Organization (WHO) that are specific to each patient.  
We will test the intervention on IHD patients who have recently undergone PCI–a 
cardiac procedure commonly used among IHD patients to improve the heart’s blood flow. We 
will also separately test the intervention on patients seen for chronic rheumatic conditions such 
as rheumatoid arthritis and spondyloarthritis followed in rheumatology outpatient clinics. The 
intervention will recruit from four Veterans Affairs Medical Centers (VAMCs) with VA Cardiac 
Catheterization Laboratories (CCLs) and rheumatology clinics, while 12 sites with CCLs and 
rheumatology clinics will serve as usual care controls. This novel approach provides greater 
statistical power by supplementing the pre-intervention/usual care observation periods of a 
stepped-wedge design with concurrent usual care observation periods from 12 additional sites. 

3 
 
List of Abbreviations 
IHD – Ischemic Heart Disease 
CVE – Cardiovascular Events 
PCI – Percutaneous Coronary Intervention 
DMARDs – Disease Modifying Anti-Rheumatic Drugs 
SMS – Short Messaging System 
IVR – Interactive Voice Response 
WHO – World Health Organization 
VAMCs – Veterans Affairs Medical Centers 
CCLs – Cardiac Catheterization Laboratories 
PDC – Proportion of Days Covered 
ICE – Incremental Cost Effectiveness 
ICERs – Incremental Cost Effectiveness Rations 
ACS – Acute Coronary Syndrome 
CART – Clinical Assessment, Reporting and Tracking Program 
RCT – Randomized Controlled Trial 
CONSORT – Consolidated Standards of Reporting of Trials 
CDW – Corporate Data Warehouse 
MI – Myocardial Infarction  
CABG – Coronary Artery Bypass Graft 
VSF – Vital Status File 
ICD-9-CM – International Classification of Diseases, 9th Revision, Clinical Modification 
CPT – Current Procedural Terminology 
SD – Standard Deviation 
ISPOR – International Society for Pharmacoeconomics and Outcomes Research 
CHEERS – Consolidated Health Economic Evaluation Reporting Standards 
PBM – Pharmacy Benefits Management 
CITI – Collaborative IRB Training Initiative 
DSMB – Data Safety Monitoring Board 
 
 

4 
 
Contents 
Protocol Title: ............................................................................................................................. 5 
1.0 
Study Personnel .............................................................................................................. 5 
2.0 
Introduction ..................................................................................................................... 5 
3.0 
Objectives ....................................................................................................................... 6 
4.0 
Resources and Personnel ............................................................................................... 7 
5.0 
Study Procedures ............................................................................................................ 8 
5.1 
Study Design ............................................................................................................... 8 
5.2 
Recruitment Methods ..................................................................................................10 
5.3 
Informed Consent Procedures ....................................................................................11 
5.4 
Inclusion/Exclusion Criteria .........................................................................................11 
5.5 
Study Evaluations .......................................................................................................12 
5.6 
Data Analysis ..............................................................................................................20 
5.7 
Withdrawal of Subjects ...............................................................................................21 
6.0 
Reporting ........................................................................................................................22 
7.0 
Privacy and Confidentiality .............................................................................................22 
8.0 
Communication Plan ......................................................................................................24 
9.0 
References .....................................................................................................................26 
 
 
 

5 
 
Protocol Title:  
Secondary Event Prevention using Population Risk Management After PCI 
and for Anti-Rheumatic Medications (SEPPRMACI-ARM) 
 
1.0 
Study Personnel 
 
Principal Investigator/Study Chair: Dr. Liron Caplan - liron.caplan@ucdenver.edu  
Principal Investigator: Dr. Michael Ho - michael.ho@va.gov 
Co-Investigators:  
Dr. Tom Maddox - tom.maddox@va.gov 
Dr. Steve Zeliadt - steve.zeliadt@va.gov 
Dr. Keith McInnes - keith.mcinnes@va.gov    
Collaborators:  
Dr. Anna Baron - anna.baron@ucdenver.edu 
Dennis Plomondon – dennis.plomondon@va.gov 
Colin O’Donnell – colin.odonnell@va.gov 
Gary Grunwald – gary.grunwald@va.gov 
Thomas Glorioso - thomas.glorioso@va.gov 
Ryan Duong - ryan.duong@ucdenver.edu 
Eric Gunnink – eric.gunnink@va.gov 
Study Coordinator: 
Kyle Brees- kyle.brees@va.gov     
 
2.0 
Introduction 
IHD and rheumatic diseases are both pervasive, expensive, and results in grave health 
consequences. IHD affects an estimated 15.4 million Americans ≥20 years of age—
representing 6.4% of the adult population.5 The direct and indirect cost of IHD has been 
estimated at $195.2 billion,6 with a doubling of cost projected by 2030.5  Similarly, the direct cost 
to the U.S. workforce for rheumatoid arthritis alone approaches $5.8 billion yearly.7 
Widely-accepted national evidence-based guidelines support the use of cardio-protective 
medications to reduce the risk of adverse consequences resulting from IHD and DMARDs to 
reduce the risk of adverse consequence in rheumatic diseases. For example, numerous 

6 
 
rigorously conducted randomized trials show that statins improve outcomes and reduce 
mortality in patients with established cardiovascular disease (i.e., secondary prevention),8,9,10 
including those undergoing PCI.11,12  The use of statins and beta-blockers have been repeatedly 
demonstrated to be cost-effective in lowering CVE event rates, in part by their effects on 
cholesterol13,14,15,16 and blood pressure, respectively.17 ,18  Accordingly, the most recent VA 
performance measures and American Heart Association guidelines encourage the use of statins 
in patients with atherosclerotic disease; beta-blockers in subjects with left ventricular systolic 
dysfunction (ejection fraction ≤40%), prior MI, or blood pressure of 140/90 or greater; and 
clopidogrel following any acute coronary syndrome (ACS) or PCI with stent.19 The rheumatology 
literature provides similar evidence for the benefit of DMARDs in rheumatic diseases,20,21 and 
guidelines strongly endorse their use.22 
Unfortunately, non-adherence to medications is common,2,23,24 and increases the risk of 
poor outcomes.3,25  Our 2011 national preliminary data from VA CCLs demonstrate that over 
6300 patients experienced at least one refill gap of >= 7 days for statins in the year following 
PCI. The mean PDC for these patients was only 75%—below the PDC threshold of 80% that 
typical defines adherent patients, based on the empiric evidence for effectiveness of 
medications at this cut-point.26  Non-adherent patients were present at all CCLs without 
substantial variation in mean PDC by center, suggesting a global problem.   
Systematic problems underlie and contribute to non-adherence to medications. Usual 
care of IHD and rheumatic disease patients is encumbered by systematic deficiencies including: 
passive monitoring (contact with patients only when initiated by the patient) and inefficiency 
(time-consuming patient-by-patient approach, rather than through population management). The 
proposed intervention addresses both the complex patient-specific factors (emphasizing 
forgetfulness and carelessness) and the systematic inadequacies using a multi-modal, 
escalating approach.  
3.0 
Objectives 
1. To assess the effectiveness of a multi-faceted patient-centered intervention versus usual 
care in improving medication adherence as measured by proportion of days covered 
(PDC, primary outcome). This will be tested among IHD patients for statins, beta-
blockers and clopidogrel in the year after PCI and among rheumatology clinic patients 
chronically prescribed DMARDs. Hypothesis: The PDC for patients in the intervention 
arm will exceed the PDC for the usual care arm by a 10% absolute difference. 
2. (Secondary outcome): To determine the effectiveness of a multi-faceted patient-centered 
intervention versus usual care in reducing secondary CVEs (myocardial infarction [MI], 
repeat revascularization [PCI or coronary bypass graft], and all-cause mortality) among 
IHD patients at 18 months post-PCI and progressive erosive disease demonstrated on 
plain film radiographs in patients with rheumatic diseases (i.e. “radiographic 
progression”). Hypothesis: The rate of CVEs and radiographic progression will be 5% 
relatively lower for patients in the intervention arm compared with usual care. 

