Clinical trial NCT04356326: Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy
Official title: Chronic Hypertension and Acetyl Salicylic Acid in Pregnancy, a Multicenter Prospective Randomized Double-blind Placebo-controlled Trial.
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Chronic Hypertension Complicating Pregnancy
Pre-Eclampsia
Intrauterine Growth Restriction
Aspirin
Perinatal Death
Placental Abruption
Lead sponsor: Centre Hospitalier Intercommunal Creteil
Sponsor class: OTHER
First posted: 2020-04-22
Enrollment: 500
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Prospective multicentric randomized double-blind superiority trial, placebo-controlled, on two parallel arms
Primary purpose: TREATMENT

Brief summary: A randomized clinical trial to assess the efficiency of acetylsalicylic acid (aspirin) 150 mg/day started before 20 weeks of gestation in the prevention on maternal and fœtal complications in pregnant women with chronic hypertension.

Detailed description: Chronic hypertension affects 1 to 5% of women of childbearing age. According to the literature, about 45% of pregnant women with chronic hypertension will develop complications such as superimposed preeclampsia (PE), placental abruption, Intra Uterine Growth Restriction (IUGR), perinatal death, maternal death, or preterm delivery. To date, there is no curative treatment of vascular complications of chronic hypertension during pregnancy. The only effective treatment, once the complications are established, is usually stopping the pregnancy and delivering the placenta. The preventive treatment of these complications is therefore an important axis in the improvement of maternal and perinatal health.

Due to the very high risk of superimposed PE in chronic hypertensive patients and despite the lack of objective evidence of the effectiveness of low-dose aspirin in the prevention of superimposed PE in this population, the NICE (National Institute for Health and Care Excellence), associated with the Royal College of Gynecology-Obstetrics, recommends since 2010-2011 the use of low-dose aspirin in the prevention of this complication in chronic hypertensive pregnant women; then it was followed by the "U.S. Preventive Services Task Force (USPTF)" in 2014. Recently, the American College of Obstetrics and Gynecology (ACOG) adopted the suggestions of the USPTF and issued the same recommendations in 2018. The French college of obstetric (CNGOF: National College of French Gynecologists and Obstetricians), however, does not recommend the use of low-dose aspirin in pregnant chronic hypertensive women because of insufficient data.

Indeed, although the efficacy of low-dose aspirin is assumed in patients with previous PE, few studies have evaluated its efficacy in patients with chronic hypertension. Moreover, most of the controlled prospective studies using very low doses of aspirin (less than 100 mg) and starting after 20 weeks of gestation do not seem conclusive. For these reasons, the investigators propose to conduct a prospective randomized double-blind placebo-controlled trial to analyze the effectiveness of aspirin dosed at 150 mg and introduced before 20 weeks of gestation in women with chronic hypertension.

The primary endpoint is a maternal and perinatal composite morbidity and mortality including superimposed PE, intrauterine growth restriction, preterm delivery \< 37 weeks of gestation, placental abruption, perinatal death, or maternal death.

The definition of superimposed PE in our study is the appearance of significant proteinuria in a chronic hypertensive pregnant woman.

In a secondary analyze, the statistician will use the new definition of superimposed PE that does not require the mandatory presence of proteinuria but the association of chronic hypertension and the appearance of neurological signs (eclampsia, persistent headache, visual disturbances, severe nausea or vomiting), pulmonary edema, persistent epigastric pain, thrombocytopenia \<100000 platelets/µL, liver enzymes at 2 times normal, renal insufficiency ( serum creatinine ≥ 97 μmol/L or 1.1 mg/dL,) or a doubling of serum creatinine in the absence of chronic renal disease or significant proteinuria after 20 weeks of gestation or postpartum.

Significant proteinuria is defined as greater than 300 mg/24 hours or when the ratio proteinuria/ creatininuria is ≥ 30 mg/mmol (ratio to 0.3 if all are in mg/dL), in a non-proteinuric women with no urinary tract infection.

