Ventricular Assist Device Anti-Factor Xa (VAD ANTIX) Monitoring Study: a Prospective Randomized Feasibility Trial
Phase: NA
Conditions: Left Sided Heart Failure, Left Ventricular Assist Device, Anticoagulant Therapy, Gastro Intestinal Bleeding, Thrombosis, LVAD, Anti-factor Xa, aPTT, Heparin
Sponsor: Washington University School of Medicine

 
 
 
 
 
 
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Ventricular Assist Device Anti-Factor Xa (VAD-AntiX) monitoring 
study: a prospective randomized feasibility trial 
 
Principal Investigator:  
Thomas J. Graetz, MD  
 
 
 
 
 
 
 
Version Date:  
August 31, 2017 
 
 

 
 
 
 
 
 
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SYNOPSIS 
Study Title 
Ventricular Assist Device Anti-Factor Xa (VAD-AntiX) monitoring study: 
a prospective randomized feasibility trial 
Objective 
I. Demonstrate the feasibility and success of implementing nomograms 
for heparin administration based on both aPTT measurement and anti-
factor Xa activity.  
 
Feasibility will be determined by: 1) Questionnaires evaluating 
the practicality and acceptably of the nomograms 2) The 
percentage of correct dosing adjustments made by the nursing 
team required to achieve first therapeutic anticoagulation 
according to the specified directions provided. 
 
Success will be determined by 1) number of dosing changes 
required to achieve first therapeutic anticoagulation 2) time (in 
hours) until achievement of first therapeutic anticoagulation 3) 
percentage of time therapeutic anticoagulation remains after it is 
achieved  
 
II. a. Explore heparin dosing and the concordance between the aPTT 
and anti-factor Xa activity in this patient population. 
    b. Explore clinical outcomes related to the heparin monitoring 
nomograms, including major bleeding, neurologic events, 
gastrointestinal bleeding and pump thrombosis. 
Study Period 
 
Planned enrollment duration: 1 year 
 
Planned study duration: 1 year 
 
Number of Patients 
20 evaluable 
 
Study Treatment  
Monitoring and adjusting heparin anticoagulation utilizing aPTT based 
heparin nomograms OR anti-factor Xa based heparin nomograms  
Study Design 
Prospective Randomized 
 
Inclusion and 
Exclusion Criteria 
Inclusion: 18 years and older undergoing LVAD implantation 
Exclusion: Patient unable to receive heparin or known hypercoagulable 
disorder, prisoners, pregnancy, or lactating women. 
Measurements 
Detailed records will be collected using a REDCap database.  Baseline 
labs will be obtained as well as aPTT and anti-factor Xa while on the 
heparin dosing nomogram/intervention.  Heparin and coumadin dosing 
details will be obtained. Clinical outcomes will be monitored. 
Statistical 
Methodology 
Chi Square and descriptive statistics used for questionnaire responses. 
Mann Whitney U test for dosing adjustments and time until first 
anticoagulation. 
Students t test or Mann Whitney U for dosing changes required, time 
until therapeutic anticoagulation, and percentage of time therapeutic 
anticoagulated 

 
 
 
 
 
 
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Concordance assessed with mixed effects model; repeated measures 
ANOVA and Turkey’s test for multiple comparisons to analyze heparin 
administration. 
Clinical outcomes will be compared with a Chi square test. 
Intention to treat analysis will be used. 
 
 
A Background and Rationale 
 
Mechanical Circulatory Support 
The prevalence of heart failure in the United States currently exceeds five million 
and continues to rise.1 It remains the primary diagnosis in over one million 
hospitalizations annually, with an economic burden exceeding $30 billion in the United 
States.2 People with severe heart failure and symptoms at rest may be treated with 
mechanical circulatory support (MCS) pumps, such as a left ventricular assist device 
(LVAD).  This pump is used as a long-term destination therapy or as a bridge to 
receiving a heart transplant.  As the number of organ donors remains relatively fixed, 
and conventional medical therapies fail, MCS is increasingly utilized in this patient 
population with total implants approaching 2,500 per year. 3 
 
Complications of Mechanical Circulatory Support 
As the incidence of MCS implantation increases, it is important to recognize the 
risks associated with these devices. The balance between bleeding and thrombotic 
complications is complex and often pose a therapeutic challenge to clinicians, as both 
are common and devastating, especially in the early postoperative period. Thrombus 
formation leads to potentially life-threatening outcomes such as stroke, heart attack and 
device failure. Pump exchange as a treatment for device failure has been associated 
with a reduction in subsequent 1-year survival. 3 Furthermore, in the recent era of MCS 
utilization, there has been higher event rates of hemolysis, stroke, and pump exchange 
than in previous eras. 3,4 Although thrombosis risks are on the rise, bleeding still remains 
the most common complication after LVAD implantation.5 Excessive anticoagulation can 
lead to serious and often fatal hemorrhage, including exsanguination from surgical sites, 
intracranial hemorrhage, retroperitoneal and gastrointestinal bleeding. Despite 
advancements in the management and understanding of these devices over the years, 
bleeding requiring re-exploration remains greater than 20%, and the requirement for 
transfusion of two or more packed red blood cells exceeds 50% over the first 30 days 6. 
 
