Genetic Determinants of Response to P2Y12 Inhibitors and Clinical Implications.

The CYP2C19 enzyme metabolizes clopidogrel, a prodrug, to its active form. Approximately 30% of individuals inherit a loss-of-function (LoF) polymorphism in the CYP2C19 gene, leading to reduced formation of the active clopidogrel metabolite. Reduced clopidogrel effectiveness has been well documented in patients with an LoF allele following an acute coronary syndrome or percutaneous coronary intervention. Prasugrel or ticagrelor is recommended in those with an LoF allele as neither is affected by CYP2C19 genotype. Although data demonstrate improved outcomes with a CYP2C19-guided approach to P2Y12 inhibitor selection, genotyping has not yet been widely adopted in clinical practice.

Exploring the therapeutic utility of the factor XIa inhibitor asundexian.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: Factor XIa inhibitors are a promising novel class of anticoagulants that attenuate pathological thrombosis with minimal interference with hemostasis. These effects contrast with those of conventional anticoagulants, which may exhibit adverse events of untoward bleeding precluding treatment in some patients. A variety of investigational pharmacological modalities have been developed and studied to target factor XIa. SUMMARY: Asundexian is a small molecule inhibitor of factor XIa that has been evaluated in several clinical studies. It has been studied as an oral, once-daily medication and found to inhibit approximately 90% of factor XIa activity at doses of 20 to 50 mg. Phase 2 trials have demonstrated the potential for improved safety compared to standard of care in certain treatment settings, such as in atrial fibrillation. For other indications, such as noncardioembolic stroke and acute myocardial infarction, asundexian has been used in addition to background antiplatelet therapy. In these instances, asundexian did not show a difference in the incidence of bleeding events compared to placebo. CONCLUSION: Phase 3 trials have recently been launched; however, the OCEANIC-AF trial was prematurely discontinued due to inefficacy of asundexian vs apixaban for stroke prevention in atrial fibrillation. Another phase 3 trial, OCEANIC-AFINA, is planned to compare asundexian to placebo in patients with atrial fibrillation at high risk for stroke who are deemed ineligible for anticoagulation.

Practical management of oral treprostinil in patients with pulmonary arterial hypertension: Lessons from ADAPT, EXPEDITE, and expert consensus.

BACKGROUND: Oral treprostinil is a prostacyclin analogue approved to treat pulmonary arterial hypertension (PAH) by delaying disease progression and improving exercise capacity. Higher doses of oral treprostinil correlate with increased treatment benefit. Titrations may be challenging due to common side effects of prostacyclin-class therapies. STUDY DESIGN AND METHODS: The multicenter, prospective, real-world, observational ADAPT Registry study followed adult patients with PAH for up to 78 weeks after initiating oral treprostinil (NCT03045029). Dosing, titration, and transitions of oral treprostinil were at the discretion of the prescriber. Patient-reported incidence and treatment of common side effects were collected to understand side effect management and tolerability. Insights from literature and expert recommendations were added to provide a consolidated resource for oral treprostinil use. RESULTS: In total, 139 participants in ADAPT completed ≥1 weekly survey; (median age 60.0 years, 76 % female). Median treatment duration of oral treprostinil was 13.1 months. During early therapy (Months 1-5), 62 % (78/126) of patients reported headache and diarrhea, and 40 % (50/126) reported nausea. At Month 6, many patients who reported side effects during early therapy reported an improvement (61 % headache, 44 % diarrhea, 70 % nausea). Common side effect treatments, including acetaminophen, loperamide, and ondansetron, were effective. Approximately one-quarter of patients reporting the most common side effects were untreated at Month 6. CONCLUSION: Patient selection for, and initiation and titration of, oral treprostinil should be individualized and may include parenteral treprostinil induction-transition for faster titration. Assertive side effect management may help patients reach higher and more efficacious doses of oral treprostinil.

Post-Discharge Treatment Patterns among Patients Treated with Apixaban or Warfarin during Hospitalization for Venous Thromboembolism (VTE).

