Pragmatic, Randomized Evaluation of Statin Active Choice to Reach Improved Outcomes Based on Evidence
Phase: NA
Conditions: Cardiovascular Diseases
Sponsor: University of Pennsylvania

Supplement 1 
Study Protocol 
Table of Contents 
1. Summary of changes to the protocol  
2. Study Protocol 
 
 
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Summary of Changes to the Protocol 
There were no changes to the study protocol.  
 
 
 
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Study Protocol 
A Randomized, Controlled Trial Using  
Active Choice to Promote Statin Prescription Initiation 
 
Study Protocol 
 
January 2017 
 
 
 
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Outline 
1. Abstract 
2. Overall objectives 
3. Aims 
 
3.1 Primary outcome 
 
3.2 Secondary outcomes 
4. Background 
5. Study design 
 
5.1 Design 
 
5.2 Study duration 
 
5.3 Target population 
 
5.4 Accrual 
 
5.5 Key inclusion criteria 
 
5.6 Key exclusion criteria 
6. Subject recruitment 
7. Subject compensation 
8. Study procedures 
 
8.1 Consent 
 
8.2 Procedures 
9. Analysis plan 
10. Investigators 
11. Human research protection 
 
11.1 Data confidentiality 
 
11.2 Subject confidentiality 
 
11.3 Subject privacy 
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11.4 Data disclosure 
 
11.5 Data safety and monitoring 
 
11.6 Risk/benefit  
 
 
11.6.1 Potential study risks 
 
 
11.6.2 Potential study benefits 
 
 
11.6.3 Risk/benefit assessment 
 
 
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1. Abstract 
Cardiovascular (CV) events are the leading cause of mortality in the United States. Statins have 
been demonstrated to be an effective tool for reducing CV events and mortality, but statins are 
often not prescribed for patients that meet evidence-based guidelines.  In this study, we will 
evaluate a health system initiative using active choice to identify eligible patients and prompt 
primary care physicians to initiate statin prescription.  In partnership with the health system, this 
will be conducted as a randomized, controlled trial to evaluate its effect  
2. Overall objectives 
The objective of the study is to evaluate the effect of a health system initiative using active 
choice with and without social comparisons feedback to encourage physicians to prescribe statins 
for patients that meet evidence-based guidelines. 
3. Aims 
 
3.1 Primary outcome 
The primary outcome measure is the change in percentage of eligible patients prescribed a statin 
medication within 2 months of intervention completion. 
 