7 
 
3. (Secondary outcome): To establish the cost to implement and maintain the intervention, 
above the cost of usual care, as well as the incremental cost effectiveness (ICE; e.g. 
cost to achieve at 10% improvement in PDC; cost per CVE prevented). Hypothesis: This 
aim does not posit a hypothesis as the objective is descriptive. The available funding for 
this project limits this outcome to IHD patients (no rheumatic disease patients will be 
analyzed according to cost). 
4.0 
Resources and Personnel 
Dr. Liron Caplan is the Principal Investigator of the study. Dr. Caplan will focus on the 
design, logistic, and analytic aspects of the study. He will have access to protected health 
information and will perform data analysis. Denver - Grade 15. 
Dr. Michael Ho is the Co-Principal Investigator of the study. Dr. Ho will focus on the 
clinical and design aspects of the study.  He will have access to protected health information 
and will perform data analysis. Denver - Grade 15. 
Dr. Tom Maddox is a Co-Investigator for the study. As Director of the VA’s Clinical 
Assessment, Reporting, and Tracking (CART) Program, Dr. Maddox will focus on clinical 
aspects of the study and recruitment. He will have access to protected health information and 
will perform data analysis. Denver - Grade 15. 
Dr. Steve Zeliadt is a Co-Investigator for the study. As a health economist, Dr. Zeliadt 
will focus on designing and supervising the cost analyses. He will have access to protected 
health information and will perform data analysis. Seattle - Grade 14. 
Dr. Keith McInnes is a Co-Investigator for the study. As an infomatician, Dr. McInnes will 
focus on the design of the texting and interactive voice response (IVR) telephone calls. Bedford 
- Grade 13. 
Dr. Anna Baron is a biostatistician. Dr. Baron will focus on designing and supervising the 
analysis of the main outcomes for the intervention. She will have access to protected health 
information and will perform data analysis. Denver - IPA at a level compatible with Grade 14. 
Eric Gunnink is an Analyst. Eric will focus on executing the cost analyses. He will have 
access to protected health information and will perform data analysis. Seattle - Grade 14. 
Dennis Plomondon is a consultant for the study. Dennis will focus on development of the 
IVR/SMS intervention. He will have access to protected health information and will perform data 
analysis. Denver 
Thomas Glorioso is an Analyst. Thomas will focus on executing the randomization and 
analysis of the main outcomes for the intervention. He will have access to protected health 
information and will perform data analysis. Denver - IPA at a level compatible with Grade 12. 

8 
 
Colin O’Donnell is an Analyst. Colin will focus on executing the randomization and 
analysis of the main outcomes for the intervention. He will have access to protected health 
information and will perform data analysis. Denver - IPA at a level compatible with Grade 13. 
Gary Grunwald is an Biostatistician. Dr. Grunwald will focus on designing and 
supervising the analysis of the main outcomes for the intervention. He will have access to 
protected health information and will perform data analysis. Denver - IPA at a level compatible 
with Grade 14. 
Ryan Duong is a Collaborator of the study. He will have access to protected health 
information and will perform data entry and data cleaning. Denver - Grade 2. 
Kyle Brees is the Study Coordinator. He will have access to protected health information 
and will perform data analysis, particularly related to tracking of recruitment and data quality 
checks. Denver - IPA at a level compatible with Grade 7. 
Local site investigators. The local site investigator (LSI) will be the Cardiac 
Catheterization Lab Director or Clinic Director at each study site. The LSI will attend the training 
session during which the research interventionalist will be educated and trained. The LSI will 1) 
serve as a local resource for additional training needs by the interventionalist, 2) provide local 
administrative oversite (i.e. obtain and maintain local R&D approval, and 3) guarantee the 
inclusion of the Patient information Sheet in the discharge paperwork for all local subjects. 
5.0 
Study Procedures 
5.1 
Study Design 
This is essentially two concurrent 4-year 
multi-site cluster stepped-wedge RCTs that 
tracks each subject for 18 months. The RCTs are 
executed simultaneously in two conditions (IHD 
and chronic rheumatic disease) at the same 
VAMCs, with enrollment periods (“observation 
phases”) of 6 months’ duration. At the 4 
intervention sites, which will be rolled-out through 
4 phases (see Figure 1), subjects undergo 
prospective monitoring for med refill gaps, with 
deployment of a multifaceted, tailored program. 
The program assists veterans using SMS, and if 
necessary, escalates to IVR, and then to 
research interventionalists. The intervention will 
determine the specific reasons for non-adherence 
for each veteran and then, based on the 
individual’s needs: facilitate drug refills, counsel 
patients on correct medication usage, simplify 
drug regimens, provide low literacy instructional 
 
 
Traditional 
Stepped Wedge 
Design 
  
Additional  
concurrent 
randomized 
control/usual 
care sites  
(novel 
modification) 
 
CCL = Cardiac Catheterization Laboratory 
(number randomly assigned) 
 = control period of observation 
 = intervention period of observation 
Each empty or full box represents a recruitment 
cohort of 30 additional subjects, on average. 
 
