Incidental Coronary Calcification Quality Improvement Project
Phase: NA
Conditions: Atherosclerotic Cardiovascular Disease, Coronary Artery Disease
Sponsor: Stanford University

 
Incidental Coronary Calcification Quality Improvement Project (ICC QI)  
 
March 10, 2021 
 
 
 

 
2 
QUALITY IMPROVEMENT PROJECT SUMMARY  
Title 
Incidental Coronary Calcification Quality Improvement Project 
Project 
Objectives 
Primary objective is to estimate the impact of notification of primary 
care provider and patient of incidental coronary artery calcification 
(CAC) on a prior non-gated chest CT on statin prescription rates at 6 
months among statin-naïve patients without a clinical history of 
atherosclerotic cardiovascular disease. 
 
Secondary objectives are to evaluate the following at 6 months after 
notification:  
 
- Specific statin medication and dose 
 
- Aspirin prescription rates 
 
- Change in cardiovascular risk factors (blood cholesterol levels, 
hemoglobin A1c levels, systolic/diastolic blood pressure, body mass 
index) 
 
- Change in 10-year pooled cohort equations risk of atherosclerotic 
cardiovascular disease (calculated from age, sex, race, systolic blood 
pressure, total cholesterol, HDL cholesterol, diabetes status, smoking 
status, blood pressure treatment status)  
 
- Number of blood pressure medications 
 
- Healthcare resource use (primary care clinical encounters, 
cardiology referrals, cardiac testing) 
 
Project Design 
This is a randomized quality improvement project evaluating the 
impact of notifying patients and their providers of an incidental finding 
of coronary artery calcification (CAC) indicating increased 
cardiovascular risk. Patients will be identified by screening previous 
non-gated chest CTs and the electronic health record. The presence 
of CAC will be confirmed by a board-certified radiologist. Eligible 
patients will be randomized in a 1:1 fashion to CAC notification or 
usual care. 
Number of 
Patients 
All eligible patients; approximately 200 patients at Stanford will be 
randomized in addition to approximately 200 patients at the Palo Alto 
VA. 
Location 
Stanford Health Care system (including Stanford Hospital and 
affiliated clinics; ValleyCare Hospital and affiliated clinics) and Palo 
Alto Veteran’s Affairs Healthcare System 
Inclusion Criteria 
• Age ³18 and <85 
• Non-gated chest CT from 2014-2019 with CAC 

 
3 
• Visit to Stanford affiliated clinician from one of the following clinics 
since 2018: 
o Stanford Internal Medicine (includes University 
affiliated clinics) 
o Stanford Family Medicine (includes University 
affiliated clinics) 
o Palo Alto VA Internal Medicine 
o Palo Alto VA Family Medicine 
 
Exclusion 
Criteria 
• Prior diagnosis of coronary artery disease, peripheral artery 
disease, or cerebrovascular disease  
• Dementia 
• Metastatic cancer or active cancer undergoing chemotherapy 
• Prior cardiac gated chest CT 
• Prior coronary angiogram 
• Current or previous statin therapy 
• History of medical non-adherence 
• Non-English speaking 
Intervention 
For patients randomized to notification, the affiliated primary care 
provider will receive an EHR message notifying them of the presence 
of CAC (with images) and the ACC/AHA guideline recommendation 
to consider starting statin therapy. We will notify the patient after 2 
weeks elapse unless the primary care provider responds that the 
patient has already been diagnosed with atherosclerotic 
cardiovascular disease, is already taking a statin, or cannot take a 
statin. 
 
Patients will then receive messages (via either EHR portal-based   
messages or US postal mail) with images showing the presence of 
CAC on their previous chest CT, and the recommendation to discuss 
statin therapy with their clinician.  
 
For the notification arm, we will check for either statin prescription or 
a documented discussion in the EHR at 3 months. For those not 
prescribed a statin and without a documented discussion in Epic at 3 
months follow-up, we will send a repeat notification to their home 
address and to their primary care provider. 
Adaptive Design 
The project will use two independent cohorts – the first 50 patients 
and then all remaining patients. At the start of the project, the first 
cohort of 50 patients will be randomized to notification or usual care. 
Based on feedback from primary care clinicians and observed statin 
rates over the subsequent 6 weeks, potential modifications to the 
protocol will be made prior to randomization of the second cohort. 
 