3.2 Secondary outcome 
Not applicable 
4. Background 
Statins, or HMG-CoA reductase inhibitors, are an effective and well tolerated treatment for 
hyperlipidemia and reduce CV event occurrence and mortality.1,2 However, despite their 
demonstrated clinical utility and wide acceptance, statins are underutilized and not prescribed to 
many patients who would benefit from them under current guidelines.3 In a recent study looking 
at the diabetic population, only about 35% of patients who were eligible and lacked 
contraindications for a statin were prescribed a statin.4 
In 2013, the American Heart Association and the American College of Cardiology created a new 
method of estimating 10-year cardiovascular disease (CVD)5. They also concurrently released 
new guidelines for statin prescription that used a combination of age, low-density lipoprotein 
cholesterol (LDL-C) levels, diabetes diagnosis, and 10-year CVD diagnosis to establish clinical 
benefit of statins.6 Although this patient information is readily available to primary care 
physicians, clinicians are not often presented with the relevant clinical information in a 
streamlined manner that aids making decisions about a particular guideline.  
Active choices, or compelling people to make a decision between alternatives, have been 
demonstrated to increase compliance to a beneficial intervention and may offer an opportunity to 
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increase statin prescription intiation.7,8  Social comparisons feedback has also been demonstrated 
to change physician behavior in many contexts including antibiotic prescribing.9  
References 
[1] Robinson  JG.  Accumulating evidence for statins in primary prevention. JAMA. 
2013;310(22):2405-2406.  
[2] Pandya A, Sy S, Cho S, Weinstein MC, Gaziano TA. Cost-effectiveness of 10-Year Risk 
Thresholds for Initiation of Statin Therapy for Primary Prevention of Cardiovascular 
Disease. JAMA.2015;314(2):142-150.   
[3] Hirsh, B. J., Smilowitz, N. R., Rosenson, R. S., Fuster, V., and Sperling, L. S. (2015). 
Utilization of and adherence to guideline-recommended lipid-lowering therapy after acute 
coronary syndrome: opportunities for improvement. J. Am. Coll. Cardiol. 66, 184–192.  
[4]  Brandy R. Pauff, Michael R. Jiroutek, Melissa A. Holland, Beth S. Sutton, Statin Prescribing 
Patterns: An Analysis of Data From Patients With Diabetes in the National Hospital Ambulatory 
Medical Care Survey Outpatient Department and National Ambulatory Medical Care Survey 
Databases, 2005–2010, Clinical Therapeutics, Volume 37, Issue 6, 1 June 2015, Pages 1329-
1339, http://dx.doi.org/10.1016/j.clinthera.2015.03.020. 
[5] 2013 Prevention Guidelines ASCVD Risk Estimator. http://www.acc.org/tools-and-practice-
support/mobile-resources/features/2013-prevention-guidelines-ascvd-risk-estimator). Accessed 
June 30, 2016. 
[6] Stone  NJ, Robinson  JG, Lichtenstein  AH,  et al; American College of Cardiology/American 
Heart Association Task Force on Practice Guidelines.  2013 ACC/AHA guideline on the 
treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of 
the American College of Cardiology/American Heart Association Task Force on Practice 
Guidelines. Circulation. 2014;129(25)(suppl 2):S1-S45.  
[7] Patel MS, Volpp KG. Leveraging Insights from Behavioral Economics to Increase the Value 
of Health-Care Service Provision. Journal of General Internal Medicine. 2012;27(11):1544-
1547. doi:10.1007/s11606-012-2050-4.  
[8] Keller AP, Harlam B, Loewenstein G, Volpp KG. Enhanced active choice: A new method to 
motivate behavior change. J Consum Psychol. 2011;21:376–383.  
[9] Meeker D, Linder JA, Fox CR, et al. Effect of Behavioral Interventions on Inappropriate 
Antibiotic Prescribing Among Primary Care Practices: A Randomized Clinical Trial. JAMA. 
2016;315(6):562-70. 
5. Study design 
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5.1 Design 
This study will use a randomized, controlled trial to evaluate a health system initiative.  The 
electronic health record will be used to generate lists of patients who meet criteria for statin 
prescription using the 2013 ACC/AHA (American College of Cardiology / American Heart 
Association) guidelines. Primary care physicians at the University of Pennsylvania Health 
System will be randomly assigned to a control group with no intervention or one of two 
intervention groups as follows: 
--Intervention 1: Active choice-- 
Primary care physicians will be prompted by email to review an online form with a list of their 
patients who are eligible for statin therapy but have not been prescribed one.  Clinical 
information including the following will be presented for each patient (as available): age, history 
of atherosclerotic cardiovascular disease (ASCVD) or diabetes, recent test results including lipid 
profiles and liver function tests.  If appropriate information is available, the ASCVD risk score 
will calculated and displayed.  
Using the form, the physician will be able to select atorvastatin 20mg for all of the patients or 
can individually review information for each patient and select from the following options: 1) 
prescribe atorvastatin 20mg once daily; 2) prescribe atorvastatin at a different dose (10mg, 40mg 
or 80mg); 3) prescribe a different statin (choose from simvastatin, pravastatin, or rosuvastatin); 
4) do not prescribe at statin and select a reason (patient declined; patient allergy; other).  
The online form will be created using a HIPAA compliant website on secure University of 
Pennsylvania Health System servers.  The website will require the physician to sign in using 
their PennKey and password.  Once the form is submitted, a member of the study team will enter 
the orders in EPIC for the physician to review and sign.  The physician will receive notification 
that these orders have been entered and are ready to review.  A letter to the patient will be 
generated describing the physician’s review of their information, prescription of a statin, and the 
risks and benefits of taking a statin medication.   
--Intervention 2: Active choice and social comparisons— 
The procedure listed above in intervention 1 will be used.  In addition, physicians in this arm will 
receive social comparisons feedback on their statin prescribing behavior as follows:  Those 
below the median will be told the statin prescribing rate for the average (50th percentile).  Those 
above the median but below the top performers will only be told the prescribing rate of the top 
performers.  Those above the 90th percentile will be told they are a top performer. 
 
5.2 Study duration 
The study is expected to begin in February 2017 and take one year to complete. 
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5.3 Target population 
Patients followed by primary care physicians at the University of Pennsylvania Health System 
who using evidence-based guidelines are eligible to be prescribed a statin.  
 