Observation phase 
CCL# 1 
2 
3 
4 
5 
1 
     
2 
     
3 
     
4 
     
5 
     
6 
     
7 
     
8 
     
9 
     
10 
     
11 
     
12 
     
13 
     
14 
     
15 
     
16 
     
Figure 1: Study Design 

9 
 
materials, facilitate communication with providers for adverse drug reactions, and engage in 
conversation about changing non-adherent behavior  Twelve control sites, matched according 
to PCI volumes & baseline adherence (median PDC), will deliver usual care.  
Our  investigation employs modifications to the classic stepped-wedge trial design by 
collecting data from concurrent controls/usual care sites (CCL#5-16 in Figure 1, as well as the 
rheumatology clinics at these sites) in addition to the typical pre-intervention/usual care 
observation periods (open boxes, CCL#1-4 in Figure 1). Because the infrastructure already 
exists to collect pharmacy data from patients treated at all CCL’s, we are able to obtain this 
additional control data. Our statistical simulations suggest this will enhance the power of our 
study.  
For the first clinical scenario (IHD), patients discharged after PCI at any one of the four 
intervention sites who fill at least one prescription from one of the three qualifying medication 
classes (statins, beta-blockers, thienopyridines) will be monitored for medication refill gaps. The 
monitoring will occur daily through automated queries of pharmacy dispensing data, leveraging 
the considerable infrastructure of the VA’s Clinical Assessment, Reporting, and Tracking 
(CART) Program. We have already developed these queries to identify when patients will need 
to refill their medications, based on the most recent medication refill date and the number of 
days supplied, but have not previously incorporated this in a real-time intervention. In the 
current study, patients with a refill gap (4 days for clopidogrel, 7 for all other medication classes) 
will be contacted in a manner that allows for simple refilling of their medication, thereby 
addressing a common cause of missed doses.22 The intervention modality will escalate through 
increasingly more intensive components, including SMS (only if patient opts in to allow SMS 
during an initial IVR call), then IVR, then research interventionalist assistance (clinical 
pharmacist), then notification of Primary Care Provider or Patient Aligned Care Team. Further, 
in order to make study subjects’ primary care team aware of a subjects’ participation in the 
study, a note will be included in the participants’ electronic medical record indicating their 
participation in the study.    
For the second clinical scenario (rheumatic diseases), patients followed in rheumatology 
clinics with diseases such as rheumatoid arthritis and spondyloarthritis who have recently filled 
at least one DMARD prescription will be monitored for medication refill gaps. The monitoring will 
occur weekly through automated queries of pharmacy dispensing data, as developed by 
analysts associated with the local pharmacy service. Since all VAMCs with Cardiac Care 
Laboratories also have rheumatology clinics, the rheumatology intervention will be conducted 
simultaneously with the IHD-intervention and at the same VAMC sites, based on the 
randomization assignment used for the IHD-intervention (described below). This approach to 
randomization is necessary because it simplifies an already complicated randomization 
procedure and allows for more efficiency by hiring interventionalists/clinical pharmacists at fewer 
sites than if the IHD and rheumatology site assignments are performed independently. The 
intervention approach (SMS, IVR, and pharmacist) will be identical to that of the IHD 
intervention, but with content adapted to DMARDs. 

10 
 
To protect confidentiality, whenever possible, study records will identify patients only by 
unique study number. The only exception will be the tracking database that will include the 
patient’s name, SSN, and telephone number which will be used to obtain pharmacy data from 
the CDW following PCI and to validate CV events in the medical record. Access to the database 
and study records will be limited to research staff. All paper records will be maintained in locked 
file cabinets within locked offices. Electronic data files will be encrypted/password-protected and 
user-restricted on computers maintained in a secure environment behind the VA firewall per VA 
security regulations. All data will be maintained in accordance with the VHA Records Control 
schedule 10-1 (v.January 2016).  
5.2 
Recruitment Methods 
This study will employ an approach to consent similar to SDP-179 Hybrid Effectiveness-
Implementation Study to Improve Clopidogrel Adherence which has previously been approved 
by CIRB (CIRB Protocol #12-12) The study will enroll all subjects undergoing PCI or using 
DMARDs at 16 VA Medical Centers (conservatively estimated at n~300 subjects from 
intervention periods at 4 sites and n~2100 at control sites for each intervention: IHD and 
rheumatic diseases; n=4800 subjects total for both RCTs). These Medical Centers are all 
tertiary referral hospitals within their respective VISN and provide a full spectrum of cardiac and 
rheumatologic care services. 
Recruitment/Consent for clusters (CCLs):  The National Program Director for 
Cardiology, Director of the National CART Program, Chair of the VA Rheumatology Field 
Advisory Committee, and President of the VA Rheumatology Consortium all strongly endorse 
this proposal and have committed to assist with recruitment of sites. Over sixty 
CCLs/rheumatology clinics are available from which to select the 16 study sites, CCL and 
Rheumatology Clinic Directors will provide formal “site-level consent” --i.e. commitment in 
writing to institute the protocol--that submits their catheterization laboratory to randomization. 
Recruitment/Consent for individual veterans:  For the IHD intervention, following their 
PCI and prior to discharge from the CCL, patients at intervention sites will be informed of the 
study. This will be achieved through a written Information Sheet that is distributed to all patients; 
it will consist of an IRB-approved document explaining the purpose of the study and intervention 
details. Individuals at the intervention site will be given the information sheet and will be called 
by a member of the study team within a few days to see if the potential participant is interested 
in participation in the study. If the individual is interested in participating then the elements of 
consent will be reviewed at that time with verbal consent if the patient agrees to participate 
(Waiver of Documentation of Informed Consent and Waiver of HIPAA are requested). For the 
rheumatic disease intervention, patients will be informed of the study by receiving a written 
Information Sheet at the end of their regularly scheduled clinic visits and will be called by a 
member of the study team to undergo the same verbal consent process used in the IHD 
intervention group if there is interest in participating.   
For the control group sites, a waiver of HIPAA authorization and a Waiver of Informed Consent 
for access and use of the data will be requested. 
 

11 
 
Randomization 
Unit of randomization:  In order to prevent cross-contamination of the intervention, a 
clustered design is being used with randomization at the level of CCL, rather than at the patient 
level.  Rheumatology Clinic assignment follows CCL assignment; that is, rheumatology clinics at 
each site allocated to the same treatment arm (intervention or control) as the CCL at that site.  
Procedures:  CCLs Directors and Rheumatology Clinic Directors will agree in writing that 
their CCLs (and the associated rheumatology clinic at each VAMC) will be randomized to 
intervention or control/usual care. A two-stage randomization procedure will be employed. First, 
consented CCLs will be grouped with the most similar sites, in terms of baseline PDC and PCI 
volumes. Using the median PDC and median PCI volume for all consented CCLs, each site will 
be assigned to one of four groups:  high PDC/high PCI volume, high PDC/low PCI volume, low 
PDC/high PCI volume and low PDC/low PCI volume. From each group of 4 consented CCLs, 
one site will be randomized to intervention and three will be randomized to control. In the 
second stage, the four intervention sites will undergo randomization to determine the order that 
sites roll-out the intervention, as is typical of stepped-wedge designs. 
Sequence Generation: Randomly permuted blocks with four centers per block (matched 
according to annual PCI volumes and center PDC) will be generated using computer-derived 
assignments. 
5.3 
Informed Consent Procedures 
For the Intervention sites, we are submitting a Waiver of Documentation of  Informed Consent 
and utilizing a verbal consent processas described above. For the Control sites, a Waiver of 
Informed Consent will be requested. 
5.4 
Inclusion/Exclusion Criteria 
Eligibility for clusters (CCL sites): In order to qualify for inclusion in the study, CCLs 
must have performed 20 PCIs within the prior year (to ensure adequate study power). In 
addition, the Directors of the local CCL and Rheumatology Clinic must agree to institute the 
intervention if randomized to the intervention arm. CCLs and rheumatology clinics with on-going 
interventions to improve med adherence will be excluded. 
Eligibility for individual veteran participants: Patients will qualify for inclusion if they 
1) undergo PCI or are prescribed a DMARD; 2) are prescribed any of the following medications: 
a statin, beta-blocker, or thienopyridines (IHD intervention) and hydroxychloroquine, oral 
methotrexate, sulfasalazine, azathioprine, leflunomide, or tofacitinib  (rheumatic disease 
intervention)  [Note: as a study focused on adherence, we will NOT address the 
appropriateness of prescribed medications, which is an important, but separate issue]; 3) 
receive their care from the VA.  This is defined by the presence of a VA-assigned-PCP in the 
year prior to PCI or in the year following PCI (IHD intervention) or in the year prior to or following 
index DMARD prescription (rheumatic disease intervention). Patients will be excluded under the 
following circumstances: 1) undergoing only diagnostic catheterization; 2) receive their index 
medicines (listed in item 2 above) from a non-VA source; 3) discharge to nursing home or 

