Assessment of Prospective CYP2C19 Genotype Guided Dosing of Anti-Platelet Therapy in Percutaneous Coronary Intervention (ADAPT)
Phase: NA
Conditions: Acute Coronary Syndrome, Cardiovascular Diseases
Sponsor: University of Pennsylvania

 
Clinical Protocol  
 
 
 
STUDY TITLE: 
Assessment of prospective CYP2C19 genotype guided Dosing of Anti-Platelet 
Therapy in Percutaneous Coronary Intervention (ADAPT) 
 
 
Principal Investigator: Sony Tuteja, PharmD, MS1  
Co-PI:  
 
Jay Giri, MD2,3 
 
Co-Investigators:        Henry Glick4 
William Matthai, MD 2,5 
Gene Chang, MD2,5 
Daniel J. Rader, MD 1 
 
 
 
 
 
Department of Medicine 
 
1Division of Translational Medicine and Human Genetics 
2 Cardiovascular Medicine Division 
4 Department of Epidemiology and Biostatistics 
Perelman School of Medicine at the University of Pennsylvania 
 
3Hospital of the University of Pennsylvania 
5Penn Presbyterian Medical Center 
 
Philadelphia, PA 
 
 
 
 
Date: 
June 1, 2017 
 
Version: 
3.0 
 
Sponsor: 
UPHS, Precision Medicine 
 
1 

TABLE OF CONTENTS 
 
 
 
 
 
 
 
PAGE NO. 
 
List of Abbreviations & Definitions 
 
 
 
 
 
 
 
3 
 
Synopsis 
 
 
 
 
 
 
 
 
 
 
4 
1.0 Ethics 
 
 
 
 
 
 
 
 
 
 
6 
2.0 Introduction 
 
 
 
 
 
 
 
 
 
6 
3.0 Objectives  
 
 
 
 
 
 
 
 
 
7 
4.0 Study Design 
 
 
 
 
 
 
 
 
 
7 
      4.1 Primary endpoint 
 
 
 
 
 
 
 
 
8 
      4.2 Secondary endpoints  
 
 
 
 
 
 
 
8 
      4.3 Tertiary endpoints 
 
 
 
 
 
 
 
 
8 
5.0 Study Population  
 
 
 
 
 
 
 
 
9 
     5.1 Inclusion criteria 
 
 
 
 
 
 
 
 
9 
      5.2 Exclusion criteria 
 
 
 
 
 
 
 
 
9 
 
 
6.0 Study Procedures  
 
 
 
 
 
 
 
 
10 
      6.1 Informed Consent 
 
 
 
 
 
 
 
 
10 
      6.2 Genotyping  
 
 
 
 
 
 
 
 
 
10 
      6.3 Clinical Data Collection 
 
 
 
 
 
 
 
10 
      6.4 Heath-related quality of life (HrQoL)  
 
 
 
 
 
10 
      6.5 Patient attitudes towards pharmacogenetic testing  
 
 
 
10 
      6.6 Provider attitudes towards pharmacogenetic testing 
 
 
 
10 
      6.7 Collection of saliva for future genetic tests  
 
 
 
 
10 
7.0  Statistical Analysis 
 
 
 
 
 
 
 
 
11 
 
7.1 Primary Endpoints 
 
 
 
 
 
 
 
11 
 
7.2 Secondary Endpoints 
 
 
 
 
 
 
 
11 
 
7.3 Tertiary Endpoints 
 
 
 
 
 
 
 
12 
 
7.4 Post-hoc analyses 
 
 
 
 
 
 
 
12 
7.5 Sample Size for primary outcome 
 
 
 
 
 
12 
 
7.5 Sample size for economic evaluation 
 
 
 
 
 
12 
8.0 Data Management 
 
 
 
 
 
 
 
 
13 
9.0 Subject Privacy/Protected Health Information 
 
 
 
 
 
13 
10.0  Risk/Benefit Assessment 
 
 
 
 
 
 
 
14 
       10.1 Potential Study Risks 
 
 
 
 
 
 
 
14 
       10.2 Potential Study Benefits                                                                                      14 
       10.3 Alternatives to Participation 
 
 
 
 
 
 
14 
       10.4 Data and Safety Monitoring 
 
 
 
 
 
 
14 
11.0 References 
 
 
 
 
 
 
 
 
 
15 
Appendices 
A. Treatment Recommendations handout for physicians  
 
 
 
16 
B. Patient survey on pharmacogenetic testing  
 
 
 
 
17 
C. Provider survey on pharmacogenetic testing  
 
 
 
 
23 
 
2 

LIST OF ABBREVIATIONS & DEFINITIONS 
 
 
CYP2C19 
 
cytochrome P450 2C19 
GCP   
 
Good Clinical Practice  
HUP 
 
 
Hospital of the University of Pennsylvania 
HrQOL  
 
health related quality of life 
ICER  
 
Incremental cost effectiveness ratio  
ICH  
 
 
International Conference on Harmonization 
LOF 
 
 
loss of function 
PCI 
 
 
percutaneous coronary intervention 
PGx 
 
 
pharmacogenetics 
PPMC  
 
Penn Presbyterian Medical Center 
PHI 
 
 
Protected health information 
QALYs  
 
Quality adjust life years 
TIA 
 
 
Transient ischemic attack 
 
3 

SYNOPSIS 
Title 
Assessment of prospective CYP2C19 genotype guided Dosing of Anti-
Platelet Therapy in Percutaneous Coronary Intervention (ADAPT) 
Objectives 
• 
To determine the effect of CYP2C19 genotyping on the prescribing of 
antiplatelet therapies following PCI 
• 
To identify factors linked with successful implementation of clinical 
pharmacogenetic (PGx) testing in a large academic medical center. 
• 
To determine the rates of clinical outcomes.  
• 
To conduct a prospective pilot study to determine means and 
variances for cost, quality adjusted life years (QALYs), and the 
correlation of cost and effect. 
Study Design 
The study utilizes a novel genotyping device, SpartanRx™ (Spartan 
Bioscience, Ottawa, Canada) that provides identification of a patient’s 
CYP2C19 *2, *3, and *17 genotypes determined from genomic DNA from a 
buccal swab sample with 1 hour turnaround time. 
 
PCI Patient Study 
This is a randomized, prospective, pragmatic open label study.  Patients 
undergoing percutaneous intervention (PCI) with stent implantation, who 
require anti-platelet therapy, will be randomized either to: Arm 1) genotype 
guided dosing of antiplatelet therapy or Arm 2) usual care.  
 
