IMplementation of a Randomized Controlled Trial (RCT) to imProve Treatment With Oral AntiCoagulanTs in Patients With Atrial Fibrillation
Phase: NA
Conditions: Atrial Fibrillation, Stroke
Sponsor: Harvard Pilgrim Health Care

 
FDA-CATALYST PROTOCOL 
 
IMPLEMENTATION OF A RANDOMIZED CONTROLLED TRIAL TO 
IMPROVE TREATMENT WITH ORAL ANTICOAGULANTS IN PATIENTS 
WITH ATRIAL FIBRILLATION (IMPACT-AFib) 
 
Prepared by: Sean D. Pokorney, MD, MBA;1 Noelle Cocoros, DSc, MPH; 2 Hussein 
Al-Khalidi, PhD;3 Kevin Haynes, PharmD, MSCE;4 Sana Al-Khatib, MD, MHS;1 Crystal 
Garcia, MPH;2 Jennifer Goldsack, MChem, MA, MBA, CPHQ;5 Thomas Harkins, MPH, 
MA;6 Robert Jin, MS;2 Daniel Knecht, MD, MBA;7 Daniel Lane, PharmD, PhD; 6 Nancy 
Lin, ScD;8 Debbe McCall, BS, MBA;9 Cheryl McMahill-Walraven, PhD, MSW;7 Vinit 
Nair, BPharm, MS, RPh;6 Emily O’Brien, PhD;1 Lauren Parlett, PhD;4 Jennifer Rymer, 
MD; 1 Ryan Saliga, BBA;2 Yunping Zhou, MS;6 Melissa Robb, RN;10 Christopher B. 
Granger, MD;1 Richard Platt, MD, MSc2  
 
Author Affiliations: 1. Duke Clinical Research Institute and Division of 
Cardiology, Duke University Medical Center, Durham, NC; 2. Department of 
Population Medicine, Harvard Pilgrim Health Care Institute and Harvard Medical 
School, Boston, MA; 3. Duke Clinical Research Institute and Department of 
Biostatistics & Bioinformatics, Duke University Medical Center, Durham, NC; 4. 
HealthCore, Inc., Alexandria, VA; 5. Clinical Trials Transformation Initiative, 
Durham, NC; 6. Comprehensive Health Insights, Humana Inc., Louisville, KY; 7. 
Aetna: Aetna Informatics, Blue Bell, PA; 8. OptumInsight Inc, Waltham, MA; 9. 
Rowan Tree Perspectives Consulting Murrieta, CA; 10. Center for Drug Evaluation 
and Research, Office of Medical Policy, FDA, Silver Spring, MD 
 
Version 1.0  March 1, 2017 
Version 2.0  October 2, 2017 
Version 3.0  November 24, 2017 
Version 4.0  April 19, 2018 
Version 5.0  March 7, 2019 
 
The Sentinel System is sponsored by the U.S. Food and Drug Administration (FDA) to proactively monitor 
the safety of FDA-regulated medical products and complements other existing FDA safety surveillance 
capabilities. The Sentinel System is one piece of FDA’s Sentinel Initiative, a long-term, multi-faceted 
effort to develop a national electronic system. Sentinel Collaborators include Data and Academic 
Partners that provide access to healthcare data and ongoing scientific, technical, methodological, and 
organizational expertise. The Sentinel Coordinating Center is funded by the FDA through the 
Department of Health and Human Services (HHS) Contract number HHSF223201400030I.  

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
 
History of Modifications 
Version 
Date 
Modification 
By 
V5.0 
03/07/2019 
• 
Updated text throughout to match decisions 
made during development of the statistical 
analysis plan (SAP) 
• 
Annotated change in study design – early 
intervention mailing occurred in two waves 
(VI. Study Design & Duration) 
• 
Updated Figures 1 and 2 for accuracy 
• 
Added link to code list for inclusion and 
exclusion criteria 
• 
Included reasons eligible members and 
providers might not be mailed the 
intervention (IX. Method of Assigning Patients 
to an Intervention) 
IMPACT-AFib 
Workgroup 
V4.0 
04/19/2018 
• 
Each Data Partner conducted its own mailing 
to trial participants. Due to the early 
intervention launch (start of follow-up) 
spanning multiple months: 
o Clarified that the follow-up period for 
primary and secondary objectives will 
be calculated based on the date on 
which at least 80% of eligible study 
participants have at least 12 months 
of follow-up time  
o Clarified that the follow-up period for 
exploratory objectives will be 
calculated based on the date on which 
at least 80% of eligible study 
participants have at least 24 months 
of follow-up time  
o Noted that all possible person-time 
will be used to assess outcomes (VI. 
Study Design & Duration) 
• 
Updated Figures 1 and 2 for accuracy 
IMPACT-AFib 
Workgroup 
V3.0 
11/03/2017 
• 
Updated anticipated trial size and power 
calculations 
• 
Included more detail about provider 
identification process for mailing (IX. Method 
of Assigning Patients to an Intervention) 
• 
Clarified population eligible for primary 
analyses (XIV. Statistical Considerations, B. 
Populations for Analysis) 
IMPACT-AFib 
Workgroup 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
 
 
 
V2.0 
10/02/2017  
• 
Clarified descriptions of the early and delayed 
intervention arms, including timing of 
mailings; noted that both arms include usual 
care and reiterated that those with recent 
OAC treatment will be excluded from mailings 
• 
Updated schematic diagrams based on 
improved descriptions of the early and 
delayed interventions 
• 
Updated Sentinel-CTTI partnership objective 
(V. Study Objectives, C. Exploratory Objectives) 
• 
Clarified medical and pharmacy coverage 
requirement (VII. Study Population, A. 
Inclusion Criteria) 
• 
Included more details about sample size and 
power calculations (XIV. Statistical 
Considerations, A. Sample Size and Power 
Calculations) 
• 
Added rationale for using INR tests/values as a 
proxy for anticoagulant dispensing(s) (VII. 
Study Population) 
• 
Added description of patient written 
education materials and clarified that 
information regarding top misperceptions will 
be provided for providers (VIII. Interventions) 
• 
Noted that feedback from the provider 
response mailers will not be linked to specific 
patients or providers (XVI. Statistical Analyses, 
B. Responses from Providers) 
• 
Made many less substantive changes in the 
interests of completeness, accuracy, and flow 
IMPACT-AFib 
Workgroup 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
 
FDA-Catalyst Protocol 
Implementation of a Randomized Controlled Trial to Improve 
Treatment with Oral Anticoagulants in Patients with Atrial Fibrillation 
(IMPACT-AFib)  
 