12 
 
skilled nursing facility; 4) individuals with impaired decision making capacity, prisoners, or 
pregnant women, or the terminally ill 
5.5 
Study Evaluations 
Data sources: Data sources for this project are described in  Table 1 on the following 
page. 
Procedural Outcomes/RE-AIM framework: To assess the potential for broader 
implementation of the intervention following this study we will use the Reach-Efficacy-Adoption-
Implementation-Maintenance (RE-AIM) framework. Major items in the RE-AIM framework are 
mapped to specific aspects of the study, as described below. 
Reach: Measurements of intervention delivery will be tracked by summarizing the 
numbers/proportion of enrolled subjects, number of excluded subjects, reason for exclusion and 
representativeness of subjects at intervention sites compared to a) control sites and b) the 
national population of veterans receiving PCIs or DMARDs. 
 Table 1: Data sources 
 
 
 
Efficacy: The primary measures of efficacy appear below for Aims 1-2 under the sub-title 
“Outcomes” (page 13). We will also perform a sub-analysis specifying the incremental benefit 
(% adherence achieved) for each intervention component. As a descriptive study, Aim 3 does 
not include measures of Efficacy.  
Adoption: We will report the absolute number, proportion, and representativeness of 
CCLs and rheumatology clinics willing to initiate the program. 
Implementation: At least 3 procedures will assess the fidelity of the study execution and 
intervention protocol at both the level of CCLs/rheumatology clinics and individual subjects, 
including: 
Source 
Data/Variables 
Clinical Assessment Reporting and Tracking 
(CART) 
Indication for PCI (ACS/non-ACS), demographic data (age, 
gender), IHD risk factors 
Pharmacy Benefits Management (PBM) 
National drug price data, Proportion of Days Covered for 
target medication classes 
VA Vital Status File (VSF) 
CV events 
VA’s Corporate Data Warehouse (Inpatient, 
Outpatient, Pharmacy, Vital Signs, Laboratory 
production domains) 
CV events 
IHD and rheumatic disease risk factors (e.g. diabetes, 
hypercholesterolemia for IHD; smoking for rheumatic 
diseases) 
IVR technology database and clinical 
pharmacists 
Veterans’ preferences for various communication 
modalities 
CV events outside the VA system 
PHQ-9 and GAD-7 results. 
Training time for staff 
Research interventionalist (clinical pharmacist) time to 
administer interventions, reasons for non-adherence, and 
specific actions taken to ameliorate non-adherence 
VA Electronic Medical Record (CPRS, CAPRI, 
VistaWeb) containing annual radiographs  
Presence of radiographic progression 

13 
 
1. Site visits to intervention CCLs/rheumatology clinics by the study PIs or study 
coordinator occurring annually to monitor study documentation and performance of the 
intervention. 
2. Centralized enrollment monitoring consisting of monthly downloads of PCI procedural 
volumes using CART data or DMARDs using CDW for intervention and control sites and 
comparison of volumes with each CCL or rheumatology clinic’s historical volumes. 
Numbers of SMS, IVR, and research interventionalist activities will be complied each 
month using centralized tracking software compared to PCI and DMARD volumes to 
gauge use of the intervention. External sites will enter data using secure logins. 
Specifically, they will employ user-restricted remote access from their VA workstation to 
the research server located at the Denver VAMC which contains the data. All of this will 
occur behind the VA firewall. 
3. Assessment of research interventionalists’ performance will be done by having a mock 
patient contact each interventionalist every 3 months. The mock patient will be the study 
coordinator. The study coordinator will describe a real-world barrier to adherence and 
the interventionalists’ actions will be reviewed. Research interventionalists will be 
unaware of which patients serve in the capacity (to avoid the “Hawthorne effect”23) and 
the barrier described will vary over the course of the study, such that all domains of the 
WHO framework are represented.  
 
Maintenance: The PDC effect size will be compared for subjects in the first 6 months 
after PCI and greater than 6 months after PCI. In the final 6 months of the project, we will survey 
the CCLs directors at intervention sites to determine whether they intend to continue the 
intervention after the study terminates and if not, the reasons for discontinuation. We will also 
assess the persistence of the intervention by reporting subjects’ PDC after the 18 month active 
intervention period for a period up to 3 years post-PCI, until the termination of the last 
observation period. 
Outcomes: 
Determination of outcome for Aim 1 (Proportion of Days Covered, PDC) The PDC for the 
targeted medication classes will be calculated for patients with any 4 day (clopidogrel) or 7 day 
(other medication classes) gap at both intervention and control sites using Corporate Data 
Warehouse (CDW) pharmacy files that are regularly exported into the CART system (i.e. an 
intention to treat analysis) and available to analysts affiliated with the principal investigator. 
Thus, if the median PDC from all control observation periods was 75%, then a median PDC of 
85% from intervention periods would meet the primary end point (85-75=10). PDC is a measure 
of med adherence based on fill dates and days’ supply for each fill of a prescription that adjusts 
for overlapping scripts. The PDC provides logistical advantages over other measures of 
adherence in that it summarizes data from multiple medications27, has established cut-points 
based on empiric evidence26, and is endorsed by the Pharmacy Quality Alliance.28  
A historical data pull (including medication, labs, vitals, inpatient and outpatient visits) 
will go back three years to establish baseline comorbidities and adherence levels at each site. 
This data will only include retrospective information, rather than prospective results that reflect 
the potential impact of the intervention.  

14 
 
Determination of outcome for Aim 2 (CVEs for IHD patients; radiographic progression for 
rheumatic disease patients)  For the IHD intervention, the outcome will consist of CV events 
including hospitalization for myocardial infarction (MI) or unstable angina, coronary artery 
bypass graft (CABG), or all-cause mortality at 18 months following index PCI. CVEs will be 
reported as a cumulative binary (yes/no) variable for each patient and will be censored after the 
initial post-PCI event. CVEs will be identified through a number of mechanisms: 1) case finding 
based on administratively coded data derived from the VA’s CDW; 2) search of CART records; 
3) queries of the VA Vital Status File (VSF); 4) keyword text searches via the VA’s national 
electronic medical record-based interface (i.e. VISTA CAPRI) ), and 5) an IVR call placed at the 
end of the observation period to the patient’s home to identify CVE’s not occurring in the VA 
system.. The administrative data queries will search for International Classification of Diseases, 
9th and 10th Revision, Clinical Modification (ICD-9-CM) diagnostic codes, and Current 
Procedural Terminology (CPT) codes in these data sources (see Table 2). We have previously 
published on the validation of these coding algorithm approaches. The coding for each event 
will be based on previously published algorithms, which we have validated.29,30 
Table 2: Coding algorithms used in present study for definition of CV event and related comorbidity 
Outcome 
Reference 
ICD-9-CM and CPT codes 
Cost 
MI 
31 32 
410.x 
411.x 
412.x 
413.x 
414.x 
429.2 
v45.81 
 
$29800 33,34 
PCI 
37 
36.01 
36.02 
36.05 
36.06 
36.07 36.09 
0.66 
99.10 
$10000 35,36 
CABG 
37 
36.1x 
  
  
  
  
  
 
 
$45,358 38 
ICD-9-CM=International Classification of Disease-9; CPT=Current Procedural Terminology; MI=myocardial 
infarction; PCI=percutaneous coronary intervention; CABG=coronary artery bypass graft.  
 
