University of Southern California Dissertations and Theses

Integrated management of atrial fibrillation in women in an underserved, safety-net health care system: a multicenter, single health system randomized control efficacy trial protocol

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Integrated management of atrial fibrillation in women in an underserved, safety-net health care system: a multicenter, single health system randomized control efficacy trial protocol

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Content Copyright 2023 Brittany G. Abt, M.D.

INTEGRATED MANAGEMENT OF ATRIAL FIBRILLATION IN WOMEN IN AN
UNDERSERVED, SAFETY-NET HEALTH CARE SYSTEM:

A MULTICENTER, SINGLE HEALTH SYSTEM RANDOMIZED CONTROL EFFICACY
TRIAL PROTOCOL

by

Brittany Gabriella Abt, M.D.

A Thesis Presented to the
FACULTY OF THE USC DEPARTMENT OF POPULATION AND PUBLIC HEALTH
SCIENCES
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(CLINICAL, BIOMEDICAL AND TRANSLATIONAL INVESTIGATIONS)

August 2023

ii

Dedication

To the patients empaneled in the Los Angeles Department of Health Services, thank you for your
generous willingness to contribute the advancement of science. It has been an honor to care for
you and learn from you.

iii

Acknowledgements

Thank you to my co-investigators Jonathan Praeger M.D. and Brandon Wiley M.D.; to our
statistician Wendy Mack Ph.D.; to our Physician Assistant Fay Purcell; to Vaughn Starnes M.D.
and the Division of Cardiac Surgery at the University of Southern California; Finally, to April
Krueger and the legal team representing her in the Krueger vs. Wyeth class action Settlement,
which has funded this study.

iv

Table of Contents

Dedication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ii

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . iii

List of Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vi

Abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

Chapter 1: Introduction 1
1.1 Sex-Based Disparities in Cardiovascular Disease, specifically Atrial Fibrillation . . . 1
1.2 Incidence and Impact of AF . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.3 Definition of Integrated Management and Outcomes of Integrated Approach in
Europe and Canada . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.4 Current Guideline Recommendations for Management of AF. . . . . . . . . . . . . 7
1.4.1 Oral Anticoagulation Recommendations. . . . . . . . . . . . . . . . . . . 7
1.4.2 Rate Control Recommendations. . . . . . . . . . . . . . . . . . . . . . . 9
1.4.3 Rhythm Control Recommendations . . . . . . . . . . . . . . . . . . . . . 9
1.4.4 Surgical MAZE Recommendations . . . . . . . . . . . . . . . . . . . . . 10
1.5 Adjudication and Application of Above Guidelines . . . . . . . . . . . . . . . . . 10
1.6 Endpoint Justification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Chapter 2: Study Aims 12
2.1 Objectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Chapter 3: Population 13
3.1 Study Population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.1.1 Inclusion Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
3.1.2 Exclusion Criteria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Chapter 4: Design 15
4.1 Study Design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.1.1 Location and Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.1.2 Consent Process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
4.1.3 Randomization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
4.1.4 Masking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
4.1.5 Sample Size Estimation . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
v
4.1.6 Treatment Interventions and Study Procedures . . . . . . . . . . . . . . . . 19
4.1.6.1 Standard of Care with “Integrated Atrial Fibrillation Management . . 20
4.1.6.2 Standard of Care + . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
4.1.7 Schedule of Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Chapter 5: Recruitment 27
5.1 Recruitment Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
5.1.1 Inclusion of Women and Minorities, Exclusion Criteria Rationale . . . . . . . . 27

Chapter 6: Statistics, Endpoints, and Definitions 30
6.1 Statistical Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
6.1.1 Primary Endpoint . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.1.2 Secondary Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.1.2.1 Clinical Endpoints . . . . . . . . . . . . . . . . . . . . . . . . . 31
6.1.2.2 Quality of Life Endpoints . . . . . . . . . . . . . . . . . . . . . . 32
6.1.2.3 Patient Centered Endpoints . . . . . . . . . . . . . . . . . . . . . 33
6.1.2.4 Economic Outcomes . . . . . . . . . . . . . . . . . . . . . . . . 33
6.1.3 Endpoint Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

Chapter 7: Event Reporting 41
7.1 Expedited Adverse Event Reporting . . . . . . . . . . . . . . . . . . . . . . . . . 41

Chapter 8: Data Collection and Management 42
8.1 Data Reporting and Validation . . . . . . . . . . . . . . . . . . . . . . . . . . 42
8.1.2 Baseline Data Collection . . . . . . . . . . . . . . . . . . . . . . . . . . 42
8.1.3 Outcome Assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
8.2 Data Entry and Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
vi

List of Tables

1.3 Summary of Previous Integrated Management vs. Usual Care Trials to Date in Europe
and Canada . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

4.1.7 Schedule of Events in Intervention and Standard of Care Arm . . . . . . . . . . . . 25

vii
Abstract

Background: Despite being the leading cause of mortality in women, women across the world
are under-diagnosed and under-treated with respect to cardiovascular disease (CVD). Atrial
fibrillation (AF), and its subsequent complications, is a leading cause of CVD worldwide. To
date, no randomized control trial has examined the efficacy of an integrated management
approach to AF, specifically in women, in a public, safety-net based practice setting wherein the
patient population is highly diverse and historically underserved.
Objective: The overall objective of this study is to evaluate whether a structured, integrated
management approach to AF can improve cardiovascular health in an underserved female
population in a large safety-net healthcare system. The primary aim is to determine whether an
integrated management approach to the management of AF in women decreases all-cause
mortality and major adverse cardiovascular events (MACE, defined as a composite of non-fatal
stroke, non-fatal myocardial infarction, and cardiovascular death) compared to women with atrial
fibrillation treated by standard of care.
Methods: This trial is a pragmatic single-healthcare system, multi-site, randomized trial in
which women with diagnosed AF will be randomized to integrated versus standard care for atrial
fibrillation in a 1:1 ratio. Accrual is expected to take 24 months. Participants will be followed for
up to 5 years. Study will end 5 years from first enrollment.
Conclusions: Such an integrated approach to AF perhaps has the most potential to alter CV
outcomes for socio-economically challenged and underserved patient populations.