Table of Contents 
I. 
PROTOCOL SYNOPSIS.......................................................................................................... 1 
II. 
INTRODUCTION.................................................................................................................. 6 
III. RESEARCH HYPOTHESIS....................................................................................................... 7 
IV. STUDY RATIONALE ............................................................................................................. 7 
V. 
STUDY OBJECTIVES ............................................................................................................. 7 
A. 
PRIMARY OBJECTIVE............................................................................................................. 7 
B. 
SECONDARY OBJECTIVE ......................................................................................................... 8 
C. 
EXPLORATORY OBJECTIVES ...................................................................................................... 8 
VI. STUDY DESIGN AND DURATION ........................................................................................... 8 
VII. STUDY POPULATION ..........................................................................................................11 
A. 
INCLUSION CRITERIA............................................................................................................11 
B. 
EXCLUSION CRITERIA ...........................................................................................................12 
VIII. INTERVENTIONS ................................................................................................................12 
A. 
PATIENT-LEVEL INTERVENTIONS (EARLY INTERVENTION ARM) ............................................................12 
B. 
PROVIDER-LEVEL INTERVENTIONS (EARLY INTERVENTION AND DELAYED INTERVENTION ARM)........................12 
IX. METHOD OF ASSIGNING PATIENTS TO AN INTERVENTION......................................................13 
X. 
ETHICAL CONSIDERATIONS .................................................................................................14 
XI. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ......................................14 
XII. INFORMED CONSENT .........................................................................................................14 
XIII. INDEPENDENT ADVISORY COMMITTEE ................................................................................15 
XIV. STATISTICAL CONSIDERATIONS ...........................................................................................15 
A. 
SAMPLE SIZE AND POWER CALCULATIONS...................................................................................15 
1. 
Primary Endpoint ........................................................................................................15 
2. 
Important Secondary Analysis of Stroke or TIA.................................................................16 
B. 
POPULATIONS FOR ANALYSIS ..................................................................................................17 
XV. OUTCOME DEFINITIONS .....................................................................................................17 
XVI. STATISTICAL ANALYSES ......................................................................................................18 
A. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS .........................................................................18 
B. 
RESPONSES FROM PROVIDERS.................................................................................................18 
C. 
EFFECTIVENESS ANALYSES .....................................................................................................18 
XVII.DISSEMINATION PLAN OVERVIEW.......................................................................................19 
XVIII. REFERENCES ....................................................................................................................20 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
I. 
PROTOCOL SYNOPSIS 
Protocol Title: 
IMplementation of a randomized controlled trial to imProve 
treatment with oral AntiCoagulanTs in patients with Atrial 
Fibrillation (IMPACT-AFib) 
Research Hypothesis: 
Education on stroke prevention in atrial fibrillation (AF) among AF 
patients and their providers can result in increased use of oral 
anticoagulants (OAC) for stroke prevention among those AF 
patients with guideline-based indications for oral anticoagulation 
(CHA2DS2-VASc score of 2 or greater) 
Study Schema and Length of 
Trial: 
Early patient and provider* education interventions versus usual 
care (with delayed provider* education intervention at the date on 
which at least 80% of eligible study participants have at least 12 
months of follow-up time). Duration of follow-up for the primary 
outcome (OAC treatment) will be from the date that the early 
intervention materials are mailed through the date on which at 
least 80% of eligible study participants have at least 12 months of 
follow-up time; secondary outcomes will also be evaluated at this 
time. 
Study Objectives: 
Primary: evaluate the effect of the patient and provider education 
interventions (versus usual care with delayed provider education 
intervention) on the proportion of patients with evidence of at 
least one OAC prescription fill (defined as one OAC dispensing or 4 
INR tests) over the course of the follow-up through the date on 
which at least 80% of eligible study participants have at least 12 
months of follow-up time.  
Secondary: evaluate the impact on outcomes of the patient and 
provider education interventions over the course of the follow-up 
through the date on which at least 80% of eligible study 
participants have at least 12 months of follow-up time: 
1. Incident rate of stroke or transient ischemic attack (TIA) 
hospitalization  
2. Incident rate of hospitalization for stroke  
3. Time to first OAC prescription fill  
4. Proportion of days covered by OAC prescription fills  
5. Proportion of patients actively on OAC at 12 months of 
follow-up  
6. Incident rate of hospitalization for any bleeding  
7. All-cause in-hospital mortality rates  
                                                             
 
*Where it is possible to identify an individual provider. See Section IX. Method of Assigning Patients to an 
Intervention for further information.  