 
We rationalized our choice of outcome time interval (18 months observation period), 
based on the fact that the benefits of aggressive medical management can become apparent in 
a relatively short interval.39   
For the rheumatic disease interventions, patients’ regular annual radiographs will be 
classified by a rheumatologist blinded to group assignment as either “progressive erosive 
disease” compared with most recent baseline plain film radiographs or “stable”.  This 
assessment will be based on the appearance of new boney erosions or worsening severity of 
existing boney erosions.  This assessment, based on chart reviews, will be determined for a 
random sampling of 100 intervention subjects and 100 control subjects with rheumatic diseases. 
Sensitivity analyses will assess the potential impact of CVEs or radiographic progression 
not captured by VA data sources due to deaths occurring outside the health system and the 
results at 18-24 months following index PCI or DMARD prescription for patients with available 
follow-up.  
Exploratory outcome: Depression and anxiety will be assessed in a random sampling of 
100 intervention subjects for each clinical scenario (100 out of the 300 intervention IHD subjects 
and 100 out of the 300 rheumatic disease subjects).  Specifically, the Patient Health 
Questionnaire-9 (PHQ-9)  and GAD-7, administered via IVR call to the patient’s home at the end 

15 
 
of the observation period will be used to determine if patients with more frequent texts, IVR 
calls, and pharmacist intervention are more likely to perceive themselves as experiencing 
depression and/or anxiety.  Patients endorsing suicidality on any call or via the PHQ-9 
responses will be immediately referred to the VA Suicide Prevention Hotline.  The research 
coordinator or PI will call the patient directly and then, with patient consent, establish a 3-way 
call with the Hotline.  All study staff, including interventionalists, will review the VA’s National 
Mental Health Safety Plan as part of the study training.  
Determination of outcome for Aim 3 (Cost) The cost of the intervention will be reported in 
terms of specific activity, which appear below (see Included Costs, below), as well as for the 
intervention as a whole (cost to implement the intervention per CCL site). For the purpose of 
determining the ICER, we will employ outcomes related to those in: 
Aim 1: cost to achieve a 10% improvement in PDC. This threshold was determined as 
“clinically relevant” by the practicing cardiologists participating in this proposal. 
Aim 2: cost per CVE prevented. While CVEs represent an exploratory outcome, the 
considerable expense of CVEs justifies their inclusion in constructing the business 
case for the intervention.  
  
Details of the intervention: The intervention is depicted in Figure 2. 
Tailoring of the intervention: This study adopts a holistic approach to the problem of non-
adherence that recognizes non-adherence as a complex, multifaceted phenomenon best 
addressed by tailoring both the content (i.e. the underlying reasons for non-adherence unique to 
each patient) and the intervention modality (i.e. each patient’s preferred means of interacting 
with the health care system). While IVR and SMS provide simple, rapid, efficient,40 and novel 
Initial IVR 
(offer 
SMS)  
Research 
interventionalist* 
[6 to 11] 
SMS  
Prompt  
[4 or 7] 
Refill gap 
Begins with either 
SMS or IVR 
(depends on 
patient preference 
elicited in initial 
IVR call) 
IVR - Self 
Generated* 
[4 to 9] 
Notify 
PCP/PACT*  
[8 to 13] 
Refill gap “resets”; no 
further intervention 
until 30 days after last 
gap began. 
 Gray arrows denote the escalation of the intervention to a more intensive 
component in the event that patient is prescribed but fails to refill any of the 
qualifying medications (statins, beta-blockers, thienopyridines for IHD 
intervention; DMARDs for rheumatic disease intervention.) 
* Step that incorporates WHO Dimension-based actions (Table 3, below, page 16).  
Numbers in brackets refer to the days elapsed since the most recent refill gap began. 
IVR = Interactive Voice Response telephone technology; SMS = Short Messaging Service 
(texts);  PCP = Primary Care Provider; PACT = Patient Aligned Care Team (inter-disciplinary 
accessible, coordinated, comprehensive, patient-centered care teams, managed by 
primary care providers); DMARDs = Disease Modifying Anti-Rheumatic Drugs 
Figure 2: Intervention Flow 

16 
 
methods for addressing veterans’ most common reason for medication non-adherence,41 the 
intervention also recognizes the complicated nature of adherence barriers, and incorporates an 
appropriately multifaceted research interventionalist-led component. 
Trigger to activate intervention:  We will obtain daily updates of pharmacy fulfillment data 
with computerized monitoring of this data to identify patients with refill gaps of 4 (dual anti-
platelet therapies) to 7 (all other medication classes) or more days within 18 months following 
the hospital discharge of their index PCI or a randomly selected qualifying DMARD prescription. 
Specifically, for all eligible subjects starting on the evening following the index PCI or DMARD 
prescription, pharmacy data will be securely downloaded from local VistA pharmacy files into 
the IVR scripts and medication adherence software that we developed in prior studies. Since its 
deployment in December 2006, we have adapted this software to monitor med adherence using 
pharmacy data (including medication name, dose, dosing frequency, date dispensed and 
number of days supplied). In order to activate the intervention in real time, we will not measure 
adherence using medication possession ratio, as this is insensitive in the real-time environment. 
All subjects with a 4 or 7 day gap beyond the “date dispensed + number of days supplied” for 
any of the eligible medication classes—as detected by the software program that runs nightly—
will receive the intervention, escalating from SMS (if a preference for SMS was indicated in the 
initial IVR call), to IVR after 48 hours, to the research interventionalist, if there is no response 
from subjects after another 48 hours, and finally to the patient’s Primary Care Provider (PCP) or 
Patient Aligned Care Team (PACT; inter-disciplinary accessible, coordinated, comprehensive, 
patient-centered care teams, managed by primary care providers) if there is no response from 
subjects after another 48 hours.  
Intervention components:  
1. IVR telephone calls will notify patients of the refill gap, provide patients with the 
opportunity to indicate the reason for this gap (side effects, cost of medication, confusion 
about how to take the medication),allow them to efficiently refill the medication (“If you 
simply forgot to request a medication refill and would like a new refill mailed to you, 
press 4”), and provide veterans the opportunity to receive texts in the event of 
subsequent refill gaps. If necessary, the IVR will facilitate contact with a research 
interventionalist to address adherence barriers. We have successfully employed IVR to 
address med adherence for patients following ACS.42  
2. Short Messaging Service texts will similarly notify patients of refill gaps. During an 
initial IVR call, those patients electing to incorporate SMS into their intervention will 
provide a mobile telephone number. For all subsequent refill gaps, patients will initially 
receive a text (rather than an IVR call) notifying them of the gap with instructions that 
simplify the refill process. Specifically, the text would provide the patients with the 
number to call into the IVR system and potentially connect them to a research 
interventionalist who would provide further assistance.   
3. Research interventionalist engagement: For subjects who do not refill medications in 
response to the IVR call and/or SMS text, a research interventionalist located at each 
intervention site will call the patient and pursue a tailored strategy based on the WHO 

17 
 
dimensions of adherence barriers using actions supported by scientific evidence43 (see 
Table 3). This theoretically-driven and comprehensive framework acknowledges that 
intervention strategies for individual patients must address the challenges and 
circumstances specific to each unique occurrence of a refill gap. Research 
interventionalists will follow an algorithm that determines which WHO dimension and 
adherence barriers are operative, and then pursue a course of action consistent with 
prior scripts we have developed for our prior adherence interventions, as indicated: 
Table 3: World Health Organization (WHO) framework for barriers to adherence 
 