Pharmacologic Management to Prevent Thrombosis  
One management strategy utilized to minimize the risk of thrombus formation 
within these devices is the early administration of therapeutic anticoagulation with 
intravenous (IV) unfractionated heparin (UFH) postoperatively. Current anticoagulation 
management recommendations include postoperative bridging with IV UFH, targeting 

 
 
 
 
 
 
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activated partial thromboplastin time (aPTT) goals ranging from 40 to 80 seconds, 
followed by warfarin dosed to an international normalized ratio (INR) goal of 2.0 to 3.0. 
Additionally, an antiplatelet agent, such as aspirin and/or clopidogrel or dipyridamole, is 
recommended. 5 7 8 Warfarin causes a transient prothrombotic period after initiation 
because of its variable effect on both procoagulant and anticoagulant factor activity over 
time.  These opposing effects are due to the timing of inhibition of specific factors before 
the balanced decrease of vitamin K-dependent clotting factor levels is achieved. 
Therefore, a bridging period with IV UFH is recommended. 9 Although expert guidelines 
and device specific recommendations have been made regarding pharmacologic 
management, wide variation exists between medical centers with regards to timing and 
dose of IV bridging strategies and patient-specific monitoring parameters and goal10. 
 
Monitoring UFH Therapy: aPTT vs. anti-Xa 
The pharmacokinetics of UFH are unpredictable due to the binding of UFH to a 
number of plasma proteins, macrophages, and endothelial cells. Additionally, the 
response varies among patients so it is routine practice to monitor heparin frequently 
and adjust the dose based on the results of a coagulation test.9 The aPTT, a plasma 
based assay measuring activity of intrinsic and common coagulation pathways, has 
been the most widely used method to monitor IV UFH. Interestingly, the data that 
support adjusting heparin doses to maintain a therapeutic aPTT range are based on 
weak evidence11, and heparin dosing and monitoring has not been rigorously studied in 
patients with LVADs. The International Society for Heart and Lung Transplantation MCS 
guidelines recommend titrating heparin to a target aPTT of 60-80 seconds, despite these 
known limitations.5 Although the aPTT is widely available, relatively inexpensive and has 
gained long term familiarity, many problems with the use of this assay have been 
identified. The assay is susceptible to physiological and nonphysiological factors that do 
not reflect intrinsic heparin activity, causing patients to receive unintentionally high or low 
doses of heparin.12 Lupus anticoagulant and factor XII deficiency may overestimate the 
aPTT. Common clinical features of patients with LVADs such as liver disease, 
consumptive coagulopathy, concurrent warfarin administration and hemolysis may also 
overestimate the aPTT. On the other hand, low antithrombin levels and elevated factor 
VIII levels may attenuate the expected aPTT response.12 Unlike the aPTT assay, the 
anti-Xa activity assay is a more direct measure of UFH and is unaffected by the 
presence of lupus anticoagulant, liver disease, or consumptive coagulopathy. 
Furthermore, in comparison with the aPTT, the correlation between anti-Xa activity and 
heparin concentration is more robust, the target therapeutic range is better defined, and 
anti-Xa activity is resistant to variability in the setting of stress and inflammation, which 
are features of the acute postoperative period. Conversely, this assay is not as widely 
available as the aPTT, may incur higher costs and may underestimate heparin 
concentrations in the setting of hemolysis or low antithrombin levels. In addition, 
elevated triglyceride or bilirubin levels may falsely lower the results.13 The known 
strengths and limitations of both assays make it challenging to determine which method 
of heparin monitoring is ultimately superior.12 
 

 
 
 
 
 
 
