Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry – Informing optimal antiplatelet strategies

Abstract

Dual antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a CYP2C19 no‐function allele that reduces the effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have shown improved outcomes with the integration of CYP2C19 genotyping into clinical care to guide the selection of prasugrel or ticagrelor in CYP2C19 no‐function allele carriers. However, the influence of patient‐specific demographic, clinical, and other genetic factors on outcomes with genotype‐guided DAPT has not been defined. In addition, the impact of genotype‐guided de‐escalation from prasugrel or ticagrelor to clopidogrel in patients without a CYP2C19 no‐function allele has not been investigated in a diverse, real‐world clinical setting. The Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry is a multicenter US registry of patients who underwent PCI and clinical CYP2C19 testing. The registry is enrolling a diverse population, assessing atherothrombotic and bleeding events over 12 months, collecting DNA samples, and conducting platelet function testing in a subset of patients. The registry aims to define the influence of African ancestry and other patient‐specific factors on clinical outcomes with CYP2C19‐guided DAPT, evaluate the safety and effectiveness of CYP2C19‐guided DAPT de‐escalation following PCI in a real‐world setting, and identify additional genetic influences of clopidogrel response after PCI, with the ultimate goal of establishing optimal strategies for individualized antiplatelet therapy that improves outcomes in a diverse, real‐world population.

Study Highlights.

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

CYP2C19 genotype is associated with reduced clopidogrel effectiveness following PCI. Both randomized controlled trials and observational studies have demonstrated improved outcomes with CYP2C19‐guided antiplatelet therapy after PCI.

• WHAT QUESTIONS DID THIS STUDY ADDRESS?

The Precision PCI registry aims to (1) define the influence of African ancestry and other patient‐specific factors on clinical outcomes with CYP2C19‐guided antiplatelet therapy after PCI; (2) evaluate the safety and effectiveness of CYP2C19‐guided de‐escalation of antiplatelet therapy following PCI in a real‐world setting; and (3) elucidate the effect(s) of genetic variants beyond CYP2C19 no‐function alleles on platelet reactivity and clinical outcomes with clopidogrel after PCI.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

This study will provide outcomes data with CYP2C19‐guided therapy in African ancestry patients and with CYP2C19‐guided de‐escalation of antiplatelet therapy in a diverse real‐world population. This study will also expand our understanding of genetic associations with clopidogrel response.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Data from the registry will inform improved precision medicine approaches to antiplatelet drug selection, leading to improved clinical outcomes after PCI.

INTRODUCTION

An estimated 434,000 percutaneous coronary intervention (PCI) procedures are performed annually in the US. ¹ Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y₁₂ inhibitor (clopidogrel, ticagrelor, or prasugrel) is indicated after PCI to prevent major adverse cardiovascular events (MACE). ² Compared with clopidogrel, prasugrel and ticagrelor have more consistent antiplatelet effects and were superior in preventing MACE following an acute coronary syndrome (ACS). ³ , ⁴ , ⁵ , ⁶ Thus, clinical guidelines state that it is reasonable to use prasugrel or ticagrelor over clopidogrel in ACS patients undergoing PCI. ⁷ However, prasugrel and ticagrelor have higher bleeding risks that in addition to ticagrelor‐evoked dyspnea and financial considerations, lead to higher rates of discontinuation and limit their widespread use. ⁵ , ⁶ , ⁸ , ⁹ Moreover, neither is indicated after elective PCI in chronic coronary syndrome patients. Thus, while the use of prasugrel and ticagrelor has increased, clopidogrel remains the most commonly prescribed P2Y₁₂ inhibitor, especially among older patients. ¹⁰ , ¹¹

Clopidogrel is a prodrug that requires bioactivation by the CYP2C19 enzyme. Approximately, 30% of the US population carries a CYP2C19 no‐function (also called loss‐of‐function) allele. ¹² Compared with patients without a no‐function allele, no‐function allele carriers have lower active metabolite concentrations, reduced inhibition of platelet aggregation, and increased risk for MACE after PCI with clopidogrel. ¹³ , ¹⁴ CYP2C19 genotype does not alter the clinical effectiveness of prasugrel or ticagrelor, which may have contributed to their superior efficacy in clinical trials. ¹⁵ , ¹⁶ The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines recommend avoiding clopidogrel, and instead, using either prasugrel or ticagrelor in CYP2C19 poor metabolizers (PMs) with two no‐function alleles and intermediate metabolizers (IMs) with one no‐function allele in the absence of contraindications. ¹²

