2025 Acute Coronary Syndrome Guideline: Missing the Boat on CYP2C19 Genotyping

Abstract

The 2025 American College of Cardiology/American Heart Association/American College of Emergency Physicians/National Association of Emergency Medical Services Physicians/Society for Cardiovascular Angiography & Interventions acute coronary syndrome guideline focuses on strategies to reduce bleeding risk with antiplatelet therapy yet lacks any recommendation related to CYP2C19 genotyping. The impact of CYP2C19 loss‐of‐function alleles on the effectiveness of clopidogrel is well documented, and although prasugrel and ticagrelor more effectively reduce the risk for atherothrombotic events compared with clopidogrel in patients with a CYP2C19 loss‐of‐function allele, clopidogrel reduces bleeding risk without an increase in atherothrombotic events compared with prasugrel or ticagrelor in those without a loss‐of‐function allele. Accordingly, an American Heart Association Scientific Statement supports CYP2C19 genetic testing before oral P2Y₁₂ inhibitors are prescribed. This commentary summarizes the evidence in support of CYP2C19‐guided P2Y₁₂ inhibitor selection in the context of other 2025 acute coronary syndrome guideline recommendations and urges future guidelines to incorporate recommendations for CYP2C19 genotyping, especially for those at high bleeding risk.

Nonstandard Abbreviations and Acronyms

DAPT

dual antiplatelet therapy

LOF

loss‐of‐function

MACE

major adverse cardiovascular events

The recently published American College of Cardiology/American Heart Association (AHA)/American College of Emergency Physicians/National Association of Emergency Medical Services Physicians/Society for Cardiovascular Angiography & Interventions acute coronary syndrome (ACS) guideline provides important updates on the selection and duration of oral P2Y₁₂ inhibitor therapy as well as on a number of contemporary dual antiplatelet therapy (DAPT) modulation strategies. ¹ However, the guideline lacks any recommendation related to CYP2C19 genotyping or use of CYP2C19 results to guide oral P2Y₁₂ inhibitor selection. This is despite the well accepted impact of CYP2C19 loss‐of‐function (LOF) alleles on clopidogrel bioactivation and platelet inhibitory effects as well as numerous outcome studies documenting reduced clopidogrel effectiveness at preventing major adverse cardiovascular events (MACE) and stent thrombosis after percutaneous coronary intervention (PCI) in patients with a CYP2C19 LOF genotype. ² The guideline recommends prasugrel and ticagrelor in patients with ACS and PCI, with clopidogrel recommended when prasugrel or ticagrelor is unavailable, cannot be tolerated, or is contraindicated. ¹ The latter is an important issue as both prasugrel and ticagrelor are associated with higher bleeding risk compared with clopidogrel. This, in addition to higher cost, even with the availability of a generic version of ticagrelor, and the commonly observed side effect of ticagrelor‐induced dyspnea, leads to higher discontinuation rates of both ticagrelor and prasugrel compared with clopidogrel. Because of these considerations, clopidogrel remains widely used even in patients with ACS.

CYP2C19 genotype was not considered in landmark trials that showed superiority of prasugrel and ticagrelor over clopidogrel. However, subsequent clinical trials, observational studies, and meta‐analyses demonstrated that, although ticagrelor or prasugrel reduces the risk of MACE compared with clopidogrel in CYP2C19 LOF allele carriers (~30% of the US population), clopidogrel is associated with a lower bleeding risk and no increase in MACE compared with prasugrel or ticagrelor in patients without a LOF allele (~70% of the population). ³ Based on the totality of evidence, an AHA Scientific Statement published in 2024 concluded that the current data support the benefit of CYP2C19 genetic testing before oral P2Y₁₂ inhibitors are prescribed in patients with ACS or PCI. ⁴ This follows warnings from US and European regulatory agencies, including a boxed warning (ie, highest safety‐related warning) on the Food and Drug Administration‐approved clopidogrel labeling, about reduced clopidogrel effectiveness in LOF allele carriers and Clinical Pharmacogenetic Implementation Consortium guidelines that strongly recommend avoiding clopidogrel in LOF allele carriers (also referred to as CYP2C19 intermediate and poor metabolizers) following ACS or PCI. ² Further support of CYP2C19 testing to guide oral P2Y₁₂ inhibitor prescribing in selected settings is provided in a 2024 international expert consensus statement. ⁵

