Acute Coronary Syndrome, Coronary Artery Disease, Stenosis
Conditions
Keywords
percutaneous coronary intervention, angioplasty
Brief summary
Clopidogrel is an anti-platelet medication approved by the U.S. Federal Drug Administration (FDA) for use in patients who undergo Percutaneous Coronary Intervention (PCI) with coronary stent implantation. Anti-platelet medications work to prevent blood clots from forming. Some studies have suggested that patients who have a certain genetic liver enzyme abnormality (known as cytochrome P450 2C19 \[CYP2C19\] \*2 or \*3 allele) may have a reduced ability to activate clopidogrel, and therefore may have a lowered response to clopidogrel. It is thought that perhaps people who have a coronary stent procedure may have this genetic liver enzyme abnormality. There is a research genetic test available to determine whether or not someone has this genetic liver enzyme abnormality. Ticagrelor, is a newer anti-platelet drug that is not dependent on the CYP2C19 liver enzyme for its activation and hence in poor clopidogrel metabolizers, alternative drugs like Ticagrelor have been recommended for use as an anti-platelet agent after PCI. The purpose of this study is to determine if genetic testing can identify the best anti-platelet therapy, for patients who undergo a coronary stent placement and do not activate clopidogrel very well.
Detailed description
TAILOR-PCI is a multi-site, open label, prospective, randomized trial testing the hypothesis that after percutaneous coronary intervention (PCI), using a genotyping strategy ticagrelor 90 mg twice per day is superior to clopidogrel 75 mg per day in reducing a composite endpoint of major adverse cardiovascular events (MACE), i.e., non-fatal myocardial infarction, non-fatal stroke, severe recurrent ischemia, cardiovascular (CV) death, and stent thrombosis (primary endpoints) in CYP2C19 reduced function allele patients. Patients who undergo PCI will be randomized to a conventional therapy arm (i.e., to receive clopidogrel 75 mg once daily without prospective genotyping guidance) versus a prospective CYP2C19 genotype-based anti-platelet therapy approach (ticagrelor 90 mg bid in CYP2C19 \*2 or \*3 reduced function allele patients, clopidogrel 75 mg once daily in non-\*2 or -\*3 CYP2C19 patients). Buccal swabs will be obtained for those subjects randomized to the prospective genotyping arm. All subjects will have a blood sample drawn for DNA analysis but genotyping using these DNA samples will be performed only after completion of the duration of anti-platelet therapy (i.e., after one year). The primary endpoints will be assessed prospectively and will be compared between the conventional arm and the prospective genotyping arm among those identified as reduced function CYP2C19 allele carriers according to the 1-year genotype results.
Interventions
DRUGClopidogrel
One 75 mg tablet per day by mouth for one year
DRUGTicagrelor
One 90 mg tablet twice per day by mouth for one year
Sponsors
Spartan Bioscience Inc.
Applied Health Research Centre
National Heart, Lung, and Blood Institute (NHLBI)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Inclusion * Patient \>18 years of age * Patient presents with acute coronary syndrome (ACS) or stable coronary artery disease (CAD) * Patient is eligible for PCI * Patient is willing and able to provide informed written consent 5.3 Exclusion * Patient not able to receive 12 months of dual anti-platelet therapy * Failure of index PCI * Patient or physician refusal to enroll in the study * Patient with known CYP2C19 genotype prior to randomization * Planned revascularization of any vessel within 30 days post-index procedure and/or of the target vessel(s) within 12 months post-procedure * Anticipated discontinuation of clopidogrel or ticagrelor within the 12 month follow up period, example for elective surgery * Serum creatinine \>2.5 mg/dL within 7 days of index procedure * Platelet count \<80,000 or \>700,000 cells/mm3, or white