 
4 
If any changes are made to the protocol, each cohort will be 
evaluated separately with primary analyses based on the second 
cohort. If no changes are made to the initial protocol, all analyses will 
pool both cohorts.  
Primary 
Endpoint 
6-month statin prescription rate 
Secondary 
Endpoints 
Change in the following at 6 months: 
• Statin prescription rate 
• Aspirin prescription rate 
• Lipid panel (Total cholesterol, HDL, LDL, Triglycerides) 
• Average systolic blood pressure 
• Hemoglobin A1c 
• Number of blood pressure medications 
• Body mass index 
• 10-year pooled cohort equations risk of atherosclerotic 
cardiovascular disease (calculated from age, sex, race, 
systolic blood pressure, total cholesterol, HDL cholesterol, 
diabetes status, smoking status, blood pressure treatment 
status) 
Healthcare resource use at 6 months: 
• Number of primary care clinical encounters 
• Number of cardiology referrals 
• Number of cardiovascular diagnostic tests ordered 
Other Outcomes 
of Interest 
• Specific statin prescribed and dose at 6 months 
 
Assessment 
Schedule 
• Eligibility screening using list of prior CT scans and electronic 
health record 
• AI algorithm CT screening for presence of coronary artery 
calcification 
• Manual electronic health record review to confirm clinical 
inclusion/exclusion criteria 
• Manual radiologist review of CT scan to confirm the presence of 
CAC followed by randomization 
• 3-month assessment of statin prescription rates using electronic 
health record evaluation 
• 6-month assessment of outcomes using electronic health record 
evaluation 
Duration 
At each site, we will enroll a maximum of 3 patients per primary care 
provider notified per week. Expected follow-up will be 6 months for all 
primary and secondary endpoints. 

 
5 
Statistical 
Considerations 
A sample size of 150 randomized patients has 87% power to detect a 
20% higher absolute statin prescription rate (to a rate of 30%) among 
the notification arm compared with an estimated rate of 10% in the 
usual care arm. Additional power estimates conditional on sample 
size are listed below. 
 
 

 
6 
TABLE OF CONTENTS 
 
1.  
LIST OF ABBREVIATIONS AND DEFINITONS 
5 
2. 
BACKGROUND AND RATIONALE 
6 
3. 
HYPOTHESIS 
8 
4.  
PROJECT OBJECTIVES 
9 
5. 
PROJECT DESIGN 
10 
6. 
PROJECT PROCEDURES 
13 
7. 
TREATMENT ARMS 
17 
8. 
PROJECT ASSESSMENT AND SCHEDULE 
18 
9. 
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
21 
10. DATA HANDLING AND RECORD KEEPING 
22 
11. ETHICAL CONSIDERATIONS 
23 
12. REFERENCES 
24 
 

 
7 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS  
ACC 
American College of Cardiology 
ASCVD 
atherosclerotic cardiovascular disease 
AHA 
American Heart Association 
CAC 
coronary artery calcification 
CAD 
coronary artery disease 
CPT 
Current Procedural Terminology 
CT 
Computed Tomography 
ECG 
electrocardiogram 
EHR 
electronic health record 
ICD-9 
International Classification of Diseases, Ninth Revision 
ICD-10 
International Classification of Diseases, Tenth Revision 
MI 
myocardial infarction 
PCE 
ACC/AHA Pooled Cohort Equations 
PHI 
protected health information 
 
 

