Heart Failure Optimization at Home to Improve Outcomes (Hozho): A Pragmatic Clinic Trial of Telephone-Based GDMT Optimization in Navajo Nation
Phase: NA
Conditions: Heart Failure
Sponsor: University of Pennsylvania

 
PROTOCOL TITLE: Hózhó (Heart Failure OptimiZation at Home to Improve Outcomes) 
Trial for HF Patients Receiving Care through the Indian Health Service in Navajo Nation 
Version Date 9/6/2022 
Clinicaltrials.gov Registration # NCT05792085 
Protocol Synopsis 
TITLE 
Hózhó (Heart Failure OptimiZation at Home to Improve Outcomes) Trial 
for HF Patients Receiving Care through the Indian Health Service in Navajo 
Nation 
SPONSOR 
University of Pennsylvania and Indian Health Service  
FUNDING 
ORGANIZATION 
Indian Health Service Quality Improvement Innovation Award 
NUMBER OF SITES 
1 (Gallup Service Unit) 
RATIONALE 
Heart failure morbidity and mortality disproportionately impact racial 
minorities, and inequitable care delivery based on race is pervasive in the 
United States. The American Indian/Alaska Native (AI/AN) population is 
one of the populations that suffers most from health disparities. AI/AN 
patients with heart failure receiving care through the IHS (IHS) face 
tremendous barriers to accessing quality care, particularly specialized 
cardiac care. Guideline-directed recommended therapy (GDMT) can 
significantly lower mortality, hospitalizations and improve quality of life in 
heart failure with reduced ejection fraction (HFrEF). However, GDMT 
utilization rates are low nationally. AI/AN patients are at particular risk of 
not receiving appropriate GDMT. Innovative models to improve uptake of 
GDMT may help improve quality of care in this patient population.  
 
Models that incorporating telemonitoring and strategies to support primary 
care physicians could be implemented to reach AI/AN patients with HFrEF 
that face barriers to accessing quality cardiovascular care, particularly those 
that receive care through the IHS, the federal healthcare agency responsible 
for providing medical and public health services to this population. A 
strategy to identify HFrEF patients and get them on appropriate therapy with 
telemonitoring should be evaluated through a pragmatic clinical trial as a 
strategy to ensure high-quality heart failure care for AI/AN patients, 

especially those living remotely and receiving care through the IHS, where 
cardiology care is often unavailable. The proposed pragmatic clinical trial 
aims to improve the quality of care of AI/AN patients with heart failure with 
reduced ejection fraction receiving care through the IHS. We will perform a 
pragmatic trial clinical that will use a stepped wedge randomized design to 
implement and evaluate the effectiveness of a strategy that leverages the 
electronic medical record to find HFrEF patients not on appropriate therapy, 
and initiates/optimizes GDMT through telemonitoring in the Navajo Nation.  
 
STUDY DESIGN 
This is cluster stepped wedge randomized control trial, with randomization 
at the patient level 
PRIMARY OBJECTIVE 
To evaluate if there is an increase in rates of guideline-directed medical 
therapy with implementation of the heart failure telemonitoring model  
SECONDARY 
OBJECTIVES 
To evaluate if there is an increase in the dose of the guideline-directed 
medical therapy with implementation of the heart failure telemonitoring 
model 
NUMBER OF 
SUBJECTS 
80-100 HFrEF patients 
SUBJECT SELECTION 
CRITERIA 
Inclusion Criteria: This care delivery model will be applied to adult patients 
(age >18 years) with heart failure with reduced ejection fraction seen cared 
for in the Gallup Service Unit in Navajo Nation (Gallup Indian Medical 
Center and Tohatchi Helath Center) with at least 1 clinical encounter in past 
12 months (including telemedicine), and has 1 active prescription at an IHS 
pharmacy in the last 12 months 
Exclusion Criteria: Anyone not willing to participate, anyone that their 
primary care physician opts out as feels is inappropriate to participate, 
anyone on hospice care.  
 
EFFICACY 
EVALUATIONS 
 
PRIMARY ENDPOINT 
The proportion of patients who have an increase in the number of prescribed 
evidence-based therapies for HFrEF (betablockers, ACE-I/ARB/ARNI, 
MRA, SGLT2i) at 30 days post implementation. This endpoint is based on 
filling of the prescription.  
SECONDARY 
ENDPOINTS 
Secondary outcomes will include: percentage of patients prescribed each 
medication class (i.e. percentage on beta-blockers, percentage on ACE-
I/ARB, percentage of ARNIs, percentage on SGLT2i, and percentage on 
MRAs), medication doses (all at 30-days as well as post-implementation at 6 
months); HF hospitalizations at each time point, 6-month mortality, 
referrals, cardiac procedures, adverse events (to include hypokalemia [K<3.0 

