ADAPT: Assessment of Prospective CYP2C19 Genotype Guided Dosing of Anti-Platelet Therapy in Percutaneous Coronary Intervention

• Sponsor: University of Pennsylvania (Other)
• Overall Status: Completed
• CT.gov ID: NCT02508116
• Collaborator: (none)
• Enrollment: 509
• Locations: 2
• Arms: 2
• Actual Duration (Months): 33
• Patients Per Site: 254.5
• Patients Per Site Per Month: 7.7

Study Details

Study Description

Brief Summary

This is a randomized, prospective, open label study to determine the cost-effectiveness of genotype-guided antiplatelet therapy. Patients undergoing percutaneous intervention (PCI) with stent implantation, will be randomized either to genotype guided dosing of antiplatelet therapy or usual care. The study utilizes a novel genotyping device, SpartanRx, to determine CYP2C19 genotypes from a buccal swab sample with 1 hour turnaround time.

Condition or Disease	Intervention/Treatment	Phase
Acute Coronary Syndrome; Cardiovascular Diseases	Genetic: CYP2C19 genotyping	N/A

Detailed Description

Clopidogrel is a thienopyridine antiplatelet agent, which inhibits the purinergic P2RY12 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 demonstrated that CYP2C192 carriers treated with clopidogrel have a higher risk for major adverse cardiac events compared to noncarriers.Therefore, clopidogrel is less effective in patients who are CYP2C19 poor metabolizers and alternative therapy is recommended. 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.

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.

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. 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, quality-adjust life years (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.

OBJECTIVES

• 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, QALYs and the correlation of cost and effect.

• To determine the rates of clinical outcomes.

APPROACH In the genotype guided arm, 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 the control arm, 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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 509 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Patients undergoing PCI are randomized to genotype guided antiplatelet therapy vs. usual care.Patients undergoing PCI are randomized to genotype guided antiplatelet therapy vs. usual care.
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Assessment of Prospective CYP2C19 Genotype Guided Dosing of Anti-Platelet Therapy in Percutaneous Coronary Intervention (ADAPT)
• Actual Study Start Date: Nov 1, 2014
• Actual Primary Completion Date: May 1, 2017
• Actual Study Completion Date: Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CYP2C19 Genotype guided Prospective CYP2C19 genotyping to decide antiplatelet therapy.	Genetic: CYP2C19 genotyping; The study utilizes a 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; Other Names: SpartanRx
No Intervention: Control group Antiplatelet therapy will be decided based on usual care

Outcome Measures

Primary Outcome Measures

1. The Number (Percentage) of Participants Receiving Prasugrel/Ticagrelor [for up to 7 days after PCI]

   The number (percentage) of participants receiving prasugrel/ticagrelor in each randomized arm

Secondary Outcome Measures

1. Number of Participants With Drug Orders in Agreement With the Genotype-guided Recommendations [for up to 7 days after PCI]

   Agreement to suggested treatment recommendations based on genotype. The agreement rate was defined as the number of participants in genotyped group with loss of function variants that received prasugrel or ticagrelor + the number of participants without these variants that received clopidogrel divided by the total number in this group.

2. Number of Participants With Major Cardiac Events [1 year]

   major cardiac events defined as occurrence of first myocardial infarction, ischemic stroke, cardiovascular death, stent thrombosis, or need for urgent revascularization

3. Number of Participants With Bleeding Events [1 year]

   major bleeding events defined by the Bleeding Academic Research Consortium (BARC) type 3 or 5. Type 3= Overt bleeding requiring: blood transfusion, surgical intervention or intravenous vasoactive agents; cardiac tamponade; intracranial hemorrhage; intraocular bleeding. Type 5= fatal bleeding

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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, TIA, and 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

8. Drug allergy to clopidogrel, prasugrel or ticagrelor.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
2	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• University of Pennsylvania

Investigators

• Principal Investigator: Sony Tuteja, PharmD, MS, University of Pennsylvania
• Principal Investigator: Jay S Giri, MD, University of Pennsylvania

Study Documents (Full-Text)

• Study Protocol - Jun 1, 2017
• Statistical Analysis Plan - Dec 1, 2017

More Information

Publications

None provided.

• Responsible Party: Sony Tuteja, Research Associate, University of Pennsylvania
• ClinicalTrials.gov Identifier: NCT02508116
• Other Study ID Numbers: 820899
• First Posted: Jul 24, 2015
• Last Update Posted: Nov 7, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by Sony Tuteja, Research Associate, University of Pennsylvania: pharmacogenetics; clopidogrel; genotype
• Additional relevant MeSH terms: Cardiovascular Diseases; Acute Coronary Syndrome

Study Results

Participant Flow

Recruitment Details	Patients, age ≥18 to ≤80 years at time of study, who were underwent PCI between November 2014 and August 2016 at the Hospital of the University of Pennsylvania or Penn Presbyterian Medical Center.