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Previous Research and Preliminary Data 
Evidence of superiority of monitoring IV UFH effects with the anti-Xa assay in 
terms of safety and effectiveness is lacking. Studies have consistently noted the 
discordance between the aPTT and the anti-Xa assay in various adult and pediatric 
populations.14,15,16,17,18,19,20,21,22,23,24,25,26  In adult patients with LVADs specifically, 
concordance rates between the assays have been reported as low. 14,15  Based on four 
patients with LVADs at our institution (Figure 1.), the average relationship between the 
aPTT and the anti-Xa assay is shown (solid blue line). The dashed green line represents 
ideal concordance between the assays.  Most of the data points show considerable 
scatter from both the average (solid black) and ideal (dashed green) relationships. The 
crude correlation co-efficient (not accounting for repeated measures) is 0.44. When 
values from both assays fall in the middle rectangle, the assays both suggest that 
heparin anti-coagulation is in the therapeutic range. Values in the discordant areas occur 
when information provided by the two assays is discrepant (e.g., one assay suggest 
therapeutic anti-coagulation, whereas the other suggests sub-therapeutic 
anticoagulation). Thus, our preliminary data in patients with LVADs at our center 
suggests that the assays are discordant and that there does not appear to be a precise 
relationship between the assays. In addition to showing discordance, studies have 
suggested that monitoring heparin with the anti-Xa activity assay may result in lower 
heparin exposure, fewer dose titrations, lower cost, and possibly less bleeding.14,15,16,17, 
18,19,20,21,22,23,24,25,26 Although there have been randomized controlled trials in patients who 
have not had LVADs or other MCS devices,17,18 these trials were small, non-blinded, and 
found no significant differences in bleeding or thrombosis between groups.  
Patients who receive LVADs experience a high rate of both thrombotic and 
hemorrhagic complications in the early postoperative period.  Our institution has data for 
604 LVADs implanted from 2005 through 2015. A total of 88 patients (14.5%) had 
suspected pump thrombosis and 164 (27%) had a clinically diagnosed gastrointestinal 
bleed (Table 1). A substantial proportion of patients develop these complications within 
30 days of implant. Since it is likely that insufficient anticoagulation with heparin 
promotes thrombotic complications, and that overzealous anticoagulation increases the 
likelihood of bleeding, it is important to identify the impact of heparin monitoring in the 
perioperative period on these complications.  Although some centers have transitioned 
heparin monitoring from aPTT to anti-Xa, based on biological plausibility and surrogate 
endpoints, no trials have compared these assays in a rigorous, randomized, comparative 
effectiveness trial in the perioperative setting. 
 
Utilization of a nursing monitored heparin nomogram with aPTT 
Currently, patients receiving IV UFH at our institution are managed with a weight-
based dosing nomogram that is monitored and adjusted by nursing utilizing aPTT 
results. Weight-based heparin dosing nomograms have been associated with a shorter 
time to achievement of therapeutic anticoagulation compared with empiric dosing by 
physicians.27,28 The nursing-driven heparin nomogram was implemented at our institution 
in 1997 and has been modified over the years in response to data collection and 
analysis in relation to aPTT targets. A recent survey completed by fifty-six nurses 

 
 
 
 
 
 
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specialized in post-cardiothoracic surgery care noted 100% satisfaction with the 
utilization and implementation of our current weight-based heparin nomogram. All nurses 
noted that the nomogram was clear and easy to follow. Fifty-five (98.2%) nurses felt the 
current dosing provided in the nomogram is feasible and 53 (94.6%) stated that they 
follow the dosing and monitoring instructions exactly as they are written. A total of 49 
(87.5%) noted that they seek clarification from a co-worker, pharmacist, nurse 
practitioner, or physician regarding the nomogram instructions. When asked about 
suggestions for improvement of the nomogram, the most common response was to 
create a nomogram that is more patient specific for surgical patients at a high risk of 
bleeding, such as patients with LVADs. These results suggest that implementing a 
second nomogram based on anti-Xa assay results, that mirrors the same instructions 
and timing of laboratory draws as the current aPTT-based nomogram, could also be 
feasible. 
 
Potential Impact of VAD ANTIX 
There is much still to be learned in the understanding of bleeding and thrombosis 
in the perioperative period. Perioperative events can lead to a great deal of variability in 
pro- and anti-thrombotic hemostatic factor levels.29 Therefore, the propensity for 
thrombosis and bleeding in individual patients is frequently unpredictable and, can 
change substantially over time. Opportunity for discovery is heightened for patients with 
LVADs, given the dearth of rigorous investigations and the unique features of the 
human-machine interface. With the recent reports of increasing suspected and 
confirmed devastating (LVAD) pump thrombosis in the early post-implant period4, 
analyses of treatment-related factors such as the method of monitoring anticoagulation 
are urgently needed. Recent studies in patients with LVADs have correlated factors such 
as international normalized ratio (INR) in the outpatient setting30, medication use31, and 
elevated systolic blood pressure32 to pump thrombosis and stroke. However, the impact 
of monitoring IV UFH therapy with aPTT or anti-Xa in the perioperative period on pump 
thrombosis, stroke and bleeding remains unknown. The early risk for both bleeding and 
thrombosis in patients with LVADs underlines the urgency of resolving how best to 
monitor and achieve appropriate anticoagulation with heparin. Given the ongoing 
challenges with these competing complications, studying the problem in earnest, while 
taking into consideration perioperative events, is crucial. Clarifying which of these two 
monitoring approaches is superior will facilitate safer and more effective anticoagulation 
with heparin in patients with LVADs. 
 