mEq/L], hyperkalemia [K >5.5 mEq/L], AKI [defined as Cr increase >0.5 
from baseline], Hyponatremia [Na<130 mg/dl], volume overload [urgent 
clinic visit/ ER visits for lower extremity edema, dyspnea, with clinical 
evaluation consistent with volume overload], hypotension (SBP <90mmHg), 
bradycardia (HR <50 bpm). Outcomes determined by review of medical, 
hospital, and billing records.  
OTHER EVALUATIONS 
None 
SAFETY 
EVALUATIONS 
Adverse events (to include hypokalemia [K<3.0 mEq/L], hyperkalemia [K 
>5.5 mEq/L], AKI [defined as Cr increase >0.5 from baseline], 
Hyponatremia [Na<130 mg/dl], volume overload [urgent clinic visit/ ER 
visits for lower extremity edema, dyspnea, with clinical evaluation 
consistent with volume overload], hypotension (SBP <90mmHg), 
bradycardia (HR <50 bpm). 
PLANNED INTERIM 
ANALYSES  
At 30-days after implementation for cluster 1, we will evaluate for safety. 
Serious adverse events will be monitored by the research team on an 
ongoing basis throughout the study. 
STATISTICS 
Primary Analysis Plan 
To assess the effectiveness of our intervention, measurement of rates of 
GDMT, including each specific medication of ACE inhibitors, ARB, ARNI, 
beta-blockers, MRA, SGLT2 inhibitors will be performed at baseline, at 
each cross-over time point, and at the conclusion of 6 months after the 
implementation of the intervention. The main analysis of our stepped wedge 
design will be based on a logistic mixed-effects model which will contain a 
random intercept to account for between-cluster variability, a fixed effect 
parameter for time, and a group indicator variable for the treatment for each 
subject and time to capture treatment differences over time. 
Rationale for Number of 
Subjects 
We anticipate there is approximately 100 patients with HFrEF actively 
engaged in care at GIMC. Our goal to enroll all patients given ethical 
concerns with withholding implementation to all patients.  
 
 
 
 
 
 
 

SECTION 1: BACKGROUND  
Statement of Purpose:  
Heart failure is the leading cause of hospitalization among older adults and has a 5-year mortality 
of up to 50%.[1][2]. There are well-established evidence-based guidelines for treating heart 
failure with reduced ejection fraction (HFrEF), a major subset of HF. The background of 
guideline-directed medical therapy (GDMT) for HFrEF now includes 4 classes of therapy: a 
beta-blocker, an angiotensin-converting enzyme inhibitor (ACE) inhibitor/angiotensin receptor 
blocker (ARB) or preferably an angiotensin receptor-neprilysin inhibitor (ARNI), a 
mineralocorticoid receptor antagonist (MRA), and a sodium glucose transporter 2 (SGLT2) 
inhibitor [3-7]. There is a cumulative risk reduction for mortality of >75% among HF patients 
receiving combined therapy with a beta-blocker, ARNI, MRA and SGLT2 inhibitor.[3] 
Therefore, the American College of Cardiology/American Heart Association guidelines 
recommend treatment with all 4 of these agents and titration to highest-tolerated dose (or target 
dose) to maximize clinical benefit.[8] However, despite clear evidence-based interventions for 
HF, suboptimal care is a major driver of poor HF-related outcomes in the U.S.[9] Guideline-
directed therapies for HFrEF are underutilized among all patients in the U.S.[10]. AI/AN patients 
receiving care through the Indian Health Service, in particular, are at high risk of not receiving 
appropriate GDMT given barriers to accessing appropriate care.[11]  
The reasons for underutilization of appropriate GDMT in HF are multifactorial. In the Indian 
Health Service, access to cardiology care is severely limited, and HF care is provided primarily 
by primary care providers. We surveyed primary providers at two Indian Health Service sites to 
identify the primary barriers to getting HFrEF patients on appropriate GDMT. The primary 
barriers identified were include lack of knowledge/comfort among providers about guidelines 
and appropriate management, clinical burden, time constraints during the visit. Given this we 
hypothesized that a model that identified HFrEF patients not on appropriate therapy, and initiated 
missing recommended therapy by the study team would be an effective way to improve HF 
quality of care and uptake of GDMT. In addition, given the rurality of the Navajo patients cared 
for at these two IHS sites, and the barriers to accessing care, we hypothesized that a 
telemonitoring model in which patients had GDMT initiation and uptitration at home, with home 
BP monitoring would be preferable.   
We therefore, in discussion with community members and primary providers at two IHS sites in 
Navajo, designed a model to identify HFrEF patients cared for in the system, identify gaps in 
their therapy, and initiate appropriate therapy by the study team with home BP and HR 
monitoring for initiation and titration of GDMT.  We propose a stepped wedge randomized trial 
to compare the implementation of this model compared to usual care over a 6 month period with 
5, 30-day cross over periods. The primary outcome for the trial will be the proportion of patients 
who have an increase in the number of prescribed evidence-based therapies for HFrEF 
(betablockers, ACE-I/ARB/ARNI, MRA, SGLT2i) 30 days post implementation. This endpoint 
is based on filling of the prescription. In addition to addition of missing GDMT, we will also 
consider a change from an ACEI/ARB to an ARNI consistent with increase in the ‘number’ of 
GDMT given their demonstrated benefit. Secondary outcomes will include: percentage of 

