The Integrating Pharmacogenetics in Clinical Care (I-PICC) Study: Protocol for a point-of-care randomized controlled trial of statin pharmacogenetics in primary care

Abstract

Background: The association between the SLCO1B1 rs4149056 variant and statin-associated muscle symptoms (SAMS) is well validated, but the clinical utility of its implementation in patient care is unknown.

Design: The Integrating Pharmacogenetics in Clinical Care (I-PICC) Study is a pseudo-cluster randomized controlled trial of SLCO1B1 genotyping among statin-naïve primary care and women's health patients across the Veteran Affairs Boston Healthcare System. Eligible patients of enrolled primary care providers are aged 40-75 and have elevated risk of cardiovascular disease by American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Patients give consent by telephone in advance of an upcoming appointment, but they are enrolled only if and when their provider co-signs an order for SLCO1B1 testing, performed on a blood sample already collected in clinical care. Enrolled patients are randomly allocated to have their providers receive results through the electronic health record at baseline (PGx + arm) versus after 12 months (PGx- arm). The primary outcome is the change in low-density lipoprotein cholesterol (LDL-C) after one year. Secondary outcomes are concordance with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for simvastatin prescribing, concordance with ACC/AHA guidelines for statin use, and incidence of SAMS. With 408 patients, the study has >80% power to exclude a between-group LDL-C difference of 10 mg/dL (non-inferiority design) and to detect between-group differences of 15% in CPIC guideline concordance (superiority design).

Conclusion: The outcomes of the I-PICC Study will inform the clinical utility of preemptive SLCO1B1 testing in the routine practice of medicine, including its proposed benefits and unforeseen risks.

Keywords: Cardiovascular disease; Pharmacogenetics; Precision medicine; Statin-associated muscle symptoms.

Published by Elsevier Inc.

Figures

Figure 1:

Map of VA Boston Healthcare System locations

Figure 2:. Major recommendations from the 2013 ACC/AHA guidelines (adapted from ).

ASCVD, atherosclerotic cardiovascular disease; HDL, high-density lipoprotein; LDL-C, low-density lipoprotein cholesterol.

Fig. 3.. Design of the I-PICC Study.

Abbreviations: CDW, Corporate Data Warehouse; EHR, electronic health record. * Provider may request that patient be removed from eligible pool.

Figure 4:

Examples of two study-related clinical alerts delivered to providers through the electronic health record in the I-PICC Study: 1) a provider informed consent note allowing the provider to sign and enroll in the study and 2) a SLCO1B1 genotyping order for the provider to sign for a specific consented patient when a clinical blood sample is available, enrolling the patient in the study.

Figure 5:

Example of SLCO1B1 results in EHR of an enrolled patient in the I-PICC Study. A clinical alert notifies the enrolled primary care provider that the result is available, but all other members of patient care team may view the results in the laboratory section of the EHR.

Figure 6:

Possible categories of statin safety and CVD prevention among patients and the potential impact of SLCO1B1 testing on these outcomes (see text).