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
8. All-cause mortality rates among patients with accurate out-
of-hospital mortality data (such as Medicare Advantage 
patients)  
9. Health care utilization for AF patients, which would be 
reported as counts of number of health care utilization 
events (outpatient visits, days hospitalized, number of 
emergency department visits, etc.)  
Exploratory: 
10. Evaluate the effect of the education interventions on the 
primary and secondary endpoints over the course of the 
follow-up through the date on which at least 80% of 
eligible study participants have at least 24 months of 
follow-up time.  
11. Explore the Clinical Trials Transformation Initiative (CTTI) 
and the FDA supported Sentinel Data Partners’ ability to 
successfully conduct a pragmatic trial to answer important 
questions to improve public health 
Study Design: 
Prospective, randomized, open-label education intervention trial. 
Patients with AF and a CHA2DS2-VASc score of 2 or greater will be 
randomized in a 1:1 ratio to (a) the early intervention arm: early 
patient and provider educational interventions for those patients 
identified at the time of randomization and (b) the delayed 
intervention arm: usual care followed by provider education 
intervention 12 months after at least 80% of early intervention 
mailing has occurred (eligibility status of these patients will be 
assessed at time of delayed mailing). All inclusion criteria, exclusion 
criteria, and outcomes will be determined through claims data. The 
primary outcome is the proportion of AF patients with evidence of 
at least one OAC prescription fill over the course of the follow-up 
through the date on which at least 80% of eligible study 
participants have at least 12 months of follow-up time. A total of 
approximately 80,000 patients will be enrolled within multiple 
major health plans across the United States. Follow-up for the 
primary outcome and secondary outcomes will be assessed 12 
months after the date on which at least 80% of eligible early 
intervention participants were mailed the early intervention 
materials. The randomization will be performed by the central 
coordinating center (Harvard Pilgrim), and statistical analyses will 
be performed by the Duke Clinical Research Institute. A second 
exploratory assessment of the primary and secondary endpoints 
will be performed once at least 80% of participants have at least 24 
months of follow-up time to assess the durability and longer-term 
outcomes of the effect of the education intervention. Because the 
Sentinel Distributed Database will be used for follow-up 
information, and this information is refreshed approximately 
quarterly and this is done on separate timetables for the different 
health plans, it is likely that when at least the required follow-up 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
time is available for at least 80% of people, there will be more than 
12 or 24 months of follow-up for over 80% of people. All possible 
person-time will be used to assess participants’ outcomes (patients 
will have different duration of follow-up). 
Accrual Goal (Total number of 
participants): 
Approximately 80,000 patients across all participating Data 
Partners (Aetna, Harvard Pilgrim, HealthCore, Humana, and 
Optum) 
Accrual Rate (Number of 
participants expected per 
month): 
All patients and providers will be randomized prior to the initiation 
of the early intervention. The enrollment date for all patients (early 
and delayed intervention patients) will be the date that the letters 
are mailed out to early intervention patients and providers by their 
respective health plans. 
Inclusion Criteria: 
1. Two or more diagnoses of AF (ICD-9 and/or ICD-10 codes) 
at least one day apart and with at least one diagnosis 
within the last 12 months prior to the last date in the 
current approved data used for cohort identification 
2. CHA2DS2-VASc score of 2 or greater  
3. Medical and pharmacy insurance coverage of at least the 
prior year as identified via administrative claims databases 
of one of the participating Data Partners as of the date of 
randomization  
4. Age 30 years or greater as of the last date in the current 
approved data used for cohort identification 
Exclusion Criteria: 
1. Evidence of OAC medication fill during the 12 months prior 
to randomization (determined at randomization for the 
early intervention cohort and 12 months post-
randomization for the delayed intervention cohort) 
2. Conditions other than AF that require anticoagulation, 
including treatment of deep venous thrombosis, 
pulmonary embolism, or ever having had a mechanical 
prosthetic heart valve prior to the last date in the current 
approved data used for cohort identification 
3. Pregnancy within 6 months of the last date in the current 
approved data used for cohort identification 
4. Any known history of intracranial hemorrhage prior to the 
last date in the current approved data used for cohort 
identification 
5. Hospitalization for any bleeding within the last 6 months of 
the last date in the current approved data used for cohort 
identification 
6. Patients with recent P2Y12 antagonist use (i.e. clopidogrel, 
prasugrel, ticlopidine, or ticagrelor) within 90 days of the 
last date in the current approved data used for cohort 
identification 
Criteria for Evaluation 
(Effectiveness, safety, stopping 
rules, etc.): 
The primary outcome is evidence of at least one OAC prescription 
fill through the date on which at least 80% of eligible study 
participants have at least 12 months of follow-up time. 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
Patient-Level Interventions 
(early intervention arm): 
• 
Letters to patients that (1) explain to the patient that he or 
she appears to have AF, characterize the risk of stroke, and 
emphasize that although there may be a medical reason, 
the patient does not seem to be on an anticoagulant and 
(2) encourage the patient to discuss this with his or her 
provider to ask if he or she might benefit from OAC therapy 
to prevent stroke  
• 
Written education materials 
• 
Website with the patient-focused information contained in 
the letters to patients 
Provider-Level Interventions 
(early intervention and 
delayed intervention arms): 
• 
Letters to providers: 
o Early intervention letters to providers that explain 
this project, the nature of the problem, and 
identify a list of the provider’s patients who have 
been contacted, as the provider and patient letters 
will be sent at approximately the same time; 
describe evidence and guidelines regarding oral 
anticoagulation 
o Delayed intervention letters to providers that 
explain this project, the nature of the problem, and 
identify a list of the provider’s patients who are at 
risk for stroke and have not been treated with an 
oral anticoagulant; describe evidence and 
guidelines regarding oral anticoagulation 
• 
Response mailer that gives the provider the opportunity to 
share the rationale for his or her patient(s) not being on 
OAC 
• 
Web portal with access to clinical practice guidelines, 
decision support tools including from professional 
societies, podcasts, and case studies targeted at improving 
the appropriate use of OAC for AF 
• 
Information sheet describing top misperceptions of 
barriers to OAC use 
o Misperception of benefit and risk of aspirin: it is 
neither safe nor effective 
o Misperception around risk of resuming OAC 
(months) after bleeding  
o Misperception regarding risk of OAC regarding 
patients who fall 
o Opportunities with novel OACs (NOACs) for 
patients who have not tolerated warfarin 
o Concern about lack of an antidote for the NOACs 
Statistics and Power 
Calculations: 
Primary outcome: proportion of AF patients with evidence of at 
least one OAC prescription fill through the date on which at least 
80% of eligible study participants have at least 12 months of 
follow-up time 
Sample size and power determination assumptions: 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
• 
33% OAC initiation rate in the delayed intervention arm 
over the first year of the study 
• 
38% OAC initiation rate in the early intervention arm (a 5% 
improvement in OAC initiation over the 33% OAC initiation 
expected in the delayed intervention arm over 1-year 
follow-up) 
• 
1-year attrition rate: 30% dropout or lost-to-follow-up 
• 
Two-sided type I error of 0.05  
• 
Roughly 10,000 patients will yield more than 99% power to 
detect a 5% absolute difference 
Secondary outcome: stroke or transient ischemic attack (TIA) over 
the course of the follow-up through the date on which at least 80% 
of eligible study participants have at least 12 months of follow-up 
time. A study with approximately 80,000 patients is reasonably 
powered to detect a reduction in stroke or TIA under assumptions 
listed below: 
• 
1-year stroke or TIA rate: 18% among patients not treated 
with OAC 
• 
1-year stroke or TIA rate: 7% among patients treated with 
at least 1 OAC fill 
• 
Duration of follow-up: 1 year  
• 
33% of delayed intervention patients will have at least 1 fill 
of OAC, meaning the 1 year stroke or TIA rate in the 
delayed intervention group would be 14.4% 
• 
If 38% of early intervention patients have at least 1 fill of 
OAC (meaning the 1 year stroke or TIA rate in the early 
intervention group would be 13.82%, i.e., an absolute 
reduction of 0.55%), the study will have 46% power to 
detect this 0.55% reduction. However, if 40.5% of early 
intervention patients have at least 1 fill of OAC (meaning 
the 1 year stroke or TIA rate in the early intervention group 
would be 13.54%, i.e., an absolute reduction of 0.83%), the 
study will have 80% power to detect this 0.83% reduction. 
• 
1-year attrition rate: 30% dropout or lost-to-follow-up 
• 
Two-sided type I error of 0.05 
• 
The sample size has 80% power to detect a 0.5% absolute 
reduction in stroke, assuming a cumulative 1-year 
incidence of stroke of 4.2% in control (delayed intervention 
arm) patients and 3.7% in intervention (early intervention 
arm) patients. The assumption is that patients not on oral 
anticoagulation have an annual stroke rate of 5%, and 
stroke will be reduced by 50% (HR=0.5) in the treated 
(anticoagulated) population. The 80% power requires that 
52% of early intervention arm patients are treated at 1-
year as compared to 33% in the control arm.  