 
8 
2. 
BACKGROUND AND RATIONALE  
 
Coronary artery disease (CAD) is the #1 cause of death in the US and globally.1 It 
develops silently over decades until it strikes as a myocardial infarction (MI) or sudden 
death. For half of people who die suddenly, death is the first symptom.1 Risk factors such 
as smoking, hypertension, and high cholesterol increase the probability of developing 
plaques inside coronary arteries that cause MI. An electrocardiogram (ECG)-gated 
computed tomography (CT) scan can identify silent disease by detecting calcification of 
plaque inside coronary arteries. ECG-gating is used to image the patient during periods of 
heart muscle relaxation to minimize motion from an otherwise moving organ. A calcium 
scoring system has been developed—the higher the score, the higher the risk of having an 
MI or dying.2-5 Studies have shown that once people learn that they have coronary artery 
calcification (CAC), they are more likely to make healthy lifestyle choices and take 
medications that reduce their risk of MI.6,7 The 2018 ACC/AHA cholesterol treatment 
guidelines recommend testing for CAC when patients are at borderline to intermediate risk 
for MI, and there is uncertainty about whether or not to prescribe a statin medication for 
cholesterol lowering.8  When the CAC score is >0 Agatston units among those >55 years 
old or >100 Agatston units (or 75th percentile of age and sex reference values) among 
those younger, these guidelines recommend consideration of statin therapy to reduce risk. 
However, CAC testing and preventive therapies remain vastly underutilized, in part 
because insurers do not pay for these tests. As a result, millions of asymptomatic people 
remain unaware of their high risk for a heart attack and remain undetected and 
undertreated.  
 
Statin medications have been shown to reduce the risk of MI and increase survival 
among patients at moderate to high risk of cardiovascular disease.9 However, use of statin 
medications in at-risk populations remains suboptimal.10 In 2013-2014, statin use among 
eligible adults in the US was estimated at 55%, and was unchanged from 2011–2012. This 
leaves an estimated 39 million adults at risk for cardiovascular disease off statin 
medications. Mechanisms to increase statin prescription rates are needed to reduce the 
impact of cardiovascular disease. 
 
A large number of non-gated chest CT scans are performed in the Stanford and 
Palo Alto VA healthcare systems annually. Although these scans include images of the 
coronary arteries, there is often underreporting of the presence of CAC. Even when CAC is 
reported in the radiology report, the implications of CAC may be poorly understood and 
statin uptake may remain suboptimal. This is especially true because the significance of 
CAC and the benefit of starting statins among these patients was unrecognized until 
recently. Identifying Stanford and Palo Alto VA patients with prior CT scans with coronary 
calcium and notifying patients and their primary care providers may help inform 
discussions between patients and their physicians regarding their cardiovascular risk and 
the appropriateness of statin therapy. Better understanding one’s risk may improve other 
cardiovascular risk factors such as diet, exercise, and blood pressure. This could provide 
an additional avenue for identifying our patients at risk for cardiovascular disease in order 
to start statins and make other changes to reduce the risk of having an MI. 
 

 
9 
3. 
HYPOTHESIS 
In our health system, notification of statin-naïve patients without a history of atherosclerotic 
cardiovascular disease and their providers about coronary artery calcification on a prior 
non-gated chest CT will lead to an increase in statin prescription rates compared with rates 
among patients who are not notified. Furthermore, as secondary hypotheses, notification 
will also lead to additional cardiovascular risk reduction at 6 months following notification: 
lower LDL-cholesterol levels, lower systolic blood pressure, lower body mass index, lower 
tobacco use rates, and a lower 10-year ACC/AHA pooled cohort equations risk.  
  
 
 

 
10 
4. 
PROJECT OBJECTIVES 
PRIMARY AIM 
The primary aim of this project is to estimate the increase in 6-month statin prescription 
among statin-naïve patients without a history of atherosclerotic cardiovascular disease with 
incidental CAC on a non-gated chest CT who are randomized to receive notification of 
their findings vs. usual care in our health system (Stanford and the Palo Alto VA). 
 
SECONDARY AIMS 
The secondary aims of this project are to compare the following outcomes in patients 
randomized to notification or usual care: 
• 3-month statin prescription rates 
• Change in 6-month aspirin prescription rates 
• Change in total cholesterol level 
• Change in high-density lipoprotein level 
• Change in low-density lipoprotein level 
• Change in triglyceride level  
• Change in average systolic blood pressure  
• Change in number of blood pressure medications 
• Change in body mass index 
• Change in hemoglobin A1c level 
• Change in 10-year Pooled Cohort Equations 10-year risk 
• Number of primary care clinical encounters 
• Number of cardiology referrals 
• Number of cardiovascular diagnostic tests ordered 
• Describe specific statin prescribed and dose 
 
 
 

 
11 
5. 
PROJECT DESIGN 
This is a multi-center, randomized quality improvement project. At least 200 statin-naïve 
patients without a history of atherosclerotic cardiovascular disease with incidental CAC on 
a prior non-gated chest CT will be enrolled across the Stanford Healthcare System and the 
Palo Alto Veteran’s Affairs Healthcare System. Patients will be randomized in a 1:1 fashion 
to notification or usual care arms. 
 
