Effectiveness of Clopidogrel vs Alternative P2Y12 Inhibitors Based on the ABCD-GENE Score.

BACKGROUND: An ABCD-GENE (age, body mass index, chronic kidney disease, diabetes, and CYP2C19 genetic variants) score ≥10 predicts reduced clopidogrel effectiveness, but its association with response to alternative therapy remains unclear. OBJECTIVES: The aim of this study was to evaluate the association between ABCD-GENE score and the effectiveness of clopidogrel vs alternative P2Y12 inhibitor (prasugrel or ticagrelor) therapy after percutaneous coronary intervention (PCI). METHODS: A total of 4,335 patients who underwent PCI, CYP2C19 genotyping, and P2Y12 inhibitor treatment were included. The primary outcome was major atherothrombotic events (MAE) within 1 year after PCI. Cox regression was performed to assess event risk in clopidogrel-treated (reference) vs alternatively treated patients, with stabilized inverse probability weights derived from exposure propensity scores after stratifying by ABCD-GENE score and further by CYP2C19 loss-of-function (LOF) genotype. RESULTS: Among patients with scores <10 (n = 3,200), MAE was not different with alternative therapy vs clopidogrel (weighted HR: 0.89; 95% CI: 0.65-1.22; P = 0.475). The risk for MAE also did not significantly differ by treatment among patients with scores ≥10 (n = 1,135; weighted HR: 0.75; 95% CI: 0.51-1.11; P = 0.155). Among CYP2C19 LOF allele carriers, MAE risk appeared lower with alternative therapy in both the group with scores <10 (weighted HR: 0.50; 95% CI: 0.25-1.01; P = 0.052) and the group with scores ≥10 (weighted HR: 0.48; 95% CI: 0.29-0.80; P = 0.004), while there was no difference in the group with scores <10 and no LOF alleles (weighted HR: 1.03; 95% CI: 0.70-1.51; P = 0.885). CONCLUSIONS: These data support the use of alternative therapy over clopidogrel in CYP2C19 LOF allele carriers after PCI, regardless of ABCD-GENE score, while clopidogrel is as effective as alternative therapy in non-LOF patients with scores <10.

Relationship of Neonatal Seizure Burden Before Treatment and Response to Initial Antiseizure Medication.

OBJECTIVE: To assess among a cohort of neonates with hypoxic-ischemic encephalopathy (HIE) the association of pretreatment maximal hourly seizure burden and total seizure duration with successful response to initial antiseizure medication (ASM). STUDY DESIGN: This was a retrospective review of data collected from infants enrolled in the HEAL Trial (NCT02811263) between January 25, 2017, and October 9, 2019. We evaluated a cohort of neonates born at ≥36 weeks of gestation with moderate-to-severe HIE who underwent continuous electroencephalogram monitoring and had acute symptomatic seizures. Poisson regression analyzed associations between (1) pretreatment maximal hourly seizure burden, (2) pretreatment total seizure duration, (3) time from first seizure to initial ASM, and (4) successful response to initial ASM. RESULTS: Among 39 neonates meeting inclusion criteria, greater pretreatment maximal hourly seizure burden was associated with lower chance of successful response to initial ASM (adjusted relative risk for each 5-minute increase in seizure burden 0.83, 95% CI 0.69-0.99). There was no association between pretreatment total seizure duration and chance of successful response. Shorter time-to-treatment was paradoxically associated with lower chance of successful response to treatment, although this difference was small in magnitude (relative risk 1.007, 95% CI 1.003-1.010). CONCLUSIONS: Maximal seizure burden may be more important than other, more commonly used measures in predicting response to acute seizure treatments.

Association of EEG Background and Neurodevelopmental Outcome in Neonates With Hypoxic-Ischemic Encephalopathy Receiving Hypothermia.