Based on strong and consistent evidence of CYP2C19 no‐function allele associations with clopidogrel effectiveness, our institutions were early adopters of clinical CYP2C19 genotyping to guide a more precise selection of DAPT after PCI. ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ On behalf of the Implementing GeNomics In PracTicE (IGNITE) Network, we led a multi‐site investigation of outcomes with implementation of CYP2C19‐guided therapy in clinical practice, which showed a significantly lower risk for MACE with CYP2C19‐guided use of prasugrel or ticagrelor in no‐function allele carriers compared with continued use of clopidogrel in a real‐world clinical setting. ²¹ , ²² In contrast, there was no difference in outcomes between PCI patients treated with prasugrel or ticagrelor and those without a no‐function allele treated with clopidogrel. These real‐world data are in line with randomized clinical trials of CYP2C19‐guided therapy. Specifically, the TAILOR PCI trial showed a 34% reduction in risk for MACE at 12 months with genotype‐guided escalation (i.e., prescribing prasugrel or ticagrelor vs. clopidogrel in patients with a no‐function allele), which just missed achieving statistical significance [adjusted hazard ratio (HR) 0.66, p = 0.056] likely because fewer events occurred than expected. ²³ The POPular Genetics trial showed that CYP2C19‐guided use of prasugrel or ticagrelor in no‐function allele carriers and clopidogrel in those without a no‐function allele was non‐inferior to universal ticagrelor or prasugrel with regard to the composite outcome of major thrombotic and bleeding events and superior with regard to decreased bleeding events requiring clinical intervention. ²⁴

Despite this accumulating evidence, important gaps remain, including the benefit of genotype‐guided therapy in patients of African ancestry, who represent ~9–14% of the US PCI population, yet comprise less than 3% of trial populations of genotype‐guided DAPT. ²⁵ , ²⁶ In addition, little is known about other patient‐specific factors, such as comorbidities and genetic factors beyond CYP2C19 no‐function alleles, that influence outcomes with CYP2C19 genotype‐guided therapy and thus should be considered to more precisely tailor P2Y₁₂ inhibitor selection. Moreover, the safety and effectiveness of switching from prasugrel or ticagrelor to less potent therapy with clopidogrel, a process referred to as de‐escalation, in a real‐world population with multiple indications for PCI and risk factors for thrombotic and bleeding events is unknown. ²⁷ The Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry (Clinical Trials.gov identifier: NCT06143709) will address these gaps in the evidence in a diverse population of at least 6000 patients who underwent PCI and CYP2C19 genotyping in a real‐world clinical setting.

METHODS

Study objectives

The primary aims of the Precision PCI registry are to (1) define the influence of African ancestry and other patient‐specific factors on clinical outcomes with CYP2C19‐guided DAPT after PCI in a real‐world setting; (2) evaluate the safety and effectiveness of CYP2C19‐guided de‐escalation of DAPT following PCI in a real‐world setting; and (3) elucidate the effect(s) of genetic variants beyond CYP2C19 no‐function alleles on platelet reactivity and clinical outcomes with clopidogrel after PCI. These aims will address several hypotheses related to CYP2C19‐guided P2Y₁₂ inhibitor selection. We specifically hypothesize that CYP2C19‐guided P2Y₁₂ inhibitor selection lowers risk of major atherothrombotic events vs. use of clopidogrel in African ancestry patients and that de‐escalation to clopidogrel in real‐world patients without a CYP2C19 no‐function allele is associated with no significant difference in risk of major atherothrombotic events compared with continued use of prasugrel or ticagrelor. We also hypothesize that genetic variants beyond CYP2C19 no‐function alleles provide additional contribution to inter‐patient variability in antiplatelet response and clinical outcomes with clopidogrel after PCI.