5.1 
PROJECT Flow 
See Figure 1 for details. All non-gated chest CTs will be screened for the presence of CAC 
using an artificial intelligence deep learning algorithm that predicts the presence of CAC on 
a concurrent gated chest CT. Identified patients will be screened for inclusion/exclusion 
criteria using electronic health record data. Patients who meet eligibility criteria will be 
sequentially randomized by the project coordinator using the REDCap randomization 
module. A maximum of 3 patients per week will be randomized to the notification arm for 
any single primary care provider. After 3 patients are enrolled and randomized to the 
notification arm for a given primary care provider in a single week, enrollment of eligible 
patients of that clinician will be delayed until the following week.  
 
Figure 1. Project Flow 
 
 
After randomization to the notification arm, the coordinator will send a standardized 
notification message using the EHR to the patient’s affiliated provider. The affiliated 
clinician will be the listed primary care provider within the health system. For patients 
without an active primary care provider, the affiliated provider can include a clinician from 
endocrinology clinic. This message will include the option for the provider to exclude their 
patient from receiving a standardized message if they note their patient has already been 
diagnosed with atherosclerotic cardiovascular disease, is already taking a statin, or cannot 
take a statin. 

 
12 
 
In the absence of the patient being excluded from notification, the coordinator will send a 
message to the patient after two weeks. For patients with active EHR patient portal 
accounts, this message will be transmitted via the EHR patient portal. For patients without 
active patient portal accounts, the message will be sent via postal mail. The message will 
include an image of the CAC from the chest CT. For patients who do not read the 
message on the EHR patient portal within 2 weeks, the message will also be sent via 
postal mail. 
 
The project will be divided into two stages using two independent cohorts. The first cohort 
will include the first 50 randomized patients. The second cohort will include all other 
patients randomized for the study. There will be a delay of at least 10 weeks between 
enrollment of the first and second cohort in order to adapt the notification as necessary 
based on observations with the first cohort. Adaptations of the notification process will be 
based on feedback from primary care clinicians based on the initial cohort and observed 
changes in statin rates in this early period. Changes to the protocol will be agreed upon by 
study investigators and documented in detail. Following finalization of the protocol for the 
second stage, the second cohort will be enrolled. 
 
At 3 months after patient notification, the coordinator will check for statin prescription or 
EHR documentation of a discussion regarding statin therapy. In the absence of statin 
prescription or a documented conversation, the coordinator will again send standardized 
messages to patients enrolled in the notification arm and their providers. Final outcome 
ascertainment will occur at 6 months after patient notification. 
 
The coordinator will have no additional communication with patients or primary care 
providers over the 6-month follow-up period. Patients will be directed to their affiliated 
clinicians (their primary care provider or endocrinologist) to discuss statin therapy or 
information regarding the notification. Clinicians will be able to contact Dr. David Maron, 
director of Stanford preventive cardiology and co-PI of the project, via electronic health 
record message or secure email, with any additional questions.  
 
All CT scans being used in this project have been interpreted previously by an attending 
radiologist and reported to the ordering provider with a standardized report according to 
clinical standards. Additionally, all clinicians have had access to the standardized report for 
at least 6 months prior to the project start date. Individuals randomized to the UC arm will 
not receive additional notification or have any communication with project staff. 
 
A member of the project team will determine primary and secondary outcomes using 
electronic health record evaluation at 6 months.  
 
5.2 
Project Population 
 
Statin-naïve patients without a history of ASCVD who underwent a prior non-gated chest 
CT found to have CAC. 
 