BACKGROUND AND OBJECTIVES: Predicting neurodevelopmental outcome for neonates with hypoxic-ischemic encephalopathy (HIE) is important for clinical decision-making, care planning, and parent communication. We examined the relationship between EEG background and neurodevelopmental outcome among children enrolled in a trial of erythropoietin or placebo for neonates with HIE treated with therapeutic hypothermia. METHODS: Participants had EEG recorded throughout hypothermia. EEG background was classified as normal, discontinuous, or severely abnormal (defined as burst suppression, low voltage suppressed, or status epilepticus) at 5 1-hour epochs: onset of recording, 24, 36, 48, and 72 hours after birth. The predominant background pattern during the entire continuous video EEG monitoring recording was calculated using the arithmetic mean of the 5 EEG background ratings (normal = 0; discontinuous = 1; severely abnormal = 2) as follows: "predominantly normal" (mean = 0), "normal/discontinuous" (0 < mean<1), "predominantly discontinuous" (mean = 1), "discontinuous/severely abnormal" (1 < mean<2), or "predominantly severely abnormal" (mean = 2). Primary outcome was death or neurodevelopmental impairment (NDI) defined as cerebral palsy, Gross Motor Function Classification Score ≥1, or cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition at age 2 years. Neurodevelopment was also categorized into a 5-level ordinal measure: no, mild, moderate, severe NDI, or death for secondary analysis. We used generalized linear regression models with robust standard errors to assess the relative risk of death or NDI by EEG background in both unadjusted and adjusted analyses controlling for the effects of treatment group, sex, HIE severity, and study recruitment site. RESULTS: Among 142 neonates, the predominant background EEG pattern was predominantly normal in 35 (25%), normal/discontinuous in 68 (48%), predominantly discontinuous in 11 (7.7%), discontinuous/severely abnormal in 16 (11%), and predominantly severely abnormal in 12 (8.5%). Increasing severity of background across monitoring epochs was associated with increasingly worse clinical outcomes. Children with severe EEG background abnormality at any time point (n = 36, 25%) were significantly more likely to die or have severe NDI at 2 years (adjusted relative risk: 7.95, 95% CI 3.49-18.12). DISCUSSION: EEG background is strongly associated with NDI at age 2 years. These results can be used to assist health care providers to plan follow-up care and counsel families for decision-making related to goals of care.

Feeding and developmental outcomes after neonatal seizures-A prospective observational study.

Objective: Among neonates with acute symptomatic seizures, we evaluated whether inability to take full feeds at time of hospital discharge from neonatal seizure admission is associated with worse neurodevelopmental outcomes, after adjusting for relevant clinical variables. Methods: This prospective, 9-center study of the Neonatal Seizure Registry (NSR) assessed characteristics of infants with seizures including: evidence of brainstem injury on MRI, mode of feeding upon discharge, and developmental outcomes at 12, 18, and 24 months. Inability to take oral feeds was identified through review of medical records. Brainstem injury was identified through central review of neonatal MRIs. Developmental outcomes were assessed with the Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS) at 12, 18, and 24 months corrected age. Results: Among 276 infants, inability to achieve full oral feeds was associated with lower total WIDEA-FS scores (160.2±25.5 for full oral feeds vs. 121.8±42.9 for some/no oral feeds at 24 months, p<0.001). At 12 months, a G-tube was required for 23 of the 49 (47%) infants who did not achieve full oral feeds, compared with 2 of the 221 (1%) who took full feeds at discharge (p<0.001). Conclusions: Inability to take full oral feeds upon hospital discharge is an objective clinical sign that can identify infants with acute symptomatic neonatal seizures who are at high risk for impaired development at 24 months.

Neonatal brain MRI and short-term outcomes after acute provoked seizures.

OBJECTIVE: We investigated how diagnosis and injury location on neonatal brain MRI following onset of acute provoked seizures was associated with short term outcome. STUDY DESIGN: A multicenter cohort of neonates with acute provoked seizures enrolled in the Neonatal Seizure Registry. MRIs were centrally evaluated by a neuroradiologist for location of injury and radiologic diagnosis. Clinical outcomes were determined by chart review. Multivariate logistic regression was used to examine the association between MRI findings and outcomes. RESULTS: Among 236 newborns with MRI at median age 4 days (IQR 3-8), 91% had abnormal MRI. Radiologic diagnoses of intracranial hemorrhage (OR 3.2 [1.6-6.5], p < 0.001) and hypoxic-ischemic encephalopathy (OR 2.7 [1.4-5.4], p < 0.003) were associated with high seizure burden. Radiologic signs of intracranial infection were associated with abnormal neurologic examination at discharge (OR 3.9 [1.3-11.6], p < 0.01). CONCLUSION: Findings on initial MRI can help with expectant counseling on short-term outcomes following acute provoked neonatal seizures.

