Cardiovascular Disease
Conditions
Keywords
Pharmacogenetics, SLCO1B1 protein, human, OATP1B1 protein, human, Simvastatin, Cardiovascular disease, Cholesterol, Statin-related myotoxicity, Veterans, Point-of-care
Brief summary
This study will determine whether using a genetic test (for the SLCO1B1 gene) can help patients and providers choose the right type and dose of cholesterol-lowering statin medications to lower the risk of cardiovascular disease, while minimizing the muscle pain side effects that sometimes occur with statins.
Detailed description
Variants at rs4149056 in the SLCO1B1 gene are associated with a greater risk of simvastatin-related myopathy. Despite the growing implementation of SLCO1B1 rs4149056 genotyping in health systems across the United States, there is little randomized controlled trial data on the impact of SLCO1B1 testing on clinical outcomes. The IPICC Study will use a randomized design to determine the impact of the clinical integration of SLCO1B1 genotype testing on important patient outcomes, including statin prescribing, LDL cholesterol, and statin-related myopathy. In addition, by enrolling statin-naive patients with a recent cholesterol panel, this trial will capture a moment of clinical decision-making when SLCO1B1 rs4149056 genotype might be most clinically relevant. This randomized-control trial has two primary aims: Aim 1 (Drug safety): To determine the impact of SLCO1B1 pharmacogenetic testing on concordance with Clinical Pharmacogenetics Implementation Consortium (CPIC) pharmacogenetic guidelines for safe simvastatin prescribing and on the incidence of statin-related myopathy in VA (drug safety). Aim 2 (Cardiovascular disease, CVD, prevention): To determine the impact of SLCO1B1 pharmacogenetic testing on LDL cholesterol levels and concordance with CVD prevention guidelines. The I-PICC Study is enrolling 408 statin-naive primary care and women's health patients across the Veteran Affairs Boston Healthcare System. Eligible patients are aged 40-75 and have elevated risk of cardiovascular disease (CVD) according to American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Primary care providers (PCPs) are also research subjects and consent via electronic health record (EHR) alerts. To model pharmacogenotyping at the point of care, the investigators are enrolling patients with recent cholesterol results when their PCPs order laboratory testing, indicating a moment of clinical decision-making about CVD risk. Enrolled patients are randomized to have their PCPs receive results through the EHR immediately (PGx+) vs. after 1 year (PGx-). The investigators will query clinical and pharmacy data for 1-year outcomes: myopathy and concordance with CPIC simvastatin guidelines (drug safety) and cholesterol levels and concordance with ACC/AHA guidelines (CVD risk reduction).
Interventions
GENETICSLCO1B1 Genotype
Polymerase chain reaction (PCR) assay for SLCO1B1 rs4149056, with possible results T/T, T/C, or C/C.
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Providers: * All providers in Primary Care and Women's Health at VA Boston Healthcare System will be eligible to participate. Patients: * Aged 40-75 years * Have no history of statin use * Have received VA care for at least the prior 6 months * Are a patient of an enrolled provider * Meet at least 1 of the following criteria: * cardiovascular disease (CVD) * diabetes * LDL cholesterol value \>= 190 mg/dL * 10-year CVD risk of 7.5%, calculated with the ACC/AHA 2013 pooled risk equations
Exclusion criteria
* Patients will be ineligible if they: * Do not meet the inclusion criteria * Pregnant * Incarcerated or institutionalized
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 12-Month Change in LDL Cholesterol | 12 months | The primary CVD prevention outcome is 12-month change in low-density lipoprotein (LDL) cholesterol, defined as LDL value at 12 months minus LDL value at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With an American College of Cardiology/American Heart Association (ACC/AHA) Guideline Concordant Statin Prescription at 12 Months | 12 months | In 2013, the ACC/AHA endorsed guidelines that recommended prescribing statins of specific intensities (moderate or high) for distinct populations. Using patient characteristics and prescription data, the investigators will generate a 2-level CVD prevention outcome (concordant vs. non-concordant) for each participant, a measure of whether a patient's statin prescription is adequate for his/her level of CVD risk. |
| Number of Participants With Chart Review Documented Statin-related Myotoxicity at 12 Months | 12 months | Chart review of all patient notes during the 12 months after enrollment will be used to determine the proportion of patients in each arm who experienced statin-related muscle side effects during the observation period. |
| Number of Participants Meeting Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Safe Simvastatin Prescription at 12 Months | 12 months | Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend specific simvastatin doses when a patient's SLCO1B1 genotype is known. The investigators will compare each patient's medication prescriptions one year after enrollment to this guideline to generate a 2-level safety outcome (potentially safe vs. potentially unsafe simvastatin prescription) for each participant. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reporting Statin-related Muscle Side Effects at 12 Months | 12 months | Assessed by phone survey 12 months after enrollment. Whether patient attributes muscle pains, weakness, or cramps to a statin taken in the prior 12 months. |
| Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | 12 months | Assessed by phone survey 12 months after enrollment. Consists of 2 items: Do you agree or disagree with these statements?: My health in the future will depend on my medicines and Medicines do more harm than good. |
| Number of Participants Recalling Pharmacogenetic Testing at 12 Months | 12 months | Assessed by phone survey 12 months after enrollment. Whether patient remembers receiving PGx results from provider and, if so, remembers the results and interpretation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| PGx+ Patients in the PGx+ (intervention) arm will have their SLCO1B1 results reported to their ordering provider immediately.
