Clinical trial NCT05709483: Predictors of Aspirin Failure in Preeclampsia Prevention
Official title: Genetic, Laboratory and Clinical Factors Associated With Low-dose Aspirin Failure in the Prevention of Preeclampsia- An Exploratory Protocol
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Preeclampsia
Lead sponsor: Rockefeller University
Sponsor class: OTHER
First posted: 2023-02-02
Enrollment: 130
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Hypertensive disorders of pregnancy (including preeclampsia) are among the leading causes of pregnancy complications and maternal deaths worldwide. They also increase the risks to the babies. Numerous interventions have been suggested in order to reduce the rate of preeclampsia. Low-dose aspirin is the most beneficial prophylactic approach in this regard. Nevertheless, aspirin failure is not uncommon. The genetic, laboratory, and clinical factors associated with low-dose aspirin failure in the prevention of preeclampsia are largely unknown. The presence of a genetic variant in PAR4 receptor expressed on platelets, is associated with increased platelet function and possibly with aspirin failure.

Detailed description: Preeclampsia is among the leading causes of maternal morbidity and mortality worldwide. The pathophysiology underling the occurrence of preeclampsia is multifactorial with many suggested theories. Among the latter, enhanced platelet activation coupled with an imbalance in prostanoid levels have been postulated as being responsible for the pathophysiologic changes in preeclampsia.

Numerous prophylactic interventions have been investigated in order to reduce the rate of gestational hypertensive disorders. It is currently well-established that administration of low-dose aspirin is the most beneficial prophylactic approach.

The major effect of aspirin is to inhibit cyclooxygenase-1 (COX-1), which reduces thromboxane A2 production in platelets and the abnormally increased thromboxane A2/prostaglandin I2 imbalance.

This improves placental function by favoring systemic vasodilatation and inhibiting platelet aggregation. Despite its well-established clinical role in the prevention of preeclampsia, aspirin failure is not uncommon. Nevertheless, the ancestry/genetic, laboratory, and clinical factors associated with low-dose aspirin failure in the prevention of preeclampsia are largely unknown.

Higher rates of aspirin failure have been reported in Black women, possibly due to genetic variants. Studies among non-pregnant patients, have identified that racial differences in PAR4 (protease- activated receptor 4) expressed on platelets, are associated with increased platelet function in Blacks compared to whites. A single-nucleotide variant (rs773902) in PAR4 gene (F2RL3), which results in alanine/threonine polymorphism, was shown to largely account for the racial difference in platelet activation by PAR4. The frequency of the variant differs widely between self-declared Black individuals and non-Black individuals, with values of \~65% versus\~20%. Thus, it is possible that the variant may contribute to the higher rate of failure of low dose aspirin in the Black population.

The study aim is to evaluate these issues.

Eligibility criteria: Inclusion Criteria:

1. Women aged 18-45 years with prior history of preeclampsia who received low dose aspirin in their subsequent gestation and either did or did not have a recurrence of preeclampsia.
2. Aspirin was given in their subsequent pregnancy in a 81 mg dose prior to 16 weeks of gestation, and was taken with a self-reported compliance rate of at least 80%
3. Subsequent pregnancy lasted beyond 20 weeks of gestation
4. Willingness to abstain from non-prescription non-steroidal anti-inflammatory drugs (NSAIDs), which are known to interfere with platelet function assays, for one week prior to platelet function analyses.
5. Healthy controls recruited for SNP assay optimization:

Women aged 18 years or older, with no other specific inclusion criteria that need to be met in order to be enrolled for the study.

Exclusion Criteria:

1. Age \<18 years or \>45 years
2. Any clinically significant adverse reaction to aspirin on prior exposure
3. Known bleeding disorder based on personal or family history
4. History of kidney or liver impairment
5. Current pregnancy
6. Current use of antithrombotic agents (e.g., aspirin, clopidogrel, warfarin, direct acting oral anticoagulants).
7. Chronic hypertension (systolic blood pressure \>140 mmHG or diastolic pressure \>90 mmHG, or use of antihypertensive drugs or diagnosis made by clinician)
8. Diabetes mellitus
9. Current known malignancy
10. History of hemorrhagic stroke
11. Participants may be excluded at the discretion of the investigator for medical, psychological or other reasons
12. Rockefeller students, and Rockefeller employees in the Coller lab, are excluded from participation.
13. Healthy controls:

A. \<18 years of age. B. Participants may be excluded at the discretion of the investigator for medical, psychological or other reasons C. Rockefeller students, and Rockefeller employees in the Coller lab, are excluded from participation.

Primary outcomes:
measure: Allelic frequency of the PAR4 variant (rs773902) in relation to aspirin success in preeclampsia prevention
timeFrame: At study enrollment
Secondary outcomes:
measure: Platelet response to aspirin as assessed by VerifyNow Aspirin Assay in relation to aspirin success in preeclampsia prevention-measured as VerifyNow Reaction Units
timeFrame: 0 and 1 hours post single dose 81 mg enteric-coated aspirin
measure: Platelet response to aspirin as assessed by VerifyNow Base Assay in relation to aspirin success in preeclampsia prevention-measured as VerifyNow Reaction Units
timeFrame: 0 and 1 hours post single dose 81 mg enteric-coated aspirin
measure: Platelet response to aspirin as assessed by aggregometry in relation to aspirin success in preeclampsia prevention-measured as VerifyNow Reaction Units
timeFrame: 0 and 1 hours post single dose 81 mg enteric-coated aspirin
measure: Thromboxane A2 levels in relation to aspirin success in preeclampsia prevention-measured in ng/mL
timeFrame: 0 and 1 hours post single dose 81 mg enteric-coated aspirin
Other outcomes:
Locations:
city: New York
country: United States
facility: Rockefeller University
state: New York
Study officials:
affiliation: Rockefeller University
name: Amihai Rottenstreich, MD
role: PRINCIPAL_INVESTIGATOR
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