Heparin for Hand Amputation

Overseen By Linda M Zhu

Age: Any Age

Sex: Any

Trial Phase: Phase 4

Sponsor: Centre hospitalier de l'Université de Montréal (CHUM)

Must not be taking: Anticoagulants

Disqualifiers: Coagulopathy, Acute ulcers, Shock, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 5 days

188 Participants Needed

Trial Summary

What is the purpose of this trial?

The purpose of this study is to determine the effectiveness of therapeutic dose intravenous heparin at improving replantation/revascularization success and its indications (if any) in participants who have suffered traumatic digital amputation. Digital replantation/revascularization success will be assessed in participants who receive continuous intravenous drip of thromboprophylactic heparin at a therapeutic dose (i.e. modifies INR to the desired range) contrasted to those who do not receive therapeutic dose heparin (i.e. does not modify INR to the desired range). In the study, replantation/revascularization success is defined as a clearly viable digit at the time of discharge. Secondary objectives include assessing postoperative complications associated with heparin use, such as bleeding, hematoma or heparin induced thrombocytopenia. The investigators would also assess the impact of categorical variables such as smoking status, mechanism of injury and comorbidities, on digital survival.

Will I have to stop taking my current medications?

If you are taking anticoagulants (blood thinners) like Coumadin, Eliquis, Pradaxa, or Plavix, you cannot participate in this trial. The protocol does not specify about other medications, so it's best to discuss with the trial team.

What data supports the effectiveness of the drug Unfractionated Heparin for hand amputation?

Unfractionated Heparin (UFH) is effective in preventing complications like blood clots in various conditions, such as peripheral arterial disease and after certain heart conditions. This suggests it might help in managing blood flow and preventing clotting issues in hand amputation cases. ^{1 2 3 4 5}

Is unfractionated heparin (UFH) generally safe for humans?

Unfractionated heparin (UFH) is widely used and generally safe for humans, but it can cause side effects like bleeding, a drop in platelet count (heparin-induced thrombocytopenia), and bone thinning (osteoporosis). It requires careful monitoring to manage these risks. ^{1 3 6 7 8}

How is the drug unfractionated heparin (UFH) unique for hand amputation treatment?

Unfractionated heparin (UFH) is unique because it is administered intravenously and requires close monitoring due to its variable response and risk of side effects like bleeding and heparin-induced thrombocytopenia (a condition where the blood has a lower than normal number of platelets). Unlike newer anticoagulants, UFH's effects are less predictable, making it a challenging but established option for preventing blood clots. ^{1 3 6 9 10}

Research Team

Bruno Mastropasqua, MD FRCSC

Principal Investigator

Université de Montréal

Eligibility Criteria

This trial is for individuals who have undergone hand replantation or revascularization at the Centre hospitalier de l'Université de Montréal. It's not for those with amputations above the wrist, on certain blood thinners, with degloving injuries, or conditions that make heparin use unsafe like bleeding disorders and severe liver damage.

Inclusion Criteria

All replantation and revascularization patients who are accepted into the CEVARMU program at the Centre hospitalier de l'Université de Montréal

Exclusion Criteria

I cannot take heparin due to a health condition like bleeding disorders or severe liver damage.

I am taking blood thinners other than aspirin.

I have had an amputation above my wrist.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive intravenous unfractionated heparin or sham comparator for 5 days following digital replantation/revascularization

5 days

Daily monitoring for dosage adjustments

Follow-up

Participants are monitored for replantation/revascularization success and heparin-related complications

Up to 14 days

Regular in-person assessments

Treatment Details

Interventions

• Intravenous unfractionated heparin
• Sham

Trial Overview The study tests if intravenous unfractionated heparin improves the success of surgically reattached fingers after trauma. Participants are divided into two groups: one receiving a therapeutic dose of heparin and another without it to compare outcomes at discharge.

Participant Groups

Group I: Intravenous unfractionated heparin Experimental Treatment 1 Intervention

Administration of intravenous unfractionated heparin according to the Centre hospitalier de l'Université de Montréal (CHUM) deep vein thrombosis (DVT) protocol for 5 days after vascular anastomosis. A bolus will be administered intraoperatively based on the patient's weight. Dosages will be adjusted according to the activated partial thromboplastin time (aim for an APTT of 50-70), which will be measured 6 hours after the start of the protocol and after every dosage adjustment or every morning at 6 a.m. if no adjustments were made in the last 6 hours.

Group II: Control Placebo Group 1 Intervention

No administration of intravenous unfractionated heparin. These patients receive 5000 IU BID of heparin subcutaneously, as a standard post-operative protocol for all in-patients. The control group receives sham bolus intraoperatively of normal saline and a post-operative normal saline infusion at a fixed dose through an infusion pump to mimic IV heparin infusion.

