Heparin for Community-Acquired Pneumonia

(ATTACC-CAP Trial)

Recruiting at 82 trial locations

Overseen By Chantale Pineau

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: University of Manitoba

Must not be taking: Dual antiplatelets

Disqualifiers: Active COVID-19, Ventilation, Bleeding disorders, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

4000 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether heparin, an anticoagulant used to prevent and treat blood clots, can improve outcomes for patients hospitalized with community-acquired pneumonia. Researchers compare therapeutic doses of heparin to the usual dose given to prevent blood clots. The trial targets patients admitted to the hospital with pneumonia who need extra oxygen. Participants should not have COVID-19 or other serious conditions requiring intensive care. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are currently using dual anti-platelet inhibitors, you may not be eligible to participate.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that heparin is generally safe for humans. Although specific safety data for its use in treating community-acquired pneumonia is lacking, extensive knowledge about its safety comes from other applications. Heparin has been widely used in various medical situations, enhancing understanding of its safety profile.

Past studies have tested heparin at treatment doses in patients with other illnesses, such as COVID-19, who were not critically ill. These studies suggest it can improve patient outcomes without major safety issues. However, all medications can have side effects, which should be considered when deciding to join a trial.

Prospective participants might find reassurance in knowing that heparin is already a well-tolerated treatment for other conditions. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pneumonia?

Researchers are excited about using therapeutic-dose heparin for community-acquired pneumonia because it offers a new approach to treatment. Unlike standard care, which typically involves lower-dose anticoagulation to prevent blood clots, therapeutic-dose heparin directly targets the blood clotting process more aggressively. This method could potentially reduce inflammation and improve respiratory function more rapidly, as it addresses the underlying coagulation issues that can worsen pneumonia symptoms. By exploring this higher dosing strategy, researchers hope to enhance patient outcomes and speed up recovery times.

What evidence suggests that heparin might be an effective treatment for community-acquired pneumonia?

Research has shown that therapeutic-dose heparin, which participants in this trial may receive, might help people with community-acquired pneumonia. One study found that heparin was associated with more days without the need for organ support, meaning patients either survived without dying in the hospital or required less machine assistance. Another study indicated that heparin could reduce the risk of dying in the hospital, especially for patients with moderate sepsis-induced coagulopathy, a condition where blood clotting is impaired. Heparin may also improve short-term survival for critically ill patients with pneumonia-related sepsis. Overall, these findings suggest that therapeutic-dose heparin could benefit patients with severe pneumonia. ^{1 2 5 6 7}

Who Is on the Research Team?

Alexis Turgeon, MD

Principal Investigator

L'Universite Laval

Ryan Zarychanski, MD

Principal Investigator

University of Manitoba

Patrick Lawler, MD

Principal Investigator

University Health Network and McGill University

Sylvain Lother, MD

Principal Investigator

University of Manitoba

Are You a Good Fit for This Trial?

Adults hospitalized with community-acquired pneumonia (CAP) needing oxygen, expected to stay at least 72 hours post-randomization. They must have a primary diagnosis of CAP with new or worsening lung infiltrates and symptoms of lower respiratory infection. Excluded are those admitted over 72 hours, on chronic ventilation, not using thromboprophylaxis, needing full anticoagulation for other reasons, suspected COVID-19, in ICU on life support measures at enrollment time, or with bleeding risks.

Inclusion Criteria

I am in the hospital with pneumonia confirmed by a lung scan and symptoms.

I need extra oxygen to help me breathe.

My doctor diagnosed me with community-acquired pneumonia.

Exclusion Criteria

I am in the ICU receiving support like ventilation or ECLS.

I need blood thinners for a health condition unrelated to the trial.

I am not planned to be given drugs to prevent blood clots.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive therapeutic-dose heparin or usual care thromboprophylaxis for up to 14 days or until hospital discharge

2 weeks

Daily administration in hospital

Follow-up

Participants are monitored for survival, bleeding events, and thrombotic events

30 days

Extended Follow-up

Participants are monitored for thrombotic events and health-related quality of life

90 to 180 days

What Are the Treatments Tested in This Trial?

Interventions

• Heparin

Trial Overview

The trial is testing if therapeutic-dose heparin improves outcomes compared to standard care in hospitalized patients with CAP. It's an international study where participants are randomly assigned to receive either heparin or usual care and the results will be evaluated adaptively as they come in.

How Is the Trial Designed?

Group I: Therapeutic-Dose Heparin Experimental Treatment 1 Intervention

Participants randomized to the investigational arm will receive a pragmatic strategy of therapeutic-dose low molecular-weight heparin (LMWH) or unfractionated heparin (UFH) administered daily for up to 14 days or until hospital discharge, whichever occurs first. Participants should start receiving study drug as soon as possible following randomization.

Group II: Usual Care Active Control 1 Intervention

Participants randomized to the control arm will receive usual care thromboprophylactic dose anticoagulation according to local practice. To ensure adequate separation between the study groups, the dose of heparin/LMWH used in the usual care arm should not equal more than half of the approved therapeutic dose for that agent according to local VTE treatment protocols.