A major focus of the 2025 American College of Cardiology/AHA/American College of Emergency Physicians/National Association of Emergency Medical Services Physicians/Society for Cardiovascular Angiography & Interventions ACS guideline is on strategies to reduce bleeding with antiplatelet therapy especially by modulating (ie, reducing) the intensity of platelet inhibition, also known as deescalation. This includes Class 1, Level of Evidence A recommendation to transition from DAPT with ticagrelor plus aspirin to ticagrelor monotherapy ≥1 month after PCI as well as a Class 2b, Level of Evidence B‐R recommendation to de‐escalate DAPT in an unguided fashion (ie, without platelet function or genetic testing) from ticagrelor or prasugrel to clopidogrel ≥1 month after PCI. For the latter, the ACS guideline cites 2 trials, TOPIC (Timing of Platelet Inhibition After Acute Coronary Syndrome) and TALOS‐AMI (Ticagrelor Versus Clopidogrel in Stabilized Patients With Acute Myocardial Infarction). ⁶ , ⁷ Both trials randomized patients with ACS who were treated with prasugrel or ticagrelor‐based DAPT for 1 month following PCI to either unguided switching to clopidogrel‐based DAPT or continued prasugrel or ticagrelor‐based DAPT. At 1 year post ACS, both trials showed a reduction in the primary composite outcome of net adverse clinical events (consisting of MACE plus bleeding) with unguided de‐escalation that was driven primarily by a reduction in bleeding. ⁶ , ⁷ However, both trials enrolled low‐risk patients with ACS, and the findings may not be generalizable to patients at higher ischemic risk, such as those undergoing complex PCI or those with poor clopidogrel responsiveness (eg, those with a CYP2C19 LOF genotype). ⁶ In addition, TOPIC was a single‐center study, and TALOS‐AMI was conducted in an East Asian population, further limiting generalizability given lower ischemic event rates and higher bleeding risk generally observed in this population. ⁵ The guideline also cites 2 meta‐analyses as additional support for unguided deescalation, despite that 1 analysis exclusively examined a guided (not an unguided) approach and the other included trials of both guided (by genotype or platelet function testing) and unguided deescalation strategies. ⁸ , ⁹

One could argue that the data supporting a CYP2C19 genotype‐guided approach to P2Y₁₂ inhibitor deescalation as a bleeding risk mitigation strategy are at least as strong as the data supporting an unguided approach. The multicenter POPular Genetics (CYP2C19 Genotype‐Guided Antiplatelet Therapy in ST‐Segment Elevation Myocardial Infarction Patients — Patient Outcome after Primary PCI) trial randomized patients undergoing PCI for ST‐segment–elevation myocardial infarction to CYP2C19‐guided deescalation of DAPT (switching to clopidogrel plus aspirin in LOF allele noncarriers and continuing ticagrelor or prasugrel plus aspirin for LOF allele carriers) or standard treatment with ticagrelor or prasugrel (plus aspirin). ¹⁰ Similar to TOPIC and TALOS‐AMI, POPular Genetics demonstrated a significant reduction in bleeding at 1 year with DAPT deescalation without a compromise in ischemic risk. However, in contrast to TOPIC and TALOS‐AMI, POPular Genetics was conducted in a population at high ischemic risk, and deescalation to clopidogrel occurred during the index PCI hospitalization supporting the safety of clopidogrel in the early period after PCI in high thrombotic risk patients (ie, ST‐segment–elevation myocardial infarction) without a LOF allele.