1
Chapter 1

Introduction

1.1 Sex-Based Disparities in Cardiovascular Disease, specifically Atrial
Fibrillation

Cardiovascular disease (CVD) is the leading cause of mortality for women; responsible
for 35% of total deaths in women in the United States in 2019.
1
Despite being the leading cause
of mortality in women, women across the world are under-diagnosed and under-treated with
respect to CVD and furthermore, are under-represented and under-reported in cardiovascular
clinical trials. The sex-specific factors contributing to these facts are magnified further in women
of lower socioeconomic class. These inequities have become so prominently recognizable that in
2021, the Lancet created a commission aimed at reducing the global burden of CVD in women
by 2030.
2

Figure 1: Deaths and Disability-Adjusted Life Years attributable to cardiovascular causes in
women vs. men. Right two figures show absolute numbers while left two figures show percent.
Females are represented by green. Males are represented by purple.
2

With respect to AF specifically, the largest study on stand-alone AF surgery to date,
which utilized Society of Thoracic Surgeons Adult Cardiac Surgery Database (STS ACSD) data
from 2011-2017, found that only 30% of people receiving stand-alone AF surgery were female.
3

Despite women being largely underrepresented in the AF literature, the body of current literature
consistently suggests that sex differences exist within the full scope of AF diagnosis, treatment,
and outcomes. To briefly summarize the literature, women with AF are more likely to be
symptomatic, but less likely to be managed with rhythm control, i.e. less oral antiarrhythmics,
less cardioversion, and less catheter ablations.
4, 5, 6, 7
Not only are women with AF less likely to
be prescribed oral anticoagulants,
8
but they are also less likely to experience successful catheter-
directed ablation and instead have an increased chance of recurrence of AF after catheter-directed
ablation when compared to their male counterparts.
9, 10, 11, 12
Finally, women with AF report
worse quality of life than their male counterparts.
5, 7

The sex-based disparities in CVD run deeper than just differences in diagnosis and
treatment. In fact, a growing body of literature suggests that men and women experience risk
factors for CVD differently. Recent large meta-analyses have demonstrated that AF is a stronger
risk factor for CVD in women compared to men; concluding that AF was associated with a
higher risk of all-cause mortality in women (ratio of relative risks for women compared with
men 1.12, 95% confidence interval 1.07 to 1.17) and a significantly stronger risk of stroke (RR
1.99, 95% confidence interval 1.46 to 2.71), cardiovascular mortality (RR 1.93, 95% confidence
interval 1.44 to 2.60), cardiac events (RR 1.55, 95% confidence interval 1.15 to 2.08), and heart
failure (RR 1.16, 95% confidence interval 1.07 to 1.27).
13

3

In summary, women with AF are at a higher risk for myocardial infarction (MI), ischemic
heart disease, stroke, and increased mortality. Thus, as AF is one of the strongest risk factors for
CVD, identifying women with AF functions as an excellent proxy for and means of identifying
women at risk for CVD.

1.2 Incidence and Impact of AF

AF is the most common sustained cardiac arrhythmia, affecting at least 3 million
Americans and significantly burdening the American healthcare system with a direct patient cost
of approximately 6 billion annually.
14, 15
Globally, AF and its associated complications are a
leading cause of CVD worldwide. According to the Global Health Data Exchange, the
prevalence of AF worldwide and in the United States is 30 million and 3.4 million, respectively.
The prevalence of AF is projected to continue to increase.

AF is often accompanied by a host of other comorbid conditions, including diabetes,
obesity, hypertension, CAD, CHF, and structural heart disease. The interplay between a patient’s
AF management and management of other comorbidities with respect to overall mortality and
adverse cardiovascular outcomes ought not to be overlooked.

4

1.3 Definition of Integrated AF Management and Outcomes of Integrated
Approach in Europe and Canada

Given AF’s association with other comorbid conditions and its ability to act as a
harbinger for CVD, truly integrated AF management needs to address the following:
(1) acute stabilization of patients presenting with AF and hemodynamic compromise,
(2) detection and treatment of underlying and accompanying cardiovascular conditions,
(3) stroke risk assessment and oral anticoagulation for stroke prevention,
(4) rate control,
(5) rhythm control therapy.
16

Such an integrated approach perhaps has the most potential to alter outcomes for socio-
economically challenged and underserved patient populations. To date, no randomized control
trial has examined the effectiveness of an integrated management approach to AF in a public-
health, safety-net based practice setting wherein the patient population is highly diverse and
historically underserved. A small number of similar studies have demonstrated the positive
impact of integrated AF management in Europe and Canada, which are summarized below and in
Figure 2.
17, 18, 19, 20

5
Most notably, the ALL-IN trial was a multicenter, prospective, open-label, cluster
randomized pragmatic trial in patients with AF aged 65 years or older, managed in primary care
in the Netherlands.
17
This trial randomized 26 family practice locations throughout the
Netherlands to receive either integrated AF care or usual care. Integrated care intervention
included quarterly AF check-ups by trained nurses in primary care, monitoring of anticoagulation
therapy in primary care, and coordinated consultations from cardiologists and anticoagulation
clinics if deemed necessary. The primary endpoint was all-cause mortality. The ALL-IN trial
found that all-cause mortality rates were significantly lower in the intervention arm (3.5 per 100
patient-years in the intervention arm vs. 6.7 per 100 patient-years in the control arm). Integrated
care for elderly AF patients in primary care showed a 45% reduction in all-cause mortality when
compared with usual care.
17

Other studies evaluating the effects of integrated AF management have similarly
demonstrated positive results. Hendricks et al. found a significantly decreased rate of
cardiovascular death and cardiovascular hospitalizations in their integrated approach arm;
18

Gallagher et al. demonstrated that all-cause mortality decreased by 49% in patients receiving
integrated care, and CV hospitalizations decreased by 42% in patients receiving integrated care;
19

Carter et al. found that patients treated with an integrated approach had significantly decreased
death from any cause, cardiovascular hospitalization, or AF-related ED visit at 12 month
compared to those receiving usual care.
20

6
Study Study Design and Patient Population Primary and Secondary Endpoints/Power Estimation Assumptions Results
ALL-IN Multi-center prospective, open-label, cluster randomized pragmatic
trial in patients with AF aged 65 years or more, managed in primary
care in the Netherlands.

Randomization was performed at the level of the clinics in a 2:1
allocation model.

Study population consisted of patients age 65 years or more with
documented AF in the primary care practice (identified by an ECG or
specialist’s letter to the GP).
Primary endpoint was all-cause mortality.

Secondary Endpoints:
cardiovascular mortality, cardiovascular and non-cardiovascular
hospitalizations, major adverse cardiac events
(MACE), stroke, major bleeding, clinically relevant
non-major bleeding (CRNMB), quality of life and cost-effectiveness

Power calculation- based on assumption that all-cause mortality will occur in 8% of the patients
receiving usual care versus 4% in those receiving the intervention with integrated AF management
39 patients in the intervention arm and 96 patients in the control
arm died (7.4% and 13.5%, respectively).  The all-cause
mortality rate was 3.5 per 100 patient-years in the intervention arm
vs. 6.7 per 100 patient-years in the control arm [adjusted hazard
ratio (HR) 0.55; 95% confidence interval (CI) 0.37–0.82].

Hendricks et
al.

Prospective, randomized controlled trial of
Newly diagnosed AF patients.

Participants were randomized into two groups for clinical
management by a cardiologist.
(Usual care group) or management in the nurse-led,
guidelines-based, software-supported AF-Clinic (intervention
group).

Study population: Patients referred to the outpatient clinic of the
Cardiovascular Centre of the Maastricht University Hospital who met
the following eligibility criteria: newly diagnosed AF detected on
electrocardiogram (ECG), and age >18 years
Primary endpoint: hospital admission rate for any cardiovascular reason and/or cardiovascular death.