blood cell count \<3,000 cells/mm3 if persistent (at least 2 abnormal values) within 7 days prior to index procedure. * History of intracranial hemorrhage * Known hypersensitivity to clopidogrel or ticagrelor or any of its components * Patient is participating in an investigational drug or device clinical trial that has not reached its primary endpoint * Patient previously enrolled in this study * Patient is pregnant, lactating, or planning to become pregnant within 12 months * Patient has received an organ transplant or is on a waiting list for an organ transplant * Patient is receiving or scheduled to receive chemotherapy within 30 days before or after the procedure * Patient is receiving immunosuppressive therapy or has known immunosuppressive or autoimmune disease (e.g., human immunodeficiency virus, systemic lupus erythematous, etc.) * Patient is receiving chronic oral anticoagulation therapy (i.e., vitamin K antagonist, direct thrombin inhibitor, Factor Xa inhibitor) * Concomitant use of simvastatin/lovastatin \> 40 mg qd * Concomitant use of potent CYP3A4 inhibitors (atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and voriconazole) or inducers (carbamazepine, dexamethasone, phenobarbital, phenytoin, rifampin, and rifapentine) * Non-cardiac condition limiting life expectancy to less than one year, per physician judgment (e.g. cancer) * Known history of severe hepatic impairment * Patient has a history of bleeding diathesis or coagulopathy or will refuse blood transfusions * Patient has an active pathological bleeding, such as active gastrointestinal (GI) bleeding * Inability to take aspirin at a dosage of 100 mg or less * Current substance abuse (e.g., alcohol, cocaine, heroin, etc.)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of the a Major Adverse Cardiovascular Event in Subjects Identified as CPY2C19 LOF Carriers by TaqMan. | 1 year after percutaneous coronary intervention (PCI) | Number of subjects who experienced major adverse cardiovascular event as defined as cardiovascular death, myocardial infarction, stroke, severe recurrent ischemia, and stent thrombosis in subjects identified as CPY2C19 LOF carriers by TaqMan. |
| Occurrence of the a Major Adverse Cardiovascular Event | Approximately 3 years after percutaneous coronary intervention (PCI) | Number of subjects to experience a major adverse cardiovascular event as defined as cardiovascular death, myocardial infarction, stroke, severe recurrent ischemia, and stent thrombosis. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Thrombolysis in Myocardial Infarction Major or Minor Bleeding in Subjects Identified as CPY2C19 LOF Carriers by TaqMan. | 1 year after percutaneous coronary intervention (PCI) | Number of subjects that experienced thrombolysis in myocardial infarction major or minor bleeding in subjects identified as CYP2C19 LOF carriers by TaqMan |
| Thrombolysis in Myocardial Infarction Major or Minor Bleeding | Approximately 3 years after percutaneous coronary intervention (PCI) | Number of subjects that experienced thrombolysis in myocardial infarction major or minor bleeding |
Countries
Canada, Mexico, South Korea, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Genotype-Guided Therapy Subjects will be genotyped prospectively for CYP2C19\*2, \*3 and \*17 alleles and will receive treatment based on their genotype. In this group, patients who have the CYP2C19 reduced function allele \[i.e., \*2 allele (heterozygous or homozygous) or \*3 allele (heterozygous or homozygous)\] patients will receive ticagrelor 90 mg bid. The WT YP2C19 patients will receive clopidogrel 75 mg once daily.
Clopidogrel: One 75 mg tablet per day by mouth for one year
Ticagrelor: One 90 mg tablet twice per day by mouth for one year | 2,641 |
| Conventional Therapy Subjects will receive clopidogrel once daily after the index PCI and will be retrospectively genotyped for CYP2C19\*2, \*3 and \*17 alleles after completion of one year of treatment with clopidogrel.
