Low Molecular Weight hEparin vs. Aspirin Post-partum
Phase: NA
Conditions: Venous Thromboembolism
Sponsor: Mount Sinai Hospital, Canada

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Version 3.1: November 10, 2022 
Low Molecular Weight hEparin vs. Aspirin Post-partum (LEAP)  
Version 1: October 25, 2020 
Version 2: July 27 2021– changes as per minor protocol change on randomization system and data 
collection table, indicated on the pink highlights with comment. 
Version 2.1: September 13, 2021- reference list added, indicated on the yellow highlights.  
Version 2.2: October 29, 2021 - Screening time changed in the table, Randomization section updated as 
per suggestions 
Version 2.3: November 11, 2021- Screening time changed in the table from day -14 to day -1 to week -8 to 
day -1, Randomization section updated in the latest version of Protocol from September 29 
Version 2.4: December 13, 2021- In ‘Trial Schematic Table’ data will be collected for concurrent medication 
at 3 month follow up. 
Version 2.5: December 29, 2021- In ‘Trial Schematic Table’ Bleeding Assessment Score has been added for 3 
week follow up, 6 week follow up, early discontinuation form. 
 
Version 2.6: January 14, 2022- In ‘Trial Schematic Table’ Data for Quality Of Life Assessment will not be 
collected on dosing day. 
Version 3: October 11, 2022- Study title changed to Low Molecular Weight hEparin vs. Aspirin Post-partum 
(LEAP)  
 

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Version 3.1: November 10, 2022 
Low Molecular Weight hEparin vs. Aspirin Post-partum (LEAP) Title 
Low Molecular Weight hEparin vs. Aspirin Post-partum (LEAP)  
Aim and Overall Objective 
The principal question to be addressed, in a large definitive trial, is whether a combination of low 
molecular weight heparin (LMWH) and low dose aspirin is non-inferior to standard of care of LMWH for 
venous thromboembolism prophylaxis (VTE) postpartum. This single-center randomized pilot feasibility 
study will address enrollment, adherence and feasibility for the definitive trial. 
Introduction 
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’ guidelines recommends 
a minimum of 6 weeks of prophylactic LMWH for patients with a history of VTE or high- risk 
thrombophilias. This recommended duration is based on expert consensus and observational data that 
do not clearly define the risk of VTE and the risk reduction with LMWH therapy. LMWH requires daily 
subcutaneous injections, is associated with an increased risk of bleeding and is expensive. 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 setting, and high-quality randomized trials are warranted (Bain et al., 2014). 
A recent RCT randomized patients following total hip and knee arthroplasty (surgery associated with a 
high risk of VTE) to limited duration of prophylactic anticoagulation followed by aspirin (ASA) compared 
to the standard practice of prophylactic anticoagulation treatment. Limited duration of anticoagulation 
followed by ASA was found to be non-inferior to LMWH (Anderson et al., 2018). The combination of 
standard prophylactic anticoagulation for a reduced duration followed by ASA may also be non-inferior 
for postpartum prophylaxis. This proposal is the first step to determine whether postpartum prophylactic 
LMWH for women requiring prophylaxis with 3 weeks of LMWH followed by 3 weeks of low dose ASA is 
non-inferior to 6 weeks of prophylactic LMWH. The safety of ASA in the antepartum period (Rolnik et al., 
2017; CLASP study, 1994) and during breastfeeding (Datta et al., 2017) has been well established. 
Background 
 
For women not already receiving extended duration therapeutic anticoagulant therapy who have a history of 
VTE that was unprovoked or associated with a hormonal risk factor, the ASH guidelines recommend 
postpartum anticoagulant prophylaxis for 6 weeks. VTE occurring within 6 weeks postpartum affects 6.5% of 
pregnancies in women with a history of VTE (95% CI, 4.3%-9.7%) (Rodger et al., 2014), compared with a risk 
of approximately 0.6 of every 1000 deliveries for the general population (Tepper et al., 2014; Kourlaba et al., 
2016; Parunov et al., 2015; Kamel et al., 2014). Overall, the incidence during the 1st week postpartum is 9 in 
10,000 deliveries, reducing to 2.5 and 1.5 in 10,000 by the 2nd and 3rd week postpartum, respectively (Tepper 
et al., 2014). In women with a history of VTE who were treated with postpartum prophylaxis (LMWH, UFH), 
the risk of postpartum VTE was substantially lower at 1.7% (95% CI, 1.2%-2.7%) (Roger et al., 2014), 
representing a decrement in risk similar to that seen with extended LMWH prophylaxis after high-risk 
orthopedic procedures (Hull et al., 2001). In the presence of a high-risk thrombophilia and LMWH prophylaxis 
postpartum, the pooled VTE incidence was 0.2% (95% CI, 0%-1.2%). 
 
 
In contrast to LMWH, which is expensive and requires daily subcutaneous injections, ASA is an inexpensive, 
generic, and widely available oral antiplatelet drug. Furthermore, in the postpartum period LMWH is 
associated with a 0.3% (95% CI: 0%-1%) risk of major bleeding events, 1.8% risk of skin reactions and 
wound complications after cesarean delivery. ASA use compared to placebo in the antenatal period did 
not demonstrate increased bleeding complications in 798 patients, with no gastrointestinal (GI) bleeding 
noted (Rolnik et al., 2017), and in the orthopedic setting with a two-week administration post total knee 

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replacement, the GI bleeding was 1.7 per 1000 patient-years in the ASA group compared to 31.9 per 1000 
patient-years with LMWH (Nielen et al., 2016). Clinical trials and meta-analyses have suggested that ASA is 
non-inferior for the prevention of VTE in patients post- operatively (Anderson et al., 2018; PEP trial, 2000; 
Antiplatelet Trialists' Collaboration, 1994). Notably, orthopedic patients are at particularly high risk of DVT/ PE 
within 90 days following total hip and knee replacement (incidence 5% and 2%, respectively), despite 
treatment with either warfarin, LMWH or ASA (Matharu et al., 2020). ASA administered daily post-operatively 
has been shown to be non-inferior to LMWH when used for VTE thromboprophylaxis following these 
procedures (RR 0.76; 95% CI, 0.37- 1.56), and has a similar safety profile (Matharu et al., 2020). 
Furthermore, Anderson et al., 2018, NEJM, 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. 
 
It has been suggested that overall, the highest risk period for VTE in all postpartum women is between 1-3 
weeks, with a sharp decline documented following this time period (Abdul Sultan et al., 2014). The weekly 
distribution incidence of all VTEs within a 6 week period is 61.1%, 16.3%, 9.9%, 6.3%, 4.0% and 2.4% 
respectively, with an incidence of 9.41/10,000 in the 1st week, 2.58/10,000 in the 2nd , 1.62/10,000 in the 3rd, 
1.00/10,000 in the 4th and 0.67 and 0.40/10,000 in the 5th and 6th week respectively (Tepper et al., 2014). The 
median time for readmission with VTE in a retrospective study of 6,269,641 patients between 2013 and 2014 
using a Nationwide Readmissions Database in the USA was 14 and 11.7 days for deep vein thrombosis and 
pulmonary thromboembolism, respectively (Wen et al., 2018). This data clearly emphasizes the sharp 
reduction in risk of VTE one week after delivery, followed by a significantly lower risk 3-6 weeks postpartum. 
 
