Acute Bleeding on Long-Term Anticoagulation TherapyPhase 4kcentraNCT03064035
Fixed Versus Variable Dosing of 4-factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal
A Phase 4 study testing 4-factor prothrombin complex concentrate (4FPCC) in people with Acute Bleeding on Long-Term Anticoagulation Therapy and Hemorrhage, run by HealthPartners Institute at 1 site in United States.
Trial summary
The goal of this study is to determine if a fixed dose of 4-factor prothrombin complex concentrate (4FPCC) is as effective as the current standard of care. 4FPCC is used to reverse the effects of warfarin when a patient has emergent bleeding. Read more about this study
- Who is it for?
- Ages 18 to 125 years
- Conditions the study is for
- Acute Bleeding on Long-Term Anticoagulation Therapy, Hemorrhage, Significant Bleeding in Patients With a Coagulopathy (Prolonged Thrombin Time)
- What is being tested?
- 4-factor prothrombin complex concentrate (4FPCC)
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 79 participants
- Where
- 1 siteUnited States
- Study dates
- 5 Apr 2017to 24 Apr 2019
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 125 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Chronic anticoagulation with warfarin and initial INR ≥2
- Emergent bleeding (i.e. intracranial hemorrhage, gastrointestinal hemorrhage, urgent invasive procedures, etc.) or urgent surgery requiring reversal of INR to ≤1.5
Who cannot join
- Younger than 18 years of age
- History of heparin-induced thrombocytopenia (HIT)
- Patients without initial or post-administration INR readings
- Patients with an initial INR <2
- Pregnant patients
- Prisoners
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Prospective, Randomized Study of Fixed Versus Variable Dosing of 4-factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal at a Large Tertiary Care Medical Center
The goal of this study is to determine if a fixed dose of 4-factor prothrombin complex concentrate (4FPCC) is as effective as the current standard of care. 4FPCC is used to reverse the effects of warfarin when a patient has emergent bleeding. The investigators hope that this study will help doctors treat patients quicker in the future. In addition, it may be cheaper for patients and hospitals. This is the same medication the doctor would use to reverse warfarin's effects, but at a lower dose.
Hypothesis: A fixed dose of 4FPCC will be comparable to FDA-approved variable dosing for reversal of warfarin-induced anticoagulation (defined as an international normalized ratio [INR] ≤ 1.5) in patients with an INR ≥2 experiencing an emergent bleed or requiring emergent surgery.
Read the detailed description
Warfarin is a common oral anticoagulant utilized in the United States for the treatment and prevention of thromboembolic events and conditions. Although effective, the major complication associated with warfarin is the risk of major bleeding events. Incidence of major bleeding events in long-term warfarin users is 1.5% to 5.2% per year, with mortality exceeding 13%. Among patients with an intracranial bleed, the mortality rate increases to 46%-55%. In these situations, it is imperative to reverse the pharmacologic effects of warfarin quickly in order to minimize bleeding and reduce the risk of death. Warfarin inhibits formation of vitamin K-dependent clotting factors II, VII, IX, X, and proteins C and S. An international normalized ratio (INR) is a commonly utilized laboratory test to measure the amount of anticoagulation provided by warfarin and is monitored throughout therapy. The INR is a standardized ratio utilizing prothrombin time to prevent variation between institutional laboratories. Prothrombin time is defined as the time required for plasma to clot after addition of clotting factor. A normal INR in a healthy adult can range from 0.8-1.2. The majority of patients on chronic warfarin therapy will have a target INR of 2-3.
The optimal dose of 4FPCC is currently unknown despite multiple studies evaluating different dosing regimens. The FDA-approved dosing is 25 to 50 IU factor IX per kilogram of body weight, depending on INR. It is dosed to a maximum of 100 kilograms of body weight. The FDA-approved variable dosing algorithm is as follows: initial INR 2-3.9: 25 IU/kg (maximum dose 2500 IU), initial INR 4-6: 35 IU/kg (maximum dose 3500 IU), and initial INR >6: 50 IU/kg (maximum dose 5000 IU). Exact doses of 4FPCC administered may vary slightly from the calculated doses as the amount of 4FPCC differs based on the vials utilized.
By incorporating a fixed dose of 1500 IU, presenting INR and body weight may not need to be determined prior to administration. This may allow for early administration and prevent delay for warfarin reversal in patients with emergent bleeding. This research may determine whether a fixed dose is effective for reversing warfarin to a target INR less than 1.5 compared to FDA-approved variable dosing. In addition, the lower fixed-dose will significantly reduce costs to the institution.
Hypothesis: A fixed dose of 4FPCC will be comparable to FDA-approved variable dosing for reversal of warfarin-induced anticoagulation (defined as an international normalized ratio [INR] ≤ 1.5) in patients with an INR ≥2 experiencing an emergent bleed or requiring emergent surgery.
- Conditions
- Acute Bleeding on Long-Term Anticoagulation Therapy, Hemorrhage, Significant Bleeding in Patients With a Coagulopathy (Prolonged Thrombin Time), Urgent Reversal of Vitamin K Antagonist (VKA) Anticoagulation
- Being tested
- 4-factor prothrombin complex concentrate (4FPCC)
- Medical subject headings
- Hemorrhage
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
4-factor prothrombin complex concentrate (4FPCC)Drug
4-factor prothrombin complex concentrate (4FPCC) contains all of the vitamin K-dependent clotting factors inhibited by warfarin, making it desirable for use in warfarin reversal for emergent bleeds. Multiple guidelines currently recommend 4FPCC for warfarin reversal in vitamin K-dependent major bleeding or intracranial hemorrhage. 4FPCC has a fast onset of action and has demonstrated significant reversal of INR within 10 minutes. Its duration of action is up to 8 hours, and for this reason it should be given concurrently with vitamin K. Vitamin K has a delayed onset of action due to its need to stimulate the synthesis of clotting factors so its effects begin as the effects of 4FPCC diminish. 4FPCC is the standard of care treatment for this clinical population in the Regions Hospital Emergency Department.
| Study group | Role | What they receive |
|---|---|---|
| Fixed dose 4FPCC | Experimental | Incorporating a fixed dose of 1500 IU.
If the patient receiving the 1500 IU fixed dose remains in a bleeding state and the INR remains above goal, an additional 500 IU may be administered at the physician's discretion to minimize bleeding and attempt to achieve hemostasis. Receives: Drug: 4-factor prothrombin complex concentrate (4FPCC) |
| Variable dose 4FPCC | Active comparator | The FDA-approved variable dosing algorithm is as follows:
initial INR 2-3.9: 25 IU/kg (maximum dose 2500 IU), initial INR 4-6: 35 IU/kg (maximum dose 3500 IU), and initial INR >6: 50 IU/kg (maximum dose 5000 IU). The patient weight will be obtained using a scale and documented by the treating registered nurse Receives: Drug: 4-factor prothrombin complex concentrate (4FPCC) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants Who Demonstrated Significant Reversal of INR Within 15 Minutes
To evaluate whether fixed dose 4FPCC is acceptably comparable to variable dosing with respect to anticoagulation reversal, as defined by a targeted INR of ≤1.5
Measured: 15 minutes
Secondary outcomes (2)
Number of Participants With a Thromboembolic Event
Study patients will be followed post-administration of 4FPCC for thromboembolic events such as deep vein thrombosis, pulmonary embolism, ischemic stroke or transient ischemic event, or myocardial infarction.
Measured: up to 7 days post administration of 4FPCC
Total Cost of Dosing Strategy
Cost outcomes will be assessed for all study patients and compared by dosing assignment. Cost of treatment was assessed based on the amount of 4FPCC doses administered during admission, using the study-contemporary rate of $1.57/unit
Measured: Hospital Stay, Up to 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Feb 2017
- Study start5 Apr 2017
- Primary completion17 Apr 2019
- Study completion24 Apr 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Acute Bleeding on Long-Term Anticoagulation TherapyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- For adults on long-term warfarin therapy who present to the ED with emergent bleeding, or who are in need of urgent invasive surgical procedures: the exposure of interest will be fixed vs. variable dose 4FPCC, to which eligible patients will be randomly assigned in a 1:1 ratio.
- Masking
- None (open label)
- Enrolment
- 79 participants (actual)
Sponsor and investigators
- Lead sponsor
- HealthPartners Institute
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Zachary Stoecker, PharmD, Principal investigator, Regions Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03064035
- Sponsor's protocol ID
- A16-732
- Acronym
- kcentra
- Status last verified
- Jun 2019
- First submitted
- 16 Feb 2017
- Last updated
- 14 Sep 2023
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 14 Sep 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Prospective, Randomized Study of Fixed Versus Variable Dosing of 4-factor Prothrombin Complex Concentrate for Emergent Warfarin Reversal at a Large Tertiary Care Medical Center
- ClinicalTrials.gov ID
- NCT03064035
- Acronym / sponsor ID
- kcentra / A16-732
- Conditions
- Acute Bleeding on Long-Term Anticoagulation Therapy, Hemorrhage, Significant Bleeding in Patients With a Coagulopathy (Prolonged Thrombin Time), Urgent Reversal of Vitamin K Antagonist (VKA) Anticoagulation
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 79 participants (actual)
- Lead sponsor
- HealthPartners InstituteUniversity, hospital or other
- Study start
- 5 Apr 2017 (actual)
- Primary completion
- 17 Apr 2019 (actual)
- Study completion
- 24 Apr 2019 (actual)
- First posted
- 24 Feb 2017 (actual)
- Results
- Posted 11 Jul 2023
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The goal of this study is to determine if a fixed dose of 4-factor prothrombin complex concentrate (4FPCC) is as effective as the current standard of care. 4FPCC is used to reverse the effects of warfarin when a patient has emergent bleeding. The investigators hope that this study will help doctors treat patients quicker in the future. In addition, it may be cheaper for patients and hospitals. This is the same medication the doctor would use to reverse warfarin's effects, but at a lower dose.
Hypothesis: A fixed dose of 4FPCC will be comparable to FDA-approved variable dosing for reversal of warfarin-induced anticoagulation (defined as an international normalized ratio [INR] ≤ 1.5) in patients with an INR ≥2 experiencing an emergent bleed or requiring emergent surgery.
Detailed description
Warfarin is a common oral anticoagulant utilized in the United States for the treatment and prevention of thromboembolic events and conditions. Although effective, the major complication associated with warfarin is the risk of major bleeding events. Incidence of major bleeding events in long-term warfarin users is 1.5% to 5.2% per year, with mortality exceeding 13%. Among patients with an intracranial bleed, the mortality rate increases to 46%-55%. In these situations, it is imperative to reverse the pharmacologic effects of warfarin quickly in order to minimize bleeding and reduce the risk of death. Warfarin inhibits formation of vitamin K-dependent clotting factors II, VII, IX, X, and proteins C and S. An international normalized ratio (INR) is a commonly utilized laboratory test to measure the amount of anticoagulation provided by warfarin and is monitored throughout therapy. The INR is a standardized ratio utilizing prothrombin time to prevent variation between institutional laboratories. Prothrombin time is defined as the time required for plasma to clot after addition of clotting factor. A normal INR in a healthy adult can range from 0.8-1.2. The majority of patients on chronic warfarin therapy will have a target INR of 2-3.
The optimal dose of 4FPCC is currently unknown despite multiple studies evaluating different dosing regimens. The FDA-approved dosing is 25 to 50 IU factor IX per kilogram of body weight, depending on INR. It is dosed to a maximum of 100 kilograms of body weight. The FDA-approved variable dosing algorithm is as follows: initial INR 2-3.9: 25 IU/kg (maximum dose 2500 IU), initial INR 4-6: 35 IU/kg (maximum dose 3500 IU), and initial INR >6: 50 IU/kg (maximum dose 5000 IU). Exact doses of 4FPCC administered may vary slightly from the calculated doses as the amount of 4FPCC differs based on the vials utilized.
By incorporating a fixed dose of 1500 IU, presenting INR and body weight may not need to be determined prior to administration. This may allow for early administration and prevent delay for warfarin reversal in patients with emergent bleeding. This research may determine whether a fixed dose is effective for reversing warfarin to a target INR less than 1.5 compared to FDA-approved variable dosing. In addition, the lower fixed-dose will significantly reduce costs to the institution.
Hypothesis: A fixed dose of 4FPCC will be comparable to FDA-approved variable dosing for reversal of warfarin-induced anticoagulation (defined as an international normalized ratio [INR] ≤ 1.5) in patients with an INR ≥2 experiencing an emergent bleed or requiring emergent surgery.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- For adults on long-term warfarin therapy who present to the ED with emergent bleeding, or who are in need of urgent invasive surgical procedures: the exposure of interest will be fixed vs. variable dose 4FPCC, to which eligible patients will be randomly assigned in a 1:1 ratio.
| Arm | Type | Receives |
|---|---|---|
| Fixed dose 4FPCC | Experimental | Drug: 4-factor prothrombin complex concentrate (4FPCC)Incorporating a fixed dose of 1500 IU. If the patient receiving the 1500 IU fixed dose remains in a bleeding state and the INR remains above goal, an additional 500 IU may be administered at the physician's discretion to minimize bleeding and attempt to achieve hemostasis. |
| Variable dose 4FPCC | Active comparator | Drug: 4-factor prothrombin complex concentrate (4FPCC)The FDA-approved variable dosing algorithm is as follows: initial INR 2-3.9: 25 IU/kg (maximum dose 2500 IU), initial INR 4-6: 35 IU/kg (maximum dose 3500 IU), and initial INR >6: 50 IU/kg (maximum dose 5000 IU). The patient weight will be obtained using a scale and documented by the treating registered nurse |
Who may qualify
- Ages
- 18 to 125 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- Chronic anticoagulation with warfarin and initial INR ≥2
- Emergent bleeding (i.e. intracranial hemorrhage, gastrointestinal hemorrhage, urgent invasive procedures, etc.) or urgent surgery requiring reversal of INR to ≤1.5
Key exclusion criteria (6 listed)
- Younger than 18 years of age
- History of heparin-induced thrombocytopenia (HIT)
- Patients without initial or post-administration INR readings
- Patients with an initial INR <2
- Pregnant patients
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 4-factor prothrombin complex concentrate (4FPCC)4-factor prothrombin complex concentrate (4FPCC) contains all of the vitamin K-dependent clotting factors inhibited by warfarin, making it desirable for use in warfarin reversal for emergent bleeds. Multiple guidelines currently recommend 4FPCC for warfarin reversal in vitamin K-dependent major bleeding or intracranial hemorrhage. 4FPCC has a fast onset of action and has demonstrated significant reversal of INR within 10 minutes. Its duration of action is up to 8 hours, and for this reason it should be given concurrently with vitamin K. Vitamin K has a delayed onset of action due to its need to stimulate the synthesis of clotting factors so its effects begin as the effects of 4FPCC diminish. 4FPCC is the standard of care treatment for this clinical population in the Regions Hospital Emergency Department. | Drug | Fixed dose 4FPCC, Variable dose 4FPCC |
Primary outcome
Number of Participants Who Demonstrated Significant Reversal of INR Within 15 Minutes
Time frame: 15 minutes
To evaluate whether fixed dose 4FPCC is acceptably comparable to variable dosing with respect to anticoagulation reversal, as defined by a targeted INR of ≤1.5
2 secondary outcomes
Number of Participants With a Thromboembolic Event
Time frame: up to 7 days post administration of 4FPCC
Total Cost of Dosing Strategy
Time frame: Hospital Stay, Up to 6 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Sep 2023.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Zachary Stoecker, PharmD principal investigator
Regions Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing 4-factor prothrombin complex concentrate (4FPCC) in people with Acute Bleeding on Long-Term Anticoagulation Therapy and Hemorrhage, run by HealthPartners Institute at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 2 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Sep 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 11 Jul 2023). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants Who Demonstrated Significant Reversal of INR Within 15 Minutes (time frame: 15 minutes). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Sep 2023.