Heparin is already approved in European Union, United States, Canada 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 circuits

Approved in United States as Heparin sodium for:

• Prevention and treatment of deep vein thrombosis and pulmonary embolism
• Prevention of postoperative deep vein thrombosis and pulmonary embolism in patients undergoing major abdominothoracic surgery
• Atrial fibrillation with embolization
• Treatment of acute and chronic consumptive coagulopathy

Approved in Canada as Heparin sodium for:

• Prevention of thromboembolic disorders
• Treatment of deep vein thrombosis
• Treatment of pulmonary embolism

Who Is Running the Clinical Trial?

University of Manitoba

Lead Sponsor

Trials

628

Recruited

209,000+

Canadian Critical Care Trials Group

Collaborator

Trials

32

Recruited

227,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Ozmosis Research Inc.

Industry Sponsor

Trials

25

Recruited

5,200+

Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network

Collaborator

Trials

12

Recruited

17,500+

Research Manitoba

Collaborator

Trials

13

Recruited

17,500+

AVANTI

Collaborator

Trials

1

Recruited

4,000+

Published Research Related to This Trial

Intranasally administered unfractionated heparin (UFH) was found to be safe in both mice and a small group of healthy human subjects, with no significant adverse effects or changes in blood coagulation parameters observed during the study.

The pharmacokinetics showed that UFH remains in the nasal cavity at potentially protective levels for up to 12 hours after administration, suggesting its potential as a prophylactic treatment for COVID-19.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Pharmacokinetics of Intranasally Administered Heparin. Harris, HM., Boyet, KL., Liu, H., et al.[2022]

Unfractionated heparin is a crucial anticoagulant for treating conditions like myocardial infarction and pulmonary embolism, but it carries a significant risk of bleeding, especially with higher doses.

To enhance safety, it is essential to use weight-based dosing guidelines and ongoing developments in automated testing and titration devices may help reduce the risk of adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bleeding complications of unfractionated heparin. Krishnaswamy, A., Lincoff, AM., Cannon, CP.[2013]

In a study of 867 adults with community-acquired pneumonia (CAP) discharged from the emergency department, those with a pneumonia severity index (PSI) score of less than 91 had very low readmission (1.9%) and death rates (0.76%) within 30 days.

Patients with higher PSI scores (>90) had increased readmission (7.14%) and death rates (9.34%), but overall, the findings support that discharging patients with CAP based on clinical guidelines is generally safe.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Patients with community acquired pneumonia discharged from the emergency department according to a clinical practice guideline. Campbell, SG., Patrick, W., Urquhart, DG., et al.[2018]

In a study of 720 patients with acute venous thromboembolism (VTE), subcutaneous unfractionated heparin (UFH) was found to be as effective as fixed-dose nadroparin for preventing recurrent thromboembolic events, with similar rates of recurrence (4.2% for UFH vs. 3.9% for nadroparin).

The safety profiles were comparable, with only 1.1% of patients on UFH and 0.8% on nadroparin experiencing major bleeding, indicating that both treatments are safe options for initial VTE management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. Prandoni, P., Carnovali, M., Marchiori, A.[2006]

Medicare beneficiaries who developed hospital-acquired pneumonia (HAP) were 2.8 times more likely to die within 90 days compared to those who did not have HAP, highlighting the serious consequences of this infection.

Patients with HAP experienced significantly longer hospital stays (6.6 more days) and incurred higher costs (averaging $14,487 more) for their care, indicating that preventing HAP could greatly improve patient outcomes and reduce healthcare expenses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of hospital-acquired pneumonia on the Medicare program. Baker, DL., Giuliano, KK., Desmarais, M., et al.[2023]

Hospitalized patients with community-acquired pneumonia (CAP) are at an increased risk of cardiovascular events (CVEs), which can significantly impact their recovery and overall health outcomes.

To improve patient care, future research should focus on identifying those at risk for CVEs during or after CAP, and consider using additional treatments like heparin or aspirin alongside antibiotics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is the association of cardiovascular events with clinical failure in patients with community-acquired pneumonia? Peyrani, P., Ramirez, J.[2013]

In a study of 3,377 patients with sepsis-induced coagulopathy, early administration of unfractionated heparin (UFH) was associated with a significant reduction in intensive care unit mortality, with a hazard ratio of 0.69, indicating a 31% lower risk of death in the ICU compared to those who did not receive heparin.

The survival benefit of UFH was particularly pronounced in patients with a sepsis-induced coagulopathy score of 4, where the hazard ratio for ICU mortality was 0.56, suggesting that targeted heparin therapy can improve outcomes in this specific patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of early heparin therapy on outcomes in critically ill patients with sepsis-induced coagulopathy. Huang, JJ., Zou, ZY., Zhou, ZP., et al.[2023]

Unfractionated heparin (UFH) is a long-established anticoagulant that is still commonly used for treating venous thromboembolism (VTE) and other related conditions, demonstrating its continued relevance in clinical practice.