Background: Oral anticoagulants (OACs), such as apixaban and warfarin, are indicated for reducing the risk of recurrent venous thromboembolism (VTE) and are often initiated in the hospital. The aim of this study was to evaluate OAC continuity from inpatient to outpatient settings and the risk of recurrent VTE among patients with an initial event. Methods: This retrospective cohort study utilized hospital charge data and medical and prescription claims from 1 July 2016 to 31 December 2022 to identify adults treated with apixaban or warfarin while hospitalized for VTE. Patients were followed to assess switching or discontinuation post-discharge and the risk of recurrent VTE. The index date was the date of the first apixaban or warfarin claim within 30 days post-discharge. Results: Of the 19,303 eligible patients hospitalized with VTE, 85% (n = 16,401) were treated with apixaban and 15% (n = 2902) received warfarin. After discharge, approximately 70% had ≥1 fill for their respective apixaban or warfarin therapy. The cumulative incidence of discontinuation over the 6 months following index was 50.5% and 52.2% for the apixaban and warfarin cohorts, respectively; the cumulative incidence of switching was 6.0% and 20.9%, respectively. The incidence rates of recurrent VTE were 1.2 and 2.5 per 100 person-years for the apixaban and warfarin cohorts, respectively. Conclusions: The majority of patients continued their apixaban or warfarin therapy following hospital discharge; however, a considerable proportion either switched or discontinued OAC upon transitioning from inpatient care. Among those who continued therapy, discontinuation, switch, and recurrent VTE occurred less often with apixaban vs. warfarin.

Clinical Outcomes Associated With Diltiazem Use in Heart Failure With Reduced Ejection Fraction After Implementation of a Clinical Support System.

BACKGROUND: Despite atrial fibrillation guideline recommendations, many patients with heart failure with reduced ejection fraction (EF) continue to receive IV diltiazem for acute rate control. OBJECTIVE: Our institution recently implemented a clinical decision support system (CDSS)-based tool that recommends against the use of diltiazem in patients with an EF ≤ 40%. The objective of this study was to evaluate outcomes of adherence to the aforementioned CDSS-based tool. METHODS: This multi-hospital, retrospective study assessed patients who triggered the CDSS alert and compared those who did and did not discontinue diltiazem. The primary outcome was the occurrence of clinical deterioration. The primary endpoint was compared utilizing a Fisher's Exact Test, and a multivariate logistic regression model was developed to confirm the results of the primary analysis. RESULTS: A total of 246 patients were included in this study with 146 patients in the nonadherent group (received diltiazem) and 100 patients in the adherent group (did not receive diltiazem). There was a higher proportion of patients experiencing clinical deterioration in the alert nonadherence group (33% vs 21%, P = 0.044), including increased utilization of inotropes and vasopressors, and higher rate of transfer to ICU. CONCLUSION AND RELEVANCE: In patients with heart failure with reduced EF, diltiazem use after nonadherence to a CDSS alert resulted in an increased risk of clinical deterioration. This study highlights the need for improved provider adherence to diltiazem clinical decision support systems.

Empowering personalized pharmacogenomics with generative AI solutions.

OBJECTIVE: This study evaluates an AI assistant developed using OpenAI's GPT-4 for interpreting pharmacogenomic (PGx) testing results, aiming to improve decision-making and knowledge sharing in clinical genetics and to enhance patient care with equitable access. MATERIALS AND METHODS: The AI assistant employs retrieval-augmented generation (RAG), which combines retrieval and generative techniques, by harnessing a knowledge base (KB) that comprises data from the Clinical Pharmacogenetics Implementation Consortium (CPIC). It uses context-aware GPT-4 to generate tailored responses to user queries from this KB, further refined through prompt engineering and guardrails. RESULTS: Evaluated against a specialized PGx question catalog, the AI assistant showed high efficacy in addressing user queries. Compared with OpenAI's ChatGPT 3.5, it demonstrated better performance, especially in provider-specific queries requiring specialized data and citations. Key areas for improvement include enhancing accuracy, relevancy, and representative language in responses. DISCUSSION: The integration of context-aware GPT-4 with RAG significantly enhanced the AI assistant's utility. RAG's ability to incorporate domain-specific CPIC data, including recent literature, proved beneficial. Challenges persist, such as the need for specialized genetic/PGx models to improve accuracy and relevancy and addressing ethical, regulatory, and safety concerns. CONCLUSION: This study underscores generative AI's potential for transforming healthcare provider support and patient accessibility to complex pharmacogenomic information. While careful implementation of large language models like GPT-4 is necessary, it is clear that they can substantially improve understanding of pharmacogenomic data. With further development, these tools could augment healthcare expertise, provider productivity, and the delivery of equitable, patient-centered healthcare services.