Study design and population

This registry will use observational study methods to analyze data from at least 6000 patients from four sites: University of Florida, Gainesville (UF‐GNV); University of Florida, Jacksonville (UF‐JAX); University of North Carolina, Chapel Hill (UNC‐CH); and University of Maryland, Baltimore (UMB). Genotyping strategies at each site have been described. ²⁸ Briefly, CYP2C19 genotyping is completed in a College of American Pathologist/Clinical Laboratory Improvement Amendments accredited laboratory, with results reported in the electronic health record (EHR). Alleles tested across sites are given in Table 1. At UF‐JAX, the genotyping order was added to the cardiac catheterization order set in 2020 as a pre‐selected test. Genotyping at other sites (UF‐GNV, UNC‐CH, UMB) is at the discretion of the ordering physician. For example, physicians at UNC generally reserve testing for patients with PCI for ACS or stable coronary disease with high‐risk anatomic features. CYP2C19 metabolizer phenotype is assigned across sites as per CPIC guidelines (Table 2). ¹²

TABLE 1.

CYP2C19 alleles genotyped across sites.

Institution	Platform	CYP2C19 allele tested
University of Florida Health, Gainesville	Custom Taqman assay, ThermoFisher (Waltham, MA)	*2, *3, *4, *5, *6, *8, *10, *17
University of Florida Health, Jacksonville	Spartan RX, Spartan Biosciences Inc (Ottawa, ON) (4/2016 to 12/2021)	*2, *3, *17
	Custom Taqman assay, ThermoFisher (Waltham, MA) (07/2020 to present)	*2, *3, *17
University of North Carolina, Chapel Hill	Custom Taqman assay, ThermoFisher (Waltham, MA)	*2, *3, *17
University of Maryland, Baltimore	Custom Taqman assay, ThermoFisher (Waltham, MA)	*2, *3, *4, *6, *8, *17

TABLE 2.

CYP2C19 phenotype assignment.

Phenotype	Genotype description	Example genotype(s)
Poor metabolizer	Two no‐function alleles	*2/*2, *2/*3
Intermediate metabolizer	One no‐function allele and one normal or increased function allele	*1/*2, *1/*3, *2/*17
Normal metabolizer	Two normal function alleles	*1/*1
Rapid metabolizer	One increased function and one normal function allele	*1/*17
Ultrarapid metabolizer	Two increased function alleles	*17/*17

There are minimal entry criteria for the registry to maximize the generalizability of results. Adults ≥18 years of age who undergo PCI for any indication with an order for clinical CYP2C19 genotyping and are treated with DAPT including a P2Y₁₂ inhibitor (clopidogrel, prasugrel, or ticagrelor) plus aspirin are eligible. Patients treated with a combination of a P2Y₁₂ inhibitor plus an oral anticoagulant are also eligible. Patients managed surgically or treated with thrombolysis within 48 hours are excluded. At least 1600 patients will be enrolled prospectively (hereafter referred to as the new cohort); their data will be combined with an existing dataset of 4404 patients who also underwent PCI and CYP2C19 genotyping across sites (hereafter referred to as the existing cohort, Figure 1).

FIGURE 1.

Precision PCI study cohort. DAPT, dual antiplatelet therapy; EHR, electronic health record; PCI, percutaneous coronary intervention; PFT, platelet function testing.

Protocol for the new cohort

Patients are being enrolled into the new cohort at the UF‐GNV, UF‐JAX, and UNC‐CH sites. After obtaining written, informed consent, a 3‐mL blood sample or mouthwash sample is collected for DNA isolation and genotyping for Aim 3. Patients are also asked to consent to the storage of their samples for future research. Per clinical care at each institution, CYP2C19 results are returned in the EHR, and prasugrel or ticagrelor is recommended in both IMs and PMs regardless of PCI indication, in line with CPIC recommendations, in the absence of contraindications, as has been described. ¹² , ²⁸ However, the ultimate choice of P2Y₁₂ inhibitor therapy is left to the prescriber's discretion as per standard practice at each site and consistent with the observational study design. Platelet function testing is being conducted for a subset of 500 clopidogrel‐treated patients. Blood samples for platelet function testing are obtained at least 2 weeks after clopidogrel initiation and 24 ± 2 h after the last clopidogrel dose. Testing is done on a VerifyNow P2Y₁₂ point‐of‐care instrument (Werfen, Bedford, MA). Study procedures and data collection for the new cohort are approved by the University of Florida Institutional Review Board (IRB), as the single IRB for the study.