5.3 
Inclusion/Exclusion Criteria  

 
13 
 
Screening for inclusion/exclusion criteria will be conducted using a non-gated CT 
screening algorithm and electronic health record evaluation. Patients will be screened for 
the following inclusion and exclusion criteria: 
5.3.1  Inclusion 
 
1. Chest CT Eligibility 
a. Non-gated chest CT between 2014-2019 
b. Algorithm identifies CAC 
c. Presence of CAC confirmed by manual review by a board-certified radiologist   
2. Clinical Eligibility 
a. Age ³18 and <85 
b.  Stanford affiliated primary care provider or endocrinologist for Stanford healthcare 
system patients and VA primary care provider for VA patients 
c. Visit (in-person or via tele-health) to listed clinician since 2018 
5.3.2 Exclusion 
1. Current or prior statin or PCSK9 inhibitor therapy 
2. Prior diagnosis of ASCVD  
a. Coronary artery disease 
b. Peripheral artery disease 
c. Cerebrovascular disease 
d. Coronary revascularization 
e. Peripheral vascular revascularization 
3. Prior coronary imaging 
a. Cardiac CT 
b. Invasive coronary angiography 
4. Dementia diagnosis 
5. Metastatic cancer or active cancer undergoing chemotherapy 
6. History of medical nonadherence 
 
 

 
14 
7. PROJECT PROCEDURES 
6.1 
Notification of Participation 
This quality improvement project involves a minimal-risk intervention. If notification 
improves statin rates and is acceptable among stakeholders, we will also apply this 
intervention routinely in the healthcare system including to the usual care arm. 
 
6.2  
Randomization 
The sequence generation process will be performed using a secure password-protected 
computerized block randomization algorithm on REDCap with a 1:1 allocation and 
randomly selected block sizes of 2, 4, and 6. There will be no stratification for the 
randomization procedure. 
 
6.3  
Notification Messages 
 
For patients randomized to the notification arm, a letter will be sent to the affiliated clinician 
using the electronic health record messaging system. The letter will include an image of 
the CAC from their CT scan. The clinician will have the opportunity to exclude a patient 
from being notified based on additional clinical considerations. We will otherwise send a 
scripted message via the EHR patient portal or postal mail after two weeks. That message 
will inform them that we identified coronary artery calcium on a previously performed CT 
scan. 
  
A member of the project team will evaluate statin rates 3 months after patient notification 
among all randomized patients. They will also evaluate for documentation of statin 
discussions among those in the notification arm not prescribed a statin. The coordinator 
will then again send notifications to patients randomized to the notification arm who were 
neither started on statin therapy nor had a documented discussion. The coordinator will 
send messages to both the patient and their primary care provider that are similar to the 
initial notification. 

 
15 
8. TREATMENT ARMS 
 
7.1  
Notification 
Patients randomized to notification will receive a message sent by either the EHR patient 
portal or postal mail that will inform them of the CAC identified on their previous chest CT. 
It will provide an overview of CAC, an image of their chest CT, and a recommendation that 
they discuss this finding with their clinician. These clinicians will be notified of these 
findings via an earlier EHR message. All communications will be signed by David Maron, 
MD, Director of Stanford Preventive Cardiology. Any treatment decisions will be made by 
the patient and their clinician. 
 
Patients randomized to notification who are not prescribed a statin medication and do not 
have a documented discussion regarding statin therapy within three months will be sent a 
second message at that time. Their primary care providers will receive a second EHR 
message concurrently. 
 
7.2 
Usual Care 
 
Both arms have previously had their CT scans reported according to standard clinical 
practice. This may include notification of the CAC in the imaging report. The usual care 
arm will not receive any additional notification beyond this standard of care. 
 
We plan to notify patients in the usual care arm at the end of 6-months unless we 
determine that notification is ineffective at increasing statin rates and is not acceptable to 
either patients or their clinicians. 
 
 

 
16 
8. PROJECT ASSESSMENTS AND SCHEDULE 
8.1 
Baseline Clinical Eligibility 
 
Baseline clinical eligibility will be determined for patients who have undergone a non-gated 
chest CT between 2014-2019. Clinical eligibility screening will be performed using EHR 
data via the STARR clinical registry. 
 
8.1.1 Affiliated Clinician 
 
Eligible patients must receive active clinical care from an affiliated primary care provider or 
endocrinology. Patients will be required to have had a visit with one of the following clinics 
since 2018: 
o Stanford Internal Medicine (including university affiliated clinics) 
o Stanford Family Medicine (including university affiliated clinics) 
o Stanford Endocrinology 
o Palo Alto VA Internal Medicine 
o Palo Alto VA Family Medicine 
 
8.1.2 Patient Age 
 
Eligible patients must be ≥18 and <85 years old at the time of screening for enrollment.  
 