The POPular Genetics findings are supported by real‐world data of patients with ACS showing a reduction in bleeding without an increase in MACE with genotype‐guided deescalation. ¹¹ Additional observational data and meta‐analyses show no difference in ischemic risk with clopidogrel versus prasugrel or ticagrelor in patients without a CYP2C19 LOF allele who predominantly present with ACS and PCI, supporting the effectiveness of clopidogrel in this population. ³ , ⁸ , ¹² One meta‐analysis demonstrated a significant reduction in bleeding without an increase in ischemic events with guided deescalation among patients following PCI for ST‐segment–elevation myocardial infarction or non–ST‐segment–elevation myocardial infarction. ⁸ Another large meta‐analysis (including 15 trials and 61 898 patients with ACS) concluded that compared with standard unguided selection of P2Y₁₂ inhibitor therapy, P2Y₁₂ inhibitor selection guided by CYP2C19 genotyping or platelet function testing, provided the most favorable balance between safety and efficacy. ¹³ A third demonstrated a reduction in bleeding without a compromise in ischemic risk with both guided and unguided de‐escalation approaches compared with standard DAPT, and although bleeding rates were lower with unguided deescalation, this is expected since, with guided therapy, patients with a LOF variant (or high platelet reactivity) remain on prasugrel or ticagrelor versus universal deescalation. ¹⁴

The 2025 ACS guideline refers to 3 trials that evaluated guided deescalation, stating that these trials either showed “a lack of benefit, noninferiority, or reductions in minor bleeding.” ¹ The 2 trials cited as showing no benefit or noninferiority evaluated platelet function testing (PFT), not genotyping, as a means of guiding therapy. ¹⁵ , ¹⁶ The other trial cited, POPular Genetics, showed superiority for reducing clinically relevant bleeding, defined as bleeding requiring medical intervention, and also demonstrated the cost effectiveness of a genotype‐guided deescalation approach, which has since been replicated in a real‐world population. ³ , ¹⁰ It is important to note, that the outcomes of the 2 trials considered to support unguided deescalation to clopidogrel‐based DAPT were also driven by minor bleeding. ⁶ , ⁷ Similar to ticagrelor‐induced dyspnea, minor bleeds increase the likelihood of premature treatment discontinuation, which in turn, increases the risk for adverse clinical outcomes, including death. Genotype‐guided deescalation provides a safe way to mitigate this risk.

From a pharmacologic perspective, switching from prasugrel or ticagrelor to clopidogrel in patients with 2 CYP2C19 LOF alleles (ie, poor metabolizers), who cannot convert clopidogrel to its active metabolite is essentially equivalent to discontinuing P2Y₁₂ inhibitor therapy. A similar concern applies to patients with a single LOF allele (ie, intermediate metabolizers), for whom the evidence suggests cannot convert enough of the parent drug to its active form to provide sufficient antiplatelet effects and who also have an increased risk for MACE when treated with clopidogrel versus those without a LOF allele. ² Consequently, unguided switching to clopidogrel, particularly in high‐risk patients with ACS, exposes patients with inadequate platelet inhibition with clopidogrel to potential harm. This consideration becomes even more critical in the context of clopidogrel monotherapy, as it would leave some patients with little to no functional antiplatelet therapy. Further research on the risks of clopidogrel monotherapy following ACS in the absence of genotype or PFT information is warranted. Given the increase in bleeding risk with prasugrel and ticagrelor compared with clopidogrel and clinical trial and meta‐analyses data showing improved outcomes with a genotype‐guided approach to antiplatelet therapy, we posit that current evidence supports at least a Class 2b recommendation and possibly a Class 2a (ie, benefit outweighs risk), Level of Evidence B‐R (ie, evidence from ≥1 more trials or meta‐analyses) recommendation for a CYP2C19‐guided approach to deescalation of DAPT from prasugrel or ticagrelor to clopidogrel.

Several barriers to CYP2C19 genotyping posed as a basis for not integrating testing into practice have been removed. Genotyping is now widely available through many commercial laboratory vendors, and its use is clinical practice has increased in parallel with increasing insurance coverage. Notably, many states have now passed bills requiring insurers to cover biomarker testing. Genetic testing turnaround time could be a barrier for institutions that must send samples out for testing. However, deescalation in patients initially treated with prasugrel or ticagrelor can be initiated once genotype results become available, recognizing that delays in genotype turnaround time may prolong exposure to more potent therapy with higher bleeding risk. For more efficient turnaround, there is now a Food and Drug Administration‐cleared rapid genotyping platform, with results available in approximately 1 hour. A similar rapid genotyping platform was used in both the POPular Genetics and TAILOR‐PCI (Tailored Antiplatelet Therapy Following PCI) trials, allowing for initiation of genotype‐guided therapy within 24 hours of randomization for most patients. ¹⁰ , ¹⁷