In Arm 1, a buccal swab will be obtained from subjects immediately following 
PCI/stent, to determine CYP2C19 genotype with the SpartanRx system.  
Subject with slow metabolizer status [1 or 2 loss-of-function (LOF) mutations 
(*2 or *3) in CYP2C19] will be recommended to initiate therapy with prasugrel 
or ticagrelor in place of clopidogrel. Subjects with normal metabolizer status 
(homozygous for the *1 allele in CYP2C19) will be recommended to initiate 
therapy with clopidogrel. Antiplatelet choice is ultimately decided by physician 
judgment incorporating all clinical factors. 
 
In Arm 2, choice of antiplatelet therapy will be decided by treating physician 
as per usual care. DNA will be collected via a saliva sample to assess 
CYP2C19 genotype at the conclusion of the study. 
 
Subjects in both groups will complete a baseline health related quality of life 
questionnaire (HrQoL) and additional clinical data pertaining to cardiac history 
will be collected from medical records.  Subjects will be contacted every three 
months for medical services utilization, clinical information, and HrQoL 
assessments for a total of one year. Medical records will be reviewed for 
clinical outcomes until May 31, 2017. 
Study Duration 
 3 years 
Study Centers  
Hospital of the University of Pennsylvania (HUP) 
Penn Presbyterian Medical Center (PPMC) 
Primary Objective 
To determine the effect of CYP2C19 genotyping on the prescribing of 
antiplatelet therapies following PCI. 
Secondary and 
Tertiary Objectives 
1. To determine physician adherence to genotype guided recommendations. 
2. To determine clinical outcomes (myocardial infarction, stroke, stent 
thrombosis, revascularization, death and bleeding) 
3. To determine means and variances needed for economic evaluation 
 
4 

including cost, QALYs, and the correlation between cost and effect. 
4. To estimate the incremental cost per quality-adjusted life year (QALY) 
ratio 
5. Assess patient and prescriber attitudes towards PGx testing. 
Number of subjects 
 500-600 
Inclusion criteria 
1. Male and female subjects, ≥18 to ≤80 years at time of study 
2. Status post PCI with stent implantation requiring antiplatelet therapy 
3. Willingness to comply with all study-related procedures 
Exclusion criteria 
1. Pending imminent surgery placing patients at increased risk for bleeding 
with prasugrel or ticagrelor. 
2. History of intracranial hemorrhage, transient ischemic attack (TIA), stroke 
3. Active bleeding 
4. Need for long-term anticoagulation (i.e. warfarin, dabigatran, rivaroxaban, 
apixaban, edoxaban, or lovenox). 
5. Current or prior (within the past four weeks) treatment with voraxapar 
(Zontivity).  
6. Severe renal or hepatic impairment 
7. Treating physician does not want subject to participate 
Statistical 
methodology 
For the primary outcome the number (proportion) of participants receiving 
prasugrel/ticagrelor in each randomized arm will be determined. The 
adherence rate will be determined as the number of participants in genotyped 
arm with LOF variants that received prasugrel or ticagrelor + the number of 
participants without these variants that received clopidogrel divided by the 
total number. For categorical variables, frequencies and percentages will be 
presented. For continuous variables, the number of subjects, mean, standard 
deviation, minimum, 25th percentile, median, 75th percentile and maximum 
will be presented. Reported differences will include standard errors and 95% 
CI. Analyses will be based on the modified intention to treat. 
 
 
 
 
 
5 

1.0  ETHICS 
 
The study will be conducted in accordance with the site’s clinical research standards that meet 
regulations relating to Good Clinical Practice (GCP).  These standards adhere to the following 
guidelines: 
• 
Good Clinical Practice:  ICH Consolidated Guideline (International Conference on Harmonization of 
Technical Requirements for the Registration of Pharmaceuticals for Human Use, May 1997). 
• 
United States (US) Code of Federal Regulations (21 CFR) dealing with human subject protection 
and conduct of investigational clinical studies (21 CFR parts 50, 54, 56, 312, and 314). 
• 
Declaration of Helsinki, concerning medical research in humans (“Recommendations Guiding 
Physicians in Biomedical Research Involving Human Subjects,” Helsinki 1964, amend Tokyo 1975, 
Venice 1983, Hong Kong 1989 and revised version of Somerset West, Republic of South Africa, 
October, 1996). 
 
2.0 INTRODUCTION 
 
Clopidogrel is a thienopyridine antiplatelet agent, which inhibits the purinergic P2Y12 receptor on 
platelets and prevents their aggregation.  It is commonly used in patients with acute coronary 
syndromes (ACS) undergoing percutaneous coronary intervention (PCI).  CYP2C19 is one of the 
principal enzymes involved in the bioactivation of clopidogrel from the pro-drug to its active metabolite.  
The most common loss of function (LOF) allele is *2 (c.681G>A; rs4244285), with frequencies of ~15% 
in Caucasians and Africans and 29-35% in Asians.  A large meta-analysis performed by Mega and 
colleagues demonstrated that CYP2C19*2 carriers treated with clopidogrel have a higher risk for major 
adverse cardiac events compared to noncarriers (hazard ratio (HR) of 1.55, 95%CI 1.11-2.17 for 
heterozygotes; HR 1.76, 95% CI 1.24-2.50) and higher risk of stent thrombosis (HR 2.67, 95% CI 1.69-
4.22 for heterozygotes; HR 3.97, 95% CI 1.75-9.02 for homozygotes.)1  Therefore, clopidogrel is less 
effective in patients who are CYP2C19 poor metabolizers and alternative therapy is recommended.2 
 
A newer-generation thienopyridine, prasugrel, was found to be associated with a reduction in major 
adverse cardiac events (death, myocardial infarction, stroke) compared to clopidogrel, but with an 
increased risk of fatal and major bleeding events.3   
 
While a body of observational literature1 and clinical guidelines4 suggest prescribing alternative 
antiplatelet therapy in carriers of CYP2C19 LOF alleles, it is unknown whether physicians will follow 
genotype guided recommendations when pharmacogenetic (PGx) results are presented to them in a 
real world setting. To provide evidence regarding the implementation and effectiveness of PGx testing 
following PCI, we will examine the differences in prescribing of antiplatelet drugs when presented with 
genotype data. We will also evaluate physician’s adherence to the genotype guided antiplatelet 
recommendations.  
 