8.1.3 Exclusion Criteria 
 
Eligible patients will be initially screened for exclusion using EHR structured data elements 
of medications, diagnostic coding, and procedure coding. A list of diagnostic and 
procedural codes are attached in Appendix A. 
8.2 
Non-gated CT Scan Evaluation: AI Algorithm 
 
Among patients who meet the baseline clinical eligibility, Stanford non-gated chest CT 
scans performed between 2014-2019 will be screened using an automated algorithm that 
will identify patients with a very high probability of a CAC score >0 Agatston units. This 
was developed at Stanford using a deep learning model based on patients who had a non-
gated chest CT scan within 1 year of a gated coronary CT scan. 
 
8.3  
Confirm Clinical Eligibility Based on Manual EHR Review 
 
Patients with CAC >0 based on the AI algorithm will then undergo a manual EHR chart 
review to confirm they meet the inclusion/exclusion criteria. This will evaluate the same 
criteria evaluated based on the baseline clinical eligibility screen above in 8.1 to ensure 

 
17 
non-structured data elements are captured. Additionally, the manual review evaluates the 
following exclusion criteria.  
• Active malignancy with one of the following two characteristics 
o Active chemotherapy 
o Metastatic disease 
• Medical nonadherence 
 
8.4  
Non-Gated CT Scan Evaluation: Manual Review 
 
All patients who meet the clinical eligibility criteria with CAC on non-gated CT scan based 
on the AI algorithm will then undergo a manual review of the chest CT by a board-certified 
radiologist. The manual review will confirm the accuracy of the algorithm and the presence 
of CAC. 
 
8.5 Baseline Clinical Data 
Baseline clinical values of the following will be extracted from the EHR: 
• Demographic characteristics (age, sex, race) 
• Aspirin prescription 
• Number of blood pressure medications prescribed 
• Most recent blood cholesterol levels (Total cholesterol, HDL, LDL, Triglycerides) 
• Most recent hemoglobin A1c level 
• Average systolic blood pressure over previous 3 months 
• Most recent BMI 
• Comorbidities using diagnosis coding 
o Diabetes mellitus 
o Hypertension 
o Hyperlipidemia 
o Smoking status 
o Cancer (non-metastatic, not on active chemotherapy) 
• Date of Chest CT 
• Chest CT indication 
• Prior Clinic Experience (specific to the affiliated clinician’s clinic) 
o Date of last clinic visit 
o Number of clinic visits since 2018 
o Number of clinic encounters since 2018 
• Other Healthcare utilization 
o Number of total clinic visits since 2018 (tele-health and in-person) 
o Prior cardiology outpatient encounters 
o Prior cardiovascular diagnostic tests ordered (diagnostic tests ordered (CAC 
scan, electrocardiogram, echocardiogram, exercise electrocardiogram, stress 
echocardiogram, stress nuclear, CT coronary angiography, invasive coronary 
angiography) 

 
18 
o Number of health system ED visits since 2018 
o Number of health system hospitalizations since 2018 
 
For all eligible patients without missing data, 10-year Pooled Cohort Equations risk 
(calculated from age, sex, race, systolic blood pressure, total cholesterol, HDL cholesterol, 
diabetes status, smoking status, blood pressure treatment status) will be calculated. 
 
8.4 Endpoint Assessments 
Primary and secondary endpoints will be assessed using EHR structured data elements. 
Endpoints will be assessed by a member of the project team who will be blinded to 
allocation. The following will be assessed at 3-months after patient notification: 
• Statin prescription rates 
 
The following will be assessed at 6-months after patient notification: 
• Specific statin prescribed, dose, and type of statin (high-, moderate-, or low-
intensity) 
• Aspirin prescription 
• Number of blood pressure medications prescribed 
• Most recent total cholesterol level 
• Most recent high-density lipoprotein level 
• Most recent low-density lipoprotein level 
• Most recent triglyceride level  
• Most recent hemoglobin A1c level 
• Average systolic blood pressure over previous month 
• Most recent body mass index 
• 10-year Pooled Cohort Equations risk (calculated from age, diabetes status, sex, 
race, smoking status, total cholesterol, HDL cholesterol, systolic blood pressure, 
blood pressure treatment status) 
• Number of primary care clinical encounters 
• Cardiology outpatient encounters 
• Number of cardiovascular diagnostic tests ordered (CAC scan, electrocardiogram, 
echocardiogram, exercise electrocardiogram, stress echocardiogram, stress 
nuclear, CT coronary angiography, invasive coronary angiography) 
 
Patients in the first cohort will also have statin prescription rates assessed at 8 weeks 
following notification. This information will guide potential changes to the protocol prior to 
randomization of the second cohort. 
 