Detailed description of research interventionalist actions. The interventionalist/ 
pharmacist will invoke specific strategies to circumvent the adherence barriers responsible for 
each instance of a medication refill gap. For example, patients with motivational deficits will be 
targeted for barrier assessment (assessment and response to individual patient barriers) with a 
focus on changing non-adherent behavior. These sessions allow the patient to identify, 
verbalize, and reinforce their own positive attitudes and perceived normative support 
contributing to medication adherence. The interventionalist employs techniques such as open-
ended questioning, positive messaging, reflective listening, constructive feedback, and goal 
negotiation. As an additional example, patients who tend to forget to take medications would be 
encouraged to use a medication diary, involve a caretaker, or if necessary receive weekly SMS 
prompts. Based on data from out prior studies, most interactions with the interventionalist are 
10-15 minutes in duration. Pharmacists may provide brief telephone consultation with a VA 
social worker or written remote consultation with the subject’s primary care provider (per the 
C3P study, conducted by our center). Of note, pharmacists can generate CPRS notes and 
related orders, such as simplifying dosing regimen, which providers can sign if in agreement. 
Local resources and practices will dictate the specific interaction but in all cases 
interventionalists will have comprehensive contact lists for resources that the research team will 
assist in assembling. The interventionalist will mediate the activation of resources directly and 
follow-up within 1 week to ensure the barrier is addressed, rather than passively referring the 
patient.  
Veteran Advisory Board (VAB) input: the recently established DiSCoVVR COIN board of 
12 veterans receiving care within the Department of Veterans Affairs will review all materials 
(including text/IVR messages and interventionalist scripts) before they are adopted to ensure 
they are not intrusive/coercive. 
WHO Dimension Adherence Barrier 
Research Interventionalist Action 
Health system 
Health system access 
Facilitate refills/scheduling of appointments for patient 
Condition 
Mental health disorder 
Engagement with PCP/mental health provider 
Patient 
Forgetful 
Initiate weekly SMS or IVR prompts/medication diaries/corrective 
feedback  
Motivational deficits 
Barrier Assessment  
Educational deficits  
Counseling on appropriate usage & self-care 
Patient repeating back information 
Therapy 
Regimen complexity 
Conversion to extended release formulation/fix dose combinations 
Pill organizer/calendars 
Adverse drug reaction 
Communication with provider/Convert to alternate drug product 
Socio-economics Low literacy 
Encourage social support/distribute low literacy instructional materials 
Cost 
Referral to VA social worker 

18 
 
Period of observation for each patient: 18 months (primary outcome), from the date of 
discharge following the index PCI or randomly selected qualifying DMARD prescription. Note 
that as an exploratory outcome, we will assess the persistence of the intervention by reporting 
subjects’ PDC after the 18 month active intervention period for a period up to 3 years post-PCI, 
until the termination of the last observation period for that sub-group of subjects enrolled in the 
first 3 phases.  
Escalation Time: 48 hours. This “fail time” is defined as the allowable elapse time 
between each intervention modality without a successful refill before escalation to the 
subsequent modality (e.g. patients with a 7 day gap are contacted via SMS; if no refill occurs 
within 48 hours, the IVR component is triggered on day 9). 
Quality Assurance Procedures: Multiple controls will ensure fidelity with the intended 
protocol, including: 
1. Detailed written manual of operation (essentially, this study protocol) for all components 
of the intervention, available via the VA intranet. 
2. Standardized in-person initial training session for the project coordinator and research 
interventionalists, with annual teleconferenced refresher training session. 
Interventionalist training will use the approach and schedule of our prior studies, which 
budget 80 hours over 6 months prior to intervention initiation and 20 hours subsequent 
to initiation of the intervention. The co-PIs and interventionalists previously involved in 
med adherence RCTs have developed a curriculum covering adherence theory, medical 
knowledge of cardiovascular disease/PCI therapy and rheumatic disease/DMARD 
therapy, barrier assessment, and provides them with local contacts for ancillary services 
(social work, Patient Aligned Care Team), among other topics. Training is performed 
through a variety of forms including interactive small group instruction, mock patient 
sessions, and written reference materials. 
3. Rigorous validation procedures for CVEs’ (see Determination of outcome for Aim 2). 
Details of usual care:  Control CCLs and rheumatology clinics will perform post-PCI 
follow-up according to the practice standards currently being delivered at each hospital and their 
CCLs. In general, this consists of a scheduled appointment with the patient’s primary care 
provider or cardiologist 2-4 weeks post-PCI. Similarly, control rheumatology clinics will perform 
follow-up based on routine care for any patients precribed DMARDs—generally routine visits 
every 3-4 months. Any monitoring for medication adherence is left to the discretion of the 
managing provider. For most providers, the identification of adherence gaps is passive and 
occurs after-the-fact. Patients resolve barriers to medication adherence by 1) discussing issues 
with administrative or clinical staff (providers, pharmacists, nurses) during previously scheduled 
appointments [or occasionally on a drop-in basis]; 2) contacting clinics and pharmacy staff on 
the telephone either directly or through a call center; and 3) sending electronic messages to 
providers and staff using the My HealtheVet online patient portal. CCLs and rheumatology 
clinics in the control arm will refrain from participating in any other study or intervention focusing 

19 
 
on IHD or DMARD medication adherence during the period of planning or observation for this 
proposal. 
Details of Aim 3 (cost analysis): 
This is a prospective observational study to establish the cost to implement and maintain 
the IHD intervention, above the cost of usual care. This aim intends to encourage broad 
adoption of the intervention by demonstrating the costs required to achieve a 10% or greater 
improvement in adherence (Aim 1), and potentially demonstrate a positive return on investment 
from a net savings associated with reduced CVE rates (Aim 2) with the intervention. All costs 
will be estimated in 2019 dollars based on salary and drug costs at the end of the study. 
National cost data and Medicare price adjustors will be used to reduce the influence of regional 
variation in salaries and prices. Data for this study will be assembled concurrently from the 
multi-site cluster stepped-wedge RCT in Aims 1&2.  
Setting, Perspective, Time Horizon: Costs and effort expended will be recorded at the 4 
intervention sites randomly selected for Aims 1&2. All cost comparisons will include data from 
the full study sample at these four sites.  Costs will be reported from the perspective of 
individual medical center intervention sites, since medical centers maintain budgetary and 
administrative authority over programs enacted at their affiliate CCLs and bear the long-term 
economic burden for non-adherent patients.  We will employ a 5 year time horizon. Costs and 
effects will not be discounted because discounting is anticipated to have minimal effect over the 
relatively short follow-up period 
Included Costs: 
1. Implementation & training costs (fixed costs):  Using methods previously developed 
in Seattle for implementation studies,44 we will quantify the direct costs required to 
implement and maintain the proposed intervention. Specifically, we will obtain thorough 
and precise activity logs all effort and investment necessary to initiate the intervention, 
construct timelines that describe the implementation, account for evolving 
implementation efforts over time, assign costs to discreet implementation activities, and 
characterize the variation between sites for each of these items. These expenses will 
include primarily personnel costs for the planning purposes, interactions with technical 
consultants/staff responsible for SMS and IVR development, conference calls, training 
activities, and e-mail communications related to start-up. Data sources for estimates of 
costs and/or hours will also include e-mail, which will be collected and archived from 
projects sites, as well as the study listserve, according to established procedures that 
transform these emails into time commitments.44  Hours for all technical and staff 
member will be recorded and national GS-level and salary rates will be applied.45 Non-
personnel costs will include initial software licenses fees and hardware for the IVR and 
SMS systems and travel. For our primary analysis, we will average these fixed costs 
across intervention subjects. Projections of fixed costs for scaling the intervention will be 
based on estimates of projected patient volume in each CCL over a 5-year time horizon.  
2. Per-patient intervention costs. Intervention activities provided by research 
interventionalist will be tracked for each non-adherent 7-day gap event after the 