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
II. 
INTRODUCTION 
Atrial fibrillation (AF) is the most common arrhythmia seen in clinical practice, accounting for one-third 
of rhythm-related hospitalizations.1 The prevalence of AF in the United States is 1% overall and more 
than 10% in people over age 80 years, with approximately 70% of cases in patients between 65 and 85 
years of age.2 As Americans age, the number of patients with AF is expected to increase 150% by 2050, 
with more than 50% of patients being octogenarians or older.3-8 The increasing burden of AF is expected 
to lead to a higher incidence of stroke, as patients with AF have a five to seven fold greater risk of stroke 
than the general population.9-11 The incidence of stroke in AF patients is 4 to 5% per year.12 Patients with 
a stroke due to AF have worse prognoses than patients with stroke without AF.13,14 Oral anticoagulants 
(OACs) are an important therapy for patients with AF as they decrease the rate of stroke by more than 
two-thirds.15 
The clinical benefit of warfarin is only seen in patients who consistently maintain their international 
normalized ratio (INR) values within the therapeutic range (2.0-3.0).16 The median times in the 
therapeutic range in the ARISTOTLE17, ROCKET AF18, RE-LY19, and ENGAGE20 trials were 62%, 55%, 64%, 
and 68%, respectively. As part of quality improvement efforts, there is significant interest in measuring 
and improving performance of physicians in prescribing anticoagulation for patients with AF. The 
CHADS2 and CHA2DS2-VASC scores have been developed to support providers in identifying patients with 
AF who are at an increased risk for stroke.21,22 Paradoxically, anticoagulation use is no higher, or 
declines, as the risk of stroke, as measured by these scores, increases.23 This is in large part due to the 
fact that physicians and patients are concerned about the risk of bleeding in higher-risk populations, and 
they may underappreciate the net benefit from anticoagulants, including stroke prevention. In any case, 
approximately 40-60% of patients with AF at risk of stroke are not prescribed anticoagulation 
therapy.15,24-30 This translates to over 50,000 preventable strokes each year in the United States with a 
number needed to treat of approximately 25 patients to prevent 1 stroke.  
The specific reasons for not using an anticoagulant in eligible AF patients are poorly defined. The 
AVERROES trial provided some insight into reasons for patients deemed “unsuitable for warfarin” with 
42% unable to maintain therapeutic INR, 43% unlikely to monitor INR, and 37% refusing warfarin.31 The 
reasons for underuse of oral anticoagulation are likely related to three types of barriers: patient-level 
barriers (i.e. overestimation of risk of bleeding, underestimation of risk of stroke, misperceptions of 
adverse events from OACs), provider-level barriers (i.e. overestimation of risk of bleeding, 
underestimation of risk of stroke, misperceptions of adverse events from OACs, misperceptions about a 
patient’s fall risk, misperceptions of the benefits of aspirin in stroke prevention), and system-level 
barriers (i.e. lack of time in a clinic visit to discuss stroke prevention, access to care such as an 
anticoagulation clinic, cost of OACs, feasibility of warfarin monitoring). 
Another issue driving under-treatment with oral anticoagulants is poor medication adherence, which 
may be driven by patient barriers or system-level barriers. Medication non-adherence is defined as a 
patient’s passive failure to follow a prescribed drug regimen. An average of 50% of patients are non-
adherent to their prescribed treatment regimens for chronic diseases, such as AF.32 Non-adherence 
rates are similar across disease states, treatment regimens, and age groups, with the first several 
months of therapy characterized by the highest rates of discontinuation.33 Interventions to support 
patient management of medications have fallen short, and sustainable adherence rates have not 
improved.34,35 

 
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 IMPACT-AFib 
The cost to the health care system of hospitalizations due to medication non-adherence for all disease 
states may be as high as approximately $100 billion annually.36 Patient-provider communication 
regarding medication use is poor, and opportunities to document and provide feedback on metrics for 
medication adherence are not readily available in EMR applications.37 Meaningful and measurable 
improvements in adherence require a comprehensive, multifaceted intervention in which all 
participants, including physicians, play an active part. 
III. 
RESEARCH HYPOTHESIS 
Among AF patients with guideline indications for OAC for stroke prevention who have not received any 
OAC dispensing for at least one year, an education intervention at the patient-level and the provider-
level will increase the proportion of patients started on OAC for stroke prevention. 
IV. 
STUDY RATIONALE 
Preliminary data from three Sentinel Data Partners between 1/1/2006 and 6/30/2015, identified 
231,696 patients (1.4%) with at least 2 diagnoses of AF (ICD-9 codes of 427.31 or 427.32) over the study 
period, among 16.2 million covered lives. Within the 231,696 AF patients, there were 201,882 with a 
CHA2DS2-VASc score of 2 or greater (based on administrative claims data in the Sentinel Distributed 
Database), which is an American Heart Association (AHA)/American College of Cardiology (ACC) 
guideline indication for OAC. Over the study period from 2006 through 2015, 52% (n=105,256) patients 
filled at least one prescription for anticoagulation, meaning that 48% of patients with CHA2DS2-VASc 
score of 2 or greater never had a pharmacy claim submitted for an OAC during the study period. While 
there may be clinical or health system related reasons for not treating some of these patients, this 
apparent significant gap of guideline-based adherence is a public health issue of interest. The presented 
protocol is an opportunity to test the potential for developing and testing a health plan (Data Partner) 
based education intervention to improve the quality of care. 
V. 
STUDY OBJECTIVES 
A. PRIMARY OBJECTIVE 
The primary objective is to evaluate the effect of the patient and provider education interventions 
(versus usual care with delayed provider education intervention) on the proportion of patients with 
evidence of at least one OAC prescription fill (defined as one OAC dispensing or 4 INR tests) over the 
course of the follow-up through the date on which at least 80% of eligible study participants have at 
least 12 months of follow-up time. 
 