Implementation of CYP2C19 genotyping to guide proton pump inhibitor use at an academic health center.

PURPOSE: To describe the implementation of CYP2C19 testing into clinical practice at University of Florida (UF) Health Gainesville hospital to guide proton pump inhibitor (PPI) dosing and the lessons learned from this experience. SUMMARY: Different CYP2C19 genotypes are associated with variability in PPI plasma concentrations and intragastric pH, which may contribute to the risk of treatment failure due to subtherapeutic concentrations and adverse effects (eg, infection, bone fracture, renal dysfunction) with sustained supratherapeutic concentrations. Based on evidence available prior to the availability of pertinent Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines, the UF Health Precision Medicine Program (PMP) developed clinical recommendations, provided through automated alerts at the time of a PPI order, to (1) increase the PPI dose for individuals with genotypes linked to increased CYP2C19 enzyme activity (ie, rapid and ultrarapid metabolizers) to improve the likelihood of drug effectiveness and (2) decrease the dose for individuals with decreased CYP2C19 activity (ie, intermediate and poor metabolizers) to reduce the risk of harm. The CYP2C19-PPI implementation was an iterative process that taught us key implementation lessons. Most notably, physician engagement is essential, problem lists in the medical record are unreliable, and special populations (eg, pediatric patients) need to be considered. CONCLUSION: Guiding PPI prescribing based on CYP2C19 genotype is a practical approach to potentially improve the benefit-risk ratio with PPI therapy. Physician engagement is key for successful implementation. A CPIC guideline on CYP2C19 genotype-guided PPI dosing is now available, and automated alerts may be instituted to facilitate implementation.

Assessing the Clinical Treatment Dynamics of Antiplatelet Therapy Following Acute Coronary Syndrome and Percutaneous Coronary Intervention in the US.

Importance: A platelet ADP P2Y12 receptor (P2Y12) inhibitor plus aspirin is standard therapy for patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS). Compared with clopidogrel, prasugrel and ticagrelor are associated with superior antiatherothrombotic effects but increased bleeding risk; with recent guideline updates, it is important to describe current treatment patterns and the role of bleeding risk in treatment choice. Objective: To describe secular trends and determinants of initial P2Y12 inhibitor choice and switching, including deescalation (switch from prasugrel or ticagrelor to clopidogrel). Design, Setting, and Participants: This retrospective cohort study used MarketScan Commercial Claims Data from 2010 to 2019 for patients aged 18 years or older who underwent PCI for ACS, had no P2Y12 inhibitor use in the past year, and filled a P2Y12 inhibitor prescription within 30 days after PCI hospitalization discharge. Data were analyzed from February to May 2022. Exposures: Clopidogrel, prasugrel, and ticagrelor, with determinants including bleeding risk measured using Academic Research Consortium for High Bleeding Risk criteria, sociodemographic characteristics, P2Y12 inhibitor copays, and bleeding events during follow-up. Main Outcomes and Measures: The prevalence of each P2Y12 inhibitor among patients who initiated the drugs and the prevalence of switching within 12 months after PCI were evaluated. The association between baseline bleeding risk and bleeding manifestations during follow-up and initial treatment and deescalation were calculated using multivariable logistic and Cox proportional hazards regression models. Results: Between 2010 and 2019, 62 423 patients were identified who initiated P2Y12 inhibitors (females, 22.4%; males, 77.6%; mean [SD] age, 54.32 [7.13] years). The prevalence of clopidogrel as initial therapy decreased from 77.5% in 2010 to 29.6% in 2019, while initial use of prasugrel or ticagrelor increased from 22.5% to 60.4%. Within 1 year after PCI, 11.0% of patients switched therapy, mostly for deescalation. Deescalation prevalence increased from 1.8% in 2010 to 12.6% in 2018. Between 2016 and 2018, 8588 of 22 886 (37.5%) patients had major baseline bleeding risk, which decreased the selection of prasugrel or ticagrelor as initial therapy (adjusted odds ratio, 0.78; 95% CI, 0.74-0.84). Among 11 285 patients who initiated prasugrel or ticagrelor, major bleeding risk at baseline (adjusted hazard ratio, 1.11; 95% CI, 1.00-1.23) and the occurrence of bleeding during follow-up (adjusted hazard ratio, 4.42; 95% CI, 3.62-5.93) were associated with deescalation. Conclusions and Relevance: A strong shift in preference for prasugrel and ticagrelor as initial therapy following PCI for ACS was observed. Deescalation increased over the study period. Major bleeding risk at baseline was moderately associated with initial treatment choice but had a limited association with deescalation. The increasing use of more potent P2Y12 inhibitors emphasizes opportunities to enhance preemptive patient-centered treatment strategies to maintain optimal antiplatelet activity while reducing bleeding risk during the subacute period following PCI for ACS.

