LEAP Pilot: Low Molecular Weight Heparin Vs. Aspirin Postpartum

Background Expert opinion from the American Society for Hematology (ASH), the Royal College of Obstetricians and Gynecologists, UK, as well as the 'Society of Obstetricians and Gynecologists of Canada guidelines recommend a minimum of 6 weeks of prophylactic LMWH for patients with a history of venous thromboembolism (VTE) or high-risk thrombophilia. There are no randomized controlled trials (RCTs) determining the optimal duration of anticoagulation postpartum. A 2014 Cochrane review concluded that there is insufficient evidence on which to base thromboprophylaxis in the pregnancy postpartum setting, and high-quality randomized trials are warranted. Clinical trials and meta-analyses have suggested that ASA administered daily post-operatively may be non-inferior to LMWH for VTE prophylaxis; (RR 0.76; 95% CI, 0.37- 1.56 in one study), with a similar safety profile. Furthermore, in 2018 Anderson et al. demonstrated clinical safety and non-inferiority of a combination of 5 days of rivaroxaban followed by 81mg of ASA for 30 days after total hip arthroplasty and 9 days after total knee arthroplasty.

The principal question to be addressed in a large definitive randomized controlled trial (RCT) is whether a combination of prophylactic LMWH for 3 weeks followed by low-dose ASA for the following 3 weeks is non-inferior to the standard of care of prophylactic LMWH for 6 weeks postpartum. This single-center pilot RCT addresses enrollment, adherence and feasibility required prior to conducting a definitive trial.

Study Design and Methods Inclusion criteria: 1) Personal history of VTE prior to pregnancy and not prescribed therapeutic anticoagulation 2) Family history of VTE and antithrombin deficiency, protein C or protein S deficiency 3) Combined thrombophilia or homozygous for factor V Leiden mutation or prothrombin gene mutation, regardless of family history. Sample size: 50 patients, 25 patients treated according to each strategy. Primary outcomes: 1) Enrollment/consent rate 2) Adherence to study protocol 3) Loss to follow-up/missing data. Secondary outcomes: 1) VTE rate 2) Bleeding rate three months following delivery 3) Quality of life assessment (QoL) (Duke Anticoagulation Satisfaction Scale).

Results The enrollment rate was 69.2%, with 18 of 26 patients agreeing to participate. Of the 18 recruited, one was randomized in error, one had an early pregnancy loss, and one developed a superficial vein thrombosis antenatally due to non-compliance with antepartum anticoagulation, leaving 15 patients satisfying inclusion criteria. 9 patients have completed their 3-month postpartum follow-up, with no patients lost to follow-up. The adherence to treatment at 3 weeks was 96.4% and 94.0% in Group A (LMWH and ASA) and B (LMWH), respectively (p=0.7). At 6 weeks postpartum, there was a trend toward greater treatment compliance in Group A vs Group B (98.2 vs 94.1%); however, this was not statistically significant (p=0.52).

With regards to secondary outcomes, there was no VTE documented in either treatment group. One patient in each group reported mild gingival bleeding. No other bleeding events were reported. The QoL assessment score in Group A improved by 56% following the change from LMWH to ASA (39.5 to 16.8), whilst it deteriorated in Group B by 2% (24.5 vs 25.2). At 6 weeks postpartum, the QoL score improved by 33.3% in Group A vs Group B (P=0.01).

Conclusion Our data shows promising enrollment, adherence, loss to follow-up and feasibility of our ongoing pilot trial. The results of this study will be used to design first a multicenter pilot study then a large definitive multicentered trial. Demonstration of non-inferiority of ASA and LMWH to LMWH will lead to a shorter course of LMWH postpartum, potentially reducing bleeding risk, need for subcutaneous injections, as well as cost, while improving quality of life. If the definitive trial does not show non-inferiority, the results will provide evidence that six weeks of postnatal thromboprophylaxis with LMWH is warranted.

Malinowski:Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Consultancy.