The secondary endpoints:
(1) guideline concordance with the 2006 ACC/AHA/ESC guidelines for AF
(2) patient quality of life,
(3) patient-reported anxiety and/or depression
(4) patient satisfaction
(5) patients’ knowledge of AF
(6) patients’ self-reported adherence with medication
(7) the cost of the intervention by means of a cost effectiveness analysis

A sample-size of 349 patients in each the intervention and control groups (698 total) was calculated
based on a reduction from 35% to 25% for any cardiovascular reason and/or cardiovascular death
after 18 months using an alpha of
0.05 and a power of 0.80.
During a mean follow-up of 22 months, the primary outcome was
reached in 125 patients: 51 patients (14.3%) in the nurse-led care
and 74 (20.8%) in the control group (hazard ratio: 0.65; 95% CI
0.45–0.93). After adjustment the hazard ratio was 0.63; 95% CI
0.44–0.90.

Rate of cardiovascular death:
significantly lower in the nurse-led care group compared with the
usual care group (1.1 and 3.9%, respectively, hazard ratio: 0.28;
95% CI 0.09–0.85)

Rate of cardiovascular hospitalizations
significantly lower in the nurse-led care group (13.5 vs. 19.1%,
respectively, hazard ratio: 0.66; 95% CI: 0.46–0.96). The adjusted
hazard ratio is 0.64; 95% CI 0.44–0.93.
Gallagher Systematic review and meta-analysis examining the impact of the
integrated care approach in the AF population, compared with usual
care.

Three studies, with a total study population of 1383, were identified
that compared integrated care approaches with usual care in AF
populations.
Outcomes included: mortality, hospitalizations, emergency department presentations, cerebrovascular
outcomes and patient-reported outcomes, including quality of life, anxiety and depression
> all-cause mortality: decreased by 49% in patients receiving
integrated care
> CV hospitalizations: decreased by 42% in patients receiving
integrated care. The absolute event rate was 8.0 per 100 person-
years in the integrated care arm (95% CI 2.56 to 25.02) compared
with 11.87 in the control group (95% CI 4.59 to 30.71).
> AF related hospitalization rates: 5.5/100 person years in
intervention arm vs. 7.0/100 person years in care as usual arm (not
statistically significant) ((OR 0.82, 95% CI 0.56 to 1.19, p=0.29)
> Cerebrovascular event rates: 1.1/100 person years in intervention
arm vs. 1.8/100 person years in care as usual arm (not statistically
significant)(OR 1.00, 95% CI 0.48 to 2.09, p=1.00)
Carter et al.

Performed a “before-and-after” study where patients who presented
with new-onset AF to the emergency department were studied during
2 phases: the usual-care (before phase) and subsequently the AF
clinic (after phase)

Study population consisted of patients aged ≥18 years who presented
to 1 of the 3 EDs in Nova Scotia between January 1, 2009 and
January 31, 2014, with a new diagnosis of AF confirmed on ECG
and who were referred and evaluated by a specialist.

All patients were followed in both groups for a minimum of 12
months from their initial presentation. The patients in the usual-care
group, although identified retrospectively, were followed
prospectively from their ED visit for an additional 12 months after
the last patient was enrolled into the group, while the patients in the
intervention group were enrolled prospectively and followed
henceforth for the same follow-up period of 12 months, after the final
patient was enrolled.
Primary endpoint: a composite of death from any cause, cardiovascular hospitalization, or AF-related
emergency visit at 12 months.

Secondary endpoints: the individual components of the primary outcome, stroke, major bleeding,
minor bleeding, and the degree of adherence to practice guidelines

The sample size for each arm was estimated to be 150.
Assuming:
- A relative risk reduction of 40% was deemed the minimally clinically important difference
- A 90% power, an a of 0.05, and a loss to follow-up of 20%
There were 185 patients enrolled into the AF clinic group and 228
patients in the usual-care group

The primary outcome occurred in 34 of 185 (18.4%) patients in the
AF clinic, as compared to 65 of 228 (28.5%) patients in the usual-
care group (OR 0.57; 95% CI [0.35, 0.9] P=0.017)

Hospitalization Rates for CV reasons:
-AF group: 11/185 (5.9%)
-Usual Care group: 20/228 (8.8%)
(OR 0.66, 95% CI [0.31, 1.41] P=0.28)

Table 1: Summary of Previous Integrated Management vs. Usual Care Trials to Date in Europe
and Canada
7
1.4 Current Guideline Recommendations for Management of AF

The American College of Cardiology (ACC) and American Heart Association (AHA)
have published quite detailed and specific clinical practice guidelines for patients with AF based
on the review of scientific evidence intended to improve cardiovascular health. The latest
guidelines for management of patients with AF were published in 2014, with a focused update in
2019. The main goal of guideline-directed AF therapy is to prevent thromboembolism and to
control symptoms. Thus, these guidelines focus primarily on anticoagulation strategies, rate
control, and pharmacological, interventional, and surgical methods of rhythm control. While
below is not intended to be a complete summary of recommendations, it is especially pertinent to
this trial to review several of these guideline recommendations.

1.4.1 Oral Anticoagulation Recommendations

According to the 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ ACC/HRS
Guideline for the Management of Patients With Atrial Fibrillation, selection of anticoagulation
should be based on the risk of thromboembolism (Class I LOE B), however the anticoagulation
strategy ought to be both individualized to the patient and based on a shared decision making
model which balances the risks of stroke and bleeding with patient preferences and values (Class
I LOE C). Additionally, reevaluation of the need for and choice of anticoagulants is
recommended at periodic intervals to reassess stroke risks and bleeding risks (Class I LOE C).

8
Oral anticoagulation (Warfarin, Dabigatran, Rivaroxaban, Apixaban, or Edoxaban) are
recommended for patients with AF and an elevated CHA2DS2-V ASc (risk of stroke calculator in
non-rheumatic AF) score of 2 or greater in men or 3 or greater in women (Class I, LOE A-B
based on selection of specific oral anticoagulant). For those taking warfarin, the International
Normalized Ratio (INR) should initially be checked weekly until stable, and then monthly (Class
I, LOE A). NOACs (novel oral anticoagulants including dabigatran, rivaroxaban, apixaban, and
edoxaban) are recommended over warfarin in NOAC-eligible patients with AF so long as such
patients do not have moderate-to-severe mitral stenosis or a mechanical heart valve (Class I,
LOE A). For patients being prescribed a NOAC, renal function and hepatic function should be
evaluated before initiation of a NOAC and should be reevaluated at least annually (Class I LOE
B-NR).

Oral anticoagulation may be considered in patients with lower CHA2DS2-V ASc scores.
According to the updated guidelines, for patients with AF (except with moderate-to-severe mitral
stenosis or a mechanical heart valve) and a CHA2DS2-V ASc score of 1 in men and 2 in women,
prescribing an oral anticoagulant to reduce thromboembolic stroke risk may be considered (Class
IIb LOE C-LD).

Oral anticoagulation may be omitted for patients with AF (except with moderate-to-
severe mitral stenosis or a mechanical heart valve) and a CHA2DS2-V ASc score of 0 in men or 1
in women (Class IIa LOE B).
9

1.4.2 Rate Control Recommendations

With respect to rate control, 2014 AHA/ ACC/HRS guidelines recommend control of the
ventricular rate using a beta blocker or nondihydropyridine calcium channel antagonist for
paroxysmal, persistent, or permanent AF (Class I LOE B), with resting rate of less than 80 bpm
for symptomatic management (Class IIa LOE B). When pharmacological therapy is inadequate
for rate control and rhythm control is not advised, A V nodal ablation with permanent ventricular
pacing is reasonable to control heart rate (Class IIa LOE B).

