Effect of Gender on Clinical Outcomes in Patients Receiving
            <i>CYP2C19</i>
            Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

Gustafson, Chelsea; Gower, Megan; Williams, Alexis K.; Pauley, Eric; Weck, Karen E.; Lee, Craig; Stouffer, George A.

doi:10.1161/circgen.120.003023

“…A prior single center observational report of 1260 of patients undergoing CYP2C19 genetic testing at the time of PCI (62% with ACS, and 31% female) demonstrated a 2‐3‐fold higher risk of MACE, but not bleeding, among LOF carriers receiving clopidogrel, compared with prasugrel or ticagrelor; this effect was observed among both men and women. 21 The POPular‐GENETICS study (CYP2C19 Genotype‐Guided Antiplatelet Therapy in ST‐Segment Elevation Myocardial Infarction Patients – Patient Outcome After Primary PCI) demonstrated the noninferiority of using a GG approach to de‐escalate antiplatelet therapy to clopidogrel from more potent P2Y12 inhibitors such as ticagrelor or prasugrel in patients with ST‐segment–elevation myocardial infarction. 22 In addition, this study demonstrated lower rates of PLATO (The Prospective, Randomized, Platelet Inhibition and Patient Outcomes) trial major or minor bleeding and BARC 2‐3‐5 bleeding using a GG strategy among patients with ST‐segment–elevation myocardial infarction as compared with prescribing ticagrelor/prasugrel for all.…”

Section: Discussionmentioning

confidence: 99%

Sex‐Specific Differences in Clinical Outcomes After Percutaneous Coronary Intervention: Insights from the TAILOR‐PCI Trial

Madan

¹

,

Abbott

²

,

Lennon

³

et al. 2022

JAHA

4

0

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Background TAILOR‐PCI (Tailored Antiplatelet Initiation to Lessen Outcomes due to decreased Clopidogrel Response After Percutaneous Coronary Intervention) studied genotype‐guided selection of antiplatelet therapy after percutaneous coronary intervention versus conventional therapy with clopidogrel. The presence of CYP2C19 loss‐of‐function alleles in patients treated with clopidogrel may be associated with increased risk for ischemic events. We report a prespecified sex‐specific analysis of genotyping and associated cardiovascular outcomes from this study. Methods and Results Associations between sex and major adverse cardiac events (MACE: cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia) and Bleeding Academic Research Consortium (BARC) bleeding at 12 months were analyzed using Cox proportional‐hazards models. Among 5276 randomized patients, loss‐of‐function carriers were observed in ≈36% of both sexes, and >80% of carriers were heterozygotes. At 12 months, after adjustment for baseline differences, risks of MACE (HR , 1.28 [0.97 to 1.68]; P =0.088) and BARC bleeding (hazard ratio [HR], 1.36 [0.91 to 2.05]; P =0.14) were comparable among women and men. There were no significant interactions between sex and treatment strategy for MACE interaction P value ( P int =0.59) or BARC bleeding ( P int =0.47) nor for sex and genotype (MACE P int =0.15, and BARC bleeding P int =0.60). Conclusions CYP2C19 loss‐of‐function alleles were present in ≈1 in 3 women and men. Women had similar adjusted risks of MACE and bleeding as men following percutaneous coronary intervention. Genotype‐guided therapy did not significantly reduce the risk of MACE or bleeding relative to conventional therapy for both sexes. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01742117.

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“…31 However, the role of sex-by-gene interactions is less studied for clopidogrel (as for other drugs); some studies report an increased risk of atherothrombotic events for female carriers of the CYP2C9*3 LOF allele, 32 while some RCTs show that the impact of genotype-guided therapy on both ischemic and bleeding outcomes is not influenced by sex. 33,34 There is little evidence to support a sexually dimorphic distribution of functional phase II gene variants or hormonal influences on the expression of these genes. Phase II metabolic conjugation processes are little understood concerning sex-gender differences, and the reported data may also include disease-related confounding factors.…”

Section: Metabolismmentioning

confidence: 99%

“…31 However, the role of sex-by-gene interactions is less studied for clopidogrel (as for other drugs); some studies report an increased risk of atherothrombotic events for female carriers of the CYP2C9*3 LOF allele, 32 while some RCTs show that the impact of genotype-guided therapy on both ischemic and bleeding outcomes is not influenced by sex. 33,34…”

Section: Pharmacokineticsmentioning

confidence: 99%

Sex Differences in Cardiovascular Management: A Call for Better Acknowledgment—Part 1 Pharmacological Differences in Women and Men; How Relevant Are They?

Ivanescu,

Dan

2024

American Journal of Therapeutics

0

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Background: Sex differences (SDs) in pharmacology of cardiovascular (CV) drugs have been described previously; however, paradoxically, there are scarce recommendations in therapy based on these differences. It is of utmost importance to identify whether these SDs determine a modified clinical response and the potential practical implications for this, to provide a base for personalized medicine. Area of uncertainty: The aim of this article was to outline the most important pharmacological drivers of cardiovascular drugs that differ between women and men, along with their implications and challenges in clinical practice. Data sources: A detailed assessment of English-written resources reflecting SDs impact in CV drug pharmacology was performed using PubMed and Embase databases. Results: Despite large variations in CV drug pharmacokinetics and pharmacodynamics in individuals, correcting for height, weight, surface area, and body composition compensate for most “sex-dependent” differences. In addition, individual, cultural, and social factors significantly impact disease management in women versus men. Gender-biased prescribing patterns and gender-dependent adherence to therapy also influence outcomes. The development of sex-specific guidelines requires that they should reflect the SDs implications for the management of a disease and that the evidence should be carefully evaluated as to whether there is an adequate representation of both sexes and whether sex-disaggregated data are reported. Conclusions: Pharmacological drivers are under the influence of an impressive number of differences between women and men. However, to establish their significance in clinical practice, an adequate representation of women in studies and the reporting of distinct results is mandatory.

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Sex differences in antiplatelet therapy: state-of-the art

Zimodro

¹

,

Appelman

²

2023

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Effect of Gender on Clinical Outcomes in Patients Receiving CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention

Cited by 3 publications

References 5 publications

Sex‐Specific Differences in Clinical Outcomes After Percutaneous Coronary Intervention: Insights from the TAILOR‐PCI Trial

Sex‐Specific Differences in Clinical Outcomes After Percutaneous Coronary Intervention: Insights from the TAILOR‐PCI Trial

Sex Differences in Cardiovascular Management: A Call for Better Acknowledgment—Part 1 Pharmacological Differences in Women and Men; How Relevant Are They?

Sex differences in antiplatelet therapy: state-of-the art

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