Now that clopidogrel is available in generic form, pharmacogenetic (PGx) screening could allow for 
individualized anti-platelet therapy in which patients with functional CYP2C19 alleles could be 
prescribed clopidogrel, and the more expensive agent would be reserved for patients with poor 
metabolizer status. A cost-effectiveness analysis of CYP2C19 screening for selection of antiplatelet 
therapy found that genotype-guided therapy would lead to more cost-effective care rather than uniform 
usage of either clopidogrel or prasugrel.5  Genotyping produced 450 fewer cardiovascular events 
compared with treating all patients with clopidogrel.  The number needed to genotype (NNG) was 23, 
i.e. one excess cardiovascular event was avoided for every 23 patients genotyped when compared to a 
clopidogrel-for-all strategy.  The NNG was 30 when comparing genotype guided therapy to prasugrel-
 
6 

for- all.  Cost-savings were not evident when genotype-guided therapy was compared to generic 
clopidogrel for all patients.  The analysis did not examine quality measures that are important in 
assessing patient outcomes.   
 
A more recent economic evaluation determined that genotyping and prescribing ticagrelor to LOF allele 
carriers was the most effective strategy when compared against routine clopidogrel or prasugrel use as 
well as genotyping and prescribing prasugrel to LOF carriers.6 However, these results were based on 
decision model of a hypothetical cohort of patients with ACS who underwent PCI and several 
assumptions were made regarding outcomes, cost and quality of life.  True costs associated with 
genotype guided antiplatelet therapy are unknown.  Future prospective studies evaluating the cost 
effectiveness of a genotype guided approach are needed.  We are proposing a pilot study which will 
provide information necessary for planning a prospective study that will directly estimate events 
averted, costs, QALYs and cost per QALY ratios. Information to be obtained in this pilot includes 
estimates of costs and their variance, preference scores (for calculating QALYs) and their variance, the 
correlation of cost and effects (required for sample size estimation for cost-effectiveness ratios), event 
rates, and implementation metrics (to estimate likely penetration of testing in the trial). The results from 
this study will provide more accurate estimates of the means and variances of cost and QALYs required 
to plan future trials.  We will also examine the cost-effectiveness of genotyping for CYP2C19 in daily 
clinical practice.      
 
3.0 OBJECTIVES 
• 
To determine the effect of CYP2C19 genotyping on the prescribing patterns of antiplatelet 
therapies following cardiac catheterization. 
• 
To determine the rates of clinical outcomes. 
• 
To identify factors linked with successful implementation of clinical pharmacogenetic (PGx) 
testing in a large academic medical center. 
• 
To conduct a prospective pilot study to determine means and variances for cost, quality-adjust 
life years (QALYs), and the correlation of cost and effect.  
• 
Assess patient and prescriber attitudes towards PGx testing. 
 
4.0 STUDY DESIGN 
 
This is a randomized, prospective, pragmatic open label pilot study (Figure 1).  Patients undergoing PCI 
with stent implantation, who require anti-platelet therapy, will be randomized to: Arm 1) genotype 
guided dosing of antiplatelet therapy or Arm 2) usual care. Randomization will be stratified by the 
occurrence of acute coronary syndrome (ACS). 
 
In Arm 1, a buccal swab will be obtained from subjects immediately following PCI/stent, to determine 
CYP2C19 genotype with the SpartanRx system.  This arm provides pharmacogenetic information to 
help guide decision making: initiation of therapy with prasugrel or ticagrelor will be recommended for 
participants found to be slow metabolizers [1 or 2 loss-of-function (LOF) mutations (*2 or *3) in 
CYP2C19]; initiation of therapy with clopidogrel will be recommended for participants found to be 
normal metabolizers (CYP2C19 *1/*1). See Table 1 and Appendix A. Antiplatelet choice will ultimately 
be decided by the treating physician taking into account all clinical factors. 
 
In Arm 2, the choice of antiplatelet therapy will be decided by the treating physician as per usual care. 
DNA will be collected by –saliva sample and CYP2C19 genotype will be determined at the completion 
of the study.  
 
 
7 

Subjects in both groups will complete baseline health related quality of life questionnaire (HrQoL).  
Subjects will be contacted every three months for clinical information, medical service utilization and 
HrQoL assessments. No specific recommendations will be made regarding use of vorapaxar, a recently 
approved anti-platelet agent for which guideline-based recommendations regarding genotyping are not 
available. 
 
 
4.1 Primary endpoint 
• 
Number of participants receiving prasugrel/ticagrelor in each arm. 
 
4.2 Secondary endpoints 
1. Implementation 
a. Adherence to suggested treatment recommendations based on genotype 
b. Reasons for non-adherence to recommendations Medical service utilization 
2. Clinical Outcomes 
a. Major adverse cardiac event (CV related death, MI, stroke, urgent need for 
revascularization, stent thrombosis, all deaths). 
b. Bleeding complications (defined by the Bleeding Academic Research Consortium).7 
c. Clinical outcomes will be ascertained by medical records until May 31, 2017. 
3. Economic- Incremental cost effectiveness ratio per quality adjusted life-year (ICER/QALYs).  
a. Medical services utilization 
b. Cost of services 
c. Preference score (SF-12 questionnaire) performed at baseline and every 3 months for 
one year for determination of QALYs. 
 
4.3 Tertiary Endpoints 
a. Additional implementation metrics 
a. Number of genotype results returned 
b. Average genotype test completion time 
c. Genotype assay failure rate (inconclusive test result) 
d. Number/reason for screening failure 
e. Time from test order to result in medical record 
b. Patient attitudes towards PGx testing as determined by questionnaire will be completed at the 3 
month phone follow-up. 
c. Prescriber attitudes towards PGx testing as determined by questionnaire that will be 
administered at the start and end of the study. 
 
8 

Table 1. Treatment recommendations for antiplatelet therapy based on CYP2C19 genotype4 
Genotype 
Phenotype 
Description 
Treatmenta 
CYP2C19 *1/*1 
Extensive 
metabolizer 
(normal) 
Two inferred normal alleles 
Clopidogrel 75 mg per 
day 
 
CYP2C19 *1/*17 
 
Ultra-rapid 
metabolizer 
 
One inferred normal allele 
One increased function 
allele 
CYP2C19 *17/*17 
Two gain of function alleles 
CYP2C19 *1/ *2 
 
Intermediate 
metabolizer 
One inferred normal allele 
One loss of function allele 
Prasugrel (Effient) 10 
mg per dayb 
 
Or 
 
Ticagrelor (Brilinta) 90 
mg twice dailyc 
CYP2C19 *1/*3 
 
One inferred normal allele 
One loss of function allele 
CYP2C19 *2/*17 
 
One loss of function allele 
One gain of function allele 
CYP2C19 *3/*17 
One loss of function allele 
One gain of function allele 
CYP2C19 *2/*2 
 
Poor metabolizer 
Two loss of function alleles 
Prasugrel (Effient) 10 
mg per dayb 
 
Or 
 
Ticagrelor (Brilinta) 90 
mg twice dailyc 
CYP2C19 *3/*3 
 
Two loss of function alleles 
CYP2C19 *2/*3 
Two loss of function alleles 
a Please consider all clinical contraindications before prescribing alternative antiplatelet agent.   
  Prasugrel and ticagrelor are recommended only when not clinically contraindicated.  
 
b Consider prasugrel 5 mg per day for patients <60 kg.  
  Individual risks/benefits of prasugrel must be carefully considered in patients over age 75. 
   Do not use prasugrel in patients with active bleeding or a history of transient ischemic attack or stroke. 
   Do not start prasugrel in patients likely to undergo urgent coronary bypass graft surgery (CABG). 
 
c Do not use ticagrelor in patients with active bleeding or a history of transient ischemic attack or stroke. 
  Do not start ticagrelor in patients likely to undergo urgent coronary bypass graft surgery (CABG). 
  Do not use maintenance aspirin does above 100 mg in combination with ticagrelor. 
 