B Study Objectives 
 
Primary Outcome: 
Demonstrate the feasibility and success of implementing nomograms for heparin 
administration based on both aPTT measurement and anti-factor Xa activity.  

 
 
 
 
 
 
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Feasibility will be determined by: 1) Questionnaires evaluating the practicality and 
acceptably of the nomograms 2) The percentage of correct dosing adjustments made by 
the nursing team required to achieve first therapeutic anticoagulation according to the 
specified directions provided. 
 
Success will be determined by 1) number of dosing changes required to achieve first 
therapeutic anticoagulation 2) time (in hours) until achievement of first therapeutic 
anticoagulation 3) percentage of time therapeutic anticoagulation remains after it is 
achieved  
 
 “Therapeutic anticoagulation” is defined as two consecutive monitoring values within the 
goal range, according to assigned monitoring assay. (either two consecutive aPTT 
values within 60-94 seconds or two consecutive anti-Xa values within 0.3-0.7 IU/ml) 
 
Secondary Outcomes: 
Explore heparin dosing and the concordance between the aPTT and anti-factor Xa 
activity in this patient population. 
 
“Concordance” is defined when simultaneously drawn aPTT values and anti-Xas values 
are within the goal range (aPTT within 60-94 seconds and anti-Xa within 0.3-0.7 IU/ml). 
 
Explore clinical outcomes including pump thrombosis, gastrointestinal bleeding, 
neurological events such as stroke, and major bleeding in this patient population. 
 
C Study Design  
 
Study setting and design  
VAD AntiX feasibility study will take place at Barnes-Jewish Hospital, an academic 
hospital in affiliation with Washington University Medical Center located in the United 
States. This trial has been designed in accordance with the SPIRIT (Standard Protocol 
Items: Recommendations for Interventional Trials) checklist33. The VAD AntiX feasibility 
study will be a stratified randomized, trial with one specific aim: (1) Demonstrate the 
feasibility of implementing nomograms for heparin administration based on aPTT 
measurement as well as anti-Xa activity. This feasibility trial will be the foundation for a 
larger pilot trial and subsequent comparative effectiveness trial that will seek to 
determine the optimal monitoring method of IV UFH in the perioperative period for LVAD 
patients.  
 
A heparin nomogram is a tool or table used to standardized heparin administration and 
dosing when heparin is administered as a continuous infusion. Dosing adjustments are 
prescribed in the table based on the laboratory results.  
 
Subject Selection 

 
 
 
 
 
 
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All patients 18 and older undergoing HeartMate II®, HeartMate III®  or HeartWare®,  
LVAD implantation at Barnes-Jewish Hospital, St. Louis, Missouri, USA will be eligible 
for enrollment in this study. This hospital is an academic medical center affiliated with 
Washington University School of Medicine. Patients will be recruited preoperatively and 
will provide written informed consent. Any patient who is unable to receive heparin [e.g. 
patients with heparin-induced thrombocytopenia (HIT)] or an anaphylactic allergy to 
heparin] will be excluded. Patients who develop HIT during the course of the study will 
remain enrolled and be included in the intention-to-treat analysis.  
 
Inclusion criteria: 
All patients 18 years of age and older who are undergoing HeartMate II®, HeartMate III®  
or, HeartWare® LVAD implantation at Barnes Jewish Hospital, St. Louis, Missouri, USA. 
Legally acceptable representatives will be able to consent for trial participation. 
 
Exclusion criteria: 
Any patient who is unable to receive heparin [e.g. patients with heparin-induced 
thrombocytopenia (HIT)] or an anaphylactic allergy to heparin] will be excluded. Patients 
who develop HIT during the course of the study will remain enrolled and be included in 
the intention-to-treat analysis. Additional exclusions include less than 18 years of age, 
patients with a known hypercoagulable disorder (factor V Leiden, Antithrombin 
deficiency, Protein C deficiency, Protein S deficiency, Antiphospholipid antibodies, or 
other thrombophilia), prisoners, pregnant or lactating women.  Also, excluded are 
patients that are recipients of additional mechanical circulatory support (including 
extracorporeal membrane oxygenation support, right ventricular assist device, and/or 
impella) during the index LVAD implantation through the end of the study period. 
 
