Prevention of Maternal and Perinatal Complications by Enoxaparin in Women With Previous Severe Preeclampsia (HEPEPE)

Study Description

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Brief Summary:

Preeclampsia (PE) complicates 2-8% of pregnancies. It is associated with an increased risk of adverse maternal (death, eclampsia, abruptio placenta, HELLP syndrome) and perinatal (perinatal death, growth restriction, prematurity) outcomes. The only definite treatment of PE remains pregnancy termination. Therefore, prevention of PE remains an important challenge. Low dose aspirin may be used in the prevention of PE, particularly in women who had a severe preeclampsia before 34 weeks. Its efficiency, however, is very weak. Recently, it has been suggested that low molecular weight heparin might be useful in the prevention of PE.

The aim of this study is to analyze the usefulness of the enoxaparin 4000 UI/day in the prevention of a composite maternal or perinatal morbidity (occurrence of one of the following events: maternal death, PE, fetal growth retardation, abruptio placenta, perinatal death) in women who previously had a severe preeclampsia at less than 34 weeks' gestation. To answer this question, the investigators propose to conduct a multicenter prospective randomized trial that will compare two groups in parallel: a group where women will have an association of enoxaparin 4000 U/day and aspirin 100 mg/day and another group where women would have only aspirin 100 mg/day. The number of patients needed is 255 (amendment n°2-approved 06/12/2011) .

Condition or disease	Intervention/treatment	Phase
Preeclampsia	Drug: Lovenox® (enoxaparin); Drug: Aspegic ® (Aspirin)	Phase 3

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Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	257 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Prevention
Official Title:	Low Molecular Weight Heparin, Enoxaparin, to Prevent Adverse Maternal and Perinatal Outcomes in Women With Previous Severe Preeclampsia at Less Than 34 Weeks' Gestation. A Prospective Randomized Trial
Study Start Date :	June 2009
Actual Primary Completion Date :	November 2015
Actual Study Completion Date :	November 2015

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Lovenox® , 4000 UI/day (+ Aspegic®); Lovenox® (enoxaparin), 4000 UI/day (+ Aspegic® (Aspirin), 100 mg)	Drug: Lovenox® (enoxaparin); Injectable solution 4000 UI
Active Comparator: Aspegic ®, 100 mg/day; Aspegic® (Aspirin),100 mg/day	Drug: Aspegic ® (Aspirin); 100 mg/day

Outcome Measures

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Primary Outcome Measures :

1. The primary outcome is a composite morbidity that may occur : maternal death, or perinatal death, or preeclampsia, or abruptio placenta, or fetal growth restriction. [ Time Frame: from randomization until one month after the delivery ]

Secondary Outcome Measures :

1. Recurrence of preeclampsia alone [ Time Frame: from randomization until one month after the delivery ]
2. Recurrence of severe preeclampsia [ Time Frame: from randomization until one month after the delivery ]
3. Fetal growth restriction alone [ Time Frame: from randomization until one month after the delivery ]
4. Severe fetal growth restriction (< 5th percentile) [ Time Frame: from randomization until one month after the delivery ]
5. Perinatal death alone [ Time Frame: from randomization until one month after the delivery ]
6. Neonatal death [ Time Frame: from randomization until one month after the delivery ]
7. Abruption alone [ Time Frame: from randomization until one month after the delivery ]
8. Maternal death [ Time Frame: from randomization until one month after the delivery ]
9. Fetal loss (10-21 weeks) [ Time Frame: from randomization until one month after the delivery ]
10. Fetal death [ Time Frame: from 15 weeks to delivery ]
11. Recurrence of preeclampsia controlled for thrombophilia analysis (polymorphism of factor V Leiden, prothrombin G20210A gene polymorphism) [ Time Frame: from randomization until one month after the delivery ]
12. Recurrence of preeclampsia controlled for angiogenic factors (free VEGF and PlGF, sFlt1, sEng) [ Time Frame: from randomization until one month after the delivery ]
13. Neonatal morbidity (NICU transfer, length of hospitalization, mechanical ventilation > 24 hours, respiratory distress syndrome, necrotizing enterocolitis, periventricular leucomalacia, bronchopulmonary dysplasia, intraventricular hemorrhage grade III-IV) [ Time Frame: from randomization until one month after the delivery ]
14. Enoxaparin toxicity: hemorrhage, skin reaction, thrombocytopenia (<100000/µL) related to heparin [ Time Frame: from randomization until one month after the delivery ]
15. Bone fracture [ Time Frame: from randomization until one month after the delivery ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Patient ≥ 18 years
• Patient with a previous severe preeclampsia that occurred at less than 34 weeks' gestation
• Patient between 7 and 13 weeks +6 days at first prenatal visit
• Singleton pregnancy
• Affiliation to social security
• Informed consent given after receiving information on the study.