1.4.3 Rhythm Control Recommendations

The following antiarrhythmic drugs are recommended for patients with AF (only after
treating reversible and precipitating causes of AF) to maintain sinus rhythm depending on
underlying heart disease and medical comorbidities—amiodarone, dofetilide, dronedarone,
flecainide, propafenone, or sotalol (Class I LOE A). A rhythm control strategy may be
recommended over rate control for patients with AF for the treatment of tachycardia-induced
cardiomyopathy (Class IIa LOE C). On the other hand, antiarrhythmic drugs for rhythm control
should not be continued when AF becomes permanent (Class III LOE C). Additionally, it should
be noted that Ablation is Class IIB recommendation for heart failure with reduced ejection
fraction insofar as it has been shown to reduce mortality and hospitalization rates in heart failure
patients.

10

1.4.4 Surgical MAZE Recommendations

For AF patients undergoing cardiac surgery for other indications, surgical ablation is
reasonable (Class IIa LOE C). Stand-alone AF surgery may be reasonable for highly
symptomatic patients AF who are not well managed by other approaches (Class IIb LOE B).

1.5 Adjudication and Application of Above Guidelines

The anticoagulation strategy, and rate and/or rhythm management will be prescribed by
the participant’s primary cardiologist/Primary Care Physician (PMD). The treatment will be
recorded and the central cardiologist will review and document guideline-directed care at the
annual visit. Central cardiologist or study physician assistant will contact primary
cardiologist/PMD as indicated to adjudicate patient care or make guideline directed
recommendations as appropriate.

Specifically with respect to anticoagulation, the HAS-BLED Score for Major Bleeding
Risk will be utilized. This score— easily calculable based off hypertensive status, presence of
renal or liver disease, stroke history, prior bleeding events, lability of INR, use of Aspirin,
clopidogrel, or NSAIDs, alcohol consumption, and age greater 65 years – estimates risk of major
bleeding for patients on anticoagulation to assess risk-benefit in atrial fibrillation care. This score
will be calculated for each patient and the study cardiologist will use this score in composite with
11
clinical judgement to determine whether or not the addition of (or cessation of) anticoagulation
should be recommended as a course of action to the patient’s PMD or primary cardiologist.

1.6 Endpoint Justification

The primary effectiveness endpoint of this trial is the composite of all-cause, overall
mortality and major adverse cardiovascular events (MACE, defined as a composite of non-fatal
stroke, non-fatal myocardial infarction, and cardiovascular death) in women at three and five
years. This composite endpoint was chosen because 7 out of 10 deaths in AF patients are
attributable to cardiovascular causes.
21
Defining what components of integrated AF management
reduce mortality is particularly important. This composite endpoint incorporates adverse events
(AEs) that are both clinically-relevant to patients with AF, carry a high morbidity burden, and
also are likely to be reduced by a strategy of integrated AF management which focuses on
expedited, guideline-directed care.

12
Chapter 2

Study Aims

2.1 Objectives

The overall objective of this trial is to evaluate whether a structured, integrated
management approach to AF can improve cardiovascular health in an underserved female
population in a large, safety-net healthcare system.

• The primary aim of this trial is to determine whether an integrated management
approach of patients with AF decreases all-cause, overall mortality and major adverse
cardiovascular events (MACE, defined as a composite of stroke, myocardial infarction,
and cardiovascular death) as compared to women with AF treated by usual care.

• The secondary aims of this trial are to determine whether an integrated management
approach to AF in women alters cardiovascular-related mortality, heart failure-related
hospitalizations, AF related hospitalizations, major bleeding events, clinically relevant
nonmajor bleeding, comorbidity control (blood pressure, lipid control, diabetes control,
risk factor modification), need and associated morbidity and mortality of interventional or
surgical procedures, quality of life, and cost-effectiveness when compared to care as
usual.

13
Chapter 3

Population

3.1 Study Population

The patient population for this trial consists of adult, female patients who carry a
diagnosis of AF, confirmed on electrocardiogram (ECG), receiving care at a Los Angeles County
Department of Health Services (LAC-DHS) facility. Specific inclusion and exclusion criteria are
listed below. All female patients who meet the eligibility criteria will be invited to participate.

3.1.1 Inclusion Criteria

1. Female sex, as assigned at birth
2. Age ≥18 years old
3. Diagnosis of AF by ECG
4. Receiving care at a LAC-DHS facility
5. Ability to provide informed consent and comply with the protocol

3.1.2 Exclusion Criteria

1. Male sex, as assigned at birth
2. Age < 18 years old
3. Cardiac surgery within 3 months prior to enrollment
4. Previous successful interventional or surgical treatment of atrial fibrillation or flutter
5. Previous left atrial appendage occlusion
14
6. Existence of underlying disease that limits life expectancy to 6 months or less
7. Participation in another randomized trial within the prior 30 days
8. Unable or unwilling to provide informed consent
9. Unable or unwilling to comply with the study treatment and follow-up protocols

15
Chapter 4

Design

4.1 Study Design

This is a multi-site, single-healthcare system, pragmatic randomized trial comparing an
integrated management system in addition to standard of care to standard of care. The study
population will include 632 eligible women diagnosed with AF within the LAC-DHS healthcare
system. The estimated enrollment period is 24 months. The total study duration will be five
years.

4.1.1 Locations and Assessment

Participants will be recruited from five Department of Health Safety Net Hospitals in Los
Angeles. These will include:

1. Harbor/UCLA Medical Center
2. LAC+USC Medical Center
3. Olive View / UCLA medical Center
4. Rancho Los Amigos National Rehabilitation Center
5. Martin Luther King/ UCLA Medical Center

Although participants will be referred from all of the above sites and their primary care
will remain at the site from which they are referred, all research-related visits including visits
16
with the physician assistant, nutrition and study cardiologist as well as the blood sampling will
take place at LAC/USC. Intervention will supplement, rather than replace their primary and
specialty care already being received.

General practitioners, hospitalists, emergency room physicians, and cardiologists within
the DHS system at the aforementioned sites will be educated about this study. These physicians
will be encouraged to refer female patients to our study coordinator. Female patients who have
AF on the ECG before referral are eligible for participation in the study. Following the
confirmation of eligibility, patients are then randomized by a dedicated software system on a 1:1
basis to either the control group (“Standard of care +”) or the intervention group (“Standard of
Care with Integrated Atrial Fibrillation Management”). Patients’ baseline characteristics will be
assessed from the medical chart and/or standard assessment forms at time zero obtained at
baseline appointment, described below. Follow-up data will be assessed from the medical chart,
standard patient assessment forms, and patient interviews at quarterly intervals or bi-annually in
the treatment and control arms, respectively, as described below.

4.1.2 Consent Process

Consent will be obtained by licensed study personnel including physicians and the study
physician assistant. An IRB approved consent form will be utilized along with an institutional
approved HIPAA form. Study procedures will begin after consent is signed.

17
Consents will be obtained in a private setting to protect potential participant privacy.
This will include face to face consents as well as the use of remote forms of consent such via
Docusign.

The study will be explained to the potential participant in her native language, using a
professional licensed interpreter. Participant will be given time to ask questions and to discuss
participation with family or friends if desired prior to signing consent form.

4.1.3 Randomization

Eligible and consented patients will be randomized 1:1 to a Standard of Care with
Integrated AF Management Strategy, or Standard of Care group. Randomization will be
stratified by referral clinical site within the single healthcare system. Randomization will be
performed centrally through a Web-based data collection system, with automated delivery of the
randomization assignments. The treatment assignment will be viewed by the study personnel, in
a secure electronic manner. Electronic verification of the treatment assignment will be required
before proceeding with the treatment intervention. From that point on, primary effectiveness will
be analyzed by intention-to-treat; that is, the patients will be grouped by their assignment at
randomization regardless of whether or not they actually received the treatment to which they
were assigned.

18
4.1.4 Masking

Neither patients nor investigators will be blinded to treatment assignment due to the
nature of the intervention and the pragmatic design of the trial. However, the central adjudication
of clinical outcomes (particularly serious adverse outcomes) will be conducted by adjudicators
(the medical monitor, and then the Data Safety Monitoring Board biannually) who are blinded to
treatment assignment.

4.1.5 Sample Size Estimation

To our knowledge, four published randomized control trials and one systematic
review/metanalysis have examined the effects of an integrated care plan for AF. None of these
published trials examine precisely the same primary endpoint as our trial, but are nonetheless
useful in power calculations as each trial reports portions of our primary endpoint. These studies
are summarized in Table 1 above. Hendricks et al. examined cardiovascular mortality (1.1% in
the nurse-led care group and 3.9% in the control group; hazard ratio 0.28; 95% CI 0.09–0.85).
The ALL-IN trial examined all-cause mortality (7.4% and 13.5%, in the intervention and control
arms respectively). Gallagher et al. reports nonsignificant differences in cerebrovascular event
rates (1.1/100 person years in intervention arm vs. 1.8/100 person years in care as usual arm; OR
1.00, 95% CI 0.48 to 2.09, p=1.00). With respect to myocardial infarction rates in patients with
AF, there are no reports in the published randomized clinical trials. However, the annual rate of
MI in observational studies of AF patients ranges from 0.4% to 2.5%.
24

19
Based on data from these studies, we expect our primary composite endpoint to have a 1-
year event probability of 20% in the usual care group (corresponding to a control group hazard
rate of 0.225). We conservatively project a 30% reduction in the usual care hazard rate ratio
(HR), for an intervention HR of 0.70; ratios of event rates in the studies above are far less than
this HR. Additionally, since this is a safety-net hospital, the sample size estimation accounts for a
15% loss-to-follow-up rate/ year. The sample size estimate also accounts for a single interim
efficacy analysis on the primary composite outcome conducted at 60% of trial follow-up (when
the first enrolled subject has completed 3 years of follow-up). Using a two-sided alpha of 0.05, a
power of 80%, and factoring in a potential 15% loss per year and the planned interim analysis,
we need 316 in each arm to detect a hazard rate ratio of at least 0.70. The estimated enrollment
period is 24 months. The total study duration will be five years.

4.1.6 Treatment Interventions and Study Procedures

Patients will be randomized 1:1 to the following treatment strategies—
• Treatment Arm – “Standard of Care with Integrated Atrial Fibrillation Management”
• Control Arm –“Standard of Care +”

This intervention was developed based on extensive review of the literature in
conjunction with the 2014 American College of Cardiology /American Heart Association
Clinical Performance and Quality Measures for Adults with Atrial Fibrillation or Atrial Flutter
Guidelines (Circulation, 2014; 130:d199-e267) and the 2019 AHA/ACC/HRS Focused Update of
the 2014 AHA/ ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation.
20
Additionally, this intervention was designed specifically to address the cardiovascular risk
factors of minority, women seeking care in a safety-net hospital, and to provide patient-centered
and patient-tailored care and education.

The AHP will be specifically trained to educate and instruct women with AF about their
condition, symptomatology, possible complications, and treatment in order to improve patient
knowledge and empower patients to seek additional care when necessary, and to increase
compliance with the care teams’ instructions and prescribed medication regimens.

Research visits will supplement, rather than replace, the routine visits with the
participants’ primary cardiologist and primary care physicians. They will be used for the purpose
of collecting data and lab tests, providing additional education, communicating new significant
issues to the primary physicians, coordinating additional guideline-directed care, and helping the
participants navigate the healthcare system.

Participants will be instructed that they may call during normal daytime hours, 9 AM
through 5 PM to contact the study physician assistant and to expect a response within 48 hours.
If it is an emergency, they are to contact 911 or their primary physician.

4.1.6.1 Standard of Care with “Integrated Atrial Fibrillation Management”

In the Integrated Management arm, the primary treatment intervention centers around
care coordination by a licensed and trained allied health professional (AHP) in collaboration with
the primary care physician, cardiologist, nutritionist, and anticoagulation clinics. After informed
21
consent is obtained, the patients randomized to the intervention arm will be scheduled for a
baseline appointment. At this baseline appointment, the AHP will review and confirm the
patient’s history, document any comorbid medical conditions, provide education about the
pathophysiology and treatment of AF, as well as the symptoms and complications which may
arise from AF. Subsequently, the AHP will review the patient’s medication list and ensure the
patient is up-to-date on necessary cardiac screening and diagnostic tests according with the
guidelines. This in-depth review of symptoms, comorbidities, and medications by the AHP will
be conducted using a standard assessment form.

If the participant has not had recent HbA1c if diabetic, lipid panel, thyroid panel, BNP,
CMP, and CRP drawn this will be arranged for them. The AHP will ensure that a baseline height,
weight, BMI, blood pressure and ECG is present in the electronic medical records. We will
collect and document the individual’s CHA2DS2-V ASc score (history of congestive heart failure,
hypertension, age≥75 (doubled), diabetes, stroke or Transient Ischemic Attack (TIA)
(doubled)–vascular disease, age 65–74 and female sex) and the type of AF at baseline
(paroxysmal or non-paroxysmal). We will also collect and document the HAS-BLED Score for
Major Bleeding Risk. As mentioned, this score— easily calculable based off of hypertensive
status, presence of renal or liver disease, stroke history, prior bleeding events, lability of INR, use
of Aspirin, clopidogrel, or NSAIDs, alcohol consumption, and age greater 65 years – estimates
risk of major bleeding for patients on anticoagulation to assess risk-benefit in atrial fibrillation
care. This score will be calculated for each patient and the study cardiologist will use this score
in composite with clinical judgement to determine whether or not the addition of (or cessation
22
of) anticoagulation should be recommended as a course of action to the participants’ PMD or
primary cardiologist.

Participants with newly diagnosed AF will require a transthoracic echocardiogram (TTE).
In order to ensure that participants receive a timely assessment, we will utilize Point of Care
Ultrasonography (POCUS). The POCUS will be performed by the study cardiologist and his
fellows in order to identify participants with potentially high-risk echocardiographic features
(such as mitral or aortic valve disease or depressed ejection fraction) who may require escalation
of care or referral to the cardiothoracic surgery clinic. Such participants who are identified as
“high risk” will receive expedited referral for formal, full TTE.