Platelet function testing is also available as a rapid assay and may be considered as an alternative to genotyping to guide deescalation. ⁵ The TROPICAL‐ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes) trial examined a PFT‐guided deescalation approach following ACS, in which participants were started on prasugrel for 1 week and then switched to clopidogrel for 1 week before undergoing PFT. ¹⁶ In the absence of high platelet reactivity, clopidogrel was continued. Otherwise, participants were switched back to prasugrel. The trial demonstrated that a PFT‐guided deescalation approach was noninferior to continued prasugrel treatment for the primary end point of net adverse clinical events at 12 months. Use of genotyping or PFT allows for deescalation within days of PCI, whereas unguided deescalation is generally done at 1 to 3 months. A key advantage of PFT over genetic testing is that, as a direct measure of platelet aggregation, PFT results reflect both genetic and nongenetic influences of clopidogrel response. A disadvantage, however, is that patients must first be deescalated to clopidogrel and be on treatment until steady state antiplatelet effects are achieved with the potential for patients exhibiting high platelet reactivity to be switched back to the prasugrel or ticagrelor, whereas genotype results are not dependent on antiplatelet therapy. PFT results are also subject to variability over time, potentially necessitating repeat testing to ensure clopidogrel effectiveness is maintained.

In summary, the 2025 American College of Cardiology/AHA/American College of Emergency Physicians/National Association of Emergency Medical Services Physicians/Society for Cardiovascular Angiography & Interventions guideline on the management of patients with ACS provides no recommendation regarding the role of CYP2C19 genotyping as part of a DAPT strategy to optimize outcomes even though previous guidelines, with less prospective outcomes data, provided a Class 2b recommendation that prescribers can consider CYP2C19 genotype testing in high‐risk patients undergoing PCI. ¹⁸ Moreover, the 2026 guideline for acute ischemic stroke management provides a Class 2b recommendation for genotype‐guided DAPT based on outcomes from a single trial. ¹⁹ We thus find the absence of recommendations for guided therapy in the 2025 ACS guideline to be a missed opportunity, particularly given the focus of the guideline on reducing bleeding risks and the common use of clopidogrel in clinical practice. Unguided deescalation to clopidogrel raises the potential for harm to the one third of US patients who have a CYP2C19 LOF allele, especially for higher risk patients. On the other hand, genotype‐guided deescalation to clopidogrel in those without a CYP2C19 LOF allele, who comprise 70% of the US population, represents an approach to more precisely decrease bleeding risk without increasing ischemic risk for the majority of patients. Thus, we strongly urge that recommendations for use of CYP2C19 genotyping to guide P2Y₁₂ inhibitor selection after ACS and PCI, especially for those at high bleeding risk, be made in upcoming guidelines. This would also ensure alignment in guidance provided by the Food and Drug Administration and clinical practice guidelines per recent recommendations by the American College of Cardiology/AHA Joint Committee. ²⁰

Sources of Funding

None.

Disclosures

Dr Cavallari declares that she has received research support from Werfen. Dr Lee declares that he has received research support from Werfen. Dr Sibbing received speaker fees and fees for advisory board activities from Bayer, Sanofi Aventis and Daiichi Sankyo. Dr Angiolillo declares that he has received consulting fees or honoraria from Anthos, Bayer, Boehringer Ingelheim, Bristol‐Myers Squibb, Chiesi, Faraday, Idorsia, Johnson & Johnson, Novartis, Novo Nordisk, PLx Pharma, Sanofi, SFJ Pharmaceuticals, Vectura, and Werfen; his institution has received research grants from Abbott, Amgen, AstraZeneca, Bayer, Chiesi, CSL Behring, DalCor Pharmaceuticals, Daiichi‐Sankyo, Edwards, Eli Lilly, Faraday, Janssen, Hikari DX, Novartis, Prolocor, and Vertex. Other authors have nothing to declare.