Further supporting the reduction in risk of VTE after the first few weeks postpartum are plasma levels of 
progesterone and estrogen. The association between increased serum estrogen and progesterone levels and 
VTE is clearly described in the literature of oral contraceptive (OC) use. With ‘low dose’ OC containing < 
50μg of estradiol, the risk of VTE is increased three to six-fold (World Health Organization). Furthermore, 
progestogens such as levonorgestrel have an up to a three-fold increase in VTE (Kemmeren et al., 2001), 
and OC in the presence of obesity increased the risk 10-fold. Mechanisms postulated are a documented 
acquired resistance to activated protein C (Rosing et al., 1997), and a hormone-induced venous stasis which 
in pregnancy coupled with endothelial damage and a hypercoagulable state are thought to lead to the 7-10 
fold increase in daily risk of VTE antepartum and 15-35 fold postpartum. Plasma levels of progesterone one 
week postpartum have been noted to be 1.46 ± 1.53 nmol/L, which is less than the 5.00 ± 10.39 (nmol/L) in 
non- pregnant matched controls (Abou-Saleh et al., 1998). Estrogen one week postpartum has also returned 
to non-pregnancy levels (124.40 ± 60.23 pmol/L vs 128.72 ± 395.39 pmol/L). The normalization of estrogen 
and progesterone to non-pregnancy levels at 1 week postpartum suggests a reduction in VTE risk. 
 
Based on (A) the demonstrated non-inferiority of ASA as compared to LMWH in the orthopedic cohort of 
patients whose VTE risk is known to be high and (B) taking into account that the median time for VTE 
readmission postpartum is between 11.7 and 14 days suggesting that this is the risk period for VTE, (C) that 
pregnancy hormones have returned to normal by 1 week after delivery, and (D) LMWH is associated with a 
higher risk of bleeding than ASA, I propose a pilot study to determine whether the duration of LMWH 
postpartum can be reduced to 3 weeks followed by ASA for a 3-week period. The purpose of pilot 
studies is to determine the acceptability and feasibility of the treatment strategies. It is imperative to 
determine feasibility prior to embarking on a definitive study to identify barriers to recruitment and address 
clinical uncertainty, if any.

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Version 3.1: November 10, 2022 
Study Design 
This is a single-center pilot feasibility RCT comparing 3 weeks of LMWH followed by 3 weeks of 
ASA compared to standard care of 6 weeks of LMWH prophylaxis. 
Inclusion Criteria; The inclusion criteria are to include all patients who are deemed to require 
prophylaxis for 6 weeks postpartum. 
1) Personal history of VTE prior to pregnancy and not prescribed indefinite therapeutic 
anticoagulation (ASH guidelines). 
2) Family history of VTE and antithrombin deficiency, protein C or protein S deficiency (ASH 
guidelines). 
3) Combined thrombophilia or homozygous for factor V Leiden mutation or prothrombin gene 
mutation, regardless of family history (ASH guidelines). 
4) > 18 years old 
5) English speaking and able to provide informed consent 
Exclusion criteria: 
1. Pre-existing indication for therapeutic LMWH 
2. Contraindication to ASA: 
a. Known ASA allergy 
b. Documented history of gastrointestinal ulcer 
c. Known platelet count < 50x10^9/L at any time during the current pregnancy or postpartum 
3. Contraindication to LMWH, e.g. known allergy 
4. Active bleeding at any site, excluding physiological vaginal bleeding 
5. Patients with bleeding disorders for example hemophilia or von Willebrand disease 
6. Known severe hypertension (SBP >200mm/hg and/or DBP >120mm/hg) during the current 
pregnancy or postpartum 
7. Unable to provide or declining informed consent for data collection 
Intervention: 
Patients allocated to the LMWH and ASA strategy will receive a prophylactic dose of LMWH according 
to weight (< 100kg: Dalteparin 5000 units daily, Enoxaparin 40 mg daily, Tinzaparin 4500 units daily; > 
100kg: Dalteparin 10,000 units daily, Enoxaparin 80mg daily, Tinzaparin 9000 U) by subcutaneous 
injection for 3 weeks followed by ASA 81 mg orally daily for three weeks. A clinic nurse will teach 
participants how to self-administer the LMWH injections. 
Patients randomized to the LMWH strategy will receive a prophylactic dose of LMWH according to 
weight, daily for 6 weeks. 
All participants will receive the first injection within 12 hours of delivery. 
Randomization 
Patients will be identified in the Hematology Clinic of the Special Program at Mount Sinai Hospital, where 
consent will be obtained. Patients will be randomized immediately following consent. Randomization has 
been developed for RedCap to allocate the patient into one of the two strategies in a 1:1 ratio, with the 
assistance of a statistician from Princess Margaret Hospital. Following delivery, the research assistant 
will dispense the assigned medication to the participant. Blinding or masking of treatment allocation will 
not be used in the pilot but a placebo control for ASA is intended for the definitive trial. 