 

 
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 IMPACT-AFib 
B. SECONDARY OBJECTIVE 
The secondary objectives are to evaluate the impact on outcomes of the patient and provider education 
interventions over the course of the follow-up through the date on which at least 80% of eligible study 
participants have at least 12 months of follow-up time: 
1. Incident rate of stroke or transient ischemic attack (TIA) hospitalization  
2. Incident rate of hospitalization for stroke  
3. Time to first OAC prescription fill  
4. Proportion of days covered by OAC prescription fills  
5. Proportion of patients actively on OAC at 12 months of follow-up  
6. Incident rate of hospitalization for any bleeding  
7. All-cause in-hospital mortality rates  
8. All-cause mortality rates among patients with accurate out-of-hospital mortality data (such as 
Medicare Advantage patients)  
9. Health care utilization for AF patients, which would be reported as counts of number of health 
care utilization events (outpatient visits, days hospitalized, number of emergency department 
visits, etc.)  
C. EXPLORATORY OBJECTIVES 
The exploratory objectives are to: 
1. Evaluate the effect of the early and delayed education interventions on primary and secondary 
endpoints over the course of the follow-up through the date on which at least 80% of eligible 
study participants have at least 24 months of follow-up time. 
2. Explore the CTTI and the FDA supported Sentinel Data Partnership’s ability to successfully 
conduct a pragmatic trial to answer important questions to improve public health. 
VI. 
STUDY DESIGN AND DURATION 
The study is a prospective, randomized, and open-label education intervention trial. Patients with AF 
and a CHA2DS2-VASc score of 2 or greater will be randomized in a 1:1 ratio to an early intervention 
cohort and a delayed intervention cohort within each participating health plan. The definition for OAC 
medication fill will be an OAC medication dispensing or at least 4 INR tests in the claims data.1 The 
claims records of the patients randomized to the early intervention cohort will then be linked to “fresh” 
(i.e. about 1-4 months old) pharmacy claims data at the time of randomization. Patients without 
evidence of an OAC medication fill during the 12 months prior to randomization will be included in the 
patient-level and provider-level early educational intervention (patients randomized to this early 
intervention with evidence of an OAC medication fill during the 12 months prior to randomization will 
be excluded from the trial.). In addition to usual care, these patients and their providers2 will receive a 
                                                             
 
1Not all OAC dispensings are well captured in pharmacy claims, particularly, for warfarin. INR tests are assumed 
indicative of OAC fills that were not billed through the claims. 4 INR tests or values within a 12-month period will 
be used as a proxy since that is roughly the number of tests administered in the process of stabilizing dose. 
2See Section IX. Method of Assigning Patients to an Intervention for detail regarding provider identification. In 
certain circumstances, a member or provider may not receive the one-time mailing. 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
one-time mailing at trial start. There will be two waves of mailings for the early intervention cohort at 
most sites due to the practical challenges of claims data: the patients are assigned to wave 1 if they have 
a provider easily identified in the data (i.e., the provider associated with the most recent AF diagnosis is 
an individual provider), and they are assigned to wave 2 if it is difficult to identify a provider (e.g., the 
first identified provider is a facility). Follow-up time will start on the date of the respective wave 1 and 
wave 2 mailings for the early intervention patients 
The delayed intervention cohort will receive usual care over the initial study period. After the date on 
which at least 80% of eligible study participants have at least 12 months of follow-up time, “fresh” 
pharmacy claims data for the delayed intervention cohort that was generated and locked at the time of 
randomization will be used to assess trial eligibility, and those patients without evidence of an OAC 
medication fill during the 12 months prior to randomization will be included in the primary and 
secondary analyses as the delayed intervention arm. Patients randomized to the delayed intervention 
arm with evidence of an OAC medication fill during the 12 months prior to randomization will be 
excluded from the trial and will not be included in analyses. The baseline characteristics of the delayed 
intervention patients will be examined at the same time point as the early intervention patients, 
meaning at the time of randomization. The primary outcome is a comparison of the proportion of 
patients not on OAC during the 12 months prior to randomization, who were started on OAC over the 
course of the follow-up through the date on which at least 80% of eligible study participants have at 
least 12 months of follow-up time in the early versus the delayed intervention arm. A total of 
approximately 80,000 patients (randomized 1:1) across all participating Data Partners (Aetna, Harvard 
Pilgrim, HealthCore, Humana, and Optum) will be enrolled from participating Data Partners across the 
United States. Similar to the early intervention cohort, the patients in the delayed intervention cohort 
will be assigned to wave 1 or wave 2 (“pseudo” wave assignments) depending on the difficulty in 
identifying the patient’s provider (the intent is to handle them the same way as was done for the early 
intervention arm). The follow-up for the delayed intervention patients will start on the date the wave 1 
or 2 mailings take place for a given Data Partner’s early intervention cohort. The follow-up time for the 
primary outcome will be 12 months from the date at which at least 80% of eligible study participates are 
enrolled (date on which early intervention materials are mailed).  
The providers of patients in the delayed cohort who did not receive OAC medication during the course 
of the 12-month study period and meet our inclusion criteria will receive the delayed intervention: the 
provider-only education intervention, a one-time mailing administered 12 months after at least 80% of 
early intervention mailing have occurred (patients will not receive any educational materials unless no 
provider can be identified for a mailing). We intend to assess the primary and secondary endpoints again 
once at least 80% of patients have at least 24 months of follow-up time to assess the durability and 
longer-term outcomes of the effect of the patient- and provider-level education intervention, as well as 
the use of OAC following the delayed provider-level education intervention. However, as this second 
assessment is exploratory, we may not conduct these analyses if the results of the primary outcome are 
null.  
Because the Sentinel Distributed Database will be used for follow-up information, and this information is 
refreshed approximately quarterly and this is done on separate timetables for the different health plans, 
it is likely that when at least the required follow-up time is available for at least 80% of people, there will 
be more than 12 or 24 months of follow-up for over 80% of people. All participants’ outcomes will be 
assessed using all possible person-time; patients will have different duration of follow-up and that will 
be accounted for in the analyses. 
 
 

 
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 IMPACT-AFib 
A schematic diagram below shows the design of the early intervention period of the study over the 
course of the follow-up through the date on which at least 80% of eligible study participants have at 
least 12 months of follow-up time: 
 

 
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 IMPACT-AFib 
A schematic diagram below shows the design of the delayed intervention portion of the study:
 
VII. 
STUDY POPULATION 
All inclusion and exclusion criteria will be determined by claims data. For entry into the study, the 
following criteria will be met: 
A. INCLUSION CRITERIA 
1. Two or more diagnoses of AF (ICD-9 and/or ICD-10 codes) at least one day apart and with at 
least one diagnosis within the last 12 months prior to the last date in the current approved data 
used for cohort identification 
2. CHA2DS2-VASc score of 2 or greater  
3. Medical and pharmacy insurance coverage of at least the prior year as identified via 
administrative claims databases of one of the participating Data Partners as of the date of 
randomization 
4. Age 30 years or greater as of the last date in the current approved data used for cohort 
identification 