5.0 STUDY POPULATION 
All patients undergoing PCI with stent implantation at HUP or PPMC who will require clopidogrel, 
prasugrel or ticagrelor treatment will be considered for this protocol.  
 
5.1 Inclusion Criteria 
1. Male and female subjects, ≥18 to ≤80 years at time of study 
2. Status post PCI with stent implantation requiring antiplatelet therapy 
3. Willingness to comply with all study-related procedures 
 
5.2 Exclusion criteria: 
1. Pending imminent surgery placing patients at increased risk for bleeding with prasugrel or 
ticagrelor. 
2. History of intracranial hemorrhage, TIA, and stroke 
3. Active bleeding 
 
9 

4. Need for long-term anticoagulation (i.e. warfarin, dabigatran, rivaroxaban, apixaban, edoxaban, or 
lovenox). 
5. Current or prior (within the past four weeks) treatment with voraxapar (Zontivity).  
6. Severe renal or hepatic impairment 
7. Treating physician does not want subject to participate 
 
 6.0 STUDY PROCEDURES  
 
6.1 Informed Consent 
Subjects will be approached for enrollment 2 hours following their PCI/stent implantation in the holding 
area or their inpatient hospital bed by the research coordinator.   
 
6.2 Genotyping  
If randomized to Arm 1 (genotyping arm), the research coordinator will obtain a buccal swab for the 
PGx test on the Spartan Rx system.  If randomized to Arm 2 (control group), a saliva sample will be 
obtained with the Oragene-DNA 500 kit (DNA Genotek, Ottawa, Canada) and the genotyping will be 
performed at the completion of the study. For Arm 2, DNA will be extracted from saliva using the 
QIAamp DNA mini kit (Qiagen, Valencia, CA). Samples will be genotyped using the Infinium Global 
Screening Array (Illumina, SanDiego, CA), a genome-wide genotyping array that also contains 
pharmacogenetic variants. Genotyping will be performed on Illumina’s iScan System at the Center for 
Advanced Genomics at the Children’s Hospital of Philadelphia. The CYP2C19 SNPs of interest *2 
(rs4244285), *3 (rs4986893) and *17 (rs12248560) will be extracted from the array data. 
 
6.3 Clinical data collection  
Subjects in both arms will have baseline clinical data collected from medical records and will be 
telephoned every 3 months for clinical endpoint collection and medical service utilization. Medical 
records will be reviewed for the occurrence of major cardiac events (CV- related death, myocardial 
infarction, stroke, urgent need for revascularization, and stent thrombosis), bleeding events and death 
until May 31, 2017. 
 
6.4 Heath-related quality of life (HrQoL) 
Subjects in both arms will complete a baseline SF-12 and 4 additional questionnaires by phone or on 
paper and returned by mail (every 3 months). 
 
6.5 Patient attitudes towards pharmacogenetic testing 
Patients will complete a paper survey at 3 months to assess their understanding and attitudes towards 
pharmacogenetic testing (Appendix B). 
 
6.6 Provider attitudes towards pharmacogenetic testing 
Treating physicians participating in the study will complete a survey at baseline and 1 year to assess 
their attitudes towards pharmacogenetic testing and needs for medical education in this area (Appendix 
C). 
 
6.7 Collection of saliva for future genetic tests 
An optional component of the study will be saliva collection for DNA biobanking.  If the subject provides 
consent for this component, a saliva sample will be collected with the Oragene-DNA 500 kit (DNA 
Genotek.  This is the same sample we are collecting in 6.2 above for the control group and not a 
separate sample.  To avoid confusion for subjects and study personnel, a saliva sample will be 
collected for all participants and the purpose will be labeled (e.g. for CYP2C19 genotyping only OR for 
biobanking and CYP2C19 genotyping). 
 
 
10 

7.0 STATISTICAL ANALYSIS 
Data collected in this study will be reported using summary tables and results will be displayed for each 
treatment arm. For categorical variables, frequencies and percentages will be presented. For 
continuous variables, the number of subjects, mean, standard deviation, minimum, 25th percentile, 
median, 75th percentile and maximum will be presented. Reported differences will include standard 
errors and 95% CI. Analyses will be based on the intention to treat. Continuous variables will be 
compared using Student’s t-test. Categorical variables will be compared using the chi-square test or 
Fisher’s exact test when appropriate.   
 
7.1 Primary endpoints 
1.  We will tabulate the number and proportion of prasugrel/ticagrelor in each Arm.  We will 
compare discharge antiplatelet therapy choice between the genotype and control arm using 
the chi-square or Fisher’s exact test. The probability of receipt of antiplatelet agents will be 
determined by logistic regression. 
 
7.2 Secondary endpoints 
1. Implementation.  
a. We will estimate adherence to suggested treatment recommendations based on results 
of the CYP2C19 genetic test. The adherence rate is defined as the number of 
participants in Arm 1 with LOF variants that received prasugrel or ticagrelor + the 
number of participants without these variants that received clopidogrel divided by the 
total number in Arm 1. 
b. We will tabulate reasons for non-adherence to recommendations. 
2. Clinical outcomes.  
a. Frequencies of CV related death, MI, stroke urgent, need for revascularization and 
stent thrombosis will be reported as will frequencies of bleeding complications. We will 
determine time to first major cardiac event as a composite endpoint (CV related death, 
MI, stroke urgent need for revascularization and stent thrombosis). The incidence of 
first MACE and first major bleeding events between the groups will be compared by 
use of Kapan-Meier estimators and statistical tests will be evaluated based on log-rank 
tests.  
b. To determine whether MACE outcomes differ in participants with ACS, an interaction 
term between ACS and group assignment will be tested in a Cox proportional hazard 
model. 
3. Medical service utilization. We will develop descriptive statistics for use of antiplatelet drugs, 
use of other cardiovascular medications, number of hospitalizations, number of physician 
visits, and use of rehabilitation services 
4. Direct medical cost. We will also develop descriptive statistics for total cost, CYP2C19 genetic 
testing cost, medication cost, hospitalization cost, physician visit cost, and rehabilitation cost. 
5. Preference scores / QALYs. We will develop descriptive statistics for the SF-12 physical and 
mental scale scores, the SF-6D, a preference-based health-related quality of life score that can 
be derived from the SF-12,8 and for QALYs, a composite measure of its quality (based on the 
SF-6D). We will also report the correlation between the difference in cost and difference in 
QALYs (this correlation will be used in sample size estimation for the full study that this pilot 
study is designed to support). 
6. Incremental cost-effectiveness ratio. Based on the differences in primary outcomes total cost 
and QALYs, we will calculate the ratio incremental costs divided by incremental QALYs, the 
95% CI for this ratio, and the cost-effectiveness acceptability curve. 
 