Intravenous unfractionated heparin is already approved in European Union, United States, Canada, Japan, China for the following indications:

Approved in European Union as Heparin Sodium for:

• Prevention of thromboembolic disorders
• Treatment of deep vein thrombosis
• Treatment of pulmonary embolism
• Prevention of clotting in extracorporeal circulation during cardiac surgery

Approved in United States as Heparin Sodium for:

• Prevention and treatment of deep vein thrombosis and pulmonary embolism
• Prevention of clotting in extracorporeal circulation during cardiac surgery
• Anticoagulant therapy in acute and chronic consumption coagulopathies

Approved in Canada as Heparin Sodium for:

• Prevention and treatment of thromboembolic disorders
• Prevention of clotting in extracorporeal circulation during cardiac surgery

Approved in Japan as Heparin Sodium for:

• Prevention and treatment of deep vein thrombosis and pulmonary embolism
• Prevention of clotting in extracorporeal circulation during cardiac surgery

Approved in China as Heparin Sodium for:

• Prevention and treatment of thromboembolic disorders
• Prevention of clotting in extracorporeal circulation during cardiac surgery

Who Is Running the Clinical Trial?

Centre hospitalier de l'Université de Montréal (CHUM)

Lead Sponsor

Trials

389

Recruited

143,000+

Findings from Research

In a study of 210 patients with peripheral occlusive arterial disease, enoxaparin demonstrated superior efficacy compared to unfractionated heparin (UFH), with a significantly lower rate of thromboembolic complications during endovascular interventions (10.5% vs. 2.5%).

The use of enoxaparin also resulted in quicker achievement of therapeutic anti-factor Xa levels, with 63.7% of patients reaching these levels within 15 minutes, compared to only 39.1% in the UFH group, indicating a faster onset of action.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of enoxaparin and unfractionated heparin in endovascular interventions for the treatment of peripheral arterial occlusive disease: a randomized controlled trial. Duschek, N., Vafaie, M., Skrinjar, E., et al.[2023]

In a study of 213 peripheral angioplasty procedures, 9.2% of patients experienced in-hospital major complications, including major bleeding and the need for repeat revascularization, highlighting the risks associated with using unfractionated heparin as the primary anticoagulant.

Higher doses of heparin were linked to a trend of increased complications, suggesting that careful dosing is crucial, and ongoing research is exploring the use of direct thrombin inhibitors like bivalirudin as a potentially safer alternative.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

In-hospital complications of peripheral vascular interventions using unfractionated heparin as the primary anticoagulant. Shammas, NW., Lemke, JH., Dippel, EJ., et al.[2006]

In a study of 200 patients with non-ST-elevation acute coronary syndrome, those receiving unfractionated heparin in dextrose 5% in water (UFH-D5W) achieved therapeutic anti-factor Xa levels within 24 hours 92% of the time, compared to only 67% for those receiving unfractionated heparin in normal saline (UFH-NS).

UFH-NS was associated with a significantly lower likelihood of achieving and maintaining therapeutic anticoagulation, requiring more adjustments to the infusion rate, indicating that UFH-D5W is the more effective preparation for anticoagulation in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Unfractionated Heparin in Normal Saline versus Dextrose for Achieving and Maintaining Therapeutic Anti-Factor Xa Levels in Patients with Non-ST-Elevation Acute Coronary Syndrome. Jacques, AC., Lougheed, C., Macdonald, E., et al.[2021]

In a randomized control trial involving 30 patients with acute deep vein thrombosis, low molecular weight heparin (LMWH) showed faster improvement in pain and swelling compared to unfractionated heparin (UFH), although the differences were not statistically significant.

LMWH was associated with a normal bleeding profile and significantly shorter hospital stays, with no reported mortality, while UFH had complications including prolonged bleeding and three patient deaths.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of unfractionated heparin vs low molecular weight heparin in the treatment of acute deep vein thrombosis. Naz, R., Naz, S., Mehboob, M., et al.[2009]

In a study of 45 patients who underwent embolectomy, only 37.6% of activated partial thromboplastin time (APTT) tests were within the therapeutic range, indicating that many patients were not adequately anticoagulated with intravenous unfractionated heparin (UFH).

The authors suggest that subcutaneous low molecular weight heparin (LMWH) could be a more effective and user-friendly alternative to UFH, especially given the challenges in maintaining therapeutic levels with UFH in busy clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Audit of anticoagulation after embolectomy for acute ischaemia. Robinson, T., Hunter, I., Wathes, R., et al.[2021]

Low molecular weight heparins (LMWHs) offer significant advantages over unfractionated heparin (UFH) for treating venous thromboembolism (VTE) and acute coronary syndromes, including better bioavailability, longer half-life, and predictable anticoagulant effects, allowing for less frequent dosing without the need for monitoring.