 
 
 
 

 
19 
9. STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN 
9.1  
Sample Size Assumptions 
We plan to have at least 150 patients in the second cohort. With 150 patients, we will have 
87% power for a 20% higher absolute statin prescription rate (to a rate of 30%) among the 
notification arm compared with an estimated 10% statin prescription rate in the usual care 
arm. Because prior studies have demonstrated the difficulty in improving preventive 
therapy interventions, we estimated a relatively modest increase in statin initiation rates.11 
The following table lists additional sample size calculations: 
alpha 
Sample 
Size 
Control Arm 
Statin Rate 
Notification Arm 
Statin Rate 
Difference in 
Statin Rates 
Power 
0.05 
100 
0.05 
0.2 
0.15 
0.624 
0.05 
150 
0.05 
0.2 
0.15 
0.799 
0.05 
200 
0.05 
0.2 
0.15 
0.900 
0.05 
250 
0.05 
0.2 
0.15 
0.953 
0.05 
300 
0.05 
0.2 
0.15 
0.978 
0.05 
100 
0.05 
0.25 
0.2 
0.809 
0.05 
150 
0.05 
0.25 
0.2 
0.937 
0.05 
200 
0.05 
0.25 
0.2 
0.981 
0.05 
250 
0.05 
0.25 
0.2 
0.995 
0.05 
300 
0.05 
0.25 
0.2 
0.999 
0.05 
100 
0.05 
0.3 
0.25 
0.921 
0.05 
150 
0.05 
0.3 
0.25 
0.986 
0.05 
200 
0.05 
0.3 
0.25 
0.998 
0.05 
250 
0.05 
0.3 
0.25 
1.000 
0.05 
300 
0.05 
0.3 
0.25 
1.000 
0.05 
100 
0.05 
0.35 
0.3 
0.973 
0.05 
150 
0.05 
0.35 
0.3 
0.998 
0.05 
200 
0.05 
0.35 
0.3 
1.000 
0.05 
250 
0.05 
0.35 
0.3 
1.000 
0.05 
300 
0.05 
0.35 
0.3 
1.000 
0.05 
100 
0.05 
0.4 
0.35 
0.993 
0.05 
150 
0.05 
0.4 
0.35 
1.000 
0.05 
200 
0.05 
0.4 
0.35 
1.000 
0.05 
250 
0.05 
0.4 
0.35 
1.000 
0.05 
300 
0.05 
0.4 
0.35 
1.000 
0.05 
100 
0.1 
0.2 
0.1 
0.286 
0.05 
150 
0.1 
0.2 
0.1 
0.402 
0.05 
200 
0.1 
0.2 
0.1 
0.508 
0.05 
250 
0.1 
0.2 
0.1 
0.601 
0.05 
300 
0.1 
0.2 
0.1 
0.681 

 
20 
0.05 
100 
0.1 
0.25 
0.15 
0.506 
0.05 
150 
0.1 
0.25 
0.15 
0.680 
0.05 
200 
0.1 
0.25 
0.15 
0.802 
0.05 
250 
0.1 
0.25 
0.15 
0.882 
0.05 
300 
0.1 
0.25 
0.15 
0.932 
0.05 
100 
0.1 
0.3 
0.2 
0.712 
0.05 
150 
0.1 
0.3 
0.2 
0.872 
0.05 
200 
0.1 
0.3 
0.2 
0.948 
0.05 
250 
0.1 
0.3 
0.2 
0.980 
0.05 
300 
0.1 
0.3 
0.2 
0.993 
0.05 
100 
0.1 
0.35 
0.25 
0.861 
0.05 
150 
0.1 
0.35 
0.25 
0.963 
0.05 
200 
0.1 
0.35 
0.25 
0.991 
0.05 
250 
0.1 
0.35 
0.25 
0.998 
0.05 
300 
0.1 
0.35 
0.25 
1.000 
0.05 
100 
0.1 
0.4 
0.3 
0.946 
0.05 
150 
0.1 
0.4 
0.3 
0.993 
0.05 
200 
0.1 
0.4 
0.3 
0.999 
0.05 
250 
0.1 
0.4 
0.3 
1.000 
0.05 
300 
0.1 
0.4 
0.3 
1.000 
 
 

 
21 
9.2  
Statistical Analysis Plan 
This project uses an adaptive design with a potential change to the protocol following 
randomization of the first 50 patients (the first cohort). If there are any changes to the 
protocol following the first cohort, the primary analysis will only include the second cohort 
(patients randomized after the protocol change). In this case, the combined cohort will only 
be used for post-hoc analyses. The project is adequately powered based on the second 
cohort as described above in Section 9.1. If there are no changes to the protocol following 
the first cohort, the cohorts will be pooled for all analyses. 
 
The primary endpoint is the statin prescription rate at 6 months. We will compare the 
difference in proportion of patients prescribed statins between arms using either the Chi-
squared test or Fisher’s exact test depending on the number of statin initiations observed 
in either arm. Specifically, we will use the Fisher’s exact test if there are under 10 statin 
initiations in either the usual care or notification arm. Multiple pre-specified subgroups will 
be tested with formal testing for effect modification: 
- 
Age – stratified into above and below median and as a continuous variable 
- 
Sex 
- 
Prior LDL value – stratified into above or below 100mg/dL or missing  
- 
Time since last clinician visit - stratified into above and below median and as a 
continuous variable 
- 
Taking anti-hypertensive medication 
- 
Clinical site (Stanford, University Affiliated, Palo Alto VA) 
- 
Specialty of clinician notified 
- 
Estimated CAC score on AI derived score – stratified into above and below 
median and as a continuous variable 
 
For secondary endpoints, we will compare the change in continuous variables from 
baseline to 6-months across arms using analysis of covariance. The outcome variable at 6 
months will be the dependent variable while adjusting for baseline values of the outcome 
variable. The difference in healthcare resource use (number of primary care encounters,  
and cardiovascular tests ordered) will be evaluated using negative binomial regression 
models while adjusting for two baseline characteristics thought to be likely prognostic. 
These include age modeled as a cubic spline with a knot at the median, the 5th percentile, 
and 95th percentile and prior resource utilization (specific to the outcome being tested). 
The difference in cardiology encounters post-randomization will be assessed using 
multivariable logistic regression with adjustment for age (as specified above) and history of 
prior cardiology encounters. The binary endpoint, aspirin prescription, will be compared 
using Chi-squared or Fisher’s exact test depending on cell sizes as described above.  
 
Baseline characteristics will be compared using standardized mean differences to assess 
balance across arms. The analysis will use a two-sided α of 0.05 as a threshold for 
significance. 

 
22 
10. DATA HANDLING AND RECORD KEEPING 
10.1  Electronic Data Capture (EDC) System  
 
EHR data will be extracted via the STARR registry and kept on the REDCap system. After 
data extraction, patients will be de-identified and labeled with a project ID number. Linkage 
between the medical record number and project ID will be kept separately as a locked file 
and only be available to the data analyst.  
 
10.2 Data Confidentiality and Security 
Computerized data will be accessible only by password. The Stanford University computer 
network is protected by a firewall.  Patients will be identified by project number only, to 
ensure participant anonymity. No participant identifiers will be used in the presentation of 
data. Records that might identify patients will be kept confidential as required by law. 
Except when required by law, patients will not be identified by name, personal identification 
number (e.g. social security number, social insurance number), address, telephone 
number, or any other direct personal identifier in project records. 
 
10.3  Training 
 
All investigational site staff authorized to enter the project data will receive training on the 
EDC system. 
 
10.4 Records Retention  
 
Project records will be maintained by the site investigators for a period of six (6) years 
following the expiration of the grant or length of time as required by local regulations, 
whichever is longer. 
 

 
23 
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