 
 
 
11 

7.3 Tertiary endpoints 
We will also tabulate the number of genotype results returned, the average genotype test completion 
time, the genotype assay failure rate, the number of and reason for screening failure, time from test 
order to result in medical record, and patient/prescriber attitudes towards PGx test results. 
 
7.4 Post-hoc analyses 
Genotyped will be determined in the control group at the end of the trial. We will combine the groups 
and evaluate outcomes by CYP2C19 genotype and antiplatelet drugs prescribed at discharge. 
Participants will be grouped into the following categories: 1) Carriers of normal function alleles receiving 
any antiplatelet drug, 2) LOF carriers receiving clopidogrel, or 3) LOF carriers receiving prasugrel or 
ticagrelor. Time to MACE, major bleeding and a composite safety/efficacy endpoint consisting of 
MACE, major bleeding and non-cardiac mortality will be determined in the three groups.  Cox 
proportional hazards models will be used to assess the effects of having an LOF allele and receiving 
clopidogrel therapy, having an LOF allele and receiving alternative therapy, and not having an LOF 
allele on the occurrence of first MACE, first major bleed, and first composite outcome. The Cox model 
will be controlled for age at entry to the study, the date of catheterization, gender, race, hospital site, 
and history of ACS, smoking, hypertension, diabetes, and myocardial infarction. 
 
7.5 Sample size for Primary Outcome 
The sample size calculation is based on two factors: 1) the rate of pre-study prasugrel/ticagrelor 
antiplatelet therapy prescribing (20%) and 2) anticipated increase in alternative antiplatelet prescribing 
based on the frequency CYP2C19 LOF variants (~30-35%). We estimate a 15% difference in the use of 
prasugrel/ticagrelor prescriptions in the two groups (35% in the genotype group and 20% in the control 
group). A sample size of 138 per group (a total of 276) would provide 80% power at an alpha level of 
0.05 to detect this difference. We will increase our sample size to ~250 per group to allow for subgroup 
comparisons (e.g. ACS vs. stable coronary disease). 
 
7.6 Sample Size for Economic Evaluation  
While there is little published guidance on sample size determination for pilot studies9, 10, we present 
confidence intervals that will result for expected population means and standard deviations and a 
sample size of 350 per treatment arm (see Table 2). Knowing the expected mean and standard 
deviation of hospital cost will be important when designing the more definitive study of the cost-
effectiveness of genotype guided dosing of anti-platelet therapy. 
 
Given that hospital cost distributions typically have long heavy right tails11, we assume that these costs 
are distributed log normally. There are limited data on the expected cost and expected standard 
deviation for a year of hospital costs after initiation of antiplatelet therapy. We have derived our 
“baseline” assumptions (mean = $7800; SD = $9355) from Nikolic et al., a European study that may or 
may not be representative of costs in the U.S. 
 
Simulation indicates that for a sample size of 350 per group (total N = 700) if the population mean is 
7800 and the average standard deviation for repeated draws of participants is 9355, then if we 
repeated the pilot study 1000 times, in 95% of them the observed mean would range between 6851 
and 8775 and the observed standard deviation would range between 6875 and 13138 (see row 2 of 
Table 2). Rows 1 and 3 of the table indicate that if we are incorrect that the average standard deviation 
from repeated draws is 9355, the expected standard deviations in 95% of repeated experiments would 
range between 4942 and 7499 if average standard deviation for repeated draws of were 6000. It would 
range between 7853 and 19423 if the average standard deviation were 12,000. 
 
Rows 4-6 report sensitivity analyses for cases in which we assume the population mean is 10,000; 
rows 7-9 report these analyses for cases in which we assume the population mean is 15,000. In the 
 
12 

most extreme case (population mean 15,000, average SD from repeated draws of 18000), in 95% of 
repeated experiments the mean would fall in the range between 13,345 and 17,044 and the standard 
deviation would fall in the range between 13,240 and 25,658. 
 
Substitution of the more realistic assumption of log normality for the less realistic assumption of 
normality increased the magnitude of the average range of the standard deviation by more than 300%. 
Assuming log normality, but substitution of a sample size of 175 per group (total N=350) for the 
proposed 350 per group would lead to an average increase in the magnitude of the ranges of 32%. 
 
Table 2. Expected 95% Confidence Intervals for Sample Means and Sample Standard Deviations 
for Hospital Cost in Dollars Given Varying Population Means and Standard Deviations, N = 350 
per Treatment Group* 
 
Population 
Mean 
95% Confidence 
Interval for Mean 
Population 
Standard Deviation 
95% Confidence 
Interval for Standard 
Deviation 
1. 7800 
7248 to 8471 
6000 
4942 to  7499 
2. 7800 
6851 to 8775 
9355 
6875 to 13138 
3. 7800 
6633 to 9125 
12,000 
7853 to 19,423 
4. 10,000 
9300 to 10,774 
7000 
5771 to  8478 
5. 10,000 
9021 to 11,164 
10,000 
7732 to 13,529 
6. 10,000 
8715 to 11,393 
13,000 
9252 to 18,413 
7. 15,000 
13,771 to 16,249 
12,000 
9641 to  5203 
8. 15,000 
13,510 to 16,778 
15,000 
11,550 to 19,889 
9. 15,000 
13,345 to 17,044 
18,000 
13,240 to 25,638 
 
* Costs assumed to be log normally distributed. Estimates derived from simulation. 
 
8.0 DATA MANAGEMENT 
We will create a shared database with common data definitions.  This database will be programmed in 
REDCap (Research Electronic Data Capture).  REDCap is a secure, web-based application with the 
capacity for direct export to Excel and common statistical packages (SPSS, SAS, Strata, R).  REDCap 
has electronic CRFs, real-time data entry validation, audit trails, user authentication, data logging and 
encryption.  It is HIPAA compliant with mechanisms in place to ensure confidentiality. 
 
Specific forms will be used for each component of the subject’s progress.  The forms and data 
dictionary will be available online for all individuals who perform data entry.  Research personnel, 
trained on data definitions, will enter data via web-based data forms after abstraction from the primary 
medical record and source documents.  The multisite feature of REDCap will be used to restrict data 
viewing by investigators.  REDCap allows double-data entry on some or all of the data elements. We 
will apply this feature to predefined “key” variables.  In addition, logical data checks will be used to 
assess data quality for mis-entry.  Suspect data entries will be flagged for re-review and confirmation by 
the investigative team at each site.  When data are complete and all suspect entries addressed for a 
time period, the database will be “locked” for analysis.  Analysis will use only this final locked version. 
 
9.0 SUBJECT PRIVACY / PROTECTED HEALTH INFORMATION 
Protected health information (PHI) collected on the case report forms and via the electronic medical 
records will be stored in an encrypted research database. Only designated research staff will have 
access to the research database unless otherwise requested to the IRB by the Principal Investigator. 
 
 
 
13 

10.0 RISK/BENEFIT ASSESSMENT 
 
10.1 Potential Study Risks 
The primary risk is the loss of privacy and breach of confidentiality.  There will be ongoing assessment 
of the security of the data systems to ensure that subject’s PHI is protected.  
 
10.2 Potential Benefits 
The potential benefit to study subjects is having their antiplatelet medication selected based on 
genotype.  This may result in improved clinical outcomes.  The potential benefits to the health system 
include: improved clinical outcomes for subjects and decreased cost in care.  Our ultimate goal is to 
translate our molecular work into clinical practice. In particular, we believe that genotype in part predicts 
clinical outcome, and that identification of the genetic factors will assist in clinical management in the 
future. 
 
10.3 Alternatives to Participation 
The patient has the option to not participate and not sign the informed consent. If a patient declines to 
participate, there is no effect on the patient’s regular, ongoing clinical care. 
 
10.4 Data and Safety Monitoring 
The Principal Investigator and Co-Investigators will be ultimately responsible for assuring the security of 
all computer systems to minimize risk to participants. Safety data such as major bleeding events and 
major cardiovascular events will be assessed six months after enrollment begins. 
 
 
 
 
14 

References 
 
 
1. 
Mega, J.L. et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes 
among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA  304, 
1821-30 (2010). 
2. 
Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium guidelines for 
cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther  
90, 328-32 (2011). 
3. 
Wiviott, S.D. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N 
Engl J Med  357, 2001-15 (2007). 
4. 
Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for 
CYP2C19 Genotype and Clopidogrel Therapy: 2013 Update. Clin Pharmacol Ther  94, 317-23 
(2013). 
5. 
Reese, E.S., Daniel Mullins, C., Beitelshees, A.L. & Onukwugha, E. Cost-effectiveness of 
cytochrome P450 2C19 genotype screening for selection of antiplatelet therapy with clopidogrel 
or prasugrel. Pharmacotherapy  32, 323-32 (2012). 
6. 
Kazi, D.S. et al. Cost-effectiveness of genotype-guided and dual antiplatelet therapies in acute 
coronary syndrome. Ann Intern Med  160, 221-32 (2014). 
7. 
Mehran, R. et al. Standardized Bleeding Definitions for Cardiovascular Clinical Trials: A 
Consensus Report From the Bleeding Academic Research Consortium. Circulation  123, 2736-
47 (2011). 
8. 
Brazier, J.E. & Roberts, J. The estimation of a preference-based measure of health from the SF-
12. Med Care  42, 851-9 (2004). 
9. 
Hertzog, M.A. Considerations in determining sample size for pilot studies. Res Nurs Health  31, 
180-91 (2008). 
10. 
Thabane, L. et al. A tutorial on pilot studies: the what, why and how. BMC Med Res Methodol  
10, 1 (2010). 
11. 
Glick, H., Doshi, J., Sonnad, S. & Polsky, D. Economic Evaluation in Clinical Trials.   (Oxford 
University Press, Oxford, 2007). 
 
 
 
 
 
 
15 

Appendix A. Treatment recommendations handout for interventional cardiologist 
Table 1. Treatment recommendations for antiplatelet therapy based on CYP2C19 genotype4 
Genotype 
Phenotype 
Description 
Treatmenta 
CYP2C19 *1/*1 
Extensive 
metabolizer 
(normal) 
Two inferred normal alleles 
Clopidogrel (Plavix) 75 
mg per day 
 
CYP2C19 *1/*17 
 
Ultra-rapid 
metabolizer 
 
One inferred normal allele 
One increased function allele 
CYP2C19 *17/*17 
Two gain of function alleles 
CYP2C19 *1/ *2 
 
Intermediate 
metabolizer 
One inferred normal allele 
One loss of function allele 
Prasugrel (Effient) 10 mg 
per dayb 
 
Or 
 
Ticagrelor (Brilinta) 90 
mg twice dailyc 
CYP2C19 *1/*3 
 
One inferred normal allele 
One loss of function allele 
CYP2C19 *2/*17 
 
One loss of function allele 
One gain of function allele 
CYP2C19 *3/*17 
One loss of function allele 
One gain of function allele 
CYP2C19 *2/*2 
 
Poor metabolizer 
Two loss of function alleles 
Prasugrel (Effient) 10 mg 
per dayb 
 
Or 
 
Ticagrelor (Brilinta) 90 
mg twice dailyc 
CYP2C19 *3/*3 
 
Two loss of function alleles 
CYP2C19 *2/*3 
Two loss of function alleles 
 
Table 2. Switching recommendations based on CYP2C19 genotype  
Genotype CYP2C19 
Initial loading dose  
Reload 
Maintenance a 
*1/*2, *1/*3, *2/*2, 
*3/*3, *2/*17, *3/*17  
Clopidogrel 600 mg 
Prasugrel 60 mg 
 
Prasugrel 10 mg b 
Ticagrelor 180 mg 
Ticagrelor 90 mg c 
*1/*1, *1/*17, *17/*17 
Prasugrel 60 mg 
Not needed 
Clopidogrel 75 mg 
Ticagrelor 180mg 
Clopidogrel 300 mg 
Clopidogrel 75mg 
a Please consider all clinical contraindications before prescribing alternative antiplatelet agent.  Prasugrel and ticagrelor are 
recommended only when not clinically contraindicated. See table 3 below 
 
Table 3. Clinical Contraindications to Prasugrel or Ticagrelor 
Prasugrel b 
Ticagrelor c 
1. Do not use prasugrel in patients with 
active bleeding or a history of transient 
ischemic attack or stroke. 
2. Individual risks/benefits of prasugrel 
must be carefully considered in patients 
over age 75.  
3. Do not start prasugrel in patients likely 
to undergo urgent coronary bypas graft 
surgery (CABG). 
4. Consider prasugrel 5 mg per day for 
patients <60 kg. 
1. Do not use ticagrelor in patients with 
active bleeding or a history of transient 
ischemic attack or stroke. 
2. Do not start ticagrelor in patients likely 
to undergo urgent coronary bypass 
graft surgery (CABG).  
3. Do not use maintenance aspirin dose 
above 100 mg in combination with 
ticagrelor. 
4. Avoid with strong CYP3A inhibitors or 
inducers. 
1. 
Scott, S.A. et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C19 Genotype and 
Clopidogrel Therapy: 2013 Update. Clin Pharmacol Ther  94, 317-23 (2013). 
 
