A Pilot Randomized Controlled Trial of Low Molecular Weight Heparin or no Treatment Following Cesarean Delivery
Phase: PHASE2
Conditions: Thromboembolism
Sponsor: University of Utah

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 A pilot randomized controlled trial of low molecular weight heparin or no treatment following cesarean 
delivery  
NCT06118957   
09.03.2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Study Protocol, ICF and Statistical Analysis Plan:  
Last IRB review date: 09.03.2024 
 
 
BACKGROUND 
 
Venous thromboembolism (VTE) contributes to 9% of maternal deaths but we are lacking in evidence-based 
preventative interventions. Maternal mortality rates in the U.S. exceed those of other developed countries, and 
excessive national rates have demanded attention from both the academic community and lay public. As a 
leading contributor, VTE is a prime target for practice changes. The postpartum epoch is the highest risk period 
for VTE, and national guidelines have called for institutional protocols to categorize risk in postpartum 
individuals and implement corresponding pharmacologic thromboprophylaxis in an effort to reduce the 
incidence of postpartum VTE.  
 
Pharmacologic prophylaxis with low molecular weight heparin (LMWH) is effective in reducing VTE peri-
operatively in non-obstetric surgical fields. Guidelines recommending the use of LMWH for postpartum 
populations are based on expert opinion and extrapolate from other surgical fields. The efficacy of LMWH to 
prevent VTE in obstetrics remains unproven and introduces risk of harm in the form of bleeding and wound 
complications. While use of LMWH postoperatively is standard of care for most surgical fields, we are 
uncertain if the same benefits are present for obstetric patients who are generally younger, healthier, and 
potentially more mobile post-operatively. Experts are split with some calling for more rapid and widespread 
uptake of prophylaxis in the U.S. while others recommend against widespread uptake of LMWH prophylaxis. 
The result has been highly variable practice in the U.S. with rates of pharmacologic prophylaxis ranging from 1 
to 85%. It is imperative that prospective research be performed to understand the efficacy of LMWH 
prophylaxis for reduction of VTE in postpartum individuals.  
 
Before a large-scale, multicenter, rigorous clinical trial addressing efficacy of postpartum LMWH to prevent 
VTE can be completed, we must first address critical knowledge gaps including the feasibility of such a trial 
and understanding patient perspectives and information needs on the risk-benefit tradeoffs of LMWH 
prophylaxis versus risk of VTE. A randomized controlled trial (RCT) of postpartum patients at the individual 
patient level will require thousands of patients to achieve statistical power to detect a difference in rates of VTE 
by receipt of LMWH prophylaxis versus placebo. There is an urgent need to determine whether patients are 
willing to be randomized to LMWH prophylaxis or placebo, complete the therapy and follow-up. A future trial 
should also consider patient-centered outcomes. For instance, one patient may only perceive benefit from 
LMWH prophylaxis if the underlying risk for VTE is greater than 3%, while another patient may favor the 
potential risks of LMWH prophylaxis even for a VTE risk as low as <1%. Understanding patients’ priorities in 
care and how best to educate patients to enable them to make decisions surrounding VTE prophylaxis is 
instrumental for future work.  
 
 
OBJECTIVE / STUDY AIMS 
 
 
 
Aim 1. Evaluate the feasibility of randomizing patients to LMWH versus placebo following cesarean 
delivery. Working hypothesis: Among eligible individuals, at least 35% will enroll, undergo randomization, and 
complete their allocated treatment.  
 
Aim 2. Determine information needs, values, and outcome priorities influencing postpartum VTE risk 
communication. Working hypothesis: The majority of patients will consider risks of LMWH prophylaxis 
acceptable if reduction in VTE can be achieved.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
METHODS 
 
 
 
Study Design. The proposed research design is a pilot trial of postpartum patients randomized to weight-
based LMWH prophylaxis or placebo for VTE prevention. This pilot will test the feasibility of a future large, 
multicenter RCT.  
 
Study Population and Setting. Individuals aged 18 years or older undergoing cesarean delivery at the 
University of Utah Health will be considered eligible. Exclusion criteria include: contraindication to 
anticoagulation, plan for therapeutic anticoagulation, renal dysfunction (creatinine clearance <30mL/minute), 
history of VTE, high risk thrombophilia, or receipt of antepartum anticoagulation (for >2 weeks). Eligible 
individuals will be approached prior to delivery or within 12 hours postpartum. Informed, written consent will be 
obtained.  
 
Procedures & Data Collection. Individuals will be randomized to receive either (1) weight-based dosing of 
LMWH or (2) no therapy after cesarean delivery. Weight-based dosing of LMWH will be 0.5mg/kg rounded to 
the nearest 10mg every 12 hours based on admission weight. No therapy will be no pharmacologic 
prophylaxis. Individuals will be randomized in a 1:1 ratio utilizing a permuted block method of randomization 
with a block size of 6 using REDCap. Participants and clinicians will be unblinded to randomization arm. The 
intervention, LMWH, will be initiated at 12 hours post-delivery consistent with obstetric anesthesia guidelines. 
Individuals will receive therapy inpatient and for 14 days following hospital discharge. 
 
The remainder of postpartum care will be per standard 
institutional practice. Deferral of a dose or discontinuation of 
therapy early is at the discretion of the clinical care team. All 
individuals will receive mechanical prophylaxis with 
sequential compression devices (SCDs) intraoperatively and 
postoperatively until ambulatory per institutional protocol.  
 
Detailed medical record abstraction will be completed for 
demographics, medical and obstetric history, delivery 
outcomes, and postpartum course. Final follow-up and 
outcomes will be ascertained at 6 weeks postpartum.  
 
