Clinical trial NCT02774265
Conditions: Venous Thromboembolism Pulmonary Embolism
Keywords: Fracture Prophylaxis
Sponsor: University of Maryland, Baltimore
Start date: 2016-01-01; Completion date: 2017-09-01
Enrollment: 329 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to perform a pragmatic randomized controlled trial to compare the use of low molecular weight heparin (LMWH, lovenox, enoxaparin) versus acetylsalicylic acid (ASA) for venous thromboembolism (VTE) prophylaxis in patients with high-risk lower extremity fractures.

Detailed description:
Purpose:

To perform a pragmatic randomized controlled trial of the use of low molecular weight heparin (LMWH, enoxaparin, lovenox) versus Aspirin (ASA) for VTE prophylaxis in patients with high-risk extremity fractures.

Specific Aims:

1. To compare the bleeding complication outcomes associated with LMWH versus ASA in patients receiving VTE prophylaxis following high-risk lower extremity fractures.
2. To compare the incidence of clinically important VTE events associated with LMWH versus ASA for VTE prophylaxis in patients receiving VTE prophylaxis following high-risk lower extremity fractures.
3. To compare the 6-month treatment costs associated with VTE prophylaxis using either LMWH or ASA for high-risk lower extremity fracture patients

Hypothesis:

1. Among patients with high risk lower extremity fractures receiving VTE prophylaxis, the rate of bleeding complications will be lower for patients receiving ASA compared to those receiving LMWH.
2. Among patients with high risk lower extremity fractures receiving VTE prophylaxis, the rate of VTE for patients receiving ASA will be no greater than those receiving LMWH.
3. Among patients with high risk lower extremity fractures receiving VTE prophylaxis, the 6-month treatment costs will be lower for patients receiving ASA compared to those receiving LMWH.

Methods/Outcomes:

A randomized controlled trial will be conducted to assess the use of LMWH versus ASA for VTE prophylaxis in patients with high-risk extremity fractures.

The aim-specific outcomes to be collected are as follows:

1. A composite of the following major bleeding related complications:

   1. Fatal bleeding into a critical organ (retroperitoneal, intracranial, intraocular, intraspinal)
   2. Clinically overt bleed with a \> 2g/dL drop in Hb or requiring \> 2U transfusion
   3. Wound drainage or hematoma requiring reoperation
   4. Diagnosis of deep surgical site infection
2. VTE Events defined as a composite of any symptomatic proximal DVT (in the femoral or popliteal vessels), or PE (central, segmental or subsegmental). All VTE events will be confirmed using multiplanar CT scan or formal venous duplex exam.
3. Cost of VTE prophylaxis treatment, VTE events and bleeding related complications.

Data Collection:

Patients meeting inclusion/exclusion criteria will be prospectively randomized to one of two treatment arms. Block randomization will be used. Patients will receive VTE prophylaxis as allocated, and followed for their index hospitalization and a 3month period post discharge for VTE events and bleeding complications. Outcome data will be prospectively collected during index hospitalization, and at 2 weeks and 3 months post discharge, and blind analysis and interpretation of results will be performed at 50% and 100% recruitment.

Data Analysis:

All data will be reported as mean and standard deviations for continuous variables and proportions and percentages for categorical data. Kaplan-Meier survival and Cox proportional hazard analysis will be completed for time to VTE and bleeding complication outcomes. Sub-group analysis will include Injury Severity Score and fracture location. An independent Data Safety and Monitoring Committee will complete interim analysis at 50% recruitment. A cost analysis will be conducted using a 6month and lifetime time horizon with a societal perspective. Component costs will consist of: VTE prophylaxis costs, unscheduled follow-ups, emergency room visit, hospital admission or unscheduled repeat surgical intervention for VTE or bleeding complications.

Study Treatment Arms:

1. VTE prophylaxis with Enoxaparin 30mg SC BID
2. VTE prophylaxis with ASA 81mg PO BID

Arms: arm 1: The group receiving VTE prophylaxis with enoxaparin 30mg subcutaneous BID. arm 2: The group receiving VTE prophylaxis with ASA 81mg PO BID
Interventions: intervention 1: VTE prophylaxis with Enoxaparin 30mg BID intervention 2: VTE prophylaxis with Aspirin 81mg BID
Intervention descriptions: intervention 1: Patients will receive Enoxaparin 30mg BID for DVT prophylaxis and will be followed to determine the efficacy, safety and cost when used for VTE prophylaxis in high-risk orthopedic traumas administered for the length of time indicated by standard of care based on the injury. intervention 2: Patients will receive Aspirin 81mg BID for DVT prophylaxis and will be followed to determine the efficacy, safety and cost when used for VTE prophylaxis in high-risk orthopedic traumas administered for the length of time indicated by standard of care based on the injury.

Protocol documents:
Prot_SAP_001.pdf: 
A Different Approach to Preventing Thrombosis (ADAPT): A Randomized Controlled 
Trial Comparing Low Molecular Weight Heparin to Acetylsalicylic Acid in Orthopedic 
Trauma Patients 
 
Study Protocol and Statistical Analysis Plan 
NCT02774265 
7/26/18  
 


Study Design 
ADAPT was a single-center randomized controlled trial that compared safety of low molecular 
weight heparin (LMWH) versus aspirin with respect to bleeding and wound complications in 
orthopaedic trauma patients within 90-days of their fracture. Ethics approval was obtained by the 
University of Maryland Institutional Review Board and informed consent was obtained for all 
enrolled patients. 
 