Exclusion Criteria:

• Patient under law protection
• Inability to sign written consent
• Inability to follow the protocol because of a psychiatric disease
• History of deep venous thromboembolism during previous pregnancy
• Need of low molecular weight heparin during pregnancy
• Previous arterial thrombosis
• Patient having a cardiac valvular prosthesis that necessitates anticoagulation during pregnancy
• Renal failure (creatinine clearance < 30 ml/min, or serum creatinine > 180 µmol/L
• Previous hemorrhagic disease
• A disease that might bleed (gastric ulcer)
• Antiphospholipid antibody syndrome
• Allergy to Aspirin
• Allergy to heparins
• Thrombocytopenia related to heparin use
• Thrombocytopenia <100,000 /µL at first prenatal visit
• Antecedent of osteoporosis
• Inability to do subcutaneous injection of heparin
• Weight > 100 kg
• Patient included in another interventional trial
• Patient positive for anti-phospholipids antibodies
• Patient positive for HIV or HCV or HBS

Contacts and Locations

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Locations

France
Centre Hospitalier Intercommunal de Créteil
Creteil, France

Sponsors and Collaborators

Assistance Publique - Hôpitaux de Paris

Investigators

Principal Investigator:	Bassam Haddad	Assistance Publique - Hôpitaux de Paris

More Information

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Lecarpentier E, Gris JC, Cochery-Nouvellon E, Mercier E, Touboul C, Thadhani R, Karumanchi SA, Haddad B. Angiogenic Factor Profiles in Pregnant Women With a History of Early-Onset Severe Preeclampsia Receiving Low-Molecular-Weight Heparin Prophylaxis. Obstet Gynecol. 2018 Jan;131(1):63-69. doi: 10.1097/AOG.0000000000002380.

Haddad B, Winer N, Chitrit Y, Houfflin-Debarge V, Chauleur C, Bages K, Tsatsaris V, Benachi A, Bretelle F, Gris JC, Bastuji-Garin S; Heparin-Preeclampsia (HEPEPE) Trial Investigators. Enoxaparin and Aspirin Compared With Aspirin Alone to Prevent Placenta-Mediated Pregnancy Complications: A Randomized Controlled Trial. Obstet Gynecol. 2016 Nov;128(5):1053-1063.

Responsible Party:	Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier:	NCT00986765 History of Changes
Other Study ID Numbers:	P071211
First Posted:	September 30, 2009
Last Update Posted:	January 20, 2016
Last Verified:	January 2016

Keywords provided by Assistance Publique - Hôpitaux de Paris:

Fetal growth restriction; Abruptio placentae; Perinatal death

Additional relevant MeSH terms:

Pre-Eclampsia; Hypertension, Pregnancy-Induced; Pregnancy Complications; Aspirin; Acetylsalicylic acid lysinate; Enoxaparin; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Analgesics; Sensory System Agents; Peripheral Nervous System Agents	Physiological Effects of Drugs; Anti-Inflammatory Agents; Antirheumatic Agents; Fibrinolytic Agents; Fibrin Modulating Agents; Molecular Mechanisms of Pharmacological Action; Platelet Aggregation Inhibitors; Cyclooxygenase Inhibitors; Enzyme Inhibitors; Antipyretics; Anticoagulants