Data Collection

The data collection timeline is shown in Figure 2. For the new cohort, baseline data at the time of the index PCI (i.e., PCI associated with CYP2C19 genotyping) are obtained from the EHR and include PCI indication, angiographic, and procedural features (e.g., location of PCI, stent type), CYP2C19 genotype, discharge diagnoses, and medications on admission, during hospitalization, and at discharge. Self‐reported race, socioeconomic status (including education, income and occupation, per recommendations by the National Committee on Vital and Health Statistics), ²⁹ and health insurance type are collected via patient interview. Patient follow‐up is completed at one, six, and 12 months after the index PCI or until DAPT discontinuation. Follow‐up is completed via telephone call and EHR review to assess for hospitalizations and medication changes. Medication data are also collected through EHR review at one, six, and 12 months and the time of each documented clinical event, with the time of switches in DAPT recorded. Medication data, particularly the patient's current P2Y₁₂ inhibitor therapy, and adherence to DAPT, are verified by a patient interview via a telephone call. Data collection and storage are completed using a standardized and secure REDCap electronic data capture tool hosted locally at each site. ³⁰

FIGURE 2.

Data collection. DAPT, dual antiplatelet therapy; MI, myocardial infarction; PCI, percutaneous coronary intervention.

For the existing cohort, data were retrospectively collected via manual abstraction from the EHR for patients from the UF‐GNV, UNC‐CH, and UMB sites and prospectively collected via telephone calls and EHR review from the UF‐JAX site. Baseline data were abstracted from the index PCI admission, as described for the new cohort, using a standardized data collection tool. Race, as reported in the EHR, was also collected. In addition to data collection, the UF‐JAX site collected DNA samples for future genetic analysis. All study and data collection procedures for the existing cohort were approved by the IRB at each site. Analyses of data from the existing cohort have been recently published. ³¹ , ³² , ³³ , ³⁴

Study end points

The primary end point is major atherothrombotic events, defined as the composite of cardiovascular death, myocardial infarction, ischemic stroke, stent thrombosis, and unstable angina requiring revascularization, over 12 months following PCI. The secondary end point is “net clinical benefit,” defined as major atherothrombotic events or clinically significant bleeding (moderate or severe/life‐threatening bleeding according to GUSTO criteria). ³⁵ Additional end points are MACE (composite of cardiovascular death, MI, ischemic stroke, and stent thrombosis), individual components of the primary end point, clinically significant bleeding, and all‐cause death. Events are defined according to consensus definitions. ³⁵ , ³⁶ , ³⁷ For both cohorts, hospitalization records are reviewed by independent cardiologists at each site to verify atherothrombotic and bleeding events. ³⁵ , ³⁶ Deaths will be assessed by query of the National Death Index (NDI) and North Carolina state death index after enrollment is completed.

Data analysis

Data will be curated, aggregated, and analyzed by UF‐GNV investigators. The primary analysis of outcomes with CYP2C19 genotype‐guided DAPT in African ancestry patients will focus on patients who self‐report (for prospectively enrolled patients) or are documented in the EHR (for the existing cohort) as Black or African American, as we have previously described. ³³ Our rationale for this is twofold: (1) genetic samples are only available for a subset of patients, limiting the cohort for whom genetic ancestry can be assessed; and (2) previous studies of outcomes with genotype‐guided therapy have also used self‐reported race. ²¹ , ²³ , ²⁴ , ³⁸ However, recognizing that race is a social construct, a future analysis focused on genetic ancestry is planned. Clinical characteristics and outcomes will be compared between no‐function allele carriers on clopidogrel vs. alternative therapy and between noncarriers on clopidogrel vs. alternative therapy. We will use logistic regression to construct propensity scores that estimate the probability of being on clopidogrel or alternative therapy, conditional on baseline characteristics. Propensity scores will be estimated separately for each pair‐wise comparison. We will use stabilized inverse probability for treatment weights (SIPTW) to establish a pseudocohort after trimming patients with non‐overlapping scores, and assess standardized differences in baseline characteristics after applying the weights. Standardized differences smaller than 0.1 will be considered indicative of well‐balanced covariates. ³⁹ We will estimate adjusted HRs and 95% confidence intervals (CIs) for each comparison. We estimate that at least 1200 African ancestry patients will be included in the dataset, which will provide ≥80% power at an α = 0.05 (two‐sided) to detect a HR ≥2.32 for risk of atherothrombotic events between no‐function allele carriers treated with clopidogrel vs. alternative therapy, assuming that 35% of patients will carry a no‐function allele, 60% of no‐function allele carriers will be prescribed prasugrel or ticagrelor, and 11% will have an atherothrombotic event based on previous data. ¹² , ²¹ , ⁴⁰ We expect that similar to data in other populations, patients with a no‐function allele treated with clopidogrel vs. alternative therapy will experience more atherothrombotic events in the 12 months following PCI. Among patients without a no‐function allele, we expect there to be no difference in outcomes with clopidogrel vs. alternative therapy.