20 
 
intervention is implemented at each CCL. Interventionalists will be provided with remote 
access to a centralized secure shared folder containing a customized database that 
includes an up-to-date listing of each non-adherent event. Interventionalists will 
catalogue all intervention activities from a pull down list of possible procedures for the 
duration of the study. For 2-week periods at the start of the intervention and at 6 month 
intervals, research interventionalists will also record the time (in minutes) required for 
each activity on the pull down list. Using the sample data for these 2-week periods, the 
average time per interventionalist per activity will be applied across all non-adherent 
gaps to estimate the time required for the intervention. Monitoring of completeness and 
quality of data collection will be performed centrally by study personnel through bi-
weekly checks of the database.  
3. Drug costs. Med adherence for statins, beta-blockers, and thienopyridines will be 
tracked for all subjects as part of Aim 1. Using national drug price data from the VA’s 
pharmacy benefits management database (PBM), we will estimate the total drug costs 
for both control and intervention subjects for the 18 month study period from the 
discharge date for the index PCI. 
Excluded activities / costs:  Research-related costs and PCP time devoted to direct 
patient contact would not be included. For example, effort expended for acquisition of data, 
analysis of outcomes, and preparation of IRB materials would be excluded. Patient time and 
out-of-pocket expenses will not be included because of the organizational-oriented perspective 
of this study, in accordance with the parameters outlined by our operational partners. 
5.6 
Data Analysis 
Power Analysis: (Primary outcome): Due to the modification to the traditional stepped 
wedge design, a simulation was designed in R to estimate power. Simulation studies were 
conducted by Analyst T. Glorioso, working in concert with A. Baron and A. Zhou (founding 
President, VA Statisticians' Association). We conservatively estimate 16 sites (4 intervention 
and 12 control), each enrolling 30 subjects per 6 month step, would assemble a cohort of 2400 
patients (300 intervention and 2100 control), after accounting for a 15% withdrawal rate. These 
numbers would achieve 92% power to detect a difference in PDC of 5% and 99% power for a 
difference of 10% (75% increasing to 85%). These findings assume a within-site standard 
deviation (SD) of 1.30 and between-site SD of 0.16 on the transformed scale, based on existing 
2011 CART data. Because of the multiple outcomes, we set the target two-sided significance 
test at a level of 0.01. Note that the number of eligible PCI subjects from these 16 sites should 
actually exceed 6000 (figures for 2012), providing a substantial recruitment “cushion”, in terms 
of potential study volumes.  
Analysis plan for Aim 1 & 2: Analysis of data will follow the approach outlined by Hussey 
and Hughes using patient level data.46 To account for correlated observations within sites, 
unequal cluster sizes, and non-normal responses, the primary analysis will employ generalized 
linear mixed models to establish the treatment effect, after modeling time effects. Models will 
include terms for site (random, to account for correlation of patients within sites and to identify 
site-level variables), categorical time (fixed, to avoid confounding of intervention with time 

21 
 
trends), randomization stratum (fixed, to account for confounding caused by the PDC x PCI or 
DMARD volume strata), intervention variable (fixed, usual care vs. intervention, the effect of 
interest), and patient-level covariates. Due to left skew in the distribution of the continuous 
variable (PDC) caused by the upper bound of 1, a logistic transformation will be performed on 
this variable. Back transformation inference will be made on the difference in median PDC 
between intervention and control groups. No interim analyses are planned. 
Analysis plan for Aim 3: We will assess the total intervention costs and drug costs for 
the ~300 intervention study subjects. Our primary analysis will sum the net costs for the 
intervention in numerator and compare those costs to adherence rates estimated in Aim 1. 
Confidence intervals for costs will be estimated using bootstrapping.47 Our cost approach--which 
focuses on applying prices to intervention activities--minimizes the potential effect of imbalances 
in patient characteristics across intervention and control groups. To further safeguard against 
bias, multivariate linear regression models will be used to impute missing direct cost values; 
costs will be adjusted for any baseline socio-demographic differences between veterans during 
control and intervention periods.   
 
We roughly estimate that costs of training/implementation are expected to be $31,780 
per site, increased costs of drugs among intervention subjects will be $3,260 per site for each 
18 month observation period, and costs incurred by research interventionalists to execute the 
intervention are estimated to be $11,650 per site for each 18 month observation period. Thus, 
we estimate a total cost of $46,690 per site to achieve a 10% improvement in adherence among 
300 intervention subjects. The majority of the costs are due to initial implementation and will 
likely be considerably lower when scaled across multiple years and sites:   
(CostTraining/implementation + CostInterv-per-patient + CostInterv-drug – CostCntrl-drug) / (∆ Adherence rates) 
Exploratory Return-on-Investment: We will assess CVE (Aim 2) based on the 18 month 
study period. This analysis will allow us to estimate the potential cost-savings of the intervention 
and return-on-investment to VHA. For example, based on the average cost of CVEs (see Table 
2), the intervention would be cost neutral if rates of CVE costing an average of $28,300 were 
decreased from a rate of 10 per 1000/pt-yr to 8 per 1000/pt-yr through improved medication 
adherence from our intervention. Greater reduction in CVE rates would lead to a positive return 
on investment. 
Characterization of Uncertainty: Statistical uncertainty in the cost and effect estimates 
will be modeled using nonparametric bootstrapping with 1000 replications, since this approach 
relaxes assumptions of the sampling distributions of the estimated cost or outcome.47 
Characterization of Heterogeneity: A table will convey differences in costs and cost-
effectiveness resulting from socio-demographic differences between veterans, presence or 
absence of volume discounting, variations in medication and personnel costs, and variations in 
the effectiveness of the intervention. 
5.7 
Withdrawal of Subjects 