 
 
16 

Appendix B 
 
Participant Survey- Pharmacogenetic testing 
 
Demographics 
 
1. Name: ________________________________________ 
2. Age:____________ 
3. Sex: 
  Male 
  Female 
 
4. Race (check all that apply): 
  White 
  Black/African-American 
  Asian 
  American Indian/ Alaska Native 
  Native Hawaiian/ Pacific Islander 
  Other 
 
5. Ethnicity: 
  Hispanic 
  Non-Hispanic 
 
6. Educational level: 
  Less than high school 
  High school graduate (or GED) 
  Some college/ university 
  College/university graduate 
  Post college/ university degree 
  Not provided 
 
 
 
17 

7. What is your current occupational status? (circle) 
  Employed 
  Unemployed 
  Homemaker 
  Student 
  Retired 
  Disabled 
  Other, please specific_______________ 
 
8. What is your marital status? (circle) 
  Married 
  Living as married 
  Divorced 
  Widowed 
  Separated 
  Single, never been married 
 
9. What is your combined annual income (total pre-tax income from all sources earned in the past 
year)? 
 
  $0-$9,999 
  $10,000-$14,999 
  $15,000-$19,999 
  $20,000-$34,999 
  $35,000-$49,999 
  $50,000-$74,999 
  $75,000-$99,999 
  $100,000-$199,999 
  $200,000 or more 
  Choose not to respond 
10. How would you rate your current health 
  Excellent 
  Good  
  Fair 
  Poor 
11. Have you ever experienced side effects due to your medications? 
  No 
  Yes, mild 
 
18 

  Yes, severe 
 
12. How confident are you in filling out forms in a doctor’s office by yourself? 
  Extremely 
  Quite a bit 
  Somewhat 
  A little bit 
  Not at all 
 
The following section includes questions about the role of genetics in health and disease.  
When we refer to a variant, we are referring to a change in a gene which may or may not be 
harmful.  
 
Please circle one number to indicate how much you agree or disagree with each statement. 
 
 
Strongly 
Agree 
Agree 
Neither 
agree nor 
disagree 
Disagree 
Strongly 
disagree 
13. A health care provider can always 
tell a person their exact chance of 
developing a disease based on the 
results from genetic testing. 
1 
2 
3 
4 
5 
14. Even if a person has a variant in a 
gene that affects their risk of a 
disease, they may not develop that 
disease. 
1 
2 
3 
4 
5 
15. Genetic testing may find variants in 
a person’s genes that may 
determine how they respond to 
certain medicines. 
1 
2 
3 
4 
5 
16. A person’s health habit, like diet and 
exercise, can affect whether or not 
their genes can cause disease. 
1 
2 
3 
4 
5 
17. Genetic variants in a gene can 
change over a person’s lifetime. 
1 
2 
3 
4 
5 
 
18. On a scale of 1 to 5 (1 being "Not at all important” and 5 being "very important"), how 
important is it to you to learn more about how your genes affect your chance of experiencing a 
side effect from a medication? 
Not At All Important 
                 
 
  Very Important  
       1                 2 
              3 
          4 
5 
 
 
19 

19. On a scale of 1 to 5 (1 being "Not at all important” and 5 being "very important"), how 
important is it to you to learn more about how your genes may help in predicting which 
medications will work for you? 
Not At All Important 
                 
 
  Very Important  
       1                 2 
              3 
          4 
5 
 
20. Before participating in this study how aware were you about the use of genetic testing to predict 
whether certain medications will work for you? 
 Aware 
 Not aware 
21. Did you receive genetic test result regarding CYP2C19 genotyping? 
 Yes 
 No 
  Unsure 
22. If yes in 21.  On a scale of 1 to 5 (1 being “not at all clear” and 5 being “very clear”), how 
clearly did you understand the PGx test results as it related to your antiplatelet medication? 
 
Not At All Clearly 
                 
 
  Very Clearly 
       1                 2 
              3 
          4 
5 
 
 
23. If applicable, what did you find unclear about your CYP2C19 test result? 
__________________________________________________________________________________
__________________________________________________________________________________ 
 
 
 
20 

Reminder, a pharmacogenetic test is a type of genetic test that could allow doctors to choose the right 
drug that will work for a patient while avoiding using certain drugs that may cause side effects. 
To what extent do you agree or disagree with the following statements? 
 
Strongly 
agree 
Agree 
Neither 
agree 
nor 
disagree 
Disagree 
Strongly 
disagree 
24. I feel comfortable about the 
pharmacogenetic tests that might 
be offered to me, if they could 
predict if a medication would work 
for my condition. 
1 
2 
3 
4 
5 
25. I feel comfortable about the 
pharmacogenetic tests that might 
be offered to me, if they could 
predict the correct dose of the 
medication that I needed. 
1 
2 
3 
4 
5 
26. I feel comfortable about the 
pharmacogenetic tests that might 
be offered to me, if they could 
predict a mild side effect. 
1 
2 
3 
4 
5 
27. I feel comfortable about the 
pharmacogenetic tests that might 
be offered to me, if they could 
predict a serious side effect. 
1 
2 
3 
4 
5 
28. I feel comfortable about the 
pharmacogenetic tests that might 
be offered to me, if they could 
explain a family history of 
medication side effect or 
nonresponse. 
1 
2 
3 
4 
5 
29. It is important that my health care 
provider tells me about these 
pharmacogenetic tests, before any 
of them are done. 
1 
2 
3 
4 
5 
30. If these pharmacogenetic tests 
were part of my usual blood work 
it is important that my health care 
provider seek separate approval 
from me, specifically for the 
pharmacogenetic tests. 
1 
2 
3 
4 
5 
 
21 

31. If I had to pay for the 
pharmacogenetic tests myself, 
financial costs would be one of my 
concerns about taking these tests. 
1 
2 
3 
4 
5 
32. If I took the test, I would be 
concerned that insurance 
companies may use the 
pharmacogenetic test results to 
deny healthcare coverage.  
1 
2 
3 
4 
5 
33. If I took the test, I would be 
concerned about the effect of the 
pharmacogenetic test results on 
my employment opportunities. 
1 
2 
3 
4 
5 
 
 
 
 
 
 
22 

Appendix C 
 
Provider Survey- Pharmacogenetic testing 
Demographics 
1. Sex: 
  Male 
  Female 
 
2. Race (check all that apply): 
  White 
  Black/African-American 
  Asian 
  American Indian/ Alaska Native 
  Native Hawaiian/ Pacific Islander 
  Other 
 
3. Ethnicity: 
  Hispanic 
  Non-Hispanic 
 
4. Year of gradation from medical school: _____________________ 
5. Medical Specialty: 
  Internal medicine / family medicine/ general practice 
  Cardiology 
  Gastroenterology 
  Genetics 
  Oncology 
  Surgery 
  Other: _____________________ 
6. Where do you primarily practice? 
 