After this, the AHP will see the participants in the intervention arm on a quarterly basis.
These visits will focus on screening for heart failure symptoms, other cardiac symptoms,
medication compliance, and optimization of medical comorbidities. The AHP will once again
review the patient’s medication list, assess for compliance, and ensure the patient is up-to-date on
necessary cardiac screening and diagnostic tests according with the guidelines. Blood pressure,
height, weight, and heart rate will all be obtained and documented at these routine visits. When
there is a question of adequate rate control, the patient will be sent for an ECG. At these visits,
the AHP will also administer a KCCQ short form, EQ5D and PACT-Q2 as appropriate. At these
visits, the AHP will inquire about and document any heart failure-, AF-, or cardiovascular-related
emergency room visits or hospitalizations. We also anticipate that the AHP will provide
instruction aimed at empowering patients and life-style modification (e.g. smoking cessation,
adherence to medication, moderation of alcohol intake, exercise plans, weight loss counseling,
23
etc.) when those topics are deemed applicable and when existing knowledge is considered
inadequate. The AHP will additionally coordinate a yearly visit with the study cardiologist and
will schedule any necessary cardiovascular screening exams in accordance with ACC/AHA
guidelines based on the individual patient’s risk factors and comorbidities. In coordination with
cardiology and the anticoagulation clinics, the cardiologist collaborator will be asked to
document whether or not the patient is on goal directed therapy with respect to rate (or rhythm
control) and anticoagulation. Another aspect of this intervention arm focuses on timely
coordination of referral to specialty clinics, including interventional cardiology, cardiac surgery,
or neurology, for specialized cardiovascular care as appropriate.

In addition to providing a coordinator for the various health care needs of the participant
and providing an additional layer of monitoring through the quarterly visits, participants will be
seen by a nutritionist at each visit. The nutritionist will provide unique patient directed education
for weight management, metabolic management and nutritional support. Participants will be
encouraged to set goals such as weight optimization, salt control and glucose control.

Twice a year after enrollment as appropriate for each participant, participants will have
labs to measure HbA1c, lipids, BNP, and CRP. Thyroid panels will be followed only if abnormal
at baseline. If labs were obtained within 4 weeks of a study visit by another one of the
participants’ providers, we will use these results from the medical records. Annual blood samples
will be collected for repository for potential future use including but not exclusively genetic,
molecular, and biomarker analyses (up to 12.5ml of whole blood (1 EDTA tube [10ml] and 1
PAXgene tube [2.5ml] will be collected and stored).
24

Patients can contact the AHP by telephone or secure message between planned visits as
needed.

25
4.1.6.2 Standard of Care +

After informed consent and randomization, participants in the standard of care arm will
receive guideline directed cardiovascular care provided and directed by Los Angeles County
Department of Health Services primary care, cardiology, and/or anticoagulation clinics. There
will be a semi-annual phone call visit by the study AHP to collect information about medical
status, medication compliance, and Quality of Life Assessment using the same standardized
forms employed in the intervention arm. Once a year after enrollment as appropriate for each
participant, participants will have labs to measure HbA1c, lipids, BNP, CMP, and CRP. Thyroid
panels will be followed only if abnormal at baseline. If labs were obtained within 4 weeks of
visit by another one of the participants’ providers, we will use these results from the medical
records. Annual blood samples will be collected for repository for potential future use including
but not exclusively genetic, molecular, and biomarker analyses (up to 12.5ml of whole blood (1
EDTA tube [10ml] and 1 PAXgene tube [2.5ml] will be collected and stored).

These phone visits, screenings, and labs are necessary in order to make the direct
comparisons between the intervention and control arms. AHPs will recommend that the
participant seek medical attention in the event of a significant new reported symptom, but will
not coordinate the care for them.

26
4.1.7 Schedule of Events

Screening

Baseline

Months 3, 6, 9, 12
and every 3 months
until end of study
period
*Biannually
Annually

Arm I – Standard
of Care with
Integrated
Management
Medical
History History History
Central
cardiologist

Inclusion,
Exclusion
Physical including
Vital Signs (VS)
Physical including
VS Nutritionist
Consent Weight/height Weight/height
Medications Medications
Imaging review Imaging review
Laboratory review Laboratory review
Questionnaires Adverse events
Questionnaires

Interventions if
applicable
Blood tests Blood tests*
Screening Baseline Annually
Annually—
Phone Visits
Arm 2 - Standard
of Care
Medical
History History Blood tests History

Inclusion,
Exclusion
Physical including
VS Medications
Consent Weight/height Imaging review
Medications
Laboratory
review
Imaging review Adverse events
Laboratory review Questionnaires
Questionnaires
Blood Tests
Table 2: Schedule of Events in Intervention and Standard of Care Arm

27
Chapter 5

Recruitment

5.1 Recruitment Strategies

Strategies to enhance patient enrollment at the participating LAC-DHS clinical facilities
centers may include electronic mailings to primary care physicians, cardiologists and the nursing
staff of the anticoagulation clinics. Additionally, we will provide education about the study,
patient population, and ways to refer for enrollment to the LAC-USC medicine residents and
fellows. The AHPs will regularly assess actual enrollment in relation to pre-specified goals, and
additional interventions to increase enrollment will be implemented as needed. We will maintain
a screening log to summarize the number of patients screened and reasons for non-enrollment in
the trial.

5.1.1 Inclusion of Women and Minorities, Exclusion Criteria Rationale

The inclusion of women and minorities in clinical trials is critical for scientific, ethical,
and social reasons and for the generalizability of trial results. This trial is unique in its design
insofar as it will enroll only women, the large majority of whom will be non-white given the
setting of a safety-net hospital system.

It is particularly important for such a trial to be conducted for the following reasons. Due
to challenges in accessing care, combined with social influences, misconceptions and biases
28
impacting care for women, CVD in women is often discovered in the late stages. This delay in
diagnosis often results in a preventable increase in worse outcomes for women with CVD when
compared to their male counterparts, as previously described above.

As mentioned previously, women with AF are at the greatest risk for myocardial
infarction (MI), ischemic heart disease, stroke, and increased mortality. Thus, as AF is one of the
strongest risk factors for CVD, identifying women with AF functions as an excellent proxy for
and means of identifying women at risk for CVD.

With respect to minorities, attempts will be made to ensure a balanced recruitment
strategy.

Within the DHS system, we do not anticipate that representation of minorities will be
problematic, nonetheless, the following methods will be employed to ensure adequate
representation of minority groups:

• Documentation of the number of minorities screened and enrolled via screening and
exclusion logs
• Monitoring of such logs from each clinical center on a bi-monthly basis

With respect to the exclusion criteria, given the known high incidence of AF post-
operatively after cardiac surgery, which resolves within 3 months typically, we have elected to
exclude patients who have undergone cardiac surgery within 3 months prior to enrollment. To
29
simplify treatment strategy, and avoid confounding effects of previous treatment interventions,
we will exclude those who have undergone previous interventional or surgical treatment of atrial
fibrillation or flutter such as ablations or MAZE procedures, and previous left atrial appendage
occlusion. To avoid confounding of the primary endpoint, particularly the all-cause mortality
component, we will exclude those patients with an underlying disease that limits life expectancy
to 6 months or less, for example the patient with cancer who is currently on hospice.

