Clinical trial NCT04070573: Low Doses of Aspirin in the Prevention of Preeclampsia
Official title: A Randomized Controlled Trial Comparing Low Doses Of Aspirin In The Prevention Of Preeclampsia (ASAPP)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Preeclampsia
Keywords: Preterm preeclampsia
Preeclampsia with severe features
High risk pregnancy
Low dose aspirin
Cell free RNA
Compliance
Lead sponsor: Weill Medical College of Cornell University
Sponsor class: OTHER
First posted: 2019-08-28
Enrollment: 400
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Arm 1: 81mg oral ASA daily. Arm 2: 162mg oral ASA daily. Patients will obtain their prescriptions from their respective pharmacies. Women in Arm 1, will be instructed to take one table of 81mg aspirin per day; those in Arm 2, will be asked to take two tablets simultaneously orally once per day. Therapy will be initiated at the baseline visit and continued until 1 week before planned delivery or upon admission for unplanned/imminent delivery as per clinical routine.
Primary purpose: PREVENTION

Brief summary: Preeclampsia (PE) is a morbid and potentially lethal complication of pregnancy and is more common in women with specific risk factors. Aspirin (ASA) is currently the only prophylactic therapy for preeclampsia in high-risk women to be recognized by the US Preventive Task Force and should be initiated early in the second trimester of pregnancy, before 16 weeks of gestation. However, currently there is no literature comparing various low-dose ASA formulations in the risk reduction of PE. In the United States, the currently available low-dose ASA is over the counter and is found in 81mg tablets. Therefore, when clinicians initiate therapy with low dose ASA, they may prescribe 1 or 2 tablets of 81mg aspirin per day depending on personal preference and cannot be assisted by evidence to guide their decision.This study aims to determine the incidence of preterm PE or PE with severe features in women taking either 81mg or 162mg in a randomized setting, from a single center. The investigators hypothesize that the information gained from this trial will permit a more accurate sample size calculation for a larger clinical trial powered to accept or reject our testing hypothesis. If our hypothesis is rejected and 162mg of daily ASA is not associated with a lower incidence of severe or preterm PE compared to 81mg, this may be due to lack of power to detect a smaller effect. The investigators would then evaluate the feasibility and results and determine whether a larger trial is reasonable.

Detailed description: Preeclampsia (PE) is a serious and potentially fatal complication of pregnancy. It is a placental disease characterized by an elevated blood pressure in the 3rd trimester with multisystem involvement (proteinuria, elevated liver enzymes, low platelet count and/or neurologic symptoms). PE can cause pulmonary edema, seizures, or stroke and is a leading cause of maternal mortality. The pregnancy outcomes are further worsened if PE develops before term. Women who have a history of PE in a prior pregnancy, diabetes, preexisting hypertension, kidney disease, multifetal gestation or autoimmune diseases are at an increased risk to develop PE in a subsequent pregnancy.

Clinical trials evaluating the benefits of low-dose aspirin (ASA) have used a wide range of doses from 60mg to 150mg orally daily with low-dose being defined as less than 325mg per day. Taking ASA (as opposed to placebo) is thought to reduce the risk of preeclampsia by 17%, without increasing the risk of major obstetric bleeding. The number needed to treat is only 19 women. ASA is currently the only prophylactic therapy for PE in high-risk women to be recognized by the US Preventive Task Force and should be initiated early in the second trimester of pregnancy, before 16 weeks of gestation.

There has also been more awareness that the efficacy of ASA in preventing preeclampsia is limited by the poor adherence of patients to this therapy. Indeed, a cross-sectional study has estimated that up to 46% of women (n=42) on ASA therapy may not be compliant to it, as determined by a validated Simplified Medication Adherence Questionnaire (SMAQ). Adherence is essential to the efficacy of ASA in preventing preterm preeclampsia. It would therefore be of interest to obtain more information about adherence to ASA in women who need this therapy.

Assessing molecular pathways in the development of PE may allow opportunity for earlier diagnosis, specific triaging of patients to closer monitoring and further development of preventative or curative treatment strategies. Samples will be biobanked for biomarker discovery in the future.

The current literature is lacking in evidence to recommend a specific daily dose of ASA. Recent meta-analyses have suggested that there may be a dose response in the protective effect of ASA for PE. As compared to 60mg per day, an ASA dose of 100mg per day was associated with a lower relative risk of PE (0.44 vs 0.57, p=0.36). A large study of 1776 women has compared a slightly higher dose of ASA (150mg per day) to placebo and found a decrease in preterm delivery (before 37 weeks) due to PE (OR 0.38, p=0.004). Meta-analyses have shown that any dose of ASA above 60mg per day is protective and should be used to prevent PE in high risk pregnancies.

To date, there has not been any studies comparing lower doses of ASA (such as 81mg, the traditional "baby aspirin" dose sold in the US) to higher "low-dose" ASA regimens (such as 162mg) in their ability to prevent preterm or severe PE in women who are at a high risk for this devastating disease.

Eligibility criteria: Patients are currently only being enrolled at the New York Presbyterian Weill Cornell Medicine and at the New York Presbyterian Queens campuses.

Inclusion Criteria:

Pregnant patients, ≥18 years old, at less than 16 weeks' gestation (as documented by ultrasound) with at least one of the following risk factors for developing PE:

* PE in a prior pregnancy
* Chronic hypertension (prior to pregnancy or before 20 weeks' gestation)
* Type 1 or 2 diabetes
* Renal disease (proteinuria ≥300mg/day or estimated GFR\<90mL/min/1.73 m2)
* Multifetal gestation
* Autoimmune disease (e.g. systemic lupus erythematous, antiphospholipid syndrome)

Exclusion Criteria:

* Patient with known intention to terminate pregnancy
* Major fetal malformation seen on ultrasound
* Contraindication to ASA therapy (including but not limited to allergy and high bleeding risk)

Primary outcomes:
measure: Incidence of Preterm (<37 Weeks) Preeclampsia
timeFrame: 9 months for each patient (from recruitment until 6 weeks postpartum)
measure: Incidence of Preeclampsia With Severe Features
timeFrame: 9 months for each patient (from recruitment until 6 weeks postpartum)
measure: Composite Primary Outcome
timeFrame: 9 months for each participant
Secondary outcomes:
measure: Aspirin Adherence
timeFrame: 9 months for each patient (from recruitment until 6 weeks postpartum)
measure: Maternal and Fetal Outcomes
timeFrame: 9 months for each patient (from recruitment until 6 weeks postpartum)
measure: Time-to-event for Preeclampsia: Gestational Age at Onset of Preeclampsia
timeFrame: 9 months for each patient (from recruitment until 6 weeks postpartum)
measure: Aspirin Adherence- All Time Points Together
timeFrame: 9 months for each patient (from recruitment until 6 weeks postpartum)
Other outcomes:
measure: Impact of Co-morbidities on Incidence of Preeclampsia
timeFrame: 9 months for each patient (from recruitment until 6 weeks postpartum)
Locations:
city: New York
country: United States
facility: New York Presbyterian - Weill Cornell
state: New York
city: New York
country: United States
facility: New York Presbyterian Queens
state: New York
Study officials:
affiliation: Weill Medical College of Cornell University
name: Line Malha, MD, MS
role: PRINCIPAL_INVESTIGATOR
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