Eligibility Criteria 
All adult trauma patients (age >18 years) with operative extremity fracture proximal to the 
carpals/metatarsals or any hip or acetabular fracture requiring VTE prophylaxis were included in 
the study. We excluded prisoners, pregnant patients, non-English speaking patients, patients with 
an indication for therapeutic anticoagulation or high dose aspirin (greater than 81mg daily) and 
patients receiving pre-existing confounding prophylaxis or therapeutic anticoagulation prior to 
admission or greater than two doses of prophylaxis in our hospital prior to consent. Patients with 
recent VTE within the last 6 months, impaired creatinine clearance, history of heparin-induced 
thrombocytopenia or aspirin or non-steroidal anti-inflammatory allergy or another 
contraindication to receiving one of the study medications were also excluded. 
 
Randomization and masking 
Patients were randomly assigned venous thromboembolism prophylaxis by LMWH or aspirin 
using block randomization (6 per block) with the assistance of the trial’s REDCap system by 
research staff at the study site after enrollment. Surgeons and patients were not masked to the 
treatment groups. 
 
Intervention and Procedures 
Patients allocated to the LMWH group received two 30mg BID doses daily with allowance for 
dose adjustment based on BMI or Xa levels. Patients allocated to the aspirin group received 
81mg doses, twice daily. The duration of prophylaxis was at the treating surgeon’s discretion, 
with no minimum or maximum duration. Mechanical prophylaxis with intermittent pneumatic 
compression devices is also ordered as part of clinical protocol for all inpatients. Study follow-up 
was conducted at 3-months post-fracture either at the patient’s clinic appointment or over the 
phone. A chart review was also conducted at this time.  
 
All prophylaxis doses were monitored daily during the index admission by the study’s research 
staff. Additionally, outpatient adherence was assessed at all clinical follow-up visits. Any 
contamination or unplanned crossover was closely monitored.  
 
Outcomes 
The primary endpoint was bleeding complications within 90-days from the date of injury. 
Bleeding complications included a 2g/dL or greater drop in hemoglobin, blood transfusion, 
gastro-intestinal (GI) bleeding, surgical site hematoma requiring reoperation, or other bleeding 
events requiring intervention or resulting in death. Secondary exploratory outcomes included 
wound complications defined as a deep surgical site infections (SSI) based on the Centers for 
Disease Control and Prevention criteria that required operation, and VTE (including massive, 
sub-massive, or clinically significant pulmonary embolism and clinically significant deep vein 
thrombosis (either distal or proximal)). No screening of asymptomatic patients for VTE events 


was done. All adverse events were reported to the IRB as per local requirements. Two medical 
monitors reviewed the safety of the trial and all serious adverse events.  
 
Statistical Analysis 
The study’s sample size calculations were based on a retrospective review of the study centers 
database, which determined a 1-year historic bleeding complication rate of 15% in the study 
population. Based on arthroplasty literature, we hypothesized that aspirin would be associated 
with a 5% absolute reduction bleeding complications. Using a one-sided Fisher’s Exact sample 
size calculation, an alpha of 0.05, and an allocation ratio of 1:1, a sample of 1150 patients would 
provide 80% power. This target sample was inflated to 1380 to allow for up to 20% loss to 
follow up. Within a year of starting the trial, funding was obtained to commence a large 
pragmatic trial comparing these two interventions with a primary endpoint of pulmonary 
embolism-related death. This trial was subsequently stopped after the enrollment of 329 
participants, for which the safety of these two interventions was assessed 
 
Analysis followed the intention-to-treat principle and included all patients in the groups to which 
they were randomly assigned. Bivariable analysis and multivariable logistic regression model 
were used to assess the association between type of VTE prophylaxis and the primary and 
secondary endpoints. The treatment effects were reported as odds ratios (OR) and 95% 
confidence intervals (CI). The analyses adjust for the time each patient is at risk of the analyzed 
study event, to a maximum of 90 days. Patients who did not complete the 90-day follow up were 
deemed at risk from their time of enrollment until their last documented follow-up. Kaplan-
Meier curves were used to plot the time to study events by treatment arm. 
 
Patient crossover and contamination was assessed at several thresholds including ≥5%, ≥10%, 
≥25%, ≥50% of the patient’s total study doses being the non-allocated prophylaxis medication. 
All thresholds were assessed in a secondary as-treated analysis. A threshold of more than 50% of 
the patient’s total study doses being the non-allocated prophylaxis medication is presented for 
the as-treated analysis in the results. Factors associated with patient crossover in this study 
sample were also assessed. 
 
At the completion of the trial, we investigated possible effect measure modification by patient 
smoking status, history of VTE, mechanism of injury (high energy versus low energy), fracture 
location (upper extremity versus lower extremity), fracture severity (open fracture versus closed 
fracture), and non-orthopaedic injury (abdomen, head, or chest) determined by an Abbreviated 
Injury Scale score of ≥2. Each variable was added into the primary analysis as an interaction 
term. Statistically significant interactions were then analyzed stratifying by the effect measure 
modifier. The treatment effects in the stratified analysis were reported as odds ratios (OR) and 
95% confidence intervals (CI), adjusting for time at risk. 
 
All analyses were performed using JMP Pro Version 13 (SAS Institute, Cary, NC). This study 
was registered with ClinicalTrials.gov (NCT02774265).