Pharmacogenetics of P2Y12 receptor inhibitors.

Oral P2Y12 inhibitors are commonly prescribed for cardiovascular disease and include clopidogrel, prasugrel, and ticagrelor. Each of these drugs has its strengths and weaknesses. Prasugrel and ticagrelor are more potent inhibitors of platelet aggregation and were shown to be superior to clopidogrel in preventing major adverse cardiovascular events after an acute coronary syndrome and percutaneous coronary intervention (PCI) in the absence of genotyping. However, both are associated with an increased risk for non-coronary artery bypass-related bleeding. Clopidogrel is a prodrug requiring bioactivation, primarily via the CYP2C19 enzyme. Approximately 30% of individuals have a CYP2C19 no function allele and decreased or no CYP2C19 enzyme activity. Clopidogrel-treated carriers of a CYP2C19 no function allele have decreased exposure to the clopidogrel active metabolite and lesser inhibition of platelet aggregation, which likely contributed to reduced clopidogrel efficacy in clinical trials. The pharmacogenetic data for clopidogrel are most robust in the setting of PCI, but evidence is accumulating for other indications. Guidance is available from expert consensus groups and regulatory agencies to assist with integrating genetic information into P2Y12 inhibitor prescribing decisions, and CYP2C19 genotype-guided antiplatelet therapy after PCI is one of the most common examples of clinical pharmacogenetic implementation. Herein, we review the evidence for pharmacogenetic associations with clopidogrel response and outcomes with genotype-guided P2Y12 inhibitor selection and describe guidance to assist with pharmacogenetic implementation. We also describe processes for applying genotype data for P2Y12 inhibitor therapy selection and remaining gaps in the field. Ultimately, consideration of both clinical and genetic factors may guide selection of P2Y12 inhibitor therapy that optimally balances the atherothrombotic and bleeding risks.

Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y12 Inhibitor Prescribing After Percutaneous Coronary Intervention.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from 9 sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel vs. alternative therapy) based on genotype. Of 3,342 patients included, 2,448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% vs. 29.7%, P = 0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of the last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (P = 0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (P = 0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.

Risk of seizures in neonates with hypoxic-ischemic encephalopathy receiving hypothermia plus erythropoietin or placebo.

BACKGROUND: An ancillary study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (HEAL) trial for neonates with hypoxic-ischemic encephalopathy (HIE) and treated with therapeutic hypothermia examined the hypothesis that neonates randomized to receive erythropoietin (Epo) would have a lower seizure risk and burden compared with neonates who received placebo. METHODS: Electroencephalograms (EEGs) from 7/17 HEAL trial centers were reviewed. Seizure presence was compared across treatment groups using a logistic regression model adjusting for treatment, HIE severity, center, and seizure burden prior to the first dose. Among neonates with seizures, differences across treatment groups in median maximal hourly seizure burden were assessed using adjusted quantile regression models. RESULTS: Forty-six of 150 (31%) neonates had EEG seizures (31% in Epo vs 30% in placebo, p = 0.96). Maximal hourly seizure burden after the study drug was not significantly different between groups (median 11.4 for Epo, IQR: 5.6, 18.1 vs median 9.7, IQR: 4.9, 21.0 min/h for placebo). CONCLUSION: In neonates with HIE treated with hypothermia who were randomized to Epo or placebo, we found no meaningful between-group difference in seizure risk or burden. These findings are consistent with overall trial results, which do not support Epo use for neonates with HIE undergoing therapeutic hypothermia. IMPACT: In the HEAL trial of erythropoietin (Epo) vs placebo for neonates with encephalopathy presumed due to hypoxic-ischemic encephalopathy (HIE) who were also treated with therapeutic hypothermia, electrographic seizures were detected in 31%, which is lower than most prior studies. Epo did not reduce the proportion of neonates with acute provoked seizures (31% in Epo vs 30% in placebo) or maximal hourly seizure burden after the study drug (median 11.4, IQR 5.6, 18.1 for Epo vs median 9.7, IQR 4.9, 21.0 min/h for placebo). There was no anti- or pro-convulsant effect of Epo when combined with therapeutic hypothermia for HIE.

Seizure Burden, EEG, and Outcome in Neonates With Acute Intracranial Infections: A Prospective Multicenter Cohort Study.

BACKGROUND: Limited data exist regarding seizure burden, electroencephalogram (EEG) background, and associated outcomes in neonates with acute intracranial infections. METHODS: This secondary analysis was from a prospective, multicenter study of neonates enrolled in the Neonatal Seizure Registry with seizures due to intracranial infection. Sites used continuous EEG monitoring per American Clinical Neurophysiology Society guidelines. High seizure burden was defined a priori as seven or more EEG-confirmed seizures. EEG background was categorized using standardized terminology. Primary outcome was neurodevelopment at 24-months corrected age using Warner Initial Developmental Evaluation of Adaptive and Functional Skills (WIDEA-FS). Secondary outcomes were postneonatal epilepsy and motor disability. RESULTS: Twenty-seven of 303 neonates (8.9%) had seizures due to intracranial infection, including 16 (59.3%) bacterial, 5 (18.5%) viral, and 6 (22.2%) unknown. Twenty-three neonates (85%) had at least one subclinical seizure. Among 23 children with 24-month follow-up, the WIDEA-FS score was, on average, 23 points lower in children with high compared with low seizure burden (95% confidence interval, [-48.4, 2.1]; P = 0.07). After adjusting for gestational age, infection etiology, and presence of an additional potential acute seizure etiology, the effect size remained unchanged (ß = -23.8, P = 0.09). EEG background was not significantly associated with WIDEA-FS score. All children with postneonatal epilepsy (n = 4) and motor disability (n = 5) had high seizure burden, although associations were not significant. CONCLUSION: High seizure burden may be associated with worse neurodevelopment in neonates with intracranial infection and seizures. EEG monitoring can provide useful management and prognostic information in this population.

Implementing a pragmatic clinical trial to tailor opioids for acute pain on behalf of the IGNITE ADOPT PGx investigators.

Opioid prescribing for postoperative pain management is challenging because of inter-patient variability in opioid response and concern about opioid addiction. Tramadol, hydrocodone, and codeine depend on the cytochrome P450 2D6 (CYP2D6) enzyme for formation of highly potent metabolites. Individuals with reduced or absent CYP2D6 activity (i.e., intermediate metabolizers [IMs] or poor metabolizers [PMs], respectively) have lower concentrations of potent opioid metabolites and potentially inadequate pain control. The primary objective of this prospective, multicenter, randomized pragmatic trial is to determine the effect of postoperative CYP2D6-guided opioid prescribing on pain control and opioid usage. Up to 2020 participants, age ≥8 years, scheduled to undergo a surgical procedure will be enrolled and randomized to immediate pharmacogenetic testing with clinical decision support (CDS) for CYP2D6 phenotype-guided postoperative pain management (intervention arm) or delayed testing without CDS (control arm). CDS is provided through medical record alerts and/or a pharmacist consult note. For IMs and PM in the intervention arm, CDS includes recommendations to avoid hydrocodone, tramadol, and codeine. Patient-reported pain-related outcomes are collected 10 days and 1, 3, and 6 months after surgery. The primary outcome, a composite of pain intensity and opioid usage at 10 days postsurgery, will be compared in the subgroup of IMs and PMs in the intervention (n = 152) versus the control (n = 152) arm. Secondary end points include prescription pain medication misuse scores and opioid persistence at 6 months. This trial will provide data on the clinical utility of CYP2D6 phenotype-guided opioid selection for improving postoperative pain control and reducing opioid-related risks.

Impact of the ABCD-GENE Score on Clopidogrel Clinical Effectiveness after PCI: A Multi-Site, Real-World Investigation.

The Age, Body mass index, Chronic kidney disease, Diabetes mellitus, and CYP2C19 GENEtic variants (ABCD-GENE) score was developed to identify patients at risk for diminished antiplatelet effects with clopidogrel after percutaneous coronary intervention (PCI). The objective of this study was to validate the ability of the ABCD-GENE score to predict the risk for atherothrombotic events in a diverse, real-world population of clopidogrel-treated patients who underwent PCI and received clinical CYP2C19 genotyping to guide antiplatelet therapy. A total of 2,341 adult patients who underwent PCI, were genotyped for CYP2C19, and received treatment with clopidogrel across four institutions were included (mean age 64 ± 12 years, 35% women, and 20% Black). The primary outcome was major atherothrombotic events, defined as the composite of all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina within 12 months following PCI. Major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, myocardial infarction, ischemic stroke, or stent thrombosis, was assessed as the secondary outcome. Outcomes were compared between patients with an ABCD-GENE score ≥ 10 vs. < 10. The risk of major atherothrombotic events was higher in patients with an ABCD-GENE score ≥ 10 (n = 505) vs. < 10 (n = 1,836; 24.6 vs. 14.7 events per 100 patient-years, adjusted hazard ratio (HR) 1.66, 95% confidence interval (CI), 1.23-2.25, P < 0.001). The risk for MACE was also higher among patients with a score ≥ 10 vs. < 10 (16.7 vs. 10.1 events per 100 patient-years, adjusted HR 1.59, 95% CI 1.11-2.30, P = 0.013). Our diverse, real-world data demonstrate diminished clopidogrel effectiveness in post-PCI patients with an ABCD-GENE score ≥ 10.

CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention in Diverse Clinical Settings.

Background Studies have demonstrated increased risk of major atherothrombotic events in CYP2C19 loss-of-function (LOF) variant carriers versus non-carriers treated with clopidogrel after percutaneous coronary intervention (PCI). We sought to evaluate real-world outcomes with the clinical implementation of CYP2C19-guided antiplatelet therapy after PCI. Methods and Results Data from 9 medical centers where genotyping was performed in the setting of PCI were included. Alternative therapy with prasugrel or ticagrelor was recommended for patients with a CYP2C19 LOF variant. The primary outcome was the composite of major atherothrombotic events (all-cause death, myocardial infarction, ischemic stroke, stent thrombosis, or hospitalization for unstable angina) within 12 months following PCI. Moderate or severe/life-threatening bleeding within 12 months was a secondary outcome. Among 3342 patients, 1032 (31%) were LOF carriers, of whom 571/1032 (55%) were treated with alternative therapy. In LOF carriers, the rate of major atherothrombotic events was lower in patients treated with alternative therapy versus clopidogrel (adjusted HR, 0.56; 95% CI 0.39-0.82). In those without a LOF allele, no difference was observed (adjusted HR, 1.07; 95% CI 0.71-1.60). There was no difference in bleeding with alternative therapy versus clopidogrel in either LOF carriers or those without a LOF allele. Conclusions Real-world data demonstrate lower atherothrombotic risk in CYP2C19 LOF carriers treated with alternative therapy versus clopidogrel and similar risk in those without a LOF allele treated with clopidogrel or alternative therapy. These data suggest that PCI patients treated with clopidogrel should undergo genotyping so that CYP2C19 LOF carriers can be identified and treated with alternative therapy.

Topiramate Is Safe for Refractory Neonatal Seizures: A Multicenter Retrospective Cohort Study of Necrotizing Enterocolitis Risk.