Recruitment and consent:  
Patients will be enrolled during a preoperative clinic visit at our Center for Preoperative 
Assessment and Planning, from the hospital ward at Barnes-Jewish Hospital, St. Louis, 
Missouri prior to surgery, or a pre-operative visit at the Ventricular Assist Device Surgery 
Clinic. Formal consent will be obtained from all participants prior to enrollment in the 
study.  Authorized surrogates will be able to consent for trial participation. Any subject  
will be free to withdraw their consent at any time. 
 
Interventions 
Patients will be randomized to either anti-Xa or aPTT nomograms when the decision is 
made to start anticoagulation.  Patients that receive an additional pumping support 
device during the index surgery, but prior to randomization will be withdrawn from the 
study and their baseline data will be discarded.  In the rare event the patient receives the 
assistive pumping device after the index surgery and randomization, they will be 
withdrawn from the study and the data collected up to that point will be retained for 
analysis.  Consistent with our current heparin management strategy, patients in both 
arms will be started on a fixed heparin dose (e.g. 750units/hour) on the morning of the 
first post-operative day.  On the second post-operative day, patients will be placed on a 

 
 
 
 
 
 
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weight-based nursing driven heparin nomogram starting at 12 units/kilogram/hour 
without a bolus. Patients randomized to aPTT monitoring will follow our institution’s 
current nursing-driven aPTT nomogram and the patients randomized to anti-Xa 
monitoring will follow a nursing-driven anti-Xa nomogram. Each nomogram has 
instructions regarding scheduled assay lab draws that nurses will follow. Regardless of 
group allocation, while IV UFH is administered according to one of the two nomograms, 
both the aPTT and the anti-Xa activity will be determined at specified time points, 
although clinicians will only receive the information according to group assignment. 
Clinicians will be instructed not to deviate from the randomized monitoring protocol. All 
relevant concomitant care, interventions, and laboratory draws will be at the discretion of 
the ICU and surgical teams as part of routine postoperative care. 
 
Randomization and Design:  
Following LVAD implantation, subjects will be randomized via computer-generated 
randomization by the study coordinator.  Patient randomization will be stratified by LVAD 
type with HeartMate II®, HeartMate III®, and HeartWare® patients being randomized to 
the 2 nomograms separately by the assigned study coordinator.  Randomization will take 
place within twelve hours after arrival to the ICU and be subsequent to monitoring and 
management of heparin anticoagulation with either an aPTT or anti-factor Xa based 
nomogram.  
 
Subjects in this study will be offered the opportunity to participate in the Systematic 
Assessment and Targeted Improvement of Services Following Yearlong Surgical 
Outcomes Surveys (SATISFY-SOS #201203008).   
 
aPTT and anti-Xa Nursing Driven IV UFH Nomograms 
 

 
 
 
 
 
 
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Duration of Study: 
Patients will be followed for 14 days of heparin therapy or until heparin has been 
discontinued (e.g. changed to bivalirudin for anticoagulation or completed a transition to 
warfarin) if sooner than 14 days. If the patient has not received any IV heparin for 5 
consecutive days they will be considered to have failed anticoagulation and the reason 
noted by the clinical team for discontinuation will be recorded.    
 
The requirement for clinical team training and feedback: 
A necessary first step in embarking on this feasibility trial is to train the clinical staff in the 
use of algorithms for IV UFH administration postoperatively in patients following 
implantation of the LVAD. It is important first to show that nomograms are practical such 
that clinicians can easily follow them, and second that by following the nomograms the 
target parameters are achieved. The collaborators in this study represent the key 
stakeholders responsible for the management of patients with LVADs in the 
postoperative period. As such, there is commitment from medical, nursing and pharmacy 
leadership to manage heparin administration based on either the current aPTT based or 
the new anti-Xa based nomogram (Table 2). During the feasibility phase, all the medical 
and nursing staff will undergo structured training in the rationale behind and 
implementation of the nomograms. Structured training will take place through formal 
physician and nursing in-services provided by our clinical nurse specialist and clinical 
pharmacist specialist.  The training will include background information, practical advice, 
mock scenarios, trouble shooting and safety tips.  To assess impact, questionnaires for 
the nurses taking care of the study patients will be handed out by the research team on 
each nursing shift. The research team will collect the completed forms for input into the 
database.  
 
Risks and mitigation efforts: 
Although the antifactor Xa guided heparin nomogram is standard of care at other 
institutions, BJH utilizes the aPTT guided heparin nomogram for management of 
postoperative anticoagulation of LVAD recipients. Given this, the risks to subjects in this 

 
 
 
 
 
 
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study are associated with randomization to anti-factor Xa guided heparin nomogram for 
management of anticoagulation therapy postoperatively. 
 