Management Considerations for Pulmonary Arterial Hypertension Pharmacotherapy in the Intensive Care Unit.

Pulmonary arterial hypertension is a rare and progressive disease with significant morbidity and mortality risk. Several medications targeting three major disease pathways are approved for treatment. However, the management of pulmonary arterial hypertension pharmacotherapies in a patient admitted to an intensive care unit poses unique challenges. Factors such as intubation and altered mental status may prevent the continuation of home oral and/or inhaled therapy, and the progression of the disease may require escalation of therapy. This review will focus on practical management strategies for the continuation of home pulmonary arterial hypertension pharmacotherapy and escalation of therapy.

Pharmacogenomics in the Management of Pulmonary Arterial Hypertension: Current Perspectives.

Pulmonary arterial hypertension (PAH) is a rare disease with heterogeneous causes that can lead to right ventricular (RV) failure and death if left untreated. There are currently 10 medications representative of five unique pharmacologic classes that are approved for treatment. These have led to significant improvements in overall clinical outcome. However, substantial variability in dosing requirements and treatment response is evident, leading to suboptimal outcome for many patients. Furthermore, dosing is empiric and iterative and can lead to delays in meeting treatment goals and burdensome adverse effects. Pharmacogenomic (PGx) associations have been reported with certain PAH medications, such as treprostinil and bosentan, and can explain some of the variability in response. Relevant genes associated with treprostinil include CYP2C8, CYP2C9, CAMK2D, and PFAS. CYP2C8 and CYP2C9 are the genes encoding the major metabolizing liver enzymes for treprostinil, and reduced function variants (*2, *3) with CYP2C9 were associated with lower treatment persistence. Additionally, a higher CYP2C9 activity score was associated with a significantly less risk of treatment discontinuation. Other genes of interest that have been explored with treprostinil include CAMK2D, which is associated with right ventricular dysfunction and significantly higher dose requirements. Similarly, PFAS is associated with lower concentrations of cyclic adenosine monophosphate and significantly higher dose requirements. Genes of interest with the endothelin receptor antagonist (ERA) class include GNG2 and CYP2C9. A genetic variant in GNG2 (rs11157866) was linked to a significantly increased rate of clinical improvement with ERAs. The *2 variant with CYP2C9 (encoding for the major metabolizing enzyme for bosentan) was significantly associated with a higher risk for elevations in hepatic aminotransferases and liver injury. In summary, this article reviews the relevant pharmacogenes that have been associated to date with dosing and outcome among patients who received PAH medications.

DOAC Dosing Discordance Using Different Estimates of Kidney Function and Outcomes.

Direct oral anticoagulants (DOACs) are indicated for the prevention of stroke in nonvalvular atrial fibrillation. Although Food and Drug Administration labeling for DOACs uses estimated creatinine clearance according to the Cockcroft-Gault (C-G) equation, estimated glomerular filtration rate according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation is often reported. The objectives of this study were to evaluate DOAC dosing discordance and to determine whether discordance based on various estimates of kidney function is associated with bleeding or thromboembolism. The study was an institutional review board approved retrospective analysis of patients at UPMC Presbyterian Hospital from January 1, 2010, to December 12, 2016. Data were obtained through electronic medical records. Adults who received a medication charge for rivaroxaban or dabigatran, had a diagnosis code for atrial fibrillation, and had a serum creatinine within 3 days of DOAC initiation were included. Doses were considered discordant if the calculated dose based on CKD-EPI did not match the patient's dose during index admission, if dosed correctly using C-G. Association of discordance with dabigatran, rivaroxaban, and clinical outcomes was determined using odds ratios and 95% confidence intervals. Rivaroxaban discordance was present among 49 of the 644 (8%) patients who were dosed correctly with C-G. Dabigatran discordance was present among 17 of the 590 (3%) patients who were dosed correctly. Discordance with rivaroxaban was found to increase the risk of thromboembolism when using CKD-EPI (odds ratio, 2.83; 95% CI, 1.02-7.79, P = .045) versus C-G. Our findings emphasize the need to dose DOACs, specifically rivaroxaban, appropriately in patients with nonvalvular atrial fibrillation.