 
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 IMPACT-AFib 
B. EXCLUSION CRITERIA 
1. Evidence of OAC medication fill (defined as 1 OAC dispensing or 4 INR tests) during the 12 
months prior to randomization (determined at randomization for the early intervention cohort 
and 12 months post-randomization for the delayed intervention cohort) 
2. Conditions other than AF that require anticoagulation, including treatment of deep venous 
thrombosis, pulmonary embolism, or ever having had a mechanical prosthetic heart valve prior 
to the last date in the current approved data used for cohort identification 
3. Pregnancy within 6 months of the last date in the current approved data used for cohort 
identification 
4. Any known history of intracranial hemorrhage prior to the last date in the current approved 
data used for cohort identification 
5. Hospitalization for any bleeding within the last 6 months of the last date in the current approved 
data used for cohort identification 
6. Patients with recent P2Y12 antagonist use (i.e. clopidogrel, prasugrel, ticlopidine, or ticagrelor 
within 90 days of the last date in the current approved data used for cohort identification 
The complete code list for inclusion and exclusion criteria is accessible on the Sentinel website 
(https://www.sentinelinitiative.org/FDA-catalyst/projects/implementation-randomized-controlled-trial-
improve-treatment-oral-anticoagulants-patients). 
VIII. 
INTERVENTIONS 
A. PATIENT-LEVEL INTERVENTIONS (EARLY INTERVENTION ARM) 
• 
Letters to patients that (1) explain to the patient that he or she appears to have AF, characterize 
the risk of stroke, and emphasize that although there may be a medical reason, the patient does 
not seem to be on an anticoagulant and (2) encourage the patient to discuss this with his or her 
provider to ask if he or she might benefit from OAC therapy to prevent stroke.  
• 
Written education materials about AF and anticoagulants, including answers to commonly asked 
questions 
• 
Website with the patient-focused information contained in the letters to patients 
B. PROVIDER-LEVEL INTERVENTIONS (EARLY INTERVENTION AND DELAYED INTERVENTION 
ARM) 
• 
Letters to providers: 
o Early intervention letters to providers that explain this project, the nature of the 
problem, and identify a list of the provider’s patients who have been contacted, as the 
provider and patient letters will be sent at approximately the same time; describe 
evidence and guidelines regarding oral anticoagulation 
o Delayed intervention letters to providers that explain this project, the nature of the 
problem, and identify a list of the provider’s patients who are at risk for stroke and have 
not been treated with an oral anticoagulant; describe evidence and guidelines regarding 
oral anticoagulation 
• 
Response mailer that gives the provider the opportunity to share the rationale for his or her 
patient(s) not being on OAC 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
• 
Web portal with access to clinical practice guidelines, decision support tools including from 
professional societies, podcasts, and case studies targeted at improving the appropriate use of 
OAC for AF 
• 
Information sheet describing top misperceptions of barriers to OAC use 
1. Misperception of benefit and risk of aspirin: it is neither safe nor effective 
2. Misperception around risk of resuming OAC (months) after bleeding  
3. Misperception around risk of OAC regarding patients who fall 
4. Opportunities with NOACs for patients who have not tolerated warfarin 
5. Concern about lack of an antidote for the NOACs 
IX. 
METHOD OF ASSIGNING PATIENTS TO AN INTERVENTION 
An electronic program, developed by the central coordinating center (Harvard Pilgrim), will be used by 
the participating Data Partners to identify their eligible member-patients who meet the inclusion and 
exclusion criteria for this trial. The patient billing claims records will not be linked to pharmacy data until 
after randomization, so the inclusion criterion of no OAC medication fill during the 12 months prior to 
randomization will not be applied until after randomization. This will be done immediately for the early 
intervention group, and in the delayed intervention group, not until 12 months after at least 80% of 
early intervention mailing have occurred. Patients will be randomly assigned in a 1:1 ratio, via the 
program, to early patient-level and provider-level intervention versus delayed provider-level 
intervention. A list of eligible member-patients will stay at each Data Partner, and identifiable patient-
level data will not be shared with the central coordinating center (Harvard Pilgrim) or the statistical 
analysis center (Duke Clinical Research Institute). The Data Partners will remove any individuals who 
cannot be included in research studies, which includes certain Centers for Medicare and Medicaid 
Services and Administrative Services Only patients. There are several other reasons that could prevent 
mailing of the intervention, to members and/or their providers (list may not be exhaustive): 
• 
Member is now deceased 
• 
Member disenrolls from health plan 
• 
Member transitions to a plan that does not allow for inclusion in research 
• 
Member has a recent anticoagulant dispensing  
• 
Member has an incorrect/missing/bad address 
• 
Member is added to a do-not-contact list at the health plan 
The list of randomized individuals will include the provider on each patient’s most recent encounter with 
an AF diagnosis as of the last date in the current approved data used for cohort identification. When the 
identified provider is an individual, this provider will receive the provider intervention materials. When 
the identified provider is a facility, Data Partners will select an alternate provider or conduct a member 
only mailing based on their health plan policies and the decision of the health plan’s leadership. An 
alternative provider may be a patient’s PCP or other recent clinician who provided care. At least one 
health plan intends to mail letters to the member only when an individual provider is not identified with 
the most recent AF diagnosis given the large volume of members. 
 
As with the member-patient list, the provider list will be kept by each Data Partner and not shared, as 
each Data Partner will be mailing the intervention materials to their respective patients and providers. 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
X. 
ETHICAL CONSIDERATIONS 
This study will be conducted, where appropriate, in accordance with good research practice as outlined 
by Good Clinical Practice (GCP) and the International Conference on Harmonisation (ICH) and in 
accordance with the ethical principles underlying the United States Code of Federal Regulations, 
Title 21, Part 50 (21CFR50). The study will be conducted in compliance with the protocol. The protocol 
and any amendments will receive Institutional Review Board/Independent Ethics Committee (IRB/IEC) 
approval/favorable opinion before initiation of the study. Study personnel involved in conducting this 
study will be qualified by education, training, and experience to perform their respective tasks. This 
study will not use the services of study personnel where sanctions have been invoked or where there 
has been scientific misconduct or fraud (e.g., loss of medical licensure; debarment).  
Insurance companies do not ordinarily identify their members with AF who might be appropriate 
candidates for OACs, and they perform no standard outreach to either clinicians or members regarding 
treatment of AF. Individuals who are identified for this trial will have had their health care providers bill 
under the diagnosis code of AF at least twice, with at least one billed diagnosis within the last 12 
months. Thus, this trial involves no new identification of AF, since the method of ascertainment is 
through billing by providers based on their diagnosing AF. The current standard of care is for clinicians 
and their patients with AF to decide together whether anticoagulation for the diagnosed atrial 
fibrillation is appropriate. All Data Partners collaborating in the IMPACT-AFib trial are insurers (or 
affiliates of insurers), not care providers, and the clinicians are not employees of the Data Partners.  
There is no current evidence that the communications by insurers (like those being assessed in this trial) 
will have any effect on use of anticoagulation. All eligible patients included in the trial who do not 
appear to fill an OAC prescription will receive an intervention, as they will either be in the early 
intervention or the delayed intervention cohort. 
XI. 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
Before study initiation, the co-principal investigators must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, and any other written information to be provided to 
prospective participants.  
The investigators should provide the IRB/IEC with reports, updates, and other information (e.g., 
expedited safety reports, amendments, and administrative letters) according to regulatory requirements 
or institution procedures. 
XII. 
INFORMED CONSENT 
Consent will be waived. The reasons for the waiver include:  
1. The contacting of the delayed intervention patients for consent would be an intervention by 
itself and might affect the results of the trial. 
2. The intervention is entirely consistent with a quality improvement initiative that the health 
plans could initiate on their own. Thus, the intervention is very low risk for harm. 
3. The intervention only adds on to the existing care of and programs for patients. There are no 
restrictions placed on the delayed intervention group, as a result of the trial.  
4. It would be impractical to collect informed consent on the patients included in this trial. 