The risks are anticipated to be the same in both arms of the study (anti-Xa guided 
heparin monitoring or aPTT guided heparin monitoring); namely, increased ease of 
bruising, increased ease of bleeding, feeling lightheaded, fainting, fatigue, blood in the 
urine, stool and vomit, gastrointestinal bleeding, mediastinal bleeding, retroperitoneal 
bleeding, stroke, and LVAD thrombosis. Additionally, there may be other risks such as 
changes in the frequency of occurrence of these risks when using the anti-factor Xa 
heparin nomogram that are not yet known. 
 
There is also the possibility of confidentiality breach that could be associated with 
collection of data from the subject’s medical record. 
 
Every subject will receive routine maximum acuity care by clinical teams trained to 
transition LVAD patients from surgery to heparin anticoagulation and eventually to 
warfarin therapy. Additionally, study-specific training will be conducted with the clinical 
teams to ensure correct use of each of the nomograms being compared. All the medical 
and nursing staff will undergo structured training in the rationale behind and 
implementation of the nomograms. Structured training will take place through formal 
physician and nursing in-services provided by our clinical nurse specialist and clinical 
pharmacist specialist. The training will include background information, practical advice, 
mock scenarios, trouble shooting and safety tips. 
 
The clinical team has the option of requesting the alternative monitoring test for any 
study subject (or any other laboratory assay), if they believe more information is required 
to properly assess the anticoagulation status of the subject. The clinical team also has 
the option of withdrawing the subject from the study if they feel it is in the best medical 
interest of the subject.  Subjects and their family may choose withdrawal at any time for 
any reason. 
 
In an effort to protect confidentiality, subjects will be assigned a study specific code that 
will be linked to their medical record number. The key to this code will be available only 
to members of the research team and will be stored separately from the study data in a 
locked cabinet, behind a locked door. 
 
At the conclusion of the study,14 days of heparin therapy or heparin discontinuation if 
sooner than 14 days, patients will no longer be followed as part of this study; the patients 
will continue to be monitored and cared for by their clinical team per routine care.  These 
patients may continue to be monitored and data collected as part of the separate 
SATISFY SOS study.  If patients are not co-enrolled in SATISFY SOS, then no further 
follow-up will take place. 
 

 
 
 
 
 
 
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D Study Procedures  
 
Screening and recruitment: 
We will identify potential subjects from the Ventricular Assist Device Surgery Clinic, BJH 
Medical Floors census, surgery schedule or the CPAP Clinic. We may contact them by 
phone to determine interest in participating.  If they are interested, we will arrange to 
meet with them prior to their scheduled surgery.  In order to determine minimum 
eligibility, we would screen their medical records for their name, date of birth, diagnosis, 
surgical procedure, current medications, history of heparin-induced thrombocytopenia 
[HIT], and history of allergic reaction to heparin. 
 
A member of the research team will describe verbally all study components, review the 
informed consent document, and answers all questions. Potential participants/LARs are 
informed verbally and in writing that participation is voluntary and they may refuse to 
participate or may withdraw from the study at any time without penalty. 
 
Nomogram intervention procedure: 
aPTT monitoring group: While on fixed-dose heparin (750 units/hr), an aPTT and an 
anti-Xa will be sent every 6 hours from the same tube (2.7 ml of blood in a light blue top 
tube). The tube will be sent and processed via standard procedure for the aPTT assay to 
which the patient is randomized. A paper requisition form and an assigned study ID 
number will accompany the tube with an order for an anti-Xa that will result in a research 
profile blinded to the clinical team, but available to the research team. This will be the 
process for all the subsequent aPTT/anti-Xa lab draws in the aPTT monitoring group. 
When the clinical team decides to start weight-based heparin dosing, the aPTT heparin 
nomogram order bundle will be ordered as per standard of care. The process noted 
above for lab draws and paper requisition forms will apply to the weight-based heparin 
nomogram as well. The aPTT and anti-Xa will be drawn every 6 hours until two values 
are in the therapeutic range. Once two values are within the therapeutic range, they will 
be drawn every 24 hours. All timed lab draws are current standard of care for patients 
being monitoring on heparin nomograms at BJH. 
 
anti-Xa monitoring group: While on fixed-dose heparin (750 units/hr), an anti-Xa and 
an aPTT will sent every 6 hours from one tube (2.7 ml of blood in a light blue top tube). 
Monitoring heparin therapy with this frequency is current standard of care. The tube will 
be sent and processed via standard procedure for the anti-Xa assay to which the patient 
is randomized. A paper requisition form and an assigned study ID number will 
accompany the tube with an order for an aPTT that will result in a research profile 
blinded to the clinical team, but available to the research team. This will be the process 
for all the subsequent aPTT/anti-Xa lab draws in the anti-Xa monitoring group. When the 
clinical team decides to start weight-based heparin dosing (per standard of care), the 
anti-Xa heparin nomogram order bundle will be ordered. The process noted above for 
lab draws and paper requisition forms, will apply to the weight-based heparin nomogram 

 
 
 
 
 
 
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as well. The aPTT and anti-Xa will be drawn every 6 hours until two values are in the 
therapeutic range. Once two values are within the therapeutic range, they will be drawn 
every 24 hours. All timed lab draws are current standard of care for patients being 
monitoring on heparin nomograms at BJH.  
 