BACKGROUND: A previously published, single-institution, case series suggested an association between topiramate administration in neonates and subsequent development of necrotizing enterocolitis (NEC). This contradicted our more extensive experiences using topiramate in this population. We therefore studied safety and tolerability of topiramate for treating refractory neonatal seizures, hypothesizing that the risk of developing NEC following topiramate exposure was low and that most infants tolerate topiramate. METHODS: This multicenter retrospective cohort study included seventy-five neonates who received topiramate to treat seizures from January 2011 to October 2019 at three geographically diverse level IV neonatal intensive care units affiliated with pediatric tertiary hospitals. Data included demographics, birth history, seizure etiology, treatment response, side effects, and occurrence and details of NEC. RESULTS: Three of seventy-five infants (4%) developed NEC following topiramate exposure. These infants did not differ in gestational age, birth weight, seizure etiology, postmenstrual age, weight when topiramate was initiated, or dosing of topiramate. Topiramate was well tolerated. Only three infants (4%) discontinued due to side effects. The most common side effect (20%) was weight loss (typically <5%). Topiramate was felt to be efficacious (61%). Most infants (72%) continued topiramate when discharged. CONCLUSIONS: Our multicenter, 75-infant study demonstrated that development of NEC after treatment with topiramate was rare (4%) and refutes prior literature suggesting an association. Topiramate was felt to be efficacious and was well tolerated. Although limited by retrospective design, study data are broadly applicable and support thoughtful use of topiramate as a safe, reasonable option for treating refractory neonatal seizures.

Impact of COVID-19 Pandemic on Developmental Service Delivery in Children With a History of Neonatal Seizures.

BACKGROUND: Children with a history of acute provoked neonatal seizures are at high risk for disability, often requiring developmental services. The coronavirus disease 2019 (COVID-19) pandemic has led to widespread changes in how health care is delivered. Our objective was to determine the magnitude of service interruption of among children born between October 2014 and December 2017 and enrolled in the Neonatal Seizure Registry (NSR), a nine-center collaborative of pediatric centers in the United States. METHODS: This is a prospective cohort study of children with acute provoked seizures with onset ≤44 weeks' gestation and evaluated at age three to six years. Parents of children enrolled in the NSR completed a survey about their child's access to developmental services between June 2020 and April 2021. RESULTS: Among 144 children enrolled, 72 children (50%) were receiving developmental services at the time of assessment. Children receiving services were more likely to be male, born preterm, and have seizure etiology of infection or ischemic stroke. Of these children, 64 (89%) experienced a disruption in developmental services due to the pandemic, with the majority of families (n = 47, 73%) reporting that in-person services were no longer available. CONCLUSIONS: Half of children with acute provoked neonatal seizures were receiving developmental services at ages three to six years. The COVID-19 pandemic has led to widespread changes in delivery of developmental services. Disruptions in services have the potential to impact long-term outcomes for children who rely on specialized care programs to optimize mobility and learning.

Characteristics of Neonates with Cardiopulmonary Disease Who Experience Seizures: A Multicenter Study.

OBJECTIVE: To compare key seizure and outcome characteristics between neonates with and without cardiopulmonary disease. STUDY DESIGN: The Neonatal Seizure Registry is a multicenter, prospectively acquired cohort of neonates with clinical or electroencephalographic (EEG)-confirmed seizures. Cardiopulmonary disease was defined as congenital heart disease, congenital diaphragmatic hernia, and exposure to extracorporeal membrane oxygenation. We assessed continuous EEG monitoring strategy, seizure characteristics, seizure management, and outcomes for neonates with and without cardiopulmonary disease. RESULTS: We evaluated 83 neonates with cardiopulmonary disease and 271 neonates without cardiopulmonary disease. Neonates with cardiopulmonary disease were more likely to have EEG-only seizures (40% vs 21%, P < .001) and experience their first seizure later than those without cardiopulmonary disease (174 vs 21 hours of age, P < .001), but they had similar seizure exposure (many-recurrent electrographic seizures 39% vs 43%, P = .27). Phenobarbital was the primary initial antiseizure medication for both groups (90%), and both groups had similarly high rates of incomplete response to initial antiseizure medication administration (66% vs 68%, P = .75). Neonates with cardiopulmonary disease were discharged from the hospital later (hazard ratio 0.34, 95% CI 0.25-0.45, P < .001), although rates of in-hospital mortality were similar between the groups (hazard ratio 1.13, 95% CI 0.66-1.94, P = .64). CONCLUSION: Neonates with and without cardiopulmonary disease had a similarly high seizure exposure, but neonates with cardiopulmonary disease were more likely to experience EEG-only seizures and had seizure onset later in the clinical course. Phenobarbital was the most common seizure treatment, but seizures were often refractory to initial antiseizure medication. These data support guidelines recommending continuous EEG in neonates with cardiopulmonary disease and indicate a need for optimized therapeutic strategies.