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Baseline Assessment 
Baseline assessments will be undertaken at the time of randomization and include age, weight, parity, 
indication for VTE prophylaxis, gestational age at delivery, medications and delivery complications. 
Baseline laboratory tests at the time of delivery will include complete blood count, serum creatinine level, 
coagulation profile and alanine aminotransferase. This limited testing is intended to reflect a pragmatic 
approach to this trial. 
Primary Outcomes: 
1. 
Potential enrollment rate (patients eligible) 
2. 
Consent rates (patients approached/consent obtained/rationale for non-consent) 
3. 
Adherence to study protocol (incidence and reasons for nonadherence, withdrawal of consent,                 
rates of contamination and utilization of co-interventions). 
4. 
Missing data 
Secondary Outcomes: 
1. 
VTE event rate three months following delivery 
2. 
Bleeding event rate three months following delivery 
3. 
Quality of life (QoL) assessment using the modified Duke Anticoagulation Satisfaction Scale 
(Appendix) at delivery and three and six weeks postpartum 
Confirmation of VTE 
VTE must be confirmed either by Doppler ultrasound or V/Q scan or computer tomography (CT). Imaging 
will not be performed on all patients, only those with symptoms. For the definitive trial, imaging will be 
adjudicated. 
Bleeding outcomes 
Bleeding will be reported according to the International Society on Thrombosis and Hemostasis (ISTH) 
scoring system (https://bleedingscore.certe.nl/) (Schulman et al., 2005; Schulman et al., 2009). Bleeding 
will be assessed at 3 and 6 weeks postpartum using a telephone questionnaire. 
Follow up duration 
All patients will be followed until 3 months postpartum. Patients will be contacted by telephone at 3 weeks, 
6 weeks and 12 weeks after delivery. 
Participant trial discontinuation 
Participants may discontinue the study at any time. The participant will immediately discontinue the 
study medication, and the patient will be treated according to the standard of care. The patient will have 
a discontinuation telephone follow-up visit. 
 
Statistical analysis 
The analysis of this trial is mainly descriptive, as this is a pilot study to ensure adequate enrollment and 
adherence. All demographics and baseline characteristics will be summarized using mean, median, 
standard deviation, minimum and maximum for continuous variables, and frequency and percentages for 
categorical variables. The feasibility outcomes (primary outcomes) will be summarized using frequency 
counts and percentages with associated 95% confidence intervals. 
The definitive trial is designed to show the non-inferiority of a combination of LMWH and ASA over LMWH 
in decreasing the incidence of composite VTE. However, for the pilot study, the clinical endpoints will 
only be presented using descriptive statistics. In the definitive trial, VTE, bleeding, and 

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event-free outcomes will be compared between the two arms using a stratified log-rank test. A non- 
inferiority margin of 1.0 % will be used based on expert opinion. Statistical analysis will be carried out 
using SPSS statistical software. 
The feasibility trial will be deemed a success and will proceed to a full trial under the current protocol if 
all the criteria below are met: 
 