SLCO1B1 Genotype: Polymerase chain reaction (PCR) assay for SLCO1B1 rs4149056, with possible results T/T, T/C, or C/C. | 193 |
| PGx- Patient in the PGx- (control) arm will have their SLCO1B1 results reported to their ordering provider at the end of the study (after 12 months).
SLCO1B1 Genotype: Polymerase chain reaction (PCR) assay for SLCO1B1 rs4149056, with possible results T/T, T/C, or C/C. | 215 |
| Total | 408 |
Baseline characteristics
| Characteristic | PGx+ | Total | PGx- |
|---|---|---|---|
| Age, Continuous | 64.2 years STANDARD_DEVIATION 7.8 | 64.1 years STANDARD_DEVIATION 7.8 | 63.9 years STANDARD_DEVIATION 7.7 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 8 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 187 Participants | 395 Participants | 208 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 4 Participants | 5 Participants | 1 Participants |
| Meeting ACC/AHA Criteria for Statin Therapy 10-year ASCVD risk >= 7.5% | 171 Participants | 367 Participants | 196 Participants |
| Meeting ACC/AHA Criteria for Statin Therapy ASCVD | 52 Participants | 98 Participants | 46 Participants |
| Meeting ACC/AHA Criteria for Statin Therapy Diabetes | 47 Participants | 98 Participants | 51 Participants |
| Meeting ACC/AHA Criteria for Statin Therapy LDL-C > 190 mg/dL | 5 Participants | 11 Participants | 6 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 25 Participants | 50 Participants | 25 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 7 Participants | 11 Participants | 4 Participants |
| Race (NIH/OMB) White | 156 Participants | 341 Participants | 185 Participants |
| Region of Enrollment United States | 193 Participants | 408 Participants | 215 Participants |
| Sex: Female, Male Female | 9 Participants | 25 Participants | 16 Participants |
| Sex: Female, Male Male | 184 Participants | 383 Participants | 199 Participants |
| SLCO1B1 Genotype Decrease function (T/C) | 40 Participants | 110 Participants | 70 Participants |
| SLCO1B1 Genotype Normal function (T/T) | 148 Participants | 288 Participants | 140 Participants |
| SLCO1B1 Genotype Poor function (C/C) | 5 Participants | 10 Participants | 5 Participants |
| Smokers | 59 Participants | 137 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 8 / 193 | 5 / 215 |
| other Total, other adverse events | 0 / 193 | 0 / 215 |
| serious Total, serious adverse events | 0 / 193 | 0 / 215 |
Outcome results
Primary
12-Month Change in LDL Cholesterol
The primary CVD prevention outcome is 12-month change in low-density lipoprotein (LDL) cholesterol, defined as LDL value at 12 months minus LDL value at baseline.
Time frame: 12 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| PGx+ | 12-Month Change in LDL Cholesterol | -1.1 mg/dL | Standard Error 1.2 |
| PGx- | 12-Month Change in LDL Cholesterol | -2.2 mg/dL | Standard Error 1.3 |
Secondary
Number of Participants Meeting Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Safe Simvastatin Prescription at 12 Months
Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend specific simvastatin doses when a patient's SLCO1B1 genotype is known. The investigators will compare each patient's medication prescriptions one year after enrollment to this guideline to generate a 2-level safety outcome (potentially safe vs. potentially unsafe simvastatin prescription) for each participant.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PGx+ | Number of Participants Meeting Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Safe Simvastatin Prescription at 12 Months | 193 Participants |
| PGx- | Number of Participants Meeting Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for Safe Simvastatin Prescription at 12 Months | 215 Participants |
Secondary
Number of Participants With an American College of Cardiology/American Heart Association (ACC/AHA) Guideline Concordant Statin Prescription at 12 Months
In 2013, the ACC/AHA endorsed guidelines that recommended prescribing statins of specific intensities (moderate or high) for distinct populations. Using patient characteristics and prescription data, the investigators will generate a 2-level CVD prevention outcome (concordant vs. non-concordant) for each participant, a measure of whether a patient's statin prescription is adequate for his/her level of CVD risk.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PGx+ | Number of Participants With an American College of Cardiology/American Heart Association (ACC/AHA) Guideline Concordant Statin Prescription at 12 Months | 12 Participants |
| PGx- | Number of Participants With an American College of Cardiology/American Heart Association (ACC/AHA) Guideline Concordant Statin Prescription at 12 Months | 14 Participants |
Secondary
Number of Participants With Chart Review Documented Statin-related Myotoxicity at 12 Months
Chart review of all patient notes during the 12 months after enrollment will be used to determine the proportion of patients in each arm who experienced statin-related muscle side effects during the observation period.
Time frame: 12 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PGx+ | Number of Participants With Chart Review Documented Statin-related Myotoxicity at 12 Months | 2 Participants |
| PGx- | Number of Participants With Chart Review Documented Statin-related Myotoxicity at 12 Months | 3 Participants |
Other Pre-specified
Number of Participants Recalling Pharmacogenetic Testing at 12 Months
Assessed by phone survey 12 months after enrollment. Whether patient remembers receiving PGx results from provider and, if so, remembers the results and interpretation.
Time frame: 12 months
Population: Result recall only assessed in intervention arm participants. Control participants received results 12 months after enrollment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PGx+ | Number of Participants Recalling Pharmacogenetic Testing at 12 Months | 11 Participants |
Other Pre-specified
Number of Participants Reporting Statin-related Muscle Side Effects at 12 Months
Assessed by phone survey 12 months after enrollment. Whether patient attributes muscle pains, weakness, or cramps to a statin taken in the prior 12 months.
Time frame: 12 months
Population: Data analyzed only for patients who completed the 12-month end-of-study survey.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PGx+ | Number of Participants Reporting Statin-related Muscle Side Effects at 12 Months | 3 Participants |
| PGx- | Number of Participants Reporting Statin-related Muscle Side Effects at 12 Months | 3 Participants |
Other Pre-specified
Participant Response Distributions to Belief in Medications Questionnaire at 12 Months
Assessed by phone survey 12 months after enrollment. Consists of 2 items: Do you agree or disagree with these statements?: My health in the future will depend on my medicines and Medicines do more harm than good.
Time frame: 12 months
Population: Data analyzed only for patients who completed the 12-month end-of-study survey.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| PGx+ | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | My health in the future will depend on my medicines. | Agree | 65 Participants |
| PGx+ | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | My health in the future will depend on my medicines. | Strongly agree | 28 Participants |
| PGx+ | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | My health in the future will depend on my medicines. | Uncertain | 29 Participants |
| PGx+ | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | My health in the future will depend on my medicines. | Disagree | 29 Participants |
| PGx+ | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | My health in the future will depend on my medicines. | Strongly disagree | 17 Participants |
| PGx+ | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | Medicines do more harm than good. | Strongly agree | 9 Participants |
| PGx+ | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | Medicines do more harm than good. | Agree | 26 Participants |
| PGx+ | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | Medicines do more harm than good. | Uncertain | 46 Participants |
| PGx+ | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | Medicines do more harm than good. | Disagree | 63 Participants |
| PGx+ | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | Medicines do more harm than good. | Strongly disagree | 24 Participants |
| PGx- | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | Medicines do more harm than good. | Uncertain | 56 Participants |
| PGx- | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | Medicines do more harm than good. | Strongly agree | 10 Participants |
| PGx- | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | My health in the future will depend on my medicines. | Strongly agree | 30 Participants |
| PGx- | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | My health in the future will depend on my medicines. | Agree | 84 Participants |
| PGx- | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | Medicines do more harm than good. | Strongly disagree | 28 Participants |
| PGx- | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | My health in the future will depend on my medicines. | Uncertain | 37 Participants |
| PGx- | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | Medicines do more harm than good. | Agree | 20 Participants |
| PGx- | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | My health in the future will depend on my medicines. | Disagree | 40 Participants |
| PGx- | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | Medicines do more harm than good. | Disagree | 89 Participants |
| PGx- | Participant Response Distributions to Belief in Medications Questionnaire at 12 Months | My health in the future will depend on my medicines. | Strongly disagree | 12 Participants |