Arm/Group Title	CYP2C19 Genotype Guided	Control Group
Arm/Group Description	Prospective CYP2C19 genotyping to decide antiplatelet therapy. CYP2C19 genotyping: The study utilizes a 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	Antiplatelet therapy will be decided based on usual care
Period Title: Overall Study
STARTED	252	257
Received Intervention as Randomized	249	255
COMPLETED	244	250
NOT COMPLETED	8	7

Baseline Characteristics

Arm/Group Title	CYP2C19 Genotype Guided	Control Group	Total
Arm/Group Description	Prospective CYP2C19 genotyping to decide antiplatelet therapy. CYP2C19 genotyping: The study utilizes a 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	Antiplatelet therapy will be decided based on usual care	Total of all reporting groups
Overall Participants	249	255	504
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	63 (9.7)	62.9 (10.2)	62.9 (10.0)
Sex: Female, Male (Count of Participants)
Female	68 27.3%	66 25.9%	134 26.6%
Male	181 72.7%	189 74.1%	370 73.4%
Race/Ethnicity, Customized (Count of Participants)
White	194 77.9%	197 77.3%	391 77.6%
Black	48 19.3%	51 20%	99 19.6%
Asian	6 2.4%	6 2.4%	12 2.4%
Other	1 0.4%	1 0.4%	2 0.4%
Region of Enrollment (participants) [Number]
United States	249 100%	255 100%	504 100%
Hospital Site (Count of Participants)
Hospital of the University of Pennsylvania	135 54.2%	141 55.3%	276 54.8%
Penn Presbyterian Hospital	114 45.8%	114 44.7%	228 45.2%
Acute coronary syndrome (Count of Participants)
Count of Participants [Participants]	124 49.8%	129 50.6%	253 50.2%
Insurance Status (Count of Participants)
Public	100 40.2%	110 43.1%	210 41.7%
Other	149 59.8%	145 56.9%	294 58.3%
Work Status (Count of Participants)
Full time	88 35.3%	92 36.1%	180 35.7%
Retired	84 33.7%	85 33.3%	169 33.5%
Disabled	12 4.8%	13 5.1%	25 5%
Not provided	45 18.1%	44 17.3%	89 17.7%
Other/unknown	20 8%	21 8.2%	41 8.1%
Tobacco use (Count of Participants)
Never	114 45.8%	123 48.2%	237 47%
Former	105 42.2%	94 36.9%	199 39.5%
Current	28 11.2%	37 14.5%	65 12.9%
unknown	2 0.8%	1 0.4%	3 0.6%
Medical history (Count of Participants)
Hypertension	190 76.3%	199 78%	389 77.2%
Hypercholesterolemia	112 45%	113 44.3%	225 44.6%
Diabetes Mellitus	89 35.7%	79 31%	168 33.3%
Previous MI	63 25.3%	67 26.3%	130 25.8%
Previous PCI	83 33.3%	83 32.5%	166 32.9%
Previous CABG	32 12.9%	36 14.1%	68 13.5%
Previous Stroke	7 2.8%	15 5.9%	22 4.4%
P2Y12 inhibitor use prior to admission (Count of Participants)
Clopidogrel	80 32.1%	85 33.3%	165 32.7%
Prasugrel	12 4.8%	9 3.5%	21 4.2%
Ticagrelor	2 0.8%	6 2.4%	8 1.6%
None	155 62.2%	155 60.8%	310 61.5%
Pharmacotherapy prior to admission (Count of Participants)
Aspirin	165 66.3%	157 61.6%	322 63.9%
ACE inhibitor or ARB	115 46.2%	109 42.7%	224 44.4%
Beta-blocker	121 48.6%	125 49%	246 48.8%
Calcium channel blocker	50 20.1%	62 24.3%	112 22.2%
Statin	112 45%	113 44.3%	225 44.6%
Other anti-anginal	83 33.3%	78 30.6%	161 31.9%

Outcome Measures

1. Primary Outcome

Title	The Number (Percentage) of Participants Receiving Prasugrel/Ticagrelor
Description	The number (percentage) of participants receiving prasugrel/ticagrelor in each randomized arm
Time Frame	for up to 7 days after PCI