  HUP 
  PPMC 
  PAH 
  VA hospital  
  Other: __________ 
 
 
23 

Pharmacogenetic (PGx) testing:   Testing to predict likelihood of drug toxicity or therapeutic efficacy.  
Testing identifies genetic variants in genes that may affect drug disposition (e.g., metabolism) or drug 
target resulting in increased risk for an adverse drug reaction or low likelihood of responding to a drug, 
respectively. 
 
7. I feel well-informed about the role of PGx testing in therapeutic decision-making. 
  Strongly agree 
  Somewhat agree 
  Neutral 
  Somewhat disagree 
  Strongly disagree 
  Prefer not to answer 
 
8. I believe that PGx testing is or will soon become a valuable tool to predict risk of adverse events 
or likelihood of effectiveness. 
  Strongly agree 
  Somewhat agree 
  Neutral 
  Somewhat disagree 
  Strongly disagree 
  Prefer not to answer 
 
9. Had you heard of pharmacogenetic (PGx) testing before this survey?  
  Yes 
  No   
 
10. Are you aware that the Food and Drug Administration (FDA) has revised drug labels to include 
information about pharmacogenetics?  
  
  Yes 
  No  
 
 
 
 
24 

11. Please indicate where and/or how you have learned about pharmacogenetics. (Please check all 
that apply.)  
  Genetics training in medical school  
  Genetics training in residency 
  Continuing medical education (CME) meeting, in-person course, grand rounds 
  CME distance learning (mail or web-based) 
  Journals 
  Colleagues 
  Other (Please specify.) _________________________ 
  I have not had any education about pharmacogenetics. 
 
12. In your opinion, what is the BEST way to educate physicians about PGx testing? (Please select 
only one response.)   
 Genetics training in medical school  
 Genetics training in residency 
 Continuing medical education (CME) meeting, in-person course, or grand rounds 
  CME distance learning (mail or web-based) 
  Journals 
  Grand rounds or other types of in-house seminars 
  Other (Please specify.) _________________________ 
  Genetics education is not necessary 
 
13. How often do you order PGx tests? 
  Never 
  1-2 times per year 
  3-10 times per year 
  11-25 times per year 
  More than 25 times per year 
  Unsure 
 
14. In general, how likely are you to order a PGx test that predicts the efficacy of a drug for an 
individual patient? 
  Very likely 
  Somewhat likely 
  Neutral 
  Somewhat unlikely 
 
25 

  Very unlikely 
 
15. In general, how likely are you to order a PGx test that predicts the safety of a drug for an 
individual patient? 
  Very likely 
  Somewhat likely 
  Neutral 
  Somewhat unlikely 
  Very unlikely 
 
 
 
26 

16. In your opinion, when deciding whether or not to order a pharmacogenetic test to determine a potential adverse drug reaction for an 
individual patient, how important are the following considerations? 
 
Very 
important 
Somewhat 
important 
Neutral 
Somewhat 
unimportant 
Not at all 
important 
a. Severity of the potential drug reaction.  
○  
○   
○   
○   
○   
b. Prevalence of the potential drug 
reaction.  
○  
○   
○   
○   
○   
c. Predictive value of the test.  
○  
○   
○   
○   
○   
d. Availability of other clinical testing to 
monitor drug toxicity.   
○  
○   
○   
○   
○   
e. Severity of the condition being treated.  
○  
○   
○   
○   
○   
f. Prevalence of genetic variant (positive 
test result).   
○  
○   
○   
○   
○   
g. Inclusion of information about the test 
on the drug label/package insert.  
○  
○   
○   
○   
○   
h. Availability of practice guidelines for 
test use and interpretation. 
○  
○   
○   
○   
○   
i. Insurance reimbursement of test. 
○  
○   
○   
○   
○   
j. Cost of the test.   
○  
○   
○   
○   
○   
k. Turnaround time for the test results to 
be returned. 
○  
○   
○   
○   
○   
l. Cost of the drug for which test is 
ordered. 
○  
○   
○   
○   
○   
m. Availability of an alternative drug. 
○  
○   
○   
○   
○   
17.  
 
 
 
27 

18. In your opinion, when determining the value of a PGx test to identify a patient who is unlikely to respond to a drug (efficacy), how 
important are the following considerations  
 
Very 
important 
Somewhat 
important 
Neutral 
Somewhat 
unimportant 
Not at all 
important 
a. Likelihood of non-response to the drug. 
○   
○   
○   
○   
○   
b. Predictive value of the test. 
○   
○   
○   
○   
○   
c. Availability of other clinical testing to monitor drug 
response. 
○   
○   
○   
○   
○   
d. Urgency of treatment.  
○   
○   
○   
○   
○   
e. Severity of the condition being treated. 
○   
○   
○   
○   
○   
f. Likelihood of genetic variant (positive test result). 
○   
○   
○   
○   
○   
g. Inclusion of information about the test on the drug label. 
○   
○   
○   
○   
○   
h. Availability of practice guidelines for test use and 
interpretation. 
○   
○   
○   
○   
○   
i. Insurance reimbursement of the test. 
○   
○   
○   
○   
○   
j. Cost of the test. 
○   
○   
○   
○   
○   
k. Turnaround time for the test results to be returned. 
○   
○   
○   
○   
○   
l. Cost of the drug for which test is ordered.. 
○   
○   
○   
○   
○   
m. Availability of an alternative drug. 
○   
○   
○   
○   
○   
19. Please indicate which professional or group should have PRIMARY responsibility to discuss PGx test result with the patient. 
 Physician ordering the test 
 Primary care provider 
 Geneticist / Genetic Counselor 
 
28 

 
 Pharmacist 
 Genetic testing lab 
 Don’t know 
Page 29 of 29