 
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 IMPACT-AFib 
The waiver of informed consent is consistent with the approach that has been taken in several similar 
clinical trials, the first using individual patient randomization, the others cluster randomized: 
1. UH3 Pragmatic Trial of Population-based Programs to Prevent Suicide Attempt (NCT02326883) 
2. The HMO Research Network CERT: A randomized trial of direct-to-patient communication to 
enhance adherence to beta-blocker therapy following myocardial infarction (NCT00211172) 
3. MI FREE: A Randomized Evaluation of First-dollar Coverage for Post-MI Secondary Prevention 
Therapies (NCT00566774) 
4. STOPCRC: Strategies and Opportunities to Stop Colon Cancer in Priority Populations 
(NCT01742065) 
XIII. 
INDEPENDENT ADVISORY COMMITTEE 
An independent advisory committee (IAC), consisting of members independent from the study team and 
with expertise in statistics, anticoagulation for atrial fibrillation, engagement, health plan management, 
and/or in practical clinical trials, will serve to enhance patient safety and trial integrity. The IAC will meet 
with study leadership at least twice. The first meeting will occur before intervention materials are 
mailed, and the second will take place two months after all mailings are sent. In addition, other 
meetings will occur if deemed necessary by the IAC chair, study leads and/or the FDA. The study team 
will provide the IAC with the study protocol before any intervention materials are mailed and will brief 
the IAC on any issues (or lack thereof) that have been raised 2 months after the last mailing has 
occurred. The IAC will advise on concerns that arise. An IAC charter describes the roles, responsibilities, 
and operations of the IAC.  
XIV. 
STATISTICAL CONSIDERATIONS 
A. SAMPLE SIZE AND POWER CALCULATIONS 
Our target sample size is 80,000 patients. All enrolled patients and/or their providers will be targeted by 
mailing (early or delayed) provided they are eligible at time of mailing and able to be contacted.  
1. Primary Endpoint 
The following assumptions were used to determine the sample size and power for the primary endpoint 
assessing the proportion of AF patients with evidence of at least one OAC prescription fill through the 
date on which at least 80% of eligible study participants have at least 12 months of follow-up time: 
• 
33% OAC initiation rate in the delayed intervention arm over the first year of the study 
o In a Sentinel feasibility assessment of identified health plan members meeting similar 
inclusion and exclusion criteria as this trial, 33% had evidence of OAC initiation in a 1 
year period of follow-up. 
• 
38% OAC initiation rate in the early intervention arm (a 5% absolute improvement in OAC 
initiation over the 33% OA initiation expected in thedelayed intervention arm over 1-year 
follow-up) 
• 
1-year attrition rate: 30% dropout or lost-to-follow-up 
• 
Two-sided type I error of 0.05  
• 
Roughly 10,000 patients (Table below) will yield more than 99% power to detect a 5% absolute 
difference 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
 
Power Total sample size (2-arm) Early Intervention Delayed Intervention 
90% 
5610 
2805 
2805 
95% 
6910 
3455 
3455 
99% 
9718 
4859 
4859 
 
 
2. Important Secondary Analysis of Stroke or TIA 
A study with approximately 80,000 patients is well powered for the outcome of stroke or TIA over the 
course of the follow-up through the date on which at least 80% of eligible study participants have at 
least 12 months of follow-up time, under certain assumptions listed below:  
• 
1-year stroke or TIA rate: 18% among patients not treated with OAC 
• 
1-year stroke or TIA rate: 7% among patients treated with at least 1 OAC fill 
• 
Duration of follow-up: 1 year  
• 
33% of delayed intervention patients will have at least 1 fill of OAC, meaning the 1 year stroke or 
TIA rate in the delayed intervention group would be 14.4% 
• 
If 38% of early intervention patients have at least 1 fill of OAC (meaning the 1 year stroke or TIA 
rate in the early intervention group would be 13.82%, i.e., an absolute reduction of 0.55%), the 
study will have 46% power to detect this 0.55% reduction. However, if 40.5% of early 
intervention patients have at least 1 fill of OAC (meaning the 1 year stroke or TIA rate in the 
early intervention group would be 13.54%, i.e., an absolute reduction of 0.83%), the study will 
have 80% power to detect this 0.83% reduction. 

 
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 IMPACT-AFib 
• 
1-year attrition rate: 30% dropout or lost-to-follow-up 
• 
Two-sided type I error of 0.05 
• The sample size has 80% power to detect a 0.5% absolute reduction in stroke, assuming a 
cumulative 1-year incidence of stroke of 4.2% in control (delayed intervention arm) patients and 
3.7% in intervention (early intervention arm) patients. The assumption is that patients not on 
oral anticoagulation have an annual stroke rate of 5%, and stroke will be reduced by 50% 
(HR=0.5) in the treated (anticoagulated) population. The 80% power requires that 52% of early 
intervention arm patients are treated at 1-year as compared to 33% in the control arm. 
B. POPULATIONS FOR ANALYSIS 
All analyses will be based on a modified intention-to-treat principle (i.e., all identified early intervention 
patients who meet eligibility and are mailed the intervention will be included; using “pseudo” wave 
assignments, all identified delayed intervention patients who meet eligibility at the time of 
corresponding early mailings will be included in the analysis). The primary endpoint will be calculated 
based on the proportion of patients with evidence of at least one OAC prescription fill over the course of 
the follow-up through the date on which at least 80% of eligible study participants have at least 12 
months of follow-up time. An as-randomized analysis will be performed for the primary endpoint as a 
sensitivity analysis. All possible person-time will be used to assess participants’ outcomes; patients will 
have different duration of follow-up and that will be accounted for in the analyses. Patients will be 
censored from the analysis at the time of death, disenrollment from the health plan, loss of medical or 
pharmacy coverage, or change in eligibility for inclusion in research based on health plan membership. 
The statistical analysis plan (SAP) provided more information and outlines in detail how granular 
aggregate data will be received from each Data Partner in lieu of patient-level data.  
XV. 
OUTCOME DEFINITIONS 
All outcome definitions will be based on available claims data. 
1. Evidence of OAC start: the proportion of AF patients who have at least 4 INR values measured or 
who fill at least one OAC prescription for apixaban, dabigatran, edoxaban, rivaroxaban, or 
warfarin over the course of the follow-up through the date on which at least 80% of eligible 
study participants have at least 12 months of follow-up time 
2. Time to OAC start: the time to first OAC initiation, as defined by the first fill date for apixaban, 
dabigatran, edoxaban, rivaroxaban, or warfarin. If there was no prescription fill for these 
medications, but the patient had 4 or more INR values measured over the study period, the date 
of the first INR measurement will be used for initiation of OAC. 
3. OAC prescription coverage: the proportion of days that AF patients have OAC prescription fills 
over the duration of the study. The assumption is that a 30-day or 90-day supply will last for the 
planned period, even in the case of warfarin, when the length of time that a prescription lasts 
may be less well defined. Patients will only be included in this secondary analysis, if they had a 
prescription fill for apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin. 
4. OAC rates at follow-up: proportion of patients with an active oral anticoagulant dispensing at 
the end of the one-year follow-up. This will include patients with apixaban, dabigatran, 
edoxaban, rivaroxaban, or warfarin medication fills that encompass the end of the study period. 
If there was no prescription fill for these medications, this will also include patients with 4 or 