5.4 Accrual 
Primary care physicians at the University of Pennsylvania Health System will be randomly 
assigned to one of the three arms. Based on an initial data review, we have made the following 
assumptions: baseline statin initiation rate is about 65%, median number of patients eligible but 
not on a statin per primary care physician is 38, intracluster correlation for statin prescribing is 
0.026.  Given these baseline, we estimate that a sample size of 84 primary care physicians (28 
per arm) will provide at least 90% power to detect a 10% difference between each intervention 
arm and the control arm, using a Bonferroni correction to define an alpha of .017 (three 
comparisons) as our threshold for statistical significance. 
 
5.5 Key inclusion criteria 
Patients must meet the following criteria to be eligible for the study:  
1) Have a primary care physician at the University of Pennsylvania Health System; 2) Meets 
American College of Cardiology / American Heart Association (ACC/AHA) guidelines for statin 
prescription as follows: a) Any form of atherosclerotic cardiovascular disease (ASCVD); b) 
LDL-C levels of 190 mg/dL or greater on their most recent lipid panel; c) Age 40 to 75 years 
with diabetes and LDL-C levels of 70-189 mg/dL on their most recent lipid panel; d) Age 40 to 
75 years with 10-year ASCVD risk of 7.5% or greater. 
 
5.6 Key exclusion criteria 
Patients will be excluded if any of the following criteria is met: 1) Allergy to statins; 2) Severe 
renal insufficiency defined as glomerular filtration rate (GFR) less than 30 mL/min; 3) Adverse 
reaction to statins including a) myopathy, ICD-10 G72.0 G72.9, ICD-9 3594 3599; b) 
Rhabdomyolysis, ICD-10 M62.82, ICD-9 72888; c) hepatitis, ICD-10 K716, ICD-9 5733 
Physicians (and their respective patients) will be excluded if they have less than 10 patients 
among their entire panel that are eligible for a statin medication. 
6. Subject recruitment 
Information on primary care physicians and their patients at the University of Pennsylvania 
Health system will be obtained from the electronic health record using Penn Data Store and 
Clarity, an EPIC reporting database.    
7. Subject compensation 
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No compensation will be offered in this study. 
8. Study procedures 
 
8.1 Consent 
A waiver of informed consent is requested.  This is a health system initiative that will be 
implemented.  The study is to evaluate that initiative.  Therefore, physicians and their patients 
will not be consented as this is the standard of practice per the health system initiative.  Without 
a waiver of the consent, the initiative would still be implemented by the health system, but the 
study would be infeasible.  There are several additional reasons why we feel a waiver of consent 
should be granted.  First, it is not feasible to consent every patient and physician and as 
mentioned this initiative would occur with or without the study of it.  Second, if members of the 
control group were consented, they would know they were being studied and this could change 
their behavior.  This could potential disrupt the design of the study and making interpretation of 
the findings challenging.  Third, physicians are not being forced to prescribe statins for their 
patients.  Instead, they are being reminded of evidence-based guidelines and offered an 
opportunity to review pertinent information and prescribe a statin.  This is no different than 
standard of care in which a physician would review the same information and decide to prescribe 
a statin or not.  The initiative is simply a reminder for the physician and makes their standard of 
care process easier to conduct.     
 