30
Chapter 6

Statistics, Endpoints, and Definitions

6.1 Statistical Considerations

All analyses will be performed on an intention-to-treat basis. At the final analysis time,
statistical significance on all treatment group comparisons will be evaluated with a two-sided p-
value of 0.05. Continuous variables will be reported as the mean +/- standard deviation (SD), and
categorical variables as the observed number and percentage. Baseline demographic and clinical
characteristics will be presented by randomized group. We will calculate Kaplan–Meier estimates
of cumulative survival and their 95% confidence intervals (CIs) for each study group. For
primary and secondary time-to-event outcomes, Cox proportional hazards modeling will be used
to calculate hazard ratios and their 95% CIs, both crude and adjusted for clinical referral site,
age, and the presence of CVD (including heart failure, hypertension, diabetes and prior stroke, or
transient ischemic attack) at baseline. The proportional hazards assumption will be evaluated; in
the presence of non-proportional hazards, time-specific HRs and 95% CIs will be calculated and
presented. Secondary trial and cost-related surrogate outcomes that represent counts of events
over follow-up (e.g., AF-related hospitalizations, days spent in the hospital) will be analyzed by
Poisson or negative binomial regression; duration of participant follow-up will be included as an
exposure offset. Covariates will include those indicated above. Results will be presented as
incidence rate ratio with 95% confidence intervals. Secondary trial outcomes that are measured
as continuous outcomes (e.g., weight, blood pressure, HbA1c, quality of life measures) will be
evaluated using linear mixed effects regression models to accommodate the correlated outcomes
31
due to repeated measures. A random effect at the trial participant level will be specified; referral
clinical site will be tested as a possible random effect. The primary fixed effect independent
variable will be randomized group; covariates will include clinical referral site (if not included as
a random effect), age, and baseline presence of CVD.

A single interim efficacy analysis of the primary composite endpoint will be conducted
when the first enrolled participant has completed 3 years of follow-up (i.e., when the 5-year trial
has been 60% completed). One-sided boundaries at overall alpha of 0.05 will be computed using
O-Brien-Fleming alpha spending.

6.1.1 Primary Endpoint

The efficacy endpoint is the composite of overall survival and MACE in each arm.

6.1.2 Secondary Endpoints

6.1.2.1 Clinical Endpoints

The individual components of the primary endpoints
• Overall mortality
• Non-fatal stroke
• Non-fatal MI
• CV mortality
• Non-cardiovascular mortality
32
• The incidence of BARC 2 bleeding
• Incidence of cardiovascular interventional and surgical intervention, associated morbidity, and
mortality
• Incidence of non-cardiovascular interventional and surgical procedures, associated morbidity,
and mortality
• Medication compliance
• Hospitalizations (overall, cardiovascular related)
• Days spent in the hospital
• Control of comorbidities
• Weight, Height, BMI
• Blood pressure
• HbA1C
• Lipid profiles
• BNP
• CMP
• CRP
• Thyroid panel (if abnormal at baseline)

6.1.2.2 Quality of Life Endpoints

• KCCQ (short form)
• ED5D

33
6.1.2.3 Patient Centered Endpoints

• Patients’ convenience and satisfaction survey utilizing the Perception of Anticoagulation
Treatment Questionnaire (PACT-Q2)

6.1.2.4 Economic Outcomes

The following surrogates will be used to assess economic impact:
• Number of hospitalizations
• Days spent in hospital
• Days spent in ICU
• Cause of hospitalization
• Days lost from work
• Days lost from school
• Need for in home services

6.1.3 Endpoint Definitions

The primary endpoint is a composite of all-cause, overall mortality and major adverse
cardiovascular events (MACE, defined as a composite of non-fatal stroke, non-fatal myocardial
infarction, and cardiovascular death).

All-cause mortality: Defined as death from any cause.
34

Clinical Stroke: A new, temporary or permanent, focal or global neurological deficit ascertained
by a standard neurological examination (administered by a neurologist or other qualified
physician and documented with appropriate diagnostic tests and consultation note) that lasts
longer than 24 hours (or less than 24 hours if there is evidence of infarction on neuroimaging).
May be classified as ischemic or hemorrhagic as defined below.

Ischemic Stroke: Defined as a new neurological deficit that persists beyond 24 hours or less than
24 hours associated with acute infarction on a cerebral imaging study. Hemorrhagic conversion
of an ischemic stroke should be classified as ischemic.

Hemorrhagic Stroke: Defined as a new neurological deficit that persists beyond 24 hours or less
than 24 hours associated with acute cerebral bleed on a cerebral imaging study.

Myocardial Infarction (MI): MI will be adjudicated according to the Fourth Universal
Definitions
22
, as follows:

Type 1: Detection of a rise and/or fall of cardiac troponin (cTn) values with at least one value
above the 99
th
percentile upper reference limit (URL) and with at least one of the following:
• Symptoms of acute myocardial ischemia;
• New ischemic ECG changes;
• Development of pathological Q waves;
• Imaging evidence of new loss of viable myocardium or new regional wall motion
35
abnormality in a pattern consistent with an ischemic etiology;
• Identification of a coronary thrombus by angiography including intracoronary imaging
or by autopsy

Type 2: Detection of a rise and/or fall of cTn values with at least one value above the 99
th

percentile URL, and evidence of an imbalance between myocardial oxygen supply and demand
unrelated to coronary thrombosis, requiring at least one of the following:
• Symptoms of acute myocardial ischemia;
• New ischemic ECG changes;
• Development of pathological Q waves;
• Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality in a pattern consistent with an ischemic etiology.

Type 3: Patients who suffer cardiac death, with symptoms suggestive of myocardial ischemia
accompanied by presumed new ischemic ECG changes or ventricular fibrillation, who either die
before blood samples for biomarkers can be obtained, or die before increases in cardiac
biomarkers can be identified, or in whom MI is detected by autopsy examination.

Type 4:
Type 4a: an elevation of cTn values more than five times the 99
th
percentile URL in patients with
normal baseline values. In patients with elevated pre-procedure cTn in whom the cTn level are
stable (≤20% variation) or falling, the post-procedure cTn must rise by >20%. However, the
36
absolute post-procedural value must still be at least five times the 99
th
percentile URL. In
addition, one of the following elements is required:
• New ischemic ECG changes;
• Development of new pathological Q waves;
• Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality in a pattern consistent with an ischemic etiology;
• Angiographic findings consistent with a procedural flow-limiting complication such as
coronary dissection, occlusion of a major epicardial artery or a side branch
occlusion/thrombus, disruption of collateral flow, or distal embolization

Type 4b (stent thrombosis-related): applies the same criteria as type 1 MI but requires
angiographic or autopsy evidence of stent thrombosis.

Type 4c (restenosis-related): applies the same criteria as type 1 MI but requires angiographic or
autopsy evidence of restenosis.