patients prescribed each medication class (i.e. percentage on beta-blockers, percentage on ACE-
I/ARB, percentage of ARNIs, percentage on SGLT2i, and percentage on MRAs), medication 
doses, all at 30-days as well as post-implementation at 6 months; HF hospitalizations at each 
time point, 6-month mortality, adverse events (to include hypokalemia [K<3.0 mEq/L], 
hyperkalemia [K >5.5 mEq/L], AKI [defined as Cr increase >0.5 from baseline], Hyponatremia 
[Na<130 mg/dl], volume overload [urgent clinic visit/ ER visits for lower extremity edema, 
dyspnea, with clinical evaluation consistent with volume overload]. Outcomes determined by 
review of medical, hospital, and billing records.  
2    STUDY RATIONALE  
Treatment with GDMT for HFrEF with the 4 classes of recommended therapy significantly 
reduces heart failure hospitalization and overall mortality [3-8]. However, these therapies are 
underused among all patients nationally, but particularly among marginalized patient groups and 
racially minoritized patients, which is one of the factors that drives racial disparities in 
cardiovascular outcomes. Therefore, strategies to engage with marginalized patient groups in 
order to increase rates of recommended therapy are critically needed to improve cardiovascular 
outcomes and reduce disparities. American Indians are one of the most marginalized patient 
groups in the United States and the majority receive care through the Indian Health Service, 
where cardiology care is not readily available. Therefore, this study will evaluate if a model that 
leverages the electronic medical record to get American Indian patients with heart failure on 
appropriate therapy, and supports primary care providers with telemonitoring, is an effective way 
to ensure high-quality heart failure care for American Indian patients receiving care through the 
Indian Health Service in Navajo Nation.  
 
2. 1 Risk/Benefit Assessment  
This study will evaluate the effectiveness of a heart-failure care delivery model to improve rates 
of guideline recommended medical therapy through a stepped wedge randomized control trial. 
Therefore, the primary objective of this study is to evaluate if the implemented model is effective 
in increasing rates of medications that are already recommended by guidelines. All patients will 
only be started on medication after chart review by the research team which includes a 
cardiologist. Thus, patients will be started on appropriate therapy, as strongly recommended by 
current American College of Cardiology/American Heart Association Guidelines [4][8]. Since 
this model is being tested through a stepped wedge trial as a way to improve standard of care for 
heart failure patients, this study represents minimal risk to participants. The benefit is significant 
as increased use of guideline-recommended therapy and these medications has been 
demonstrated to reduce heart failure hospitalization and mortality 
 
3. STUDY OBJECTIVES 
3.1 Primary Objective 
The primary objective is to assess the clinical efficacy of a heart failure care delivery model as 
measured by the rates of patients with an increase in the number of classes of rates of guideline 
directed medical therapy over the study period. 

3.2 Secondary Objectives 
The primary objective is to assess the clinical efficacy of a heart failure care deliver model as 
measured by the change in rates of each GDMT therapy, the doses of each therapy, differences in 
HF hospitalizations, referrals, cardiac interventions, and adverse events over the study period. 
 
4. STUDY DESIGN 
4.1 Study Overview 
 
This is a single ‘center’ (Gallup Service Unit- which includes two ambulatory clinics), stepped 
wedge cluster randomized design with 5 clusters planned. We will randomize each patient to 1 of 
5 clusters, each of which has a different enrollment time point, separated 1 month apart. Each 
patient will receive intervention with the heart failure care delivery model at time of enrollment. 
Evaluations will be taken at each cross-over time point and at conclusion of 6 months. Screening 
data will be reviewed to determine subject eligibility. Subjects who meet all inclusion criteria 
and none of the exclusion criteria will be entered into the study. Prior to enrollment for ech 
patient, a message will be sent in that patient’s chart through the EHR to the patient’s primary 
provider who has 7 days to opt out if they think patient should not be enrolled.  
 
Probable Duration of Project: Total duration of subject participation will be 6 months. 
4.2 Study Setting  
This study is being conducted at the ambulatory clinics in the Gallup Service Unit at Gallup 
Indian Medical Center (GIMC) and Tohatchi Health Center. GIMC is located in Gallup, New 
Mexico and is a 99-bed hospital that serves the Navajo Nation, the largest U.S. Indian tribe [12]. 
GIMC is part of the Indian Health Service-which is a federally-funded agency within the U.S. 
Department of Health and Human services, is responsible for providing health services to AI/AN 
patients. GIMC. has one of the highest clinical volumes in the IHS—250,000 outpatient 
encounters and 5800 inpatient admissions annually—and the largest staff of all Navajo IHS 
facilities. GIMC is associated with a primary care ambulatory clinic. With a 50-mile radius 
catchment area, it serves as the major Navajo referral hospital and ambulatory clinic for the 
Navajo Nation [13][14]. Tohatchi, is a smaller health center located 45 minutes north of GIMC, 
in a more rural remote area on the Navajo Nation, in Tohatchi, NM. 
4.3 Study Design  
Stepped-wedge designs are increasingly being utilized to evaluate interventions within routine 
care and are recommended where there are limited numbers of clusters [13]. In this study, we 
will perform a prospective stepped-wedge randomized control trial, where randomization will 
occur at the patient level with 5 patient clusters.   
The randomization procedures will be managed independently at the University of Pennsylvania 
Cardiovascular Outcomes, Quality, and Evaluative Research Center. Physicians will be 
randomized through a SAS-based computer-generated randomization scheme developed by the 
study PI. Using a stepped-wedge design, each patient cluster will begin the study as a control 

site, providing treatment as usual to participants (Control). Clusters will then progressively 
commence the heart failure care delivery model and will begin contributing to the intervention 
arm of the study in a stepped fashion (Intervention; see Figure 1). An independent statistician at 
University of Pennsylvania Cardiovascular Outcomes, Quality, and Evaluative Research Center 
will randomly generate the clusters and the order of the patient cluster. CONSORT procedures 
will be followed including using an intention to treat analysis.  
 
Figure 1: Stepped-Wedge Implementation of HF Care Delivery Model  
 
Figure 1. Stepped wedge randomized controlled study design. Participants in the control 
condition will receive treatment as usual. Participants in the intervention condition will 
receive the heart failure care delivery model as described below. The patient clusters and 
order of intervention will be randomly allocated. 
 
4.4.  Randomization 
Randomization in this study will occur at the level of the patient. This is a stepped wedge trial 
design, and patients will be randomized to 1 of 5 clusters. Every cluster will have the model 
implemented, but the time point of implementation will vary based on cluster, in 30 day 
increments. Cluster 1 will have the model implemented at time 0, cluster 2 at 30 days, cluster 3 
at 60 days, etc (as shown in Figure 1).  Prior to implementation, patients in pre-implementation 
time points will receive usual care. In addition, all providers received a lecture regarding updated 
ACC/AHA/HFSA guidelines and expert consensus prior to implementation of the model. Given 
the stepped-wedge design, all patients will eventual benefit from implementation of the model, 
but it also allows us to evaluate the effect of secular trends towards better care over time (and 
ensure the model rather than trends in care are not responsible for improving care).  

 
5. CRITERIA FOR EVALUATION 
5.1 Primary Efficacy Endpoint  
The primary outcome for the trial will be the proportion of patients who have an increase in the 
number of prescribed evidence-based therapies for HFrEF (betablockers, ACE-I/ARB/ARNI, 
MRA, SGLT2i) 30 days post implementation. This endpoint is based on filling of the 
prescription. In IHS pharmacies, we are able to differentiate between active prescriptions that are 
filled/picked up, and those that are “not picked up”. We will only include filled prescriptions in 
the primary and secondary endpoints. In addition to addition of classes of GDMT, we will also 
consider a change from an ACEI/ARB to an ARNI consistent with increase in the ‘number’ of 
GDMT given their demonstrated superior benefit.[5]  
 
5.2 Secondary Efficacy Endpoints  
 
Secondary endpoints will include percentage of patients prescribed each medication class (i.e. 
percentage on beta-blockers, percentage on ACE-I/ARB, percentage of ARNIs, percentage on 
SGLT2i, and percentage on MRAs), medication doses of each therapy, all at 30-days as well as 
post-implementation at 6 months; HF hospitalizations at each time point, 6-month mortality, 
referrals, cardiac procedures. Outcomes determined by review of medical, hospital, and billing 
records.  
5.3 Safety Evaluations 
Secondary safety endpoints: Secondary safety endpoints include adverse events (to include 
hypokalemia [K<3.0 mEq/L], hyperkalemia [K >5.5 mEq/L], AKI [defined as Cr increase >0.5 
from baseline], Hyponatremia [Na<130 mg/dl], volume overload [urgent clinic visit/ ER visits 
for lower extremity edema, dyspnea, with clinical evaluation consistent with volume overload]. 
 
6. SUBJECT SELECTION 
6.1 Study Population 
All adult patients (>18 years old) with ICD code I50* (given ICDI50.2 may not always be 
selected) and echo with LVEF <=40% within the last 24 months (24 months was chosen rather 
than 12 months given limited echo availability, particularly during COVID-19). Only patients 
with active prescription through IHS and engaged in care at our centers (clinical visit within last 
12 months) will be included. Patients will be randomized to 1 of 5 clusters (which determines 
time of implementation). For ethical considerations, we aim to enroll all patients who meet 
eligibility criteria at GIMC and THC. Subjects who will be enrolled are those with a diagnosis of 

HFrEF (LVEF ≤ 40%) who are seen in an outpatient internal medicine or family medicine IHS 
clinics at GIMC or THC.   
 
6.2 Inclusion/Exclusion Criteria 
Inclusion  
- 
Age >=18 years 
- 
Seen at internal medicine or family medicine clinic at GIMC or THC in last 12 months  
- 
Left ventricular ejection fraction ≤40% 
- 
Prescription at IHS pharmacy in last 12 months  
Exclusion  
- 
Primary providers opted out of inclusion for that particular patient 
- 
Hospice care  
 
Eligibility: Eligibility of patients will be assessed by the study team based on the patient’s 
medical record. However, as detailed, if provider feels patient is inappropriate for enrollment, 
they can also opt out of enrollment. Those who meet criteria will have a EHR message sent 
through the chart to the primary provider. Primary providers have 1 week to opt out. If they do 
not opt out, patient will be automatically enrolled and placed into a randomization cluster group. 
Exclusion criteria have been kept to a minimum to ensure that the study can examine the 
effectiveness of using this heart failure care model within a ‘real world’ setting. 
 
6.3 Subject Recruitment 
 
Eligible patients are identified as above. All primary providers will be sent a message through 
the EHR in the patient chart reporting that their patient is planned to be enrolled in the study. 
Providers can sign to consent to patient enrollment, or otherwise, can opt out of the study if their 
feel patient enrollment not appropriate.  If a primary provider does not opt out within 7 days, 
then patient will be enrolled.   
 
Eligible patients are identified through a query through iCARE, a EHR based data system 
through the IHS EHR. Patients with ICD10 diagnostic criteria for HF will be identified, and then 
all those patients will have their chart reviewed to confirm LVEF less than or equal to 40% on 
echo within last 24 months. The inclusion criteria will be all adults ≥18 years, who have a 
prescription in the IHS system in the last 12 months, and have had a clinical visit at GIMC or 
THC in the last 12 months. As this is an intervention assessing a model to improve uptake of 
standard of care, we cannot inform patients of their participation in the study at the time of 
enrollment, as this would contaminate the randomized exposure.  As this study presents minimal 
risk to patients, we requested a waiver of informed consent at the patient level. 
 
 

 
7. INTERVENTIONS  
 
7.2  Intervention: Heart Failure Telemonitoring Care Delivery Model  
 
This project was implemented as an Indian Health Service Innovations Award to improve quality 
of care for patients. Once patients are at their intervention time point, they receive 
implementation of our designed HF QI model. As part of this model, all patients are given a 
home BP cuff (Omron 5 arm cuff) for home BP monitoring. Protocols for each step of this model 
are detailed in the supplement. However, in brief, as part of the intervention, these protocols 
allow the study team to identify which, if any recommended guideline-directed mediations are 
missing, identify any contraindications to therapy, and initiate therapy as directed if no 
contraindications are identified. Prescriptions for the therapy are made, appropriate follow-up lab 
testing ordered if needed, and patients are called by the study team to discuss the therapy and 
recommendations. Getting patients are low doses of all 4 therapy (or all therapies they are 
eligible on) is prioritized by the study protocol, and then doses could be secondarily uptitrated 
per recent HF Expert Consensus Statement.[8] There are protocols for overall model, and 
initiation and titration of all medications. Utilizing home blood pressure monitoring, medications 
were added and titrated as directed by study protocols, with patients coming in for lab work as 
recommended by the study protocol. All medication changes, lab work, home BP and HR 
readings, will be documented in the EHR and sent to the PCP.  Please see supplement for 
flowcharts utilized in this study. Overall model is shown in Figure 2.  
 
 
Figure 2. Overview of Model to Improve Heart Failure Care in Navajo Nation   

7.3 Control Condition- treatment as usual 
 
Participants in the Control Condition will continue to receive medical treatment as usual as 
directed by their primary care physician. All physicians at THC and GIMC will receive a lecture 
at the start of the study on updated ACC/AHA/HFSA guidelines on optimal therapy for GDMT.  
 
8. STUDY TREATMENTS  
 
8.1 Method of Assigning Subjects to Intervention Group  
 
Patients will be randomized assigned to 5 clusters cluster and timing group using a SAS-based 
computer-generated randomization scheme developed by the study PI.  The investigator or 
designee will complete a randomization worksheet, as detailed in the Study Protocol. 
 
8.2 Blinding of Intervention 
 
Patients will be informed that they are enrolled in a new quality improvement program to get 
them on optimal therapy and thus will not be blinded to their randomization status or 
participation in this trial. Provider subjects will, obviously, not be blinded to the intervention as 
they are receiving the alert and will be consenting to participate in the study. We will engage in 
both pre-trial and periodic teaching and discussion with all participating care providers to inform 
clinicians about the nature of the study and to discuss specific factors that are being measured. 
The study team is not blinded to the cluster assignment as they are implementing the model. 
However, the outcomes will be pulled from the EHR from study members that are blinded to 
randomization/cluster status of the patient.  
 
9 STUDY PROCEDURES AND GUIDELINES 
9.1 Clinical Assessments 
9.1.1. Baseline Medications 
All baseline medications and their doses will be documented at enrollment of a patient’s 
physician, as well as at each assessment cross-over time point. Dose, route, unit frequency of 
administration, will be captured. We only consider a patient to be on a medication if they have an 
filled prescription for the medication.  
9.1.2. Demographics  
Demographic information (date of birth, sex, race) will be recorded at start of the study. 

9.1.3. Medical History  
Relevant medical history, including comorbidities, LVEF from echo, prior cardiac imaging and 
ischemic evaluation (coronary angiography, stress testing) will be captured at start of the study 
from the EHR. 
 
9.1.4  Vital Signs 
Most recent blood pressure, pulse will be extracted from the chart from the most recent clinic 
visit which is closest to enrollment.  
9.1.5  Clinical Laboratory Measurements  
Most recent laboratory evaluation will be extracted from the chart from the most recent lab check 
that closest to enrollment. 
9.1.4. Adverse Events 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates), severity/grade, outcome, treatment and relation to guideline-
directed medical therapy will be recorded. 
9.2 Clinical Laboratory Measurements  
9.1.5. Blood Chemistry Profile 
After initiation of a recommended medical therapy by the study team, the team will order basic 
metabolic panel if clinically appropriate based on predetermined protocols (see supplement), 
which is the typical standard of care when starting certain medications (all but beta blockers). 
Blood will be obtained at the GIMC lab and will be reviewed by the study team for 
determination of serum sodium, potassium, chloride, bicarbonate, random glucose, BUN, 
creatinine. 
 
10. ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
10.1. Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical investigation of a patient 
administered the treatment arm and that does not necessarily have a causal relationship with the 
treatment.  An AE is therefore any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the administration of 
medication, whether or not related to that therapy. Adverse events will be recorded in the patient 
chart and a case report form (CRF.)  Adverse events will be described by duration, severity, 
outcome, treatment and relation to GDMT if related (or unrelated). Our Data Safety Monitoring 
committee will perform an interim analysis of the data after 1 cluster enrollment/implemented at 
30 days. 
 
 

AE Severity 
The National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) 
Version 3.0 should be used to assess and grade AE severity, including laboratory abnormalities 
judged to be clinically significant. The modified criteria can be found in the study manual.  If the 
experience is not covered in the modified criteria, the guidelines shown in Table 1 below should 
be used to grade severity.  It should be pointed out that the term “severe” is a measure of 
intensity and that a severe AE is not necessarily serious. 
Table 1.  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. The subject may be aware of the sign 
or symptom but tolerates it reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal medical 
intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy required, 
hospitalizations possible. 
Life-threatening (4) 
The subject is at risk of death due to the adverse experience as it 
occurred. This does not refer to an experience that hypothetically 
might have caused death if it were more severe. 
 
Adverse Events Description  
There are well known side effects of GDMT, which patients will be counseled on prior to 
initiation of therapy.  Common side effects, or adverse events of therapy will be defined as in 
Table 2.  
Table 2.  AE Definitions  
AE 
Definition  
Hypokalemia 
K <3.0 mEq/L 
Hyperkalemia 
K >5.5 mEq/L 
Hyponatremia 
Na <130 mg/dL 
Acute Kidney 
Injury  
Increase in creatinine from baseline of >0.5 
Hypotension 
SBP <90 mmHg 
Bradycardia 
HR <50 bpm  
Urinary Tract 
Infection (UTI) 
Symptoms of UTI and urinalysis/urine culture consistent with infection and/or 
treated by primary provider for UTI 

Candidal 
vulvovaginitis  
Consistent symptoms of infection and/or treated for presumed infection  
10.2. Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
• 
death 
• 
a life-threatening adverse experience 
• 
inpatient hospitalization  
• 
a significant disability/incapacity 
Other important medical events may also be considered an SAE when, based on appropriate 
medical judgment, they jeopardize the subject or require intervention to prevent one of the 
outcomes listed.  
 
10.2.1. Serious Adverse Experience Reporting 
The study team will document all SAEs that occur (whether or not related to implementation) per 
Penn CER guidelines. The collection period for all SAEs will begin after the first patient cluster 
has enrolled and end 3 months post study period.  
 
In accordance with the standard operating procedures and policies of the local Institutional 
Review Board (IRB)/Independent Ethics Committee (IEC), the site investigator will report SAEs 
to the Navajo Nation Human Research Review Board.   
   
11. STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed.  The SAP will contain any modifications 
to the analysis plan described below.   
11.1. Data Sets Analyzed 
All heart failure patients with reduced ejection fraction that have a primary provider that has 
been randomized into the heart failure care delivery model intervention will be included in each 
analysis. 
11.2. Demographic and Baseline Characteristics 
The following demographic variables for each patient upon enrollment will be summarized: race, 
tribal affiliation, gender, age, BMI.  
The following clinical variables and baseline characteristics will be summarized: most recent 
blood pressure and heart rate, baseline creatinine, baseline potassium, most recent brain 

natriuretic peptide, if any heart failure hospitalization in last 12 months, ischemic or non-
ischemic cardiomyopathy based on coexisting validated ICD for ischemic cardiomyopathy [ICD 
codes: ICD 9 414.8, ICD 10 I25.5]), comorbidities to include coronary artery disease, diabetes, 
chronic kidney disease (including stage, end-stage renal disease), atrial fibrillation, hypertension, 
hyperlipidemia, left ventricular ejection fraction on most recent echocardiography, and prior 
cardiac studies including coronary angiography, stress test, or cardiac MRI.  
11.3. Analysis of Primary and Secondary Endpoints 
To assess the effectiveness of our intervention, measurement of rates of GDMT, including each 
specific medication of ACE inhibitors, ARB, ARNI, beta-blockers, MRA, SGLT2 inhibitors will 
be performed at baseline, at each cross-over time point. The main analysis of our stepped wedge 
design will be based on a logistic mixed-effects model which will contain a random intercept to 
account for between-cluster variability, a fixed effect parameter for time, and a group indicator 
variable for the treatment for each subject and time to capture treatment differences over time. 
Safety and tolerability data will be summarized by intervention group.   
Adverse event rates will be coded by body system and MedDra classification term. Adverse 
events will be tabulated by treatment group and will include the number of patients for whom the 
event occurred, the rate of occurrence, and the severity and relationship to newly started therapy.   
Statistical Analysis:  The primary analysis will utilize the intention to treat principle. A 
generalized linear model will be used to assess the relationship between randomization cluster  
status and the primary outcome. The model will use a log-link and independent correlation 
structure to allow for calculation of adjusted risk ratios. Statistical significance will be based on a 
P value of <0.05. For categorical secondary outcomes, a similar generalized linear modeling 
approach will be used. For continuous secondary outcomes, a generalized linear model will be 
used.  
Assessment of contamination: Providers may learn to better treat heart failure as consistent with 
evidence-based therapies over time.  Given we are not clustering by provider, but rather patients, 
it is possible that providers will take what is being implemented on their patient that is in an 
active implementation phase, and apply it to a patient in a non-active implementation phase.  
Therefore, there is a high risk of contamination. However, with the stepped wedge design, we 
will be able to also see how GDMT rates increase over the study period for those clusters who 
are not immediately in an active implementation arm. We will be able to better understand if 
increases in GDMT are related to the intervention or just due to increases over time due to 
improved knowledge of providers over time.   
Interim Analysis: We plan to have interim analyses at 30-days after enrollment of the first 
cohort. The interim analyses will allow us to stop the trial earlier for ethical considerations, 
unexpected adverse events. If there is high efficacy, we will continue the trial as all patients will 
be enrolled as per the stepped wedge design. Earlier stopping will be considered for the reason of 
safety and efficacy.  

11.4. Sample Size  
The outcomes of interest measured will be rates of each GDMT therapy. Assuming there are 20 
patients per cluster (which is reasonable based on preliminary data from GIMC), five time-points 
with one baseline measurement, and four clusters, we will have >95% power to detect a change 
in proportion of patients on appropriate GDMT (one therapy) from 25% to 50%, with Type I 
error rate of 5%. Given the low documented use of SGLT2 inhibitors and ARNIs (~25%) in 
preliminary data, the study is primarily powered to detect increase of 25% in those two 
medications in particular.  
 
12. DATA COLLECTION, RETENTION AND MONITORING 
12.1. Data Collection Instruments 
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each patient who is started on a guideline-
directed medical therapy.   
The PI is responsible for all information collected on subjects enrolled in this study.  All data 
collected during the course of this study must be reviewed and verified for completeness and 
accuracy by the Investigator.   
12.2. Data Management Procedures 
The data will be entered into a validated database, which will be on encrypted computer, 
password protected, and only available to study personnel. All procedures for the handling and 
analysis of data will be conducted using good computing practices meeting standard guidelines 
for the handling and analysis of data for clinical trials. Only data, as collected during set time 
points from the EHR will be obtained. Data includes medical record elements such as 
demographics, pharmacy records such as medication prescription and dosing, laboratory values, 
and administrative codes. All data will be stored without PHI. However, we will retain a linking 
dataset to be able to re-link individual data to actual patients for future studies and ongoing 
efforts through the HIS.  Access to individually identifiable information will be limited to the PI 
of the study, and only then via a linking file as aforementioned. All data used for analysis and 
dissemination to other investigators will be de-identified.  
12.3. Data Quality Control and Reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Queries are entered, 
tracked, and resolved through the system directly.  The study database will be updated in 
accordance with the resolved queries.  All changes to the study database will be documented. 
12.4. Archival of Data 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be 
maintained.  Databases are backed up by the database administrator in conjunction with any 
updates or changes to the database.   

At critical junctures of the protocol (e.g., production of interim reports and final reports), data for 
analysis is locked and cleaned per established procedures. 
12.5. Availability and Retention of Investigational Records 
The Investigator is unable to make data accessible unless indicated by the Navajo Nation Human 
Research Review Board.  All study documents (patient files, signed informed consent forms, 
Study File Notebook, etc.) must be kept secured for a period of two years following completion 
of the study.  
12.6. Subject Confidentiality 
In order to maintain subject confidentiality, only deidentified will be analyzed as detailed above.   
 
12.7 Protection of Human Subjects:  
This study is aimed at implementing a model to get patients on appropriate standard of care, 
guideline directed therapy. Therefore, this poses a minimal risk to patients. We have met with 
HF experts at the University of Pennsylvania, primary care providers, QI and safety officers at 
the IHS, nurses to ensure that the design of this study, including the implemented protocols, 
minimize any risk to the patients. We will restrict the study only to GIMC and THC. Our Data 
Safety Monitoring committee will perform an interim analysis of the data after 1 cluster 
enrollment/implemented at 30 days.  
Human subjects’ involvement, characteristics and design: The studies outlined in this proposal 
depend on the enrollment of individuals with heart failure. No vulnerable populations are being 
specifically targeted. We are limiting enrollment to individuals above age 18 years as the 
etiology and practices surrounding heart failure in pediatrics populations differ significantly from 
those in adults. All data is transmitted in encrypted and secure fashion, stored on servers with 
"triple-lock" certification, and is available only to members of the study team, IRB, and any state 
or federal agencies with auditing power.  
Sources of Materials: No biological materials will be obtained or stored as part of these studies.  
Over or under treatment: Implementation of the model, and all of the medication changes will be 
sent to the primary provider. It is possible that not only those patients, but then other patients 
cared for by those providers may be more likely to be started on evidence based medical 
therapies. These interventions fall within the standard-of-care and may benefit patients, but it is 
also possible that additional interventions may not benefit patients and could incur additional 
costs. However, this is what we are testing as part of this pragmatic trial. 
Potential benefits of the proposed research to the subjects and others: Subjects in this study may 
directly benefit from being started on evidence-based therapies for their heart failure. In addition, 
providers will be able to see implementation and medication changes, which may improve their 
education and comfort with updated HFrEF guidelines, leading to improved care for other 
patients. Additionally, regardless of the outcome for participants, the results of these studies may 
lead to significant benefit in the IHS and other health systems where access to care, especially 

cardiology care is limited. This model could be similarly expanded to other sites and to other 
disease entities. The risk/benefit ratio, given the minimal risk to study subjects, is more than 
acceptable in this series of studies. 
 
13. ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). 
To maintain confidentiality, all evaluation forms, reports and other records will be identified by a 
coded number and initials only.  All study records will be kept in a locked file cabinet and code 
sheets linking a patient’s name to a patient identification number will be stored separately in 
another locked file cabinet. Clinical information will not be released without written permission 
of the subject, except as necessary for monitoring by the IRB or sponsoring organization.  The 
Investigator must also comply with all applicable privacy regulations (e.g., Health Insurance 
Portability and Accountability Act of 1996, EU Data Protection Directive 95/46/EC). 
13.1. Protocol Amendments 
Any amendment to the protocol will be written by the PI.  Protocol amendments cannot be 
implemented without prior written IRB approval except as necessary to eliminate immediate 
safety hazards to patients.  A protocol amendment intended to eliminate an apparent immediate 
hazard to patients may be implemented immediately, provided the IRBs are notified within five 
working days. 
13.2. Institutional Review Boards  
The protocol and consent form will be reviewed and approved by the IRB of both the Navajo 
Nation/IHS as well as University of Pennsylvania. Serious adverse experiences regardless of 
causality will be reported to the IRBs in accordance with the standard operating procedures and 
policies of the IRBs, and the Investigator will keep the IRBs informed as to the progress of the 
study.  The Investigator will obtain assurance of IRB compliance with regulations. 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning patient 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB.  The IRB written unconditional approval of the study protocol and the 
informed consent form will be in the possession of the Investigator before the study is initiated.  
The IRB/IECs unconditional approval statement will be transmitted by the Investigator to the 
Sponsor prior to the shipment of study supplies to the site.  This approval must refer to the study 
by exact protocol title and number and should identify the documents reviewed and the date of 
review. 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB approval except when necessary to eliminate immediate hazards to the patients or 
when the change(s) involves only logistical or administrative aspects of the study.  Such 

modifications will be submitted to the IRB and written verification that the modification was 
submitted and subsequently approved should be obtained.   
The IRB must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect 
adversely the safety of the patients of the conduct of the study; an annual update and/or request 
for re-approval; and when the study has been completed. 
13.3. Publications  
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and participating institutions.  The publication or presentation of any study results shall comply 
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability 
and Accountability Act of 1996.  
13.4. Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying 
the Sponsor, except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 
 
 
 

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