The PARTUM Trial: Postpartum Aspirin to Reduce Thromboembolism Undue Morbidity

The PARTUM trial design is a Prospective Randomized Open Blinded End-point (PROBE) non-inferiority trial. Participants with risk factors for venous thromboembolism (VTE) as defined by the inclusion criteria will be identified during pregnancy, labor and delivery, and up to 48 hours after delivery.

Eligible and consenting participants will be randomly assigned to one of two study arms: Low-dose aspirin (75-100mg according to country availability) daily for 42 days post-randomization, or a usual care site-specific low-molecular-weight-heparin (LMWH) regimen with the dose and duration of LMWH determined by the participant's healthcare provider.

Follow-up will occur at 6 weeks and 90 days post-randomization.

• Aspirin (Drug): 75-100 mg taken once daily by mouth.
• Low-molecular-weight heparin (Drug), also known as Dalteparin, Enoxaparin, Nadroparin, Tinzaparin: Low-molecular-weight heparin injections daily as prescribed by the treating physician.

Primary outcomes

• Symptomatic VTE [6 weeks]: Proximal lower or upper extremity DVT, PE involving segmental or higher arteries or multiple subsegmental arteries, and unusual site \[non-limb\] venous thromboembolism

Secondary outcomes

• Late symptomatic VTE [90 days]: Proximal lower or upper extremity DVT, PE involving segmental or higher arteries or multiple subsegmental arteries, and unusual site \[non-limb\] venous thromboembolism
• Superficial vein thrombosis [At 6 weeks and at 90 days]: A non-compressible vein segment on ultrasound that involves the superficial veins in the lower or upper extremity
• Distal deep vein thrombosis [At 6 weeks and at 90 days]: A non-compressible vein segment on ultrasound involving the deep veins that is distal to the popliteal vein in the lower extremity, or distal to the axillary vein in the upper extremity
• Single subsegmental pulmonary embolism (SSPE) [At 6 weeks and at 90 days]: Intraluminal filling defect that involves one subsegmental artery only
• Major bleeding [At 6 weeks and at 90 days]: Based on the ISTH definition
• Clinically relevant non-major bleeding [At 6 weeks and at 90 days]: Based on the ISTH definition
• Wound hematoma requiring intervention [At 6 weeks and at 90 days]: Requiring intervention such as hematoma evacuation or wound packing
• Symptomatic arterial thromboembolism [At 6 weeks and at 90 days]: Ischemic stroke/transient ischemic attack, myocardial infarction, or peripheral arterial embolism
• Postpartum preeclampsia [At 6 weeks and at 90 days]: New preeclampsia presenting in the postpartum period
• Heparin-induced thrombocytopenia [At 6 weeks and at 90 days]: According to a priori categories of definite or possible HIT.
• All-cause mortality [At 6 weeks and at 90 days]

Sex: Female, ages: 18 Years to any

Inclusion Criteria:

* ONE (or more) First Order Criterion:

  1. Known inherited thrombophilia diagnosed prior to enrolment, regardless of family history of VTE:

     i. Heterozygous factor V Leiden, or ii. Heterozygous prothrombin gene variant, or iii. Protein C deficiency, or iv. Protein S deficiency, and/or
  2. Antepartum immobilization for ≥7 days. Immobilization is defined as bed rest with 90% of waking hours spent in bed at any time during the antepartum period AND/OR

TWO (or more) Second Order Criteria:

1. Pre-pregnancy BMI ≥30 kg/m²
2. Smoking in the current pregnancy or within 3 months prior to pregnancy
3. Previous clinical history of superficial vein thrombosis
4. Preeclampsia
5. Current pregnancy ending in stillbirth (pregnancy loss >20 weeks gestation)
6. Unplanned cesarean delivery (unplanned = not a scheduled cesarean delivery)
7. Small-for-gestational-age infant at time of delivery (<3rd percentile adjusted for gestational age and sex)
8. Peripartum or postpartum infection (symptoms/signs of infection and documented fever and laboratory evidence of infection with positive blood cultures or an elevated white blood cell count based on local laboratory cutoffs)
9. Postpartum hemorrhage (≥1000 mL of blood loss, regardless of delivery mode)

Exclusion Criteria:

1. More than 48 hours since delivery at the time of randomization
2. Received more than 1 dose of LMWH since delivery
3. Need for postpartum LMWH prophylaxis or systemic anticoagulation as judged by their physician and/or local investigator. May include but is not limited to:

   1. Documented history of provoked or unprovoked VTE
   2. Mechanical heart valve(s)
   3. Known antiphospholipid syndrome (APS)
   4. Known high-risk inherited thrombophilia i) Antithrombin deficiency, or ii) Homozygous factor V Leiden, or iii) Homozygous prothrombin gene mutation, or iv) More than 1 thrombophilia: any combination of 2 or more: factor V Leiden, prothrombin gene mutation, protein C deficiency, protein S deficiency
4. Need for postpartum ASA as judged by their physician and/or local investigator. May include but is not limited to:

   1. Documented history of myocardial infarction
   2. Documented history of ischemic stroke or transient ischemic attack (TIA)
5. Active bleeding, excluding normal vaginal bleeding, at the time of randomization
6. Known medical condition as judged by their physician and/or local investigator to be a contraindication to ASA or LMWH including known ASA or LMWH allergy
7. <18 years of age
8. Unable or declined consent

• Leslie Skeith, MD, Principal investigator, University of Calgary
• Marc Rodger, MD, Principal investigator, McGill University Health Centre/Research Institute of the McGill University Health Centre