Timing for Restarting DOACs After Gastrointestinal Bleeding

(PANTHER-GI Trial)

Recruiting at 1 trial location

Overseen By Deborah M Siegal, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Ottawa Hospital Research Institute

Must be taking: Direct oral anticoagulants

Disqualifiers: Mechanical heart valve, GI cancer, others

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

Approved in 6 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 1-2 weeks

100 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a plan for safely restarting blood thinners in patients who have had serious digestive system bleeding and are at high risk of both re-bleeding and blood clots. The timing of restarting the medication will be based on each patient's risk of developing blood clots.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking all your current medications, but it does require that you stop taking oral anticoagulants (blood thinners) due to the current gastrointestinal bleeding. You will resume these medications after the bleeding is managed.

What data supports the effectiveness of the drug DOACs after gastrointestinal bleeding?

Research shows that DOACs are effective for preventing strokes and treating blood clots, and they are often preferred over older drugs like warfarin because they work more predictably and don't require regular blood tests. However, while they may cause more frequent gastrointestinal bleeding than warfarin, restarting DOACs after such bleeding does not seem to increase the risk of rebleeding. ^{1 2 3 4 5}

Is it safe to restart DOACs after gastrointestinal bleeding?

Direct oral anticoagulants (DOACs) generally have a favorable safety profile, but they can increase the risk of gastrointestinal bleeding compared to other treatments. Among DOACs, apixaban is associated with the lowest risk of major gastrointestinal bleeding, while edoxaban has a lower risk than rivaroxaban when used in low doses. ^{1 6 7 8 9}

How is the drug DOAC different from other treatments for gastrointestinal bleeding?

DOACs (Direct Oral Anticoagulants) are unique because they have a rapid onset of action and a short half-life, meaning they work quickly and leave the body faster compared to traditional blood thinners like warfarin. Unlike other treatments, DOACs do not require routine blood tests to monitor their effect, making them more convenient for patients. ^{1 2 4 10 11}

Research Team

Deborah Siegal, MD

Principal Investigator

Ottawa Hospital Research Institute

Eligibility Criteria

This trial is for adults over 18 who were hospitalized with major non-variceal GI bleeding while on blood thinners, have stopped the thinner due to the bleed and haven't restarted it yet. They must need long-term anticoagulation for conditions like atrial fibrillation or VTE and be at risk of re-bleeding. Excluded are those with very low platelets, severe kidney issues, GI cancer history, surgical management of their bleed, short life expectancy from other causes, mechanical heart valve or certain types of VTE.

Inclusion Criteria

I stopped my blood thinner due to a recent stomach bleed and haven't restarted it.

I plan to restart my blood thinner medication after a bleeding event.

I am hospitalized due to severe GI bleeding while on blood thinners.

Exclusion Criteria

I had surgery to stop GI bleeding.

My kidney function is low (Creatinine Clearance <30 mL/min).

I have or had gastrointestinal cancer.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants resume direct oral anticoagulants (DOACs) after major GI bleeding based on thrombotic risk

1-2 weeks

1 visit (in-person) for clinical hemostasis assessment

Follow-up

Participants are monitored for safety and effectiveness, including quality of life and functional status assessments

90 days

Multiple visits (in-person and virtual) for assessments

Registry

Parallel registry to assess differences between enrolled and non-enrolled patients and explore barriers to enrollment

18 months

Treatment Details

Interventions

• DOAC

Trial Overview The PANTHER-GI Pilot Study is testing when to safely restart blood thinners (DOACs) after a major gastrointestinal bleed—either within 7 days or between 7 to 14 days after stopping the bleeding. It aims to find out if this can prevent further bleeding and clotting in patients at moderate to high risk.

Participant Groups

Group I: Moderate thrombotic risk Experimental Treatment 1 Intervention

For patients at moderate thrombotic risk, DOACs will be resumed between 7 and 14 days of clinical hemostasis after GI bleeding.

Group II: High thrombotic risk Experimental Treatment 1 Intervention

For patients at high thrombotic risk, DOACs will be resumed within 7 days of clinical hemostasis after GI bleeding.

DOAC is already approved in European Union, United States, Canada, Japan, China, Switzerland for the following indications:

Approved in European Union as DOACs for:

• Atrial fibrillation
• Deep vein thrombosis
• Pulmonary embolism
• Venous thromboembolism

Approved in United States as DOACs for:

• Atrial fibrillation
• Deep vein thrombosis
• Pulmonary embolism
• Venous thromboembolism
• Stroke prevention

Approved in Canada as DOACs for:

• Atrial fibrillation
• Deep vein thrombosis
• Pulmonary embolism
• Venous thromboembolism

Approved in Japan as DOACs for:

• Atrial fibrillation
• Deep vein thrombosis
• Pulmonary embolism
• Venous thromboembolism

Approved in China as DOACs for:

• Atrial fibrillation
• Deep vein thrombosis
• Pulmonary embolism
• Venous thromboembolism

Approved in Switzerland as DOACs for:

• Atrial fibrillation
• Deep vein thrombosis
• Pulmonary embolism
• Venous thromboembolism

Who Is Running the Clinical Trial?

Ottawa Hospital Research Institute

Lead Sponsor

Trials

585

Recruited

3,283,000+

Findings from Research

Direct oral anticoagulants (DOACs) do not significantly increase the risk of major gastrointestinal bleeding compared to vitamin K antagonists (VKAs), based on a review of various studies including randomized controlled trials and large cohort studies.

Gastrointestinal bleeding in patients taking DOACs tends to be less severe and requires less intensive management, with common causes identified as gastroduodenal ulcers for upper bleeding and diverticula for lower bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Review Article: Gastrointestinal Bleeding Risk with Direct Oral Anticoagulants. Benamouzig, R., Guenoun, M., Deutsch, D., et al.[2022]

In a study of 6793 older adults who experienced bleeding while on oral anticoagulants (OACs), resuming OACs was linked to a significant reduction in rates of thrombosis (by 40%) and mortality (by 46%).

However, resuming OACs also led to a higher risk of rebleeding (88% increase), highlighting the need for careful consideration when deciding to restart anticoagulant therapy after a bleeding event.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rates of rebleeding, thrombosis and mortality associated with resumption of anticoagulant therapy after anticoagulant-related bleeding. Little, DHW., Sutradhar, R., Cerasuolo, JO., et al.[2021]

In a study of 61 patients on direct-acting oral anticoagulants (DOACs) and 123 patients on warfarin, those on DOACs experienced fewer hospitalizations and required fewer blood transfusions for gastrointestinal bleeding, suggesting that their bleeding episodes may be less severe despite a higher frequency of bleeding reported in previous studies.

The study found no significant differences in mortality rates among patients taking DOACs, warfarin, or those not on anticoagulation, indicating that while DOACs are associated with gastrointestinal bleeding, the outcomes may be less severe compared to warfarin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severity of Gastrointestinal Bleeding in Patients Treated with Direct-Acting Oral Anticoagulants. Brodie, MM., Newman, JC., Smith, T., et al.[2022]

Restarting direct oral anticoagulants (DOACs) after gastrointestinal bleeding (GIB) does not significantly increase the risk of rebleeding, based on a meta-analysis of four studies involving 1722 patients.

Despite these findings, the overall quality of evidence is low, indicating a serious risk of bias, and highlights the need for more high-quality randomized clinical trials to confirm these results.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

No Association between Gastrointestinal Rebleeding and DOAC Therapy Resumption: A Systematic Review and Meta-Analysis. Pálinkás, D., Teutsch, B., Gagyi, EB., et al.[2023]

In a meta-analysis of 18 studies with 41,447 participants, direct oral anticoagulants (DOACs) were found to significantly reduce the incidence of all bleeding events, major bleeding, and all-cause death in patients with liver disease compared to warfarin or low molecular weight heparin (LMWH).

Specifically, DOACs reduced the risk of gastrointestinal bleeding and intracranial hemorrhage, particularly in patients with mild to moderate cirrhosis, indicating a safer profile for anticoagulation in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of direct oral anticoagulants in patients with liver disease: a systematic review and meta-analysis. Zhao, Y., Zhu, L., Yang, Y., et al.[2023]

In a study of 26 patients experiencing bleeding from direct oral anticoagulants (DOACs) like dabigatran and rivaroxaban, 42% had intracranial bleeds and 50% had gastrointestinal bleeds, highlighting the serious risks associated with these medications.

The management of DOAC-related bleeding was inconsistent across cases, leading to complications such as five thromboembolic events and six deaths, indicating a need for standardized treatment protocols and clinical trial data for effective reversal strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bleeding complications from the direct oral anticoagulants. Sholzberg, M., Pavenski, K., Shehata, N., