Inpatient Monitoring of Unfractionated Heparin

Unfractionated heparin (UFH) is the most widely used intravenous (IV) anticoagulant for treating and preventing thromboembolic disease (e.g., blood clots ). UFH must be closely monitored and adjusted in the hospital. There are two assays used to monitor UFH: 1) the activated partial thromboplastin time (PTT) and 2) the chromogenic anti-factor Xa assay (anti-Xa). This study aims to compare PTT and anti-Xa methods for monitoring UFH in a pragmatic, randomized controlled trial to determine which helps patients reach a therapeutic anticoagulation range faster.

Study Overview

• Status: Enrolling by invitation
• Conditions: Thrombosis; Blood Clot
• Intervention / Treatment: Other: PTT protocol; Other: anti-Xa protocol

Detailed Description

Unfractionated heparin (UFH) is the most widely used intravenous (IV) anticoagulant for the treatment and prevention of thromboembolic disease (e.g., blood clots ). When administered by intravenous injection, the onset of action is immediate. Indications for use of UFH include venous thromboembolism, acute coronary syndrome, and acute ischemic stroke. UFH is used to prevent thrombosis in the setting of arrhythmias, extracorporeal membrane oxygenation (ECMO), cardiopulmonary bypass (CPB), and endovascular procedures. The unpredictable pharmacokinetics of UFH and interpatient variability result in a narrow therapeutic index restricting its use to the hospital setting with close monitoring and adjustments.

Two validated assays exist and are in use at the VUMC adult hospital for the monitoring of unfractionated heparin: 1) the activated partial thromboplastin time (PTT) and 2) the chromogenic anti-factor Xa assay (anti-Xa). At VUMC, the PTT protocol is managed by nursing; the anti-Xa protocol is managed by clinical pharmacy. Both are clinically acceptable methods for titration and adjustment of unfractionated heparin. Assessing the therapeutic effect of unfractionated heparin is most often performed with the PTT, which requires institutional calibration to a specific heparin level to account for the variable PTT responses with different commercial reagents and laboratory instruments. The PTT can be influenced by various elements during sample processing, laboratory analysis, and patient biological factors that may cause it to be an inaccurate indication of the degree of anticoagulation. This can lead to patients not getting the correct heparin dosing for their clinical needs.

The anti-Xa assay is another method of measuring the degree of therapeutic effect of heparin. In routine clinical practice the anti-Xa is not as widely available and less familiar among many providers. This assay can be impacted by variability in sample collection and processing and laboratory analysis. Compared to the PTT assay, however, it is much less influenced by patient-specific biological factors. This may help improve heparin monitoring and titration to ensure patients receive therapeutic levels of anticoagulation and do not get too much or too little heparin. However, large studies using anti-Xa for management of heparin in the treatment of venous thromboembolism have not been performed.

PTT and anti-Xa heparin monitoring protocols have not been compared in a prospective, randomized setting. The study team will conduct a pragmatic, randomized clinical trial comparing the effectiveness of both methods for optimal monitoring of intravenous unfractionated heparin for systemic anticoagulation in hospitalized adult patients.

• Study Type: Interventional
• Enrollment (Estimated): 700
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients at Vanderbilt University Hospital age 18 years and older who are admitted as observation or inpatients for whom intravenous unfractionated heparin (monitored via the PTT nurse-managed protocol) is ordered.
• Baseline PTT value is ≥0 and ≤ 36.0 seconds
• Baseline heparin level anti-Xa assay value is ≥0 and ≤0.3

Exclusion Criteria:

• Indication for anticoagulation is extracorporeal membrane oxygenation or cerebrovascular ischemic event.
• Provider determines patient is not appropriate for the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Health Services Research
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Active Comparator: PTT protocol; Patients randomized to this arm will be monitored using the nurse-managed PTT guided protocol. This includes patients on both high- and low-dose heparin protocols.	Other: PTT protocol; Patients will be monitored using the nurse-managed PTT protocol.
Active Comparator: Active Comparator: anti-Xa protocol; Patients randomized to this arm will be monitored using the pharmacy-managed anti-Xa protocol. This includes patients on both high- and low-dose heparin protocols.	Other: anti-Xa protocol; Patients will be monitored using the pharmacy-managed anti-Xa protocol.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to therapeutic anticoagulation range	Time to reach therapeutic anticoagulation range by coagulation assay	Randomization to hospital discharge at approximately 5-7 days post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measurements in therapeutic anticoagulation range	Percent of measurements in therapeutic range per coagulation assay, as defined by assay protocol	Randomization to hospital discharge at approximately 5-7 days post-randomization
Coagulation laboratory measurements	The number of coagulation laboratory measurements for overall in-hospital coagulation time.	Randomization to hospital discharge at approximately 5-7 days post-randomization
New thrombotic events	Incidence of new thrombotic events on anticoagulation and within 24 hours of anticoagulation cessation	Randomization to hospital discharge at approximately 5-7 days post-randomization and for 24 hours after anticoagulation cessation.
Heparin rate changes	Total number of heparin rate changes for overall in-hospital coagulation time	Randomization to hospital discharge at approximately 5-7 days post-randomization
New clinically relevant bleeding events	Incidence of clinically relevant bleeding adverse events defined as: fatal bleeding, or overt events causing a decline in hemoglobin >2 g/dL over a 24-hour period, or bleeding leading to transfusion of two or more units of whole blood or red blood cells within 48 hours of anticoagulation cessation, or intracranial bleeding events.	Randomization to 24 hours after anticoagulation cessation, approximately 5-7 days post-randomization
New coagulation events	Incidence of new coagulation events on anticoagulation, including thrombotic events and clinically relevant bleeding adverse events as defined in Outcomes 5 and 6.	Randomization to 24 hours after anticoagulation cessation, approximately 5-7 days post-randomization

Collaborators and Investigators

• Sponsor: Vanderbilt University Medical Center
• Investigators: Principal Investigator: Benjamin Tillman, MD, Vanderbilt University Medical Center

Publications and helpful links

General Publications

• Smythe MA, Priziola J, Dobesh PP, Wirth D, Cuker A, Wittkowsky AK. Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016 Jan;41(1):165-86. doi: 10.1007/s11239-015-1315-2.
• Eikelboom JW, Hirsh J. Monitoring unfractionated heparin with the aPTT: time for a fresh look. Thromb Haemost. 2006 Nov;96(5):547-52.
• Olson JD, Arkin CF, Brandt JT, Cunningham MT, Giles A, Koepke JA, Witte DL. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med. 1998 Sep;122(9):782-98.
• Marlar RA, Clement B, Gausman J. Activated Partial Thromboplastin Time Monitoring of Unfractionated Heparin Therapy: Issues and Recommendations. Semin Thromb Hemost. 2017 Apr;43(3):253-260. doi: 10.1055/s-0036-1581128. Epub 2016 Jun 6.
• Hirsh J, Warkentin TE, Raschke R, Granger C, Ohman EM, Dalen JE. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1998 Nov;114(5 Suppl):489S-510S. doi: 10.1378/chest.114.5_supplement.489s. No abstract available.
• Wool GD, Lu CM; Education Committee of the Academy of Clinical Laboratory Physicians and Scientists. Pathology consultation on anticoagulation monitoring: factor X-related assays. Am J Clin Pathol. 2013 Nov;140(5):623-34. doi: 10.1309/AJCPR3JTOK7NKDBJ.

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): July 1, 2026

Study Registration Dates

• First Submitted: March 19, 2024
• First Submitted That Met QC Criteria: March 19, 2024
• First Posted (Actual): March 26, 2024

Study Record Updates

• Last Update Posted (Actual): April 20, 2026
• Last Update Submitted That Met QC Criteria: April 14, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: anticoagulation; heparin; anti-Xa; PTT
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Embolism and Thrombosis; Thrombosis; Molecular Mechanisms of Pharmacological Action; Fibrin Modulating Agents; Fibrinolytic Agents; Anticoagulants; Heparin, Low-Molecular-Weight; Dalteparin
• Other Study ID Numbers: 232192

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Individual participant data that underlie the results reported will be made available (including data dictionaries) after de-identification.
• IPD Sharing Time Frame: The data will become available 3 months following publication of outcomes and will remain available for at least 5 years.
• IPD Sharing Access Criteria: Data will be made available to researchers who provide a methodologically sound proposal that has been approved by the Vanderbilt Institutional Review Board and the study executive committee.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No