Despite its extensive use over nearly a century, there are still important questions about the best dosing and monitoring practices for UFH that need further investigation to optimize its effectiveness and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Unfractionated heparin for the treatment of venous thromboembolism: best practices and areas of uncertainty. Cuker, A.[2012]

In a study of 720 patients with acute venous thromboembolism (VTE), subcutaneous unfractionated heparin (UFH) was found to be as effective as fixed-dose nadroparin for preventing recurrent thromboembolic events, with similar rates of recurrence (4.2% for UFH vs. 3.9% for nadroparin).

The safety profiles were comparable, with only 1.1% of patients on UFH and 0.8% on nadroparin experiencing major bleeding, indicating that both treatments are safe options for initial VTE management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Critical appraisal: Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism. Prandoni P, Carnovali M, Marchiori A, Galilei investigators. Arch Intern Med 2004; 164: 1077-83]. Burotto, M., Gabrielli, L., Crossley, N.[2019]

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]

In a study involving 29 male Wistar rats with endotoxin-induced acute lung injury, nebulized unfractionated heparin (UFH) at doses of 6 U/g and 12 U/g significantly reduced levels of thrombin-antithrombin complex (TATc) and tumor necrosis factor-α (TNF-α), indicating effective inhibition of coagulation and inflammation.

The results suggest that the optimal dose of nebulized UFH for treating acute lung injury should not exceed 12 U/g, as higher doses (18 U/g) led to increased inflammation and lung injury, highlighting the importance of dose management in therapeutic interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The effects of three dosages of nebulized unfractionated heparin on alveolar coagulation and tissue inflammation injury in endotoxin-induced acute lung injury rat model]. Wang, ZY., Wu, SN., Zhu, X.[2012]

In a study involving 161 patients with hospital-acquired pneumonia, moxifloxacin demonstrated a clinical success rate of 87%, compared to 83% for ceftriaxone, indicating that moxifloxacin is an effective treatment option.

Both moxifloxacin and ceftriaxone were found to be safe and well tolerated, suggesting that moxifloxacin can be considered a viable alternative for treating mild-to-moderate pneumonia in patients without risk factors for resistant infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized study of sequential intravenous/oral moxifloxacin in comparison to sequential intravenous ceftriaxone/oral cefuroxime axetil in patients with hospital-acquired pneumonia. Höffken, G., Barth, J., Rubinstein, E., et al.[2018]

Ceftobiprole treatment showed a higher rate of early clinical response compared to other antibiotics in high-risk patients with pneumonia, particularly in elderly patients (≥75 years) and those with chronic obstructive pulmonary disease (COPD).

This analysis included 398 community-acquired pneumonia (CAP) patients and 307 hospital-acquired pneumonia (HAP) patients, suggesting that ceftobiprole may be more effective in achieving early improvement in these vulnerable groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early improvement in severely ill patients with pneumonia treated with ceftobiprole: a retrospective analysis of two major trials. Scheeren, TWL., Welte, T., Saulay, M., et al.[2023]

Intranasally administered unfractionated heparin (UFH) was found to be safe in both mice and a small group of healthy human subjects, with no significant adverse effects or changes in blood coagulation parameters observed during the study.

The pharmacokinetics showed that UFH remains in the nasal cavity at potentially protective levels for up to 12 hours after administration, suggesting its potential as a prophylactic treatment for COVID-19.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Pharmacokinetics of Intranasally Administered Heparin. Harris, HM., Boyet, KL., Liu, H., et al.[2023]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11903409/

Unfractionated heparin may improve near-term survival in ...

This study aimed to assess whether heparin administration improves near-term survival in critically ill patients with pneumonia-induced sepsis

2.

withpower.com

withpower.com/trial/phase-3-pneumonia-4-2023-eb706

Heparin for Community-Acquired Pneumonia

This trial is testing if higher doses of heparin, a blood thinner, can help patients hospitalized with pneumonia. These patients often have blood clot ...

3.

sciencedirect.com

sciencedirect.com/science/article/pii/S2772963X23008116

Heparin Dose Intensity and Organ Support-Free Days in ...

Heparin, compared with usual care, was associated with improved OSFDs, a combination of in-hospital death and days free of organ support.

4.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2103417

Therapeutic Anticoagulation with Heparin in Critically Ill ...

We hypothesized that therapeutic-dose anticoagulation would improve outcomes in critically ill patients with Covid-19.

5.

thrombosisresearch.com

thrombosisresearch.com/article/S0049-3848(24)00227-5/fulltext

Efficacy of unfractionated heparin in patients with moderate ...

Early heparin administration upon admission is associated with lower in-hospital mortality, especially in moderate sepsis-induced coagulopathy.

6.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2105911

Therapeutic Anticoagulation with Heparin in Noncritically Ill ...

We hypothesized that therapeutic-dose anticoagulation may improve outcomes in noncritically ill patients who are hospitalized with Covid-19.

7.

clinicaltrials.gov

clinicaltrials.gov/study/NCT04528888

Steroids and Unfractionated Heparin in Critically Ill Patients ...

Despite the biological plausibility, no good evidence is available on the efficacy and safety of heparin on sepsis patients, and many issues have to be ...