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	CYP2C19 Genotype Guided	Control Group
Arm/Group Description	Prospective CYP2C19 genotyping to decide antiplatelet therapy. CYP2C19 genotyping: The study utilizes a 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	Antiplatelet therapy will be decided based on usual care
Measure Participants	249	255
Clopidogrel	174 69.9%	201 78.8%
Prasugrel/ticagrelor	75 30.1%	54 21.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CYP2C19 Genotype Guided, Control Group
	Comments	The sample size calculation was based on two factors: 1) the rate of pre-study prasugrel/ticagrelor use (~20%) and 2) anticipated increase in prasugrel/ticagrelor prescribing based on the frequency CYP2C19 LOF variants (~30-35%). We estimated a 15% difference in the use of prasugrel/ticagrelor in the two groups (35% in the genotyped 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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments
	Method	Regression, Logistic
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.6
	Confidence Interval	(2-Sided) 95%; 1.07 to 2.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Drug Orders in Agreement With the Genotype-guided Recommendations
Description	Agreement to suggested treatment recommendations based on genotype. The agreement rate was defined as the number of participants in genotyped group with loss of function variants that received prasugrel or ticagrelor + the number of participants without these variants that received clopidogrel divided by the total number in this group.
Time Frame	for up to 7 days after PCI

Outcome Measure Data

Analysis Population Description

Subjects with genotype data available

Arm/Group Title	CYP2C19 Genotype Guided	Control Group
Arm/Group Description	Prospective CYP2C19 genotyping to decide antiplatelet therapy. CYP2C19 genotyping: The study utilizes a 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	Antiplatelet therapy will be decided based on usual care
Measure Participants	242	226
Count of Participants [Participants]	172 69.1%	133 52.2%

3. Secondary Outcome

Title	Number of Participants With Major Cardiac Events
Description	major cardiac events defined as occurrence of first myocardial infarction, ischemic stroke, cardiovascular death, stent thrombosis, or need for urgent revascularization
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

Intent to treat

Arm/Group Title	CYP2C19 Genotype Guided	Control Group
Arm/Group Description	Prospective CYP2C19 genotyping to decide antiplatelet therapy. CYP2C19 genotyping: The study utilizes a 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	Antiplatelet therapy will be decided based on usual care
Measure Participants	249	255
Count of Participants [Participants]	34 13.7%	26 10.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CYP2C19 Genotype Guided, Control Group
	Comments	The incidence of first MACE between the groups were compared by use of Kaplan-Meier estimators; statistical tests were based on log-rank tests.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.27
	Comments
	Method	Log Rank
	Comments

4. Secondary Outcome

Title	Number of Participants With Bleeding Events
Description	major bleeding events defined by the Bleeding Academic Research Consortium (BARC) type 3 or 5. Type 3= Overt bleeding requiring: blood transfusion, surgical intervention or intravenous vasoactive agents; cardiac tamponade; intracranial hemorrhage; intraocular bleeding. Type 5= fatal bleeding
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	CYP2C19 Genotype Guided	Control Group
Arm/Group Description	Prospective CYP2C19 genotyping to decide antiplatelet therapy. CYP2C19 genotyping: The study utilizes a 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	Antiplatelet therapy will be decided based on usual care
Measure Participants	249	255
Count of Participants [Participants]	6 2.4%	7 2.7%