Clopidogrel: One 75 mg tablet per day by mouth for one year | 2,635 |
| Total | 5,276 |
Baseline characteristics
| Characteristic | Genotype-Guided Therapy | Conventional Therapy | Total |
|---|---|---|---|
| Age, Continuous | 62 years | 62 years | 62 years |
| Race/Ethnicity, Customized African America | 57 Participants | 67 Participants | 124 Participants |
| Race/Ethnicity, Customized East Asian | 595 Participants | 592 Participants | 1187 Participants |
| Race/Ethnicity, Customized Hispanic or Latinx ethnicity | 78 Participants | 70 Participants | 148 Participants |
| Race/Ethnicity, Customized Other, Unknown or Not Reported | 123 Participants | 102 Participants | 225 Participants |
| Race/Ethnicity, Customized South Asian | 116 Participants | 120 Participants | 236 Participants |
| Race/Ethnicity, Customized White | 1750 Participants | 1754 Participants | 3504 Participants |
| Region of Enrollment Canada | 577 participants | 580 participants | 1157 participants |
| Region of Enrollment Mexico | 51 participants | 47 participants | 98 participants |
| Region of Enrollment South Korea | 654 participants | 650 participants | 1304 participants |
| Region of Enrollment United States | 1359 participants | 1358 participants | 2717 participants |
| Sex: Female, Male Female | 648 Participants | 645 Participants | 1293 Participants |
| Sex: Female, Male Male | 1993 Participants | 1990 Participants | 3983 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 95 / 2,641 | 98 / 2,635 |
| other Total, other adverse events | 0 / 2,641 | 0 / 2,635 |
| serious Total, serious adverse events | 0 / 2,641 | 0 / 2,635 |
Outcome results
Primary
Occurrence of the a Major Adverse Cardiovascular Event
Number of subjects to experience a major adverse cardiovascular event as defined as cardiovascular death, myocardial infarction, stroke, severe recurrent ischemia, and stent thrombosis.
Time frame: Approximately 3 years after percutaneous coronary intervention (PCI)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Genotype-Guided Therapy | Occurrence of the a Major Adverse Cardiovascular Event | 262 Participants |
| Conventional Therapy | Occurrence of the a Major Adverse Cardiovascular Event | 269 Participants |
Primary
Occurrence of the a Major Adverse Cardiovascular Event in Subjects Identified as CPY2C19 LOF Carriers by TaqMan.
Number of subjects who experienced major adverse cardiovascular event as defined as cardiovascular death, myocardial infarction, stroke, severe recurrent ischemia, and stent thrombosis in subjects identified as CPY2C19 LOF carriers by TaqMan.
Time frame: 1 year after percutaneous coronary intervention (PCI)
Population: For 1 year endpoint in Genotype-Guided Therapy arm 1738 were excluded from data analysis due Identified as CYP2C19 LOF noncarriers by TaqMan or no TaqMan results available. For 1 year endpoint in Conventional Therapy arm 1689 were excluded from data analysis due Identified as CYP2C19 LOF noncarriers by TaqMan or no TaqMan results available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Genotype-Guided Therapy | Occurrence of the a Major Adverse Cardiovascular Event in Subjects Identified as CPY2C19 LOF Carriers by TaqMan. | 35 Participants |
| Conventional Therapy | Occurrence of the a Major Adverse Cardiovascular Event in Subjects Identified as CPY2C19 LOF Carriers by TaqMan. | 54 Participants |
Secondary
Thrombolysis in Myocardial Infarction Major or Minor Bleeding
Number of subjects that experienced thrombolysis in myocardial infarction major or minor bleeding
Time frame: Approximately 3 years after percutaneous coronary intervention (PCI)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Genotype-Guided Therapy | Thrombolysis in Myocardial Infarction Major or Minor Bleeding | 54 Participants |
| Conventional Therapy | Thrombolysis in Myocardial Infarction Major or Minor Bleeding | 53 Participants |
Secondary
Thrombolysis in Myocardial Infarction Major or Minor Bleeding in Subjects Identified as CPY2C19 LOF Carriers by TaqMan.
Number of subjects that experienced thrombolysis in myocardial infarction major or minor bleeding in subjects identified as CYP2C19 LOF carriers by TaqMan
Time frame: 1 year after percutaneous coronary intervention (PCI)
Population: For 1 year endpoint in Genotype-Guided Therapy arm 1738 were excluded from data analysis due Identified as CYP2C19 LOF noncarriers by TaqMan or no TaqMan results available. For 1 year endpoint in Conventional Therapy arm 1689 were excluded from data analysis due Identified as CYP2C19 LOF noncarriers by TaqMan or no TaqMan results available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Genotype-Guided Therapy | Thrombolysis in Myocardial Infarction Major or Minor Bleeding in Subjects Identified as CPY2C19 LOF Carriers by TaqMan. | 16 Participants |
| Conventional Therapy | Thrombolysis in Myocardial Infarction Major or Minor Bleeding in Subjects Identified as CPY2C19 LOF Carriers by TaqMan. | 14 Participants |