Outcomes data 
Data collected includes surrogate markers of hemorrhage such as number of blood 
transfusions and hemoglobin/hematocrit values during IV UFH anticoagulation 
administration.  Surrogate markers of device thrombosis such as lactate dehydrogenase 
values, haptoglobin values, and device malfunction and/or device power will also be 
collected. Diagnostic imaging will be reviewed to assess for bleeding and/or thrombotic 
complications. Once surrogate makers are collected, The Interagency Registry for 
Mechanically Assisted Circulatory Support (INTERMACS) definitions for LVAD 
thrombosis, neurologic dysfunction, and major bleeding will be utilized.34  
As such, suspected LVAD thrombosis will be defined as two of the following three 
criteria: presence of hemolysis defined as LDH > 1000 IU, presence of heart failure not 
explained by structural heart disease and/or abnormal pump parameters. Confirmed 
pump thrombosis will be defined as major pump-related malfunction in which thrombus 
is confirmed within the blood contact surfaces of device inflow cannula or outflow conduit 
or grafts.  
 
Neurologic Dysfunction will be defined as a new, temporary or permanent, focal or global 
neurologic dysfunction ascertained by standard neurologic exam or surveillance 
neuroimaging.  Event should be further subclassified by event types: 1) transient 
ischemic attach, defined as acute neurologic dysfunction, which resolves in 24 hours 
and not associated with infarction on brain imaging. 2) ischemic stroke defined as a new 
acute neurologic deficit of any duration associate with acute infarction on imaging 
corresponding anatomically to the clinical deficit. 3) Acute symptomatic intracranial 
hemorrhage, defined as a new acute neurologic deficit attributable to intracranial 
hemorrhage (ICH).  ICH subtype should be specified as one or a combination of 
subarachnoid, intraventricular, parenchymal, subdural. 4) Clinically covert ischemic 
stroke or ICH: infarction or ICH seen on surveillance imaging, without conical finding of 
stroke or ICH at the time of event recognition. 5) Hypoxic-ischemic encephalopathy due 
to hypoxic-ischemic injury (HIE), manifest as clinically evident signs or symptoms or 
subclinical electrographic seizures found by complete neurological diagnostic evaluation 
to be attributable to acute global or focal hypoxic or ischemic brain injury not meeting 
one of ischemic stroke or ICH events noted above. 6) Acute new encephalopathy due to 
other cause, manifest as clinically evident signs or symptoms or subclinical 
electrographic seizures found by complete neurological diagnostic evaluation to be 
attributable to causes other than stroke, ICH, or HIE.  
Major bleeding will be defined as suspected internal or external bleeding resulting in 
death, re-operation, hospitalization, or transfusion.  If transfusion is the metric used to 
determine major bleeding, must be greater than or equal to four packed red blood cells 

 
 
 
 
 
 
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within any 24 hours period during the first  7 days postoperatively or after 7 days, a 
transfusion of packed any red cells will be used and the number transfused noted. 
 
Reporting adverse and serious adverse events 
The potential serious risks attributable to avoiding anticoagulation as well as providing 
heparin and warfarin anticoagulation are well known and include gastrointestinal 
bleeding, mediastinal bleeding, retroperitoneal bleeding, stroke, LVAD thrombosis, and 
potentially death. As these are known and anticipated, they will be reported annually to 
the IRB. All unexpected adverse events associated with research participation or study 
intervention will be reported to the WUSTL IRB per their Reportable Event Reporting 
guidelines [WUSTL IRB Policies and Procedures, Section X]. All safety events, including 
adverse events and/or laboratory abnormalities identified in the protocol as critical to 
safety evaluations will be reported to the PI in a timely fashion. 
 
The specific monitoring plan for this investigation is commensurate with the risks and the 
size and complexity of the investigations planned with this feasibility trial. Should there 
be an unanticipated serious adverse event that potentially increases the risks to the 
participants, the study will be stopped, an investigation will be conducted by the PI and 
research team members, and a findings report will be generated and submitted to IRB 
before the study is resumed. The safety data will be monitored and reviewed every 3 
months. 
 