UFH is associated with risks such as bleeding and heparin-induced thrombocytopenia, while LMWHs reduce these risks and improve patient convenience, highlighting the shift towards LMWHs in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives on antithrombotic agents: from unfractionated heparin to new antithrombotics. Agnelli, G., Sonaglia, F.[2005]

Unfractionated heparin (UFH) is the standard anticoagulant used during cardiopulmonary bypass (CPB), but it can lead to the development of heparin-dependent antibodies in 25% to 50% of patients, which may cause heparin-induced thrombocytopenia (HIT) in 1% to 3% of cases, resulting in serious complications.

For patients with a history of HIT or positive antibody titers requiring urgent cardiac surgery, alternative anticoagulants like lepirudin or bivalirudin are recommended, as well as the use of platelet antagonists to mitigate the risk of thromboembolic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anticoagulation management and cardiac surgery in patients with heparin-induced thrombocytopenia. Riess, FC.[2019]

A pharmacokinetic-pharmacodynamic (PKPD) model for unfractionated heparin (UFH) was developed using data from 64 children undergoing cardiac procedures, showing that fat-free mass (FFM) significantly influences drug clearance.

While the model accurately described UFH effects in the studied population, it overpredicted activated partial thromboplastin time (aPTT) responses when simulating lower UFH doses, suggesting a potential nonlinear relationship in heparin's pharmacokinetics and pharmacodynamics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of a population pharmacokinetic-pharmacodynamic model of a single bolus dose of unfractionated heparin in paediatric patients. Al-Sallami, H., Newall, F., Monagle, P., et al.[2021]

Unfractionated heparin (UFH) has been used for over 50 years to treat and prevent thrombosis, but its variable composition and unpredictable pharmacokinetics limit its effectiveness and complicate monitoring.

Newer anticoagulants, such as low-molecular-weight heparins and direct thrombin inhibitors, offer more predictable effects and eliminate the risk of heparin-induced thrombocytopenia (HIT), making them preferable alternatives to UFH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Challenges in variation and responsiveness of unfractionated heparin. Francis, JL., Groce, JB.[2019]

A machine learning algorithm was developed to predict activated partial thromboplastin time (aPTT) after administering unfractionated heparin (UFH), potentially improving the dosing process which currently takes over 36 hours to optimize.

The best-performing model achieved a root mean square error of 31.35 in predicting aPTT, demonstrating its effectiveness in a cohort of 3019 patient episodes across five hospitals, marking a significant advancement in the management of UFH therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predicting Therapeutic Response to Unfractionated Heparin Therapy: Machine Learning Approach. Abdel-Hafez, A., Scott, IA., Falconer, N., et al.[2022]

References

1. England pubmed.ncbi.nlm.nih.gov

Comparison of enoxaparin and unfractionated heparin in endovascular interventions for the treatment of peripheral arterial occlusive disease: a randomized controlled trial. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

In-hospital complications of peripheral vascular interventions using unfractionated heparin as the primary anticoagulant. [2006]

3. Canada pubmed.ncbi.nlm.nih.gov

Effectiveness of Unfractionated Heparin in Normal Saline versus Dextrose for Achieving and Maintaining Therapeutic Anti-Factor Xa Levels in Patients with Non-ST-Elevation Acute Coronary Syndrome. [2021]

4. Pakistan pubmed.ncbi.nlm.nih.gov

Comparison of unfractionated heparin vs low molecular weight heparin in the treatment of acute deep vein thrombosis. [2009]

5. England pubmed.ncbi.nlm.nih.gov

Audit of anticoagulation after embolectomy for acute ischaemia. [2021]

6. Italy pubmed.ncbi.nlm.nih.gov

Perspectives on antithrombotic agents: from unfractionated heparin to new antithrombotics. [2005]

7. United States pubmed.ncbi.nlm.nih.gov

Anticoagulation management and cardiac surgery in patients with heparin-induced thrombocytopenia. [2019]

8. England pubmed.ncbi.nlm.nih.gov

Development of a population pharmacokinetic-pharmacodynamic model of a single bolus dose of unfractionated heparin in paediatric patients. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Challenges in variation and responsiveness of unfractionated heparin. [2019]

10. Canada pubmed.ncbi.nlm.nih.gov

Predicting Therapeutic Response to Unfractionated Heparin Therapy: Machine Learning Approach. [2022]