Adverse Events

Time Frame	1 year
Arm/Group Title	CYP2C19 Genotype Guided		Control Group
Arm/Group Description	Prospective CYP2C19 genotyping to decide antiplatelet therapy. CYP2C19 genotyping: The study utilizes a 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		Antiplatelet therapy will be decided based on usual care
All Cause Mortality
	CYP2C19 Genotype Guided		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/249 (3.2%)		7/255 (2.7%)
Serious Adverse Events
	CYP2C19 Genotype Guided		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	132/249 (53%)		115/255 (45.1%)
Blood and lymphatic system disorders
Anemia	2/249 (0.8%)	2	3/255 (1.2%)	3
Cardiac disorders
angina pectoris	33/249 (13.3%)	33	21/255 (8.2%)	21
angina unstable	1/249 (0.4%)	1	1/255 (0.4%)	1
atrial fibrillation	4/249 (1.6%)	4	3/255 (1.2%)	3
bradyarrhythmia	0/249 (0%)	0	1/255 (0.4%)	1
bradycardia	1/249 (0.4%)	1	0/255 (0%)	0
cardiac arrest	3/249 (1.2%)	3	0/255 (0%)	0
cardiac failure	2/249 (0.8%)	2	1/255 (0.4%)	1
cardiac failure congestive	3/249 (1.2%)	3	4/255 (1.6%)	4
cardiomyopathy	1/249 (0.4%)	1	0/255 (0%)	0
myocardial infarction	8/249 (3.2%)	8	11/255 (4.3%)	11
pericarditis	1/249 (0.4%)	1	0/255 (0%)	0
tachyarrhytmia	1/249 (0.4%)	1	0/255 (0%)	0
ventricular arrythmia	3/249 (1.2%)	3	0/255 (0%)	0
cardiac transplantation	0/249 (0%)	0	1/255 (0.4%)	1
Gastrointestinal disorders
abdominal pain	1/249 (0.4%)	1	1/255 (0.4%)	1
diarrhea	0/249 (0%)	0	2/255 (0.8%)	2
gastrointestinal hemmorhage	2/249 (0.8%)	2	1/255 (0.4%)	1
gastrointestinal ulcer	1/249 (0.4%)	1	0/255 (0%)	0
hemorrhoids	1/249 (0.4%)	1	0/255 (0%)	0
hernia	1/249 (0.4%)	1	0/255 (0%)	0
inguinal hernia	0/249 (0%)	0	1/255 (0.4%)	1
melena	1/249 (0.4%)	1	0/255 (0%)	0
nausea	1/249 (0.4%)	1	0/255 (0%)	0
pancreatitis	0/249 (0%)	0	1/255 (0.4%)	2
rectal hemorrhage	2/249 (0.8%)	2	0/255 (0%)	0
General disorders
drug intolerance	1/249 (0.4%)	1	1/255 (0.4%)	1
Hepatobiliary disorders
bile duct stone	0/249 (0%)	0	1/255 (0.4%)	1
cholelithiasis	0/249 (0%)	0	1/255 (0.4%)	1
Immune system disorders
lung transplant rejection	0/249 (0%)	0	1/255 (0.4%)	1
Infections and infestations
bronchitis	1/249 (0.4%)	1	1/255 (0.4%)	1
cellulitis	0/249 (0%)	0	1/255 (0.4%)	1
endocarditis	1/249 (0.4%)	1	1/255 (0.4%)	1
gastroenteritis	0/249 (0%)	0	1/255 (0.4%)	1
groin abscess	1/249 (0.4%)	1	0/255 (0%)	0
influenza	0/249 (0%)	0	1/255 (0.4%)	1
osteomyelitis	0/249 (0%)	0	2/255 (0.8%)	2
pneumonia	4/249 (1.6%)	4	5/255 (2%)	5
septic shock	1/249 (0.4%)	1	0/255 (0%)	0
Injury, poisoning and procedural complications
stent thrombosis	1/249 (0.4%)	1	5/255 (2%)	5
coronary artery restenosis	1/249 (0.4%)	1	1/255 (0.4%)	1
fall	2/249 (0.8%)	2	1/255 (0.4%)	1
road traffic accident	1/249 (0.4%)	1	2/255 (0.8%)	2
subdural hematoma	0/249 (0%)	0	1/255 (0.4%)	1
tibia fracture	0/249 (0%)	0	1/255 (0.4%)	1
wound dehiscence	1/249 (0.4%)	1	0/255 (0%)	0
Investigations
hemoglobin decrease	1/249 (0.4%)	1	0/255 (0%)	0
Metabolism and nutrition disorders
diabetes mellitus	1/249 (0.4%)	1	0/255 (0%)	0
hyperglycemia	1/249 (0.4%)	1	0/255 (0%)	0
Musculoskeletal and connective tissue disorders
arthralgia	0/249 (0%)	0	1/255 (0.4%)	1
lumbar spinal stenosis	1/249 (0.4%)	1	0/255 (0%)	0
pain in extremity	0/249 (0%)	0	1/255 (0.4%)	1
rhabdomyolysis	0/249 (0%)	0	1/255 (0.4%)	1
spinal stenosis	1/249 (0.4%)	1	0/255 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
rectal mass	0/249 (0%)	0	1/255 (0.4%)	1
thyroid cancer	0/249 (0%)	0	1/255 (0.4%)	1