Treatment of Neonatal Seizures: Comparison of Treatment Pathways From 11 Neonatal Intensive Care Units.

OBJECTIVE: Seizures are a common neonatal neurologic emergency. Many centers have developed pathways to optimize management. We evaluated neonatal seizure management pathways at level IV neonatal intensive care units (NICUs) in the United States to highlight areas of consensus and describe aspects of variability. METHODS: We conducted a descriptive analysis of 11 neonatal seizure management pathways from level IV NICUs that specialize in neonatal neurocritical care including guidelines for electroencephalography (EEG) monitoring, antiseizure medication (ASM) choice, timing, and dose. RESULTS: Study center NICUs had a median of 70 beds (interquartile range: 52-96). All sites had 24/7 conventional EEG initiation, monitoring, and review capability. Management pathways uniformly included prompt EEG confirmation of seizures. Most pathways included a provision for intravenous benzodiazepine administration if either EEG or loading of ASM was delayed. Phenobarbital 20 mg/kg IV was the first-line ASM in all pathways. Pathways included either fosphenytoin or levetiracetam as the second-line ASM with variable dosing. Third-line ASMs were most commonly fosphenytoin or levetiracetam, with alternatives including topiramate or lacosamide. All pathways provided escalation to continuous midazolam infusion with variable dosing for seizures refractory to initial medication trials. Three pathways also included lidocaine infusion. Nine pathways discussed ASM discontinuation after resolution of acute symptomatic seizures with variable timing. CONCLUSIONS: Despite a paucity of data from controlled trials regarding optimal neonatal seizure management, there are areas of broad agreement among institutional pathways. Areas of substantial heterogeneity that require further research include optimal second-line ASM, dosage, and timing of ASM discontinuation.

Clinical RNA sequencing confirms compound heterozygous intronic variants in RYR1 in a patient with congenital myopathy, respiratory failure, neonatal brain hemorrhage, and d-transposition of the great arteries.

BACKGROUND: Defects in the RYR1 (OMIM#180901) gene lead to Ryanodine receptor type 1-related myopathies (RYR1-RM); the most common subgroup of congenital myopathies. METHODS: Congenital myopathy presents a diagnostic challenge due to the need for multiple testing modalities to identify the many different genetic etiologies. In this case, the patient remained undiagnosed after whole-exome sequencing (WES), chromosomal microarray, methylation analysis, targeted deletion and duplication studies, and targeted repeat expansion studies. Clinical whole-genome sequencing (WGS) was then pursued as part of a research study to identify a diagnosis. RESULTS: WGS identified compound heterozygous RYR1 intronic variants, RNA sequencing confirmed both variants to be pathogenic causing RYR1-RM in a phenotype of severe congenital hypotonia with respiratory failure from birth, neonatal brain hemorrhage, and congenital heart disease involving transposition of the great arteries. CONCLUSION: While there is an ongoing debate about the clinical superiority of WGS versus WES for patients with a suspected genetic condition, this scenario highlights a weakness of WES as well as the added cost and delay in diagnosis timing with having WGS follow WES or even ending further genetic testing with a negative WES. While knowledge gaps still exist for many intronic variants, transcriptome analysis provides a way of validating the resulting dysfunction caused by these variants and thus allowing for appropriate pathogenicity classification. This is the second published case report of a patient with pathogenic intronic variants in RYR1-RM, with clinical RNA testing confirming variant pathogenicity and therefore the diagnosis suggesting that for some patients careful analysis of a patient's genome and transcriptome are required for a complete genetic evaluation. The diagnostic odyssey experienced by this patient highlights the importance of early, rapid WGS.