E Statistical Plan  
Sample size: 
For the planned feasibility study, we have selected a convenience sample of 20 patients; 
10 patients randomized to the anti-Xa monitoring arm and 10 patients randomized to the 
aPTT monitoring arm.  Data collected on subjects that were excluded based on receipt 
of an additional pumping device during the index surgery but prior to randomization will 
not be included in the dataset.  Data from subjects excluded based on receipt of an 
additional pumping device after randomization will be retained and analyzed up to the 
point of withdrawal from the study. 
 
No power analysis is planned for this feasibility trial.  
 
Descriptive statistics will be performed looking at the study groups. 
 
For feasibility, questionnaires completed by the nursing staff evaluating the practicality 
and acceptably of the nomograms will be analyzed with descriptive statistics and 
compared between the two groups using a Chi square test.  The percentage of correct 
dosing adjustments made by the nursing team required to achieve first therapeutic 
anticoagulation will be compared between the two groups using a Mann Whitney U test.   
For success, the number of dosing changes required to achieve first therapeutic 

 
 
 
 
 
 
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15
anticoagulation, the time (in hours) to achievement of first therapeutic anticoagulation, 
and the percentage time therapeutic anticoagulation remains after it is achieved will be 
compared between the two groups using a Student’s t-test if data is normally distributed 
or a Mann-Whitney U test if data is not normally distributed. 
 
If possible based on population size, concordance between groups of aPTT and anti-
factor Xa activity will be assessed with a suitable (parametric or non-parametric) mixed 
effects statistical model. This approach is likely to yield more accurate information than 
crude correlation assessments that have been used in other studies, which have not 
taken into account repeated measures within patients. We will use repeated measures 
ANOVA and Tukey’s test for multiple comparisons to analyze heparin administration in 
the two groups. With a mixed effects model, we will compare heparin dose in the two 
groups, while controlling for confounders, including the effect of time on the dose of 
heparin administered, and assuming an autoregressive covariance structure (the nature 
of the correlations between measurements for the same patient), as well as a random 
intercept to allow for some of the effect of potential unknown confounders.  
 
If possible based on study size, markers of gastrointestinal bleeding, major bleeding, 
neurologic events, and thrombotic complications will be compared with a Chi-square 
test. Additionally, as able, adjusted logistic regression will be used to explore risk factors 
for complications. We will use intent-to-treat approach in our analyses. We will also use 
appropriate imputation methods and test the sensitivity of our results. No imputation is 
planned for missing primary outcomes data.   
F Data Handling and Record Keeping  
 
Data Collection and Methods 
All questionnaire’s performed will be collected and responses recorded. 
 
At the time of enrollment, detailed patient characteristics and baseline laboratory values 
will be obtained from the electronic medical record. All patients will have the following 
laboratory values drawn at baseline (if not already available) and clinicians will have the 
results readily available: complete blood count (CBC) and complete metabolic panel 
(CMP) as part of routine patient monitoring.  During days 1-7 and 8-14 the lowest 
hemoglobin, Hematocrit will be collected during each interval. During days 1-7 and 8-14 
the highest bilirubin and triglycerides will be collected during each interval. All PT/INR 
values will be collected during the study.  
 
Surrogate markers of device thrombosis such as lactate dehydrogenase values, 
haptoglobin values, and device power will also be collected. 
 
Any other operations during the study interval will be recorded as well as the details 
associate with the operation. 

 
 
 
 
 
 
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16
 
Any endoscopies or evaluations to identify gastrointestinal bleeding, neurologic events, 
or major bleeding will be recorded. 
 
Additionally, blood will be drawn at randomization, day 2 of heparin, day 4 of heparin, 
day 8 of heparin and day 12 of heparin (5mL of blood per specimen, with maximum of 
25mL).  These specimens will only be collected if patient has not completed the 
intervention (e.g. has not bridged to warfarin).   This specimen will be frozen for later 
analysis to further interrogate the hemostatic system.  Thrombin generation will be 
assessed with the use of a functional thrombin generation assay (TGA) 
(Technothrombin) on the frozen specimen.   
 
Data Management  
A database for this study will be created using REDCap (Research Electronic Data 
Capture). REDCap uses browser-based software for managing research data. We will 
have access to REDCap through the Division of Biostatistics and Informatics at 
Washington University. REDCap servers are securely housed and managed by the 
Division of Biostatistics. All REDCap data transmission is encrypted following the 
HIPAA-Security guidelines. Patient safety in this study will be addressed with a 
comprehensive data safety and monitoring plan that complies with National Institutes of 
Health guidelines. We plan to produce detailed standard operating procedures for all 
members of the research team. We also plan to train all members of the research team 
to take proactive steps to minimize the risk for missing data. Protected health information 
will only be shared with the research team members 
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