Other planned analyses include the evaluation of the predictive properties of the ABCD‐GENE score across ancestry groups, focusing on clopidogrel‐treated patients. This score includes CYP2C19 genotype and clinical factors (age > 75 years, body mass index >30 kg/m², chronic kidney disease, and diabetes) independently associated with high platelet reactivity with clopidogrel. ⁴¹ We will also assess outcomes of CYP2C19‐guided de‐escalation of DAPT in patients initiated on prasugrel or ticagrelor during the index PCI. De‐escalation will be defined as a switch to clopidogrel at any timepoint after the index PCI. The primary comparison will be made between patients without a no‐function allele who are de‐escalated to clopidogrel vs. those who remain on alternative therapy. Similar to the analysis described above, for each end point and each pair‐wise comparison group, we will fit Cox proportional hazard models, weighted by SIPTWs that consider baseline characteristics as well as time‐varying characteristics that might be relevant for switching decisions. Finally, we will utilize a pathway‐based approach to interrogate single‐nucleotide polymorphisms across gene regions for proteins in the clopidogrel pharmacokinetic and platelet aggregation pathways for their association with both platelet reactivity and clinical outcomes with clopidogrel treatment after PCI in our diverse real‐world cohort. Data for pathway analysis will be generated using the Infinium Global Diversity Array (Illumina, San Diego, CA). Genetic associations with the primary outcome will be assessed with Cox proportional hazards regression under an additive genetic model.

For all analyses, discontinuation of or non‐adherence to antiplatelet therapy will be ascertained from clinical notes, prescribing records or patient interviews for prospectively enrolled patients. We may also consider linkage to administrative billing records for verification. Patients identified as having discontinued therapy will be censored. To guard against protopathic bias or reverse causation, we will compare patients who continued vs. discontinued therapy and consider the use of analytical methods such as inverse probability of censoring weights if indicated.

Progress to date

Patients in the existing cohort underwent PCI and CYP2C19 genotyping beginning in 2012. The first patient was enrolled into the new cohort on July 23, 2020. As of early March 2024, 1533 patients have been enrolled in the new cohort across sites. Characteristics of patients in each cohort are given in Table 3.

TABLE 3.

Characteristics of patients in the Precision PCI registry.