22 
 
For patients who decline participation, the patients’ name, state, and the current 
date will be recorded by the project coordinator in a centralized password-protected list 
that is accessible only from a computer terminal behind the VA firewall. Reporting 
Authority for monitoring data and safety will reside with the VA-mandated National Data 
Safety Monitoring Board (DSMB) for multi-site interventional health services studies/randomized 
trials. The National DSMB will hold the PIs and other investigators responsible for data quality 
and completeness, safeguard the safety of all study participants, and ensure all ethical 
principles are respected. The PI will classify all suspected adverse events (mild / severe) and 
forward them immediately to the DSMB and CIRB. The principal investigator, Dr. Liron Caplan, 
will monitor for unanticipated, serious and related problems, and report them to CIRB, VA 
Research and the DSMB immediately. All other adverse events will be reported in summary 
format at continuing review. If CIRB or DSMB deems it necessary to disseminate information on 
unanticipated problems involving risk to participants, this information will be communicated to all 
participating sites PIs via email within 48 hours. This information will also be reinforced during 
bi-weekly teleconferences. 
The completeness and accuracy of variables in CART are reviewed regularly by 
Program personnel. The biostatistician co-Investigator affiliated with this project will also 
conduct regular annual queries to ensure the integrity of the data, including evaluations of 
missing data and monitoring for outliers. The PIs will review recruitment and enrollment on a 
monthly basis to appraise the study progress and, if necessary, replace underperforming study 
sites. 
6.0 
Privacy and Confidentiality 
Potential risks: 
The proposed intervention is expected to pose minimal research risks for patients. There 
have been no reported adverse events with use of IVR or adherence interventions conducted by 
the assembled group of investigator in the past (rather, the increased surveillance may be a 
patient safety measure). A risk for all participants is the potential loss of confidentiality, a risk 
that is possible with all non-anonymous research and no greater than risks encountered in every 
day outpatient practice. However, based upon the mechanisms in place, this concern is very 
minimal.  
No experimental devices or drugs will be used, minimizing the therapeutic risks of the 
present study. Because the decision to institute treatment (statins, beta-blockers, clopidogrel, or 
DMARDs) occurs prior to the proposed intervention (and is, in fact, an eligibility criteria), the 
physical, psychological, social, and legal risks are low. Nevertheless, this is a randomized trial 
and we will monitor patients closely to detect any problems posed by the intervention, and will 
follow all standards of the IRB and privacy (HIPAA) review and monitoring. 
Measures to protect from risk: 
Measures around patient tracking: To protect confidentiality, wherever possible, study 
records will identify patients only by unique study number. The only exception will be the 
tracking database that will include the patient’s name, SSN, and telephone number which will be 

23 
 
used to obtain pharmacy data from the CDW following PCI and to validate CV events in the 
medical record. Access to the database and study records will be limited to research staff. All 
paper records will be maintained in locked file cabinets within locked offices. Electronic data 
files will be encrypted/password-protected and user-restricted on computers maintained in a 
secure environment behind the VA firewall per VA security regulations. All data will be 
maintained in accordance with the Records Control schedule and not indefinitely.  
Measures for SMS/IVR: Our prior experience with IVR-based interventions has allowed 
us to develop systems that strictly protect patient privacy. No PHI is transmitted on outbound 
IVR calls, and we will continue to enforce this policy for SMS messaging. Rather, out-bound 
calls only employ generic terms and access to any PHI requires that the respondent confirm 
their identity using a patient-specific security code.  
Measures related to Recruitment and Informed Consent: The approach to recruitment 
and consent is described in detail above (see Recruitment/Consent). Because our study 1) 
focuses on ensuring that patients are following the standard of care [i.e., filling and taking CV or 
DMARD medications as prescribed]; 2) involves no experimental medical procedures or 
medications; 3) relies on existing clinical data; and 4) does not pose a substantial burden 
beyond that encountered in patients’ current health care setting, the risk to subjects has been 
classified as “minimal”. In accord with this characterization and following the approach we 
established previously for similar trials, we are pursuing a waiver of consent and waiver of 
authorization for individual subjects through the IRB. In addition, we anticipate submitting this 
proposal for expedited review. The protocol will be reviewed annually by the CIRB and at the 
R&D committees at each participating VA site.  
Based on our preliminary data indicating low PDC for the target medication classes, 
adherence to medications is likely to be poor and may place patients at higher risk of CV 
events. 
As a workflow incorporated into existing clinical care, all patients at the Intervention sites 
will be provided an Patient Information form following PCI (IHD intervention) or when they leave 
the rheumatology clinic (rheumatology intervention). The Patient Informationform will include a 
telephone number for the project coordinator at the coordinating site that will allow them to ask 
questions and consider their involvement. A quiet room to consider the decision will be made 
available at each site.  Each day, the central coordinating site will remotely screen the 
discharged patient from intervention and control sites for eligibility, based on their discharge 
medications listed in the electronic medical record.  If the patient is ineligible (expected to be 
less than 5% of patients undergoing PCI and fewer than 10% of rheumatic disease patients, 
based on clinical guidelines and typical practice patterns in the VA) nothing regarding the 
screening will be recorded.  If the patient is eligible, the project coordinator will tag the patient in 
the IVR tracking software.  For patients who decline participation, the patients’ name, state, and 
the current date will be recorded by the project coordinator in a centralized password-protected 
list that is accessible only from a computer terminal behind the VA firewall.  If the patient 
indicates during the call with a member of the study staff that they wish to participate, the patient 
will be considered enrolled after verbal consent is obtained. 

24 
 
Measures related to staff training: All key personnel for this project who are responsible 
for the design and/or conduct of the proposed research have completed the appropriate training 
and continuation training for the protection of human research participants. In particular, all 
study staff will have completed Collaborative IRB Training Initiative (CITI) Course in the 
Protection of Human Subjects prior to initiation of this study. This includes a special VA module 
for investigators/staff working at VA sites. This initial CITI course includes HIPAA training and 
satisfies all IRB, VA, NIH and HIPAA requirements for research involving human subjects. 
Refresher training certificates will be updated as necessary throughout the study (per CITI and 
IRB requirements). Initial and refresher certificates of completion are kept in the IRB offices at 
all participating sites, with duplicate certificates documenting completion of initial and refresher 
courses kept by the project coordinator at the coordinating site (Denver VAMC). Reminders will 
be distributed to staff when refresher course completion is warranted. Written assurances will be 
obtained from all members of the research team mandating that the PHI will not be reused or 
disclosed to any other person or entity, except as required by law.  Study staff will be required to 
certify that they have read the manual of operations yearly. 
In addition to having the approval of the VA IRB and Research & Development (R&D) 
committees at participating sites, this research will require approval from the CART Research & 
Publications Committee. Participating site R&D approvals will be kept by the project coordinator 
at the coordinating site (Denver VAMC). 
7.0 
Communication Plan 
We will notify all engaged participating sites of any changes in the study documents. As 
soon as we receive the approved documents, we will distribute them to all the participating sites. 
We will send an e-mail notification to the Facility Directors of all facilities involved to notify them 
that they are part of the study and we will evaluate their PCI data. Documents will be obtained to 
ensure that all participating sites are following VA information security policies. We will 
communicate study events to all participating sites during regularly scheduled conference calls. 
All non-compliance events will be reviewed and reported accordingly to the VA.  
8.0 
Relevance to Veterans 
Execution of the intervention will have important ramifications for veterans’ wellness. 
First, the intervention may directly improve veterans’ quality of care, leading to better outcomes. 
Second, it will reinforce the importance of managing their IHD—a condition of widespread 
relevance to veterans. Third, the intervention will be responsive to veterans by assisting them in 
a proactive manner. Our system has the potential to make Veterans feel heard by proactively 
addressing adherence barriers, rather than placing the responsibility and burden entirely upon 
the patient to overcome obstacles and navigate the health care system. Fourth, the intervention 
provides a template for effective management of numerous similar clinical situations in which a 
procedure identifies high-risk individuals and requires med adherence to prevent recurrence or 
exacerbation of a serious condition. For example, in patients with an endoscopy that reveals a 
peptic ulcer; monitoring proton pump inhibitors adherence might avert recurrent bleeding ulcers. 
Thus, this proposal will hone our understanding of the risks for long-term untoward outcomes 

25 
 
following procedures, using some of the most common procedures for some of the most 
common diseases within the VA.  
 

26 
 
9.0 
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