Participant recruitment is > 60% 
 
Participant adherence to study drug > 80% 
 
Compliance with study procedures > 80% 
 
Proportion of participants lost to follow up <25% 
Sample size calculation: I plan to recruit 50 patients, 25 patients treated according to each strategy. The 
outcomes from these patients will be included in the definitive trial. 
Recruitment rate: Recruitment is anticipated to be completed in 18 months as we anticipate to enroll 1 
patient/week. 
Trial registration: The trial will be registered at www.clinicaltrials.gov. 
Data Management: Appropriate training and security measures will be completed. The case report form 
will be developed electronically and piloted. All patient-related information, including case report forms, 
will be kept strictly confidential. All records will be kept in a secure, locked location, and only research 
staff will have access to the records. Patients will be identified only by means of a coded number specific 
to each patient. All computerized databases will identify patients by numeric codes only, and will be 
password protected and housed in a locked office. 
Data Safety Monitoring Committee: A data safety monitoring board will be assembled, consisting of one 
hematologist and one obstetrician. Any VTE or bleeding event will be reviewed by this committee. 
Ethics: The study will be submitted for research ethics board approval. Virtual consent during the current 
COVID-19 pandemic is currently feasible and is an option for this trial. 
Safety: I will be responsible for ensuring that the patient or her substitute decision-maker understands 
the risks and benefits of participating in the study, answering any questions the patient or family member 
may have throughout the study and sharing any new information in a timely manner that may be relevant 
to the patient’s willingness to continue her participation in the trial. All study participants will be informed 
of the objectives of the study and the potential risks. Consent forms will also discuss the benefits and 
risks of of this pilot trial and the definitive study. All patients will be informed of the signs and symptoms 
of VTE that would necessitate emergency room visits as participants in both arms may develop a VTE. 
Significance: This single center pilot feasibility study will address enrollment, adherence of two 
anticoagulant strategies postpartum in women who require prophylaxis with LMWH. The results of this 
study will be used to design a large definitive multicentered trial. All clinical outcomes from the pilot study 
will be used to inform the final trial design. Demonstrating the 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 
inferiority, the results will provide evidence that six weeks of postnatal thromboprophylaxis is warranted. 

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Version 3.1: November 10, 2022 
Trial Schematic Timeline 
Participant 
Screening 
Dosing 
3-week 
phone 
call 
6-week phone 
call (end of 
study) 
3-month 
phone call 
Early 
discontinuation 
visit 
Week -8 to 
Day -1 
Day 1 
± 5 days 
± 5 days 
± 5 days 
Informed Consent 
X 
--- 
--- 
--- 
--- 
--- 
Inclusion / 
Exclusion criteria 
and Eligibility 
X 
--- 
--- 
--- 
--- 
--- 
Baseline 
demographics 
X 
--- 
--- 
--- 
--- 
--- 
Concurrent 
medications 
X 
--- 
X 
X 
X 
X 
Weight/BMI 
X 
X 
X 
X 
X 
X 
Delivery Data: 
Type of Delivery/ 
Complications 
 
--- 
 
X 
 
--- 
 
--- 
 
--- 
 
--- 
Laboratory Data: 
Complete blood 
count / Creatinine 
/ INR / aPTT / 
ALT 
--- 
X 
--- 
--- 
--- 
--- 
Drug dispensation 
--- 
X 
--- 
--- 
--- 
--- 
Adherence 
assessment 
--- 
--- 
X 
X 
--- 
X 
Bleeding 
Assessment Score 
--- 
--- 
X 
X 
--- 
X 
Quality of life 
assessment 
--- 
--- 
X 
X 
--- 
X 
APPENDIX: MODIFIED DUKE ANTICOAGULATION SCALE 
 
During the past 3 weeks… 
Strongly 
disagree 
Disagree 
Neither 
agree nor 
disagree 
Agree 
Strongly 
agree 
Fear of bleeding while taking blood 
thinners limited my participation in vigorous 
activities. 
Fear of bleeding while taking blood 
thinners limited my participation in activities 
of daily living 
I was concerned about the possibility of 
excessive bruising while taking blood 
thinners 
Taking blood thinners limited my diet (e.g. 
food or drink, including alcohol). 
Taking blood thinners added stress to my 
life 
Taking my blood thinner was difficult to 
carry out 
Taking my blood thinner required a great 
deal of time to carry out 
Taking my blood thinner caused me a 
great deal of worry 
Taking my blood thinner caused me a 
great deal of irritation 
Taking my blood thinner caused me a 
great deal of frustration. 

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Version 3.1: November 10, 2022 
Taking my blood thinner was a burden to 
me 
Taking my blood thinner negatively 
impacted my quality of life 
I have confidence that my blood thinner will 
protect my health (prevent blood clots, 
stroke, heart attack) 
I am satisfied with my blood thinner 

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Version 3.1: November 10, 2022 
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