Characteristic	Existing cohort (n = 4404)	New cohort (n = 1533) a	Total (n = 5937)
Age > 75 years	649 (14.7)	241 (15.7)	890 (15.0)
Female sex	1476 (33.5)	471 (30.7)	1947 (32.8)
Race (by self‐report)
White	3158 (71.7)	1168 (76.2)	4326 (72.9)
Black or African American	994 (22.6)	273 (17.8)	1267 (21.3)
Other or Unknown b	252 (5.7)	92 (6.0)	344 (5.8)
BMI >30 kg/m2	2013 (45.7)	714 (46.6)	2727 (45.9)
PCI indication
ACS	3158 (71.7)	800 (52.2)	3958 (66.7)
STEMI	961 (21.8)	290 (18.9)	1251 (21.1)
NSTEMI	1306 (29.7)	320 (20.9)	1626 (27.4)
Unstable angina	891 (20.2)	190 (12.4)	1081 (18.2)
Stable coronary disease/Elective	1246 (28.3)	733 (47.8)	1979 (33.3)
Medical history
Hypertension	3567 (81.0)	1303 (85.0)	4870 (82.0)
Dyslipidemia	2817 (64.0)	1165 (76.0)	3982 (67.1)
Chronic kidney disease c	991 (22.5)	584 (38.1)	1575 (26.5)
Diabetes	1726 (39.2)	616 (40.2)	2342 (39.4)
Stroke/TIA	489 (11.1)	157 (10.2)	646 (10.9)
Atrial fibrillation	370 (8.4)	134 (8.7)	504 (8.5)
Prior revascularization	1348 (30.6)	575 (37.5)	2353 (39.6)
Prior stent	1251 (28.4)	459 (29.9)	1710 (28.8)
Prior CABG	430 (9.8)	123 (8)	553 (9.3)
Prior PTCA	97 (2.2)	36 (2.3)	133 (2.2)
P2Y12 inhibitor at discharge
Clopidogrel 75 mg/day	2648 (60.1)	701 (45.7)	3513 (59.2)
Prasugrel or Ticagrelor	1719 (39.0)	831 (54.2)	2407 (40.5)
High dose clopidogrel d	16 (0.4)	0 (0)	16 (0.3)
None e	21 (0.5)	1 (0.1)	22 (0.3)
Aspirin at discharge	4298 (97.6)	1437 (93.7)	5735 (96.6)
Oral anticoagulant at discharge	396 (9.0)	173 (11.3)	569 (9.6)
CYP2C19 metabolizer phenotype
Poor metabolizer	116 (2.6)	32 (2.1)	148 (2.5)
Intermediate metabolizer	1239 (28.1)	379 (24.7)	1618 (27.3)
Normal metabolizer	1727 (39.2)	614 (40.1)	2341 (39.4)
Rapid metabolizer	1134 (25.7)	383 (25.0)	1517 (25.6)
Ultrarapid metabolizer	188 (4.3)	60 (3.9)	248 (4.2)
Unknown f	0 (0)	65 (4.2)	65 (1.0)
Provided a genetic sample	1046 (23.8)	1387 (90.5)	2461 (41.5)

Note: Values are n (%).

Abbreviations: ACS, acute coronary syndrome; BMI, body mass index; CABG, coronary artery bypass grafting; NSTEMI, non‐ST‐segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; STEMI, ST‐segment elevation myocardial infarction; TIA, transient ischemic attack.

^a Enrollment as of March 15, 2024.

^b Detailed breakdown includes patients of the following self‐reported race: Existing cohort – American Indian or Alaska Native (n = 53), Asian (n = 42), multiple races (n = 4), Native Hawaiian or Other Pacific Islander (n = 6), or unknown (n = 147). New cohort – American Indian or Alaska Native (n = 45), Asian (n = 14), multiple races (n = 11), Native Hawaiian or Other Pacific Islander (n = 2), other race (n = 14), or unknown (n = 6).

^c Estimated glomerular filtration rate < 60 mL/min/1.73 m².

^d High dose clopidogrel defined as daily dose >75 mg; n = 14 were receiving 225 mg/day and n = 2 were receiving 150 mg/day.

^e Patients either died before discharge or the P2Y₁₂ inhibitor was not continued after discharge.

^f Order placed for clinical CYP2C19 genotyping but results were either inconclusive or never resulted (e.g., sample not collected in response to the order).

DISCUSSION

A more precise understanding of who to genotype, whether genotypes beyond CYP2C19 should be determined, and how to change DAPT based on genotype results is essential to optimize the impact of genotype‐guided DAPT. The Precision PCI registry will enhance generalizability of randomized controlled trial data of CYP2C19 genotype‐guided therapy by extending data to a diverse real‐world population. This registry will provide opportunities to address pragmatic questions that cannot be easily answered through randomized clinical trials, such as which patient‐specific factors influence outcomes with genotype‐guided therapy. In addition, DNA samples collected as part of the registry will provide the opportunity to identify additional variants influencing response to DAPT.