Type 5 (CABG related): defined as elevation of cTn values >10 times the 99
th
percentile URL
in patients with normal baseline cTn values. In patients with elevated pre-procedure cTn in
whom cTn levels are stable (≤20% variation) or falling, the post-procedure cTn must rise by
>20%. However, the absolute postprocedural value still must be >10 times the 99
th
percentile
URL. Additionally, one of the following is required:
• Development of new pathological Q waves;
• Angiographic documented new graft occlusion or new native coronary artery occlusion;
37
• Imaging evidence of new loss of viable myocardium or new regional wall motion
abnormality in a pattern consistent with an ischemic etiology

Cardiovascular Death: Death is classified as cardiovascular death when the primary cause of
death is CV in nature. CV deaths include deaths that result from an AMI, sudden cardiac death,
death due to heart failure (HF), death due to stroke, death due to CV procedures, death due to CV
hemorrhage, and death due to other CV causes.
23

Secondary endpoints for the trial are defined as follows:

Overall survival: The percentage of participants who are still alive at 3 and 5 years after
randomization.

The individual components of the primary endpoints: The definitions of these components are
described above— MACE, defined as a composite of non-fatal stroke, non-fatal myocardial
infarction, and cardiovascular death.

Cardiovascular and non-cardiovascular mortality: In addition to all-cause mortality (part of the
primary endpoint), we will assess cardiovascular and non-cardiovascular mortality (including
bleeding-related, trauma-related and cancer-related death) at 3 years and 5 years after
randomization.

38
Occurrence of BARC 2 bleeding—Barc Type 2: Any clinically overt sign of hemorrhage (e.g.,
more bleeding than would be expected for a clinical circumstance, including bleeding found by
imaging alone) that is actionable but does not meet criteria for type 3, type 4 (CABG-related), or
type 5 (fatal bleeding) Bleeding Academic Research Consortium (BARC) bleeding. The bleeding
must require diagnostic studies, hospitalization, or treatment by a healthcare professional. In
particular, the bleeding must meet at least one of the following criteria: it requires intervention,
defined as a healthcare professional–guided medical treatment or percutaneous intervention to
stop or treat bleeding, including temporarily or permanently discontinuing a medication or study
drug.

Incidence of cardiovascular interventional and surgical intervention, associated morbidity, and
mortality: Defined as the rate of operative cardiac surgical interventions and cardiovascular
interventional procedures and the major morbidities and mortalities associated with the
individual intervention or surgical procedure.

Incidence of non-cardiovascular interventional and surgical procedures, associated morbidity,
and mortality: Defined as the rate of operative surgical interventions and interventional
procedures not involving the cardiopulmonary and the major morbidities and mortalities
associated with the individual intervention or surgical procedure.

Medication compliance: Defined as the degree or extent of conformity to the recommendations
about day-to-day treatment by the provider with respect to the timing, dosage, and frequency.

39
CV-related hospitalization: Any hospitalization either for a cardiac reason (including HF, MI,
AF) or related to cardiac procedure (and concomitant treatment).

Overall Hospitalization: Any hospitalization for any reason.

HF-related hospitalization
23
: Defined as an unscheduled hospital admission for a primary
diagnosis of HF (in a patient with the typical signs, symptoms, and diagnostic tests consistent
with HF) with a length of stay that either exceeds 24 hours or crosses a calendar day (if hospital
admission and discharge times are unavailable) who receive treatment specifically directed at HF
• Laboratory findings consistent with HF include: elevated natriuretic peptides,
radiological evidence of pulmonary vascular congestion, and either echocardiographic or
invasive evidence of elevated filling pressures.
• Treatment specifically directed at HF includes:
• significant augmentation in oral diuretic therapy defined as
• initiation of intravenous diuretic (even a single dose) or vasoactive agent
(eg, vasodilator, vasopressor, or inotropic therapy)
• initiation of mechanical circulatory support or fluid removal via
continuous renal replacement therapy/hemodialysis (CRRT/HD) or
thoracentesis or paracentesis

Days alive out of the hospital: Defined as total potential follow-up time minus days spent in the
hospital. To be calculated individually for each patient.

40
Control of comorbidities (measured at baseline and according to schedule of events for each arm)
as indicated by:
• Weight, Height, BMI
• Blood pressure
• HbA1C
• Lipid profiles
• BNP
• CMP
• CRP
• Thyroid panel

41
Chapter 7

Event Reporting

7.1 Expedited Adverse Event Reporting

For this protocol, all mortalities and serious adverse events (such as bleeding) will be
reported within 24 hours of discovery of the event to Institutional Review Board (IRB) and to the
medical monitor. These events must be reported to the IRB or equivalent committee in
accordance with the clinical center’s policies.

42
Chapter 8

Data Collection and Management

8.1 Data Reporting and Validation

The primary method of reporting the primary results of the statistical analyses of this
study will be a scientific publication by the principal investigators.

8.1.2 Baseline Data Collection

Data will be collected from the participants’ electronic health record, patient
questionnaires and patient interviews as described above. At baseline we will collect information
about (1) participants’ comorbidities, (2) medication list and current compliance, (3) most recent
laboratory results, (4) most recent cardiac diagnostic studies, (5) height, weight, BMI, (6) most
recent ECG, (7) type of AF at baseline (non-paroxysmal or paroxysmal), and (8) CHA2DS2-
V ASc score (history of congestive heart failure, hypertension, age≥75 (doubled), diabetes,
stroke or Transient Ischemic Attack (TIA)(doubled)–vascular disease, age 65–74 and
female sex), (9) HAS-BLED score, and (10) patient demographics.

43
8.1.3 Outcome Assessment

At end of study, primary and secondary endpoints will be evaluated. The primary
outcome will further be analyzed in one, planned interim analysis. See Statistics Considerations.

The DSMB will meet biannually to review trial protocol and conduct, trial recruitment, adverse
and serious adverse events as well as the interim analyses as indicated.

DSMB will consist of a medical monitor, a cardiac surgeon, a cardiologist, and a statistician.

8.2 Data Entry and Management

Case report forms (CRFs) will be utilized and completed by the study coordinators. To
ensure correct data upload, a data manager will corroborate data upload against source medical
records. Data will be entered into and managed using the REDCap application. REDCap data
queries will be used to identify data issues, send data queries to appropriate study personnel, and
monitor resolution of the data queries. Trial randomization will use the REDCap randomization
module. Routine reports (weekly and monthly) will be programmed to summarize trial
recruitment and retention, completion of ongoing follow-up visits and outcome data collection,
missed visits, and outstanding data queries.

44
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Asset Metadata

Creator Abt, Brittany Gabriella (author)

Core Title Integrated management of atrial fibrillation in women in an underserved, safety-net health care system: a multicenter, single health system randomized control efficacy trial protocol

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical, Biomedical and Translational Investigations

Degree Conferral Date 2023-08

Publication Date 07/10/2023

Defense Date 07/07/2023

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag atrial fibrillation,cardiovascular disease,OAI-PMH Harvest,women's health

Format theses (aat)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Mack, Wendy (committee chair), Barr, Mark (committee member), Patino-Sutton, Cecilia (committee member)

Creator Email brittany.abt@med.usc.edu,brittanyg3@gmail.com

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