Antenatal Platelet Response On Aspirin and Correlation With HDP (Hypertensive Disorders of Pregnancy) (APROACH)

This proposal has three aims to characterize the relationship between aspirin therapy, platelet function response, and prevention of hypertensive disorders of pregnancy (HDP) through a prospective, cohort study using pharmacokinetics, pharmacodynamics, pharmacogenomics and bioinformatics. The results of this proposal will provide necessary data for prospective study on individualized aspirin dose adjustment for prevention of HDP.

Study Overview

• Status: Active, not recruiting
• Conditions: Preeclampsia
• Intervention / Treatment: Drug: Aspirin 81 mg

Detailed Description

This proposal has four aims to characterize the relationship between aspirin therapy, platelet function response, and prevention of HDP through a prospective, cohort study using pharmacodynamics, pharmacogenomics and bioinformatics. The results of this proposal will provide necessary data for prospective study on individualized aspirin dose adjustment for prevention of HDP.

Aim 1: Establish pharmacodynamic endpoints for aspirin in prevention of HDP Hypothesis: PFA-100 closure time and serum thromboxane/urinary dehydrothromboxane-B2 (dTX-B2) are pharmacodynamic markers of aspirin response and are predictive of HDP high risk pregnant patients.

Aim 2: Explore aspirin pharmacogenetics by assessing the relationship between platelet receptor genotype, aspirin response, and prevention of HDP Hypothesis: Platelet receptor genotype is associated with race and may result in reduced platelet response to aspirin therapy, and increased incidence of HDP.

Aim 3: Assess the utility of circulating microRNA as a marker of aspirin response in pregnancy and risk of HDP Hypothesis: Quantitative expression of selected miRNAs are biomarkers for response to aspirin therapy and risk of HDP.

Aim 4: Evaluate aspirin pharmacokinetics/pharmacodynamics Hypothesis: Individual factors influence aspirin pharmacokinetics/pharmacodynamics and may impact individual dosing of aspirin

• Study Type: Observational
• Enrollment (Actual): 130

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19107
      • Thomas Jefferson University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 58 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Pregnant patients at high risk for preeclampsia

Description

Inclusion Criteria:

• Pregnant singleton, <16 weeks' gestation
• At least one high risk factor for preeclampsia: prior preeclampsia, chronic hypertension, pregestational diabetes, chronic kidney disease, lupus, antiphospholipid antibody syndrome

Exclusion Criteria:

• Contraindication to aspirin
• Current or planned use of any other anticoagulation
• Use of aspirin in pregnancy prior to enrollment
• Known platelet disorder at time of enrollment

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Low Dose Aspirin; Pregnant singletons at high risk for preeclampsia based on: at least one high risk factor for preeclampsia: prior preeclampsia, chronic hypertension, pregestational diabetes, lupus, antiphospholipid antibody syndrome, or chronic kidney disease. OR; at least two of the following: BMI>30, black race, state insurance, IVF pregnancy, advanced maternal age, nulliparous or >10yr from last delivery, prior adverse pregnancy outcome who are planning to, but have not yet started, aspirin therapy <16 weeks' gestation. Patients will take 81mg aspirin as prescribed.

Drug: Aspirin 81 mg; Aspirin 81mg daily PO

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aim 1: PFA-100 closure time and risk of hypertensive disorder of pregnancy (HDP)	Difference in first trimester PFA-100 closure time between patients started on aspirin who do and do not develop HDP	8 months (delivery)
Aim 2: Pharmacogenomics of aspirin	Difference in PFA-100 closure time with aspirin therapy based on platelet receptor genotype	2 weeks
Aim 3: MicroRNAs and HDP	Regression analysis to evaluate how miRNAs 223, 126, 155, 181a, 18a, 16 levels in first trimester are associated with risk of HDP	8 months (delivery)
Aim 4: Aspirin pharmacokinetics in pregnancy	Define population based pharmacokinetic model of aspirin in first trimester of pregnancy taking into consideration individual factors (gestational age, race, BMI, genotype)	2 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Aim 1: Aspirin response	Multiple logisitic regression analysis to evaluate factors (BMI, race, gestational age, genotype) associated with rate of nonresponse to aspirin therapy defined as (PFA-100>150s)	2 weeks
Aim 1: Prediction of HDP	ROCC curve to determine threshold PFA-100 closure time after 1 week of aspirin therapy that is predictive of HDP	8 months (delivery)
Aim 1: First trimester serum thromboxane and risk of HDP	Comparison between first trimester serum thromboxane in those with and without hypertensive disorder of pregnancy	8 months (delivery)
Aim 1: Third trimester serum thromboxane and risk of HDP	Comparison between third trimester serum thromboxane in those with and without hypertensive disorder of pregnancy	8 months (delivery)
Aim 2: Pharmacogenomics and Pregnancy outcome	Multiple regression analysis taking into consideration platelet receptor genotype, race, BMI, and other clinical characteristics and prediction of HDP	8 months (delivery)
Aim 3: MicroRNA profile and aspirin therapy	Paired comparison to evaluate how miRNAs 223, 126, 155, 181a, 18a, 16 levels change before and after aspirin therapy	2 weeks
Aim 4: Salicylic acid level and Serum Thromboxane	Association between serum salicylic acid with aspirin therapy and serum thromboxane with aspirin therapy	2 weeks
Predictors of preterm birth	Multivariable logistic regression to evaluate markers predictive of preterm birth	8 months (delivery)
Predictors of preeclampsia	Multivariable logistic regression to evaluate markers predictive of preeclampsia and preterm preeclampsia	8 months (delivery)

Collaborators and Investigators

• Sponsor: Thomas Jefferson University
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); March of Dimes

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2020
• Primary Completion (Anticipated): March 30, 2023
• Study Completion (Anticipated): July 30, 2023

Study Registration Dates

• First Submitted: February 4, 2020
• First Submitted That Met QC Criteria: March 2, 2020
• First Posted (Actual): March 5, 2020

Study Record Updates

• Last Update Posted (Actual): August 17, 2022
• Last Update Submitted That Met QC Criteria: August 15, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Infections; Pregnancy Complications; Hypertension, Pregnancy-Induced; Toxemia; Hypertension; Pre-Eclampsia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Antipyretics; Aspirin
• Other Study ID Numbers: 19F.887; R21HD101127 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: IPD may be shared upon individual request after publication of planned analyses

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No