Self‐reported Black or African American race is associated with higher on‐clopidogrel platelet reactivity and risk of atherothrombotic events. ⁴² , ⁴³ CYP2C19 no‐function alleles are more common in those of African ancestry, in whom the *2 allele is an independent predictor of high on‐treatment platelet reactivity (HPR). ⁴⁰ , ⁴² Association studies demonstrating reduced clopidogrel effectiveness with CYP2C19 no‐function alleles and both clinical trials and observational studies showing the benefit of genotype‐guided DAPT have been conducted almost exclusively in non‐Black or non‐African American populations; although, in an observational study conducted on behalf of the IGNITE Network, 15.7% (n = 285) were self‐reported Black or African American. ²¹ , ²⁶ An exception was an analysis of post‐MI patients from the TRIUMPH registry, which included 1421 White and 333 Black patients (by self‐report) who underwent PCI and were discharged on clopidogrel, and suggested that the *2 allele conferred a higher risk of death and recurrent MI in White, but not Black patients. ⁴⁰ Conversely, the increased function *17 allele was associated with greater mortality and bleeding risk in Black but not White patients. ⁴⁰ These data highlight the need to specifically examine outcomes with CYP2C19‐guided DAPT selection across ancestry groups to ensure similar clinical benefit across populations and determine whether there may be population‐specific variants that may improve prediction of response to clopidogrel.

In the POPular Genetics and TAILOR PCI trials, DAPT was selected solely based on genotype; yet, other factors are known to influence clopidogrel response, including age, body size, chronic kidney disease, and diabetes. ⁴¹ The Precision PCI registry aims to examine the combination of patient‐specific factors that influence outcomes with clopidogrel in order to inform more precise prediction of clopidogrel effectiveness. To this end, we have shown that among patients in our existing cohort, an ABCD‐Gene score ≥ 10 predicted worse outcomes with clopidogrel treatment following PCI. ³¹ The Precision PCI registry will allow us to expand these results and examine outcomes based on the ABCD‐GENE score in African ancestry patients and other populations (e.g., patients with a chronic coronary syndrome indication for PCI). As a step toward this goal, we recently examined outcomes by CYP2C19 genotype among 567 clopidogrel‐treated, self‐reported Black or African American patients in our existing cohort. ³³ We found that similar to prior data in non‐Black populations, carriers of a no‐function allele had a higher rate of major atherothrombotic events compared with noncarriers.

Our registry will also enable the investigation of outcomes with genotype‐guided P2Y₁₂ inhibitor de‐escalation following PCI. Use of prasugrel or ticagrelor early after ACS and PCI when the risk for atherothrombotic events is greatest, followed by de‐escalation to clopidogrel for chronic therapy has become more common in practice, in an effort to reduce early risk for major atherothrombotic events and long‐term bleeding risk. ⁴⁴ , ⁴⁵ However, there remains a paucity of data on the safety and effectiveness of this approach in a real‐world setting. There are conflicting outcomes with an empiric (un‐guided) approach, with very early de‐escalation after ACS increasing the risk of recurrent atherothrombotic events. ⁴⁴ , ⁴⁶ De‐escalation guided by platelet function testing has been shown to be non‐inferior in terms of net clinical benefit (i.e., cardiovascular death, MI, stroke, or bleeding) compared with continued prasugrel treatment. ⁴⁷ However, the use of platelet function testing to guide drug selection may not be practical in a real‐world setting as patients must be started on more potent antiplatelet therapy, then de‐escalated to clopidogrel, then return for platelet function testing after reaching steady state, and then switched back to more potent therapy if there is high platelet reactivity with clopidogrel treatment. ⁴⁸ This approach also leaves patients who are poor responders to clopidogrel vulnerable to ischemic events during the de‐escalation period. Thus, it is important to determine whether genotyping is a safe and effective risk stratification tool to guide DAPT de‐escalation and achieve optimal outcomes after PCI. While POPular Genetics data support this approach, ²⁴ generalizability to real‐world settings is limited given its focus on patients with STEMI, who represent a small proportion of patients indicated for PCI (21% in our Precision PCI population, Table 3). In addition, the prevalence of cardiovascular and bleeding risk factors in POPular Genetics trial participants is lower compared with real‐world populations. For example, 10% of POPular Genetics participants had diabetes, 9% had chronic kidney disease, and 2% had a history of stroke. In contrast, 39%, 26.5%, and 11% of patients in our registry to date have diabetes, chronic kidney disease, and history of stroke, respectively. Our study will provide novel data on outcomes with CYP2C19‐guided de‐escalation of DAPT in a high‐risk population with multiple indications for PCI in the context of real‐world practice where de‐escalation is common.