Outcomes. The primary outcome is feasibility, as defined by 
≥35% enrollment of eligible individuals and retention ≥85% of 
enrolled individuals through all study procedures.1, 2 
Secondary feasibility outcomes will include number of eligible 
patients per month, enrollment rate (proportion of eligible patients enrolled), and dropout rate. Reasons for 
enrollment refusal and withdrawal from the study will be elicited and tracked. By design, this pilot trial will not 
address efficacy or safety outcomes between intervention arms. However, these additional secondary 
outcomes will be tracked: objectively diagnosed VTE, wound hematoma, or bleeding complication (including 
readmission or return to the operating room) within 6 weeks postpartum.  
 
Sample Size. The sample size for this pilot was calculated considering available data at UUH with 4,500 
deliveries annually with a cesarean delivery rate of 22%. This provides approximately 990 patients anticipated 
to be eligible over the course of 12 months for the proposed pilot RCT. The sample size also uses statistical 
power considerations for a future multicenter RCT comparing LMWH to no therapy. Using preliminary data 
from our institution, an asymptomatic postpartum deep vein thrombosis (DVT) rate is estimated at ~2%. 
Considering a range of assumptions, 5,195 participants per group for an individual patient RCT would be 
necessary to detect a 35% reduction in rates of asymptomatic DVT. Modeled across a range of available 
centers, this trial could be completed in 1-2 years depending on annual enrollment (Figure 1).  
 
To test these assumptions at UUH, an institution anticipated to be enrolling in a future multicenter trial, we 
determined a sample size of 22 individuals per month enrolled and retained using parameters of 35% 
Specific Aim 1. Evaluate the feasibility of randomizing patients to LMWH versus placebo following 
cesarean delivery. 

enrollment of eligible individuals and 85% retention through the study procedures would be feasible. We plan 
for a one-month ramp up and three months of enrollment to assess feasibility. 
 
Statistical Analysis Plan. For all outcomes, the proportion meeting the outcome with 95% confidence interval 
will be reported. A descriptive summary of reasons for patient refusal to participate or withdrawal will also be 
reported.  
 
Potential Problems & Alternative Strategies. Some individuals may not want to participate in an RCT of 
LMWH versus no therapy, or may have stated preferences for one study arm. These perspectives are valuable 
to inform future trial modifications and determine enrollment feasibility. There are approximately 4,500 
deliveries annually at UUH with an institutional cesarean rate of approximately 22%. This will provide ample 
sample size to complete the feasibility pilot.  
 
Safety Monitoring. There is equipoise for a comparative trial between LMWH prophylaxis and no therapy. 
However, safety concerns may arise during the course of this pilot trial. Adverse events (AEs) and serious 
adverse events (SAEs) will be submitted to the institutional review board (IRB) and monitored through a data 
safety monitoring board (DSMB).  
 
 
 
Study Design. We will complete semi-structured interviews of patients to collect data on patient information 
needs and values about VTE risk communication, preventative interventions such as LMWH, and patient 
priorities related to risks of VTE versus preventative interventions. Interviews of obstetric providers will explore 
barriers to counseling on VTE risk and interventions.  
 
Study Population and Setting. Patients meeting inclusion/exclusion criteria for the pilot trial (see Specific Aim 
1) will be eligible for participation. Recruitment will be inpatient after delivery or from the UUH outpatient 
obstetric clinics at the time of postpartum clinic visit. Obstetric providers, including physicians and advanced 
practice clinicians (e.g., nurse midwives, nurse practitioners), at UUH will be asked to participate via 
departmental meetings and e-mail.  
 
Procedures & Data Collection. All interviews will be conducted, in-person or virtual, by trained personnel. 
Written informed consent will be obtained prior to interviews. Patients will be interviewed 6-12 weeks after 
delivery. Obstetric providers will be interviewed over the course of the grant period. These facilitated interviews 
will last 60 minutes. Interviews will assess perspectives on: (1) patient information needs on VTE risk; (2) 
values around interventions; (3) outcome priorities for decision-making around risks of VTE versus risks of 
preventative interventions such as LMWH. These will also assess barriers and facilitators to communication 
that may be incorporated into future decision-aids or clinical practice. Interviews will be audio recorded and 
transcribed. 
 
Detailed medical record abstraction will be completed for demographics, medical and obstetric history, delivery 
outcomes, and postpartum course for included patients. Measured characteristics of obstetric providers will 
include self-reported age, race, ethnicity, gender identity, years in practice, provider type, and provider 
services. 
 
Outcomes. The outcome of this aim will be qualitative data that will inform future development of patient and 
provider education tools to aid in decision-making around VTE prevention.  
 
Sample Size. We anticipate completing 15 semi-structured patient interviews and 10 semi-structured obstetric 
provider interviews. This sample size was selected based on available literature informing anticipated thematic 
saturation.  
 
Statistical Analysis Plan. The transcribed interviews will be imported into a qualitative analytics software 
program. Qualitative data analysis will be completed following a standardized coding framework to identify 
common themes, as previously used by Dr. Rothwell’s group.3-5 In brief, an initial coding template will be 
defined, each transcript will be coded to identify recurrent and new themes, and coding frequency will be 
summarized. 
 
Potential Problems & Alternative Strategies. There may be inadequate patient recruitment for interviews. 
However, based on the estimated population sample available for enrollment (see Specific Aim 1), relatively 
small sample size needed, and UUH record of high recruitment and retention, we anticipate adequate sample 
size will be achieved. Patient incentivization with gift cards may be added if recruitment is lower than expected. 
Specific Aim 2. Determine information needs, values, and outcome priorities influencing postpartum 
VTE risk communication. 

There are over 75 obstetric providers eligible for recruitment through UUH. Using direct solicitation, which has 
been found to be an effective method for clinician recruitment, we anticipate achieving the necessary provider 
sample size.