8.2 Procedures 
Data on primary care physicians and their patients at the University of Pennsylvania Health 
System will be obtained from Penn Data Store and Clarity (Epic’s data reporting database). 
Physician data includes demographic information (age, race, gender, type of medical degree, 
etc.) and may be also obtained from publicly available databases or websites online. Patient 
information includes demographic information, information about comorbid conditions 
(including diabetes, hypertension, and chronic kidney disease, and comorbid conditions needed 
to calculate the Charleston Comorbidity Index, laboratory test results (total cholesterol, 
triglycerides, LDL-C, HDL-C, liver function tests, creatinine, and glomerular filtration rate), and 
any contraindications to statin prescription (allergies or history of adverse reactions). 
After identifying eligible physicians and patients, block randomization will occur at the 
physician level using block sizes of three and stratifying by quartile of baseline statin prescribing 
rate.   
9. Analysis plan 
In the main analysis, we will perform unadjusted comparisons of the change in the percent of 
eligible patients that are prescribed a statin before and after the intervention by study group using 
chi-square tests.  To evaluate the robustness of the findings, a multivariate logistic regression 
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model will be fit adjusting for baseline statin prescription status as well as patient and physician 
factors.  Binary variables will be created for time (pre- and post-intervention), study arm (control 
or intervention), and statin prescription (no or yes).  The outcome of interest will be the 
interaction between the binary variables time, study arm, and statin prescription.   All hypothesis 
tests will be two-sided using an alpha of 0.017 as our threshold for statistical significance.  
Clustering will be conducted at the level of the physician.   
10. Investigators 
Mitesh Patel, MD, MBA, MS is the Principal Investigator (PI) and is an Assistant Professor of 
Medicine and Health Care Management at the Perelman School of Medicine and The Wharton 
School at the University of Pennsylvania.  He has past experience leading clinical trials to deploy 
interventions impacting patient care and outcomes.  He currently spends 80% of his effort on 
research and 20% on clinical and teaching activities. 
David Asch, MD, MBA is a co-investigator and is a Professor of Medicine and a Professor of 
Health Care Management at the Perelman School of Medicine and The Wharton School at the 
University of Pennsylvania and the Executive Director at the Center for Health Care Innovation 
at the University of Pennsylvania. He has extensive past experience conducting research, 
designing and leading clinical trials, and implementing new policies to improve patient care. 
 
11. Human research protection 
 
11.1 Data confidentiality 
Computer-based files will only be made available to personnel involved in the study through the 
use of access privileges and passwords. Wherever feasible, identifiers will be removed from 
study-related information. Precautions are already in place to ensure the data are secure by using 
passwords and HIPAA-compliant encryption. 
 
11.2 Subject confidentiality 
Data on physicians and patients will be obtained from Epic and Penn Data Store. Any 
information that is obtained will be used for research purposes only.  Information on patients will 
only be disclosed within the study team and to the patient’s primary care physician.  All study 
staff will be reminded of the confidential nature of the data collected and contained in these 
databases. 
The Leonard Davis Insitute’s Health Services Research Data Center (LDI HSRDC) will be the 
hub for the hardware and database infrastructure that will support the statistical analysis.  The 
LDI HSRDC is a secure computing environment for a large volume of highly sensitive data.  All 
members that access data must complete HIPAA training including secure data transfer, 
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passwords, computer security habits and knowledge of what constitutes misuse or inappropriate 
use of the server.  Only trained study staff will have access to the code that links the unique 
identifier to the subject’s identity. Electronic data will be stored on secure, password-protected 
firewalled servers at the University of Pennsylvania. 
 
11.3 Subject privacy 
All efforts will be made by study staff to ensure subject privacy.  Data will be evaluated in a de-
identified manner whenever possible. 
 
11.4 Data disclosure 
Information on patients will only be disclosed within the study team and to the patient’s primary 
care physician (to whom this information is already available).   
 
11.5 Data safety and monitoring 
The investigator will provide oversight for the study evaluation of this health system initiative.  
Physician practices will follow their standards of care to manage patients initiated on statins.  
11.6 Risk/benefit  
 
 
11.6.1 Potential study risks 
The potential risks associated with this study are minimal.  Breach of data is a potential risk that 
will be mitigated by using HIPAA compliant and secure data platforms for the intervention 
(Penn Medicine servers) and evaluation (LDI HSRDC server).    Statins do have known potential 
side effects, mostly commonly myopathy.  To reduce this risk, patients with document allergies 
or adverse events will be excluded from the initiative and study.  Patients with renal failure will 
also be excluded as they may require lower doses of statins than patients without renal failure.  
Prescribing statins and monitoring for known side effects are otherwise standard of care within 
primary care practices.    
 
 
11.6.2 Potential study benefits 
Statins have been demonstrated as an effective tool for reducing cardiovascular events. Early 
intervention with statins can potentially be life saving for patients who are at risk or already have 
a diagnosis of cardiovascular disease.  An intervention that prompts physicians to actively think 
about evidence-based guidelines and high-value treatment could contribute positively to patient 
care and outcomes. However, it is possible that patients will receive no benefit from this study. 
 
 
11.6.3 Risk/benefit assessment 
The risk/benefit ratio is highly favorable given the potential benefit from eligible patients being 
prescribed a statin, that prescription and monitoring of a statin is within the standards of care in a 
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primary care practice, and that efforts have been put into place to minimize the risk of breach of 
data. 
 
 
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