Another means of de‐escalation that is emerging in practice is to stop aspirin and continue with a P2Y₁₂ inhibitor alone. ²⁷ This approach could leave those with a no‐function allele especially vulnerable if treated with clopidogrel monotherapy. Our registry may provide the opportunity to examine outcomes by CYP2C19 genotype with this approach to de‐escalation.

Finally, DNA samples from registry patients allow for studies of genetic associations with platelet reactivity and clinical outcomes among clopidogrel‐treated patients. While heritability has been shown to explain over 70% of the inter‐patient variability in clopidogrel response, the CYP2C19 no‐function genotype explains only a small portion of this. ⁴⁹ Previous investigators have identified variants in the CYP2C19, CYP2B6, CYP2C9, CES1, and PEAR1 genes associated with high platelet reactivity in clopidogrel‐treated patients. ⁵⁰ Using a genetic risk score approach, risk for MACE was shown to be greater among patients with a higher number of variant alleles in these genes. These findings support polygenic associations with clopidogrel response but require confirmation in an independent population. Our population will serve as an independent population in which to replicate these associations as well as identify additional variants associated with clopidogrel response.

CONCLUSIONS

The Precision PCI registry aims to elucidate the key factors that influence outcomes with genotype‐guided DAPT after PCI in a diverse real‐world setting. The data generated from the registry will advance recent clinical trial data by addressing critical pragmatic questions, especially regarding outcomes with genotype‐guided therapy in underrepresented populations and the benefit of genotype‐guided de‐escalation in real‐world practice. Moreover, the registry will be a resource for examining genetic associations with outcomes during antiplatelet therapy after PCI. The knowledge gained from this registry is expected to inform better precision medicine approaches to DAPT, leading to improved patient outcomes after PCI.

AUTHOR CONTRIBUTIONS

L.H.C. and C.R.L. wrote the manuscript. L.H.C., C.R.L., F.F., E.C.K., J.S.R., Y.G., C.W.M., P.S., J.N.T., A.L.B., A.G.W., G.A.S., and D.J.A. designed the research. L.H.C., C.R.L., F.F., E.C.K., J.S.R., C.D.T., P.S., M.J.A.S., L.B., N.K., J.M., I.R.M., A.B.N., J.N.T., G.T., A.L.B., G.A.S., and D.J.A performed the research. L.H.C., C.R.L., C.D.T., Y.G., and C.W.M. analyzed the data.

FUNDING INFORMATION

This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute (1R01HL149752), National Human Genome Research Institute (U01HG007269), National Center for Advancing Translational Sciences (UM1TR004406, UL1TR001427), and Werfen (Bedford, MA). Spartan Bioscience Inc. (Ottawa, ON) provided the genotyping platforms and kits for initial testing at the UF Health Jacksonville site. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

CONFLICT OF INTEREST STATEMENT

F.F. has received consulting fees or honoraria from AstraZeneca; his institution has received research grants from PLx Pharma and the Scott R. MacKenzie Foundation. P.S. has received consulting fees from Medosome Biotech; A.G.W has received consulting fees from Arbor Pharmaceuticals, Bayer KG, Ipsen Pharmaceuticals and Genentech. Her institution has received funding for research for which she served as principal investigator from Merck, Sharpe and Dohme. D.J.A. has received consulting fees or honoraria from Abbott, Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi‐Sankyo, Eli Lilly, Faraday, Haemonetics, Janssen, Merck, Novartis, NovoNordisk, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura; his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi‐Sankyo, Eisai, Eli Lilly, Faraday, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, Osprey Medical, Renal Guard Solutions, and the Scott R. MacKenzie Foundation. All other authors declared no competing interests for this work.

Cavallari LH, Lee CR, Franchi F, et al. Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry – Informing optimal antiplatelet strategies. Clin Transl Sci. 2024;17:e70004. doi: 10.1111/cts.70004