 
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 IMPACT-AFib 
more INR values measured over the study period, who had an INR value measured within 60 
days of the end of the approximately one-year follow-up. 
5. Rate of stroke or TIA: the incident rate of stroke or TIA related hospitalizations; stroke, excluding 
transient ischemic attacks (TIAs), will also be assessed 
6. Rate of bleeding related hospitalization: the incident rate of hospitalizations for any bleeding 
7. Health care utilization: the total counts of health care utilization (number of outpatient visits, 
emergency department visits, hospital admissions, etc.) for AF patients, including AF and non-AF 
related care 
8. In-patient all-cause mortality: patients with in-hospital death 
9. All-cause mortality: in a subset of patients with mortality status 
XVI. 
STATISTICAL ANALYSES 
A. DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Baseline characteristics of eligible early and delayed intervention cohorts will be based on the claims 
data at the time of randomization. Frequency distribution and summary statistics for demographic and 
baseline variables will be presented by early intervention group, delayed intervention group, and for the 
overall study population. Key demographic and baseline variables to be summarized include: geographic 
region, age, sex, risk factors for stroke, risk factors for bleeding, and select comorbid conditions. 
Continuous variables will be summarized as mean (±SD) and median (25th, 75th percentiles); the 
comparison between the two groups will be conducted using Wilcoxon rank-sum test. For the 
continuous variables in combined study population, the mean will be summarized. Categorical variables 
will be presented as counts (percentages) and will be compared between groups by using Pearson’s chi-
square or Fisher’s exact test, as appropriate. 
B. RESPONSES FROM PROVIDERS 
As part of the provider intervention materials, providers will have the opportunity to respond to the 
patient’s health plan and give an explanation for why their patients were not being treated with OAC via 
a postage paid postcard. The data collected from these responses will be aggregated by rationale for 
non-treatment and reported as counts (percentages) by the coordinating center. Data will not be linked 
to specific patients or providers. 
C. EFFECTIVENESS ANALYSES 
The proportion of patients with evidence of at least one OAC medication fill over the course of the 
follow-up, the primary endpoint, will be summarized and compared between the early intervention and 
delayed intervention arms. The definition for OAC medication fill will be an OAC medication billing in the 
pharmacy claims or at least 4 INR tests billed in the laboratory claims (indicative of OAC use that was not 
billed through the pharmacy claims data). To evaluate whether the comprehensive evaluation and 
customized multilevel (patient-level and provider-level) educational interventions increases the rate of 
use of oral anticoagulants at one year post intervention, we will evaluate the odds ratio (i.e. the odds of 
an average patient in the early intervention group taking OAC at 1 year compared to the odds of an 
average patient in the delayed intervention group taking OAC at 1 year) using logistic regression to 
account for the effect of Data Ppartner and adjust for other potential baseline risk factors.38 We will 

 
FDA-Catalyst Protocol 
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 IMPACT-AFib 
present the odds ratio, 95% confidence interval, and p-value to show whether there is a difference in 
rate of use of OAC at one year post intervention between the early intervention and delayed 
intervention groups. Similarly, we will analyze the proportion of days covered with an OAC prescription 
fill over the course of the follow-up. Patients will only be included in this analysis, if they had a 
prescription fill for apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin.  
Event rates for the following secondary outcomes will be summarized by treatment group, as defined by 
claims data: 
• 
Stroke or TIA 
• 
Ischemic stroke or unknown stroke 
• 
Hemorrhagic stroke 
• 
Hospitalization for any bleeding 
• 
Composite of ischemic or hemorrhagic stroke  
• 
Composite of ischemic stroke, hemorrhagic stroke, and hospitalization for any bleeding 
For time-to-event outcomes, Kaplan-Meier cumulative incidence estimates and log-rank test will be 
utilized.39 In addition, Cox proportional hazards model with early intervention vs. delayed intervention 
as main effect will be used to assess the clinical outcomes, after adjusting for baseline risk factors. 40 A 
robust sandwich covariance estimate or a frailty model will be used to account for effect of Data 
Partner. The hazard ratio, 95% confidence interval and p-value will be presented to summarize the 
difference in the risk of clinical outcome between early intervention and delayed intervention group. In-
hospital death or medically attended death will be collected through claims data. Analyses will be 
performed using SAS software version 9.4 or higher (SAS Institute, Inc., Cary, NC).  
More details on the statistical methods and analyses will be provided in the SAP. The SAP will be 
finalized prior to study database lock, 12 months after at least 80% of the early intervention mailings. Of 
note, all patient-level data will be maintained by the Data Partners, so analyses are expected to be 
conducted via a distributed SAS programming code developed by the coordinating center and results are 
expected to be returned, by Data Partner, in aggregate to the coordinating center. Analyses will be 
examined by Data Partner and across Data Partners. 
XVII. 
DISSEMINATION PLAN OVERVIEW 
A manuscript describing the study design will be published. A manuscript will also be written describing 
the results on the primary and secondary endpoints based on the date on which at least 80% of eligible 
study participants have at least 12 months of follow-up time, and separately once at least 80% of 
members have at least 24 months of follow-up time (if 24-month aanalysis is conducted). Finally, Data 
Partner-specific results will be shared with each Data Partner at both time points. 
 

 
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XVIII. 
REFERENCES 
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