Nervous system disorders
dizziness	1/249 (0.4%)	1	0/255 (0%)	0
epilepsy	0/249 (0%)	0	1/255 (0.4%)	1
ischemic stroke	2/249 (0.8%)	2	2/255 (0.8%)	2
polyneuropathy	1/249 (0.4%)	1	0/255 (0%)	0
syncope	3/249 (1.2%)	3	0/255 (0%)	0
transient ischemic attack	1/249 (0.4%)	1	0/255 (0%)	0
Psychiatric disorders
confusional state	0/249 (0%)	0	1/255 (0.4%)	1
Renal and urinary disorders
acute renal failure	1/249 (0.4%)	1	1/255 (0.4%)	1
hematuria	0/249 (0%)	0	2/255 (0.8%)	2
renal failure	0/249 (0%)	0	1/255 (0.4%)	1
urinary retention	1/249 (0.4%)	1	0/255 (0%)	0
Respiratory, thoracic and mediastinal disorders
chronic obstructive pulmonary disease	0/249 (0%)	0	1/255 (0.4%)	1
dyspnea	3/249 (1.2%)	3	4/255 (1.6%)	4
Surgical and medical procedures
amputation	0/249 (0%)	0	1/255 (0.4%)	1
angioplasty	5/249 (2%)	5	3/255 (1.2%)	3
aortic valve replacement	3/249 (1.2%)	3	0/255 (0%)	0
coronary artery bypass grafting	5/249 (2%)	5	3/255 (1.2%)	3
gastrectomy	1/249 (0.4%)	1	0/255 (0%)	0
implantable defibrillator implantation	6/249 (2.4%)	6	0/255 (0%)	0
knee arthroplasty	3/249 (1.2%)	3	1/255 (0.4%)	1
mitral valve repair	0/249 (0%)	0	3/255 (1.2%)	3
rotator cuff repair	1/249 (0.4%)	1	0/255 (0%)	0
percutaneous coronary intervention	4/249 (1.6%)	4	2/255 (0.8%)	2
Vascular disorders
aortic aneursym	1/249 (0.4%)	1	1/255 (0.4%)	1
aortic dissection	0/249 (0%)	0	1/255 (0.4%)	1
hypotension	1/249 (0.4%)	1	1/255 (0.4%)	1
peripheral arterial occlusive disease	0/249 (0%)	0	1/255 (0.4%)	1
peripheral vascular disorder	0/249 (0%)	0	1/255 (0.4%)	3
Other (Not Including Serious) Adverse Events
	CYP2C19 Genotype Guided		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	28/249 (11.2%)		34/255 (13.3%)
Cardiac disorders
angina pectoris	6/249 (2.4%)	6	11/255 (4.3%)	11
atrial fibrillation	2/249 (0.8%)	2	0/255 (0%)	0
palpitation	1/249 (0.4%)	1	0/255 (0%)	0
Ear and labyrinth disorders
vertigo	0/249 (0%)	0	1/255 (0.4%)	1
Eye disorders
eye hemorrhage	0/249 (0%)	0	1/255 (0.4%)	1
eye pain	1/249 (0.4%)	1	1/255 (0.4%)	1
Gastrointestinal disorders
abdominal pain	1/249 (0.4%)	1	0/255 (0%)	0
diarrhea	1/249 (0.4%)	1	0/255 (0%)	0
hematemesis	0/249 (0%)	0	1/255 (0.4%)	1
melena	0/249 (0%)	0	2/255 (0.8%)	2
mouth swelling	1/249 (0.4%)	1	0/255 (0%)	0
edema peripheral	1/249 (0.4%)	1	0/255 (0%)	0
General disorders
drug intolerance	0/249 (0%)	0	2/255 (0.8%)	2
malaise	0/249 (0%)	0	1/255 (0.4%)	1
Infections and infestations
abscess	0/249 (0%)	0	1/255 (0.4%)	1
urinary tract infection	1/249 (0.4%)	1	0/255 (0%)	0
Injury, poisoning and procedural complications
upper limb injury	1/249 (0.4%)	1	0/255 (0%)	0
contusion	1/249 (0.4%)	1	0/255 (0%)	0
fall	2/249 (0.8%)	2	1/255 (0.4%)	1
Musculoskeletal and connective tissue disorders
back pain	2/249 (0.8%)	2	0/255 (0%)	0
dental pain	1/249 (0.4%)	1	0/255 (0%)	0
gouty arthritis	1/249 (0.4%)	1	1/255 (0.4%)	1
pain in extremity	2/249 (0.8%)	2	2/255 (0.8%)	2
Nervous system disorders
dizziness	1/249 (0.4%)	1	0/255 (0%)	0
headache	0/249 (0%)	0	2/255 (0.8%)	2
Psychiatric disorders
confusional state	1/249 (0.4%)	1	1/255 (0.4%)	1
Renal and urinary disorders
calculus ureteric	0/249 (0%)	0	1/255 (0.4%)	1
hematuria	0/249 (0%)	0	1/255 (0.4%)	1
Reproductive system and breast disorders
dyspnea	0/249 (0%)	0	3/255 (1.2%)	3
Respiratory, thoracic and mediastinal disorders
chronic obstructive pulmonary disease	0/249 (0%)	0	1/255 (0.4%)	1
epistaxis	1/249 (0.4%)	1	0/255 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.