Eligibility criteria: Inclusion Criteria:

* Pregnant patient between 10 and 19 weeks of gestation + 6 days
* Chronic hypertension, whether treated or not, know before pregnancy or diagnosed before randomization
* Singleton pregnancy
* Signed the written informed consent
* Affiliation to social security

Exclusion Criteria:

* ---Medical history requiring anticoagulation (antiphospholipid syndrome, deep vein thromboembolic disease, pulmonary embolism, atherothrombosis, patient with mechanical heart valves),
* Patient receiving aspirin for another indication outside pregnancy,
* Patient with significant proteinuria (\> 300mg/24 hours or a proteinuria/creatininuria ratio ≥ 30mg/mmol),
* Active bleeding,
* History of severe PE with delivery \< 34 weeks of gestation,
* Hypersensitivity to salicylates such as aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs),
* Platelet count lower than 100,000 cells/microliter (dosage less than 6 months old),
* Hemostasis disorders, including hemophilia (with thrombocytopenia)
* Any constitutional or acquired hemorrhagic disease, (including digestive hemorrhages, history of hemorrhagic stroke and thrombocytopenia
* Human immunodeficiency virus, or hepatitis B virus, or hepatitis C virus positive serum,
* Patient included in another interventional study which could interfere with the results of the study,
* Age \<18 years old,
* Women under the protection of justice,
* Patients with psychiatric follow-up, poor understanding of French or cognitive problems,
* Duodenal ulcer,
* Severe renal impairment,
* Severe hepatic insufficiency,
* Severe cardiac impairment,
* Gout,
* Patients with known glucose-6-phosphate dehydrogenase deficiency,

Primary outcomes:
measure: Composite morbidity-mortality criterion including preeclampsia, intra-uterine growth retardation <10th percentile, placental abruption, Preterm birth < 37 weeks of gestation, Perinatal death, Maternal death
timeFrame: 9 months
Secondary outcomes:
measure: IUGR (< 10th percentile of birth weight)
timeFrame: 9 months
measure: Placental abruption
timeFrame: 9 months
measure: Preterm birth < 37 weeks of gestation
timeFrame: 9 months
measure: Maternal death
timeFrame: 9 months
measure: Severe pre-eclampsia
timeFrame: 9 months
measure: Intrauterine growth restriction (IUGR)
timeFrame: 9 months
measure: Preterm delivery
timeFrame: 8 months
measure: Fetal loss
timeFrame: 5 months
measure: Fetal death
timeFrame: 5 months
measure: Neonatal death
timeFrame: 9 months
measure: Neonatal morbidity
timeFrame: 9 months
measure: Toxicity of aspirin
timeFrame: 8 months
measure: Adherence
timeFrame: 8 months
measure: Biological response to the treatment
timeFrame: 4 months
measure: Angiogenic profile
timeFrame: 9 months
measure: Child development
timeFrame: 2 years
measure: Child development
timeFrame: 4 years
measure: Subgroups analysis
timeFrame: 9 months
Other outcomes:
Locations:
city: Bordeaux
country: France
facility: CHU Bordeaux
city: Caen
country: France
facility: CHU Caen
city: Clamart
country: France
facility: CHU Antoine Béclère, AP-HP
city: Colombes
country: France
facility: Hôpital Louis Mourier, AP-HP
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal de Créteil
city: Dijon
country: France
facility: CHU Dijon
city: Le Kremlin-Bicêtre
country: France
facility: CHU Bicêtre, AP-HP
city: Lille
country: France
facility: CHRU Lille
city: Lyon
country: France
facility: CHU Lyon
city: Marseille
country: France
facility: Hôpital St Joseph
city: Nancy
country: France
facility: CHRU Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: CHU Cochin- Port Royal, AP-HP
city: Paris
country: France
facility: CHU Robert Débré, AP-HP
city: Paris
country: France
facility: CHU Tenon
city: Paris
country: France
facility: Hôpital Trousseau, AP-HP
city: Poissy
country: France
facility: CH Poissy
city: Saint-Étienne
country: France
facility: CHU St Etienne
city: Toulouse
country: France
facility: CHU Toulouse
city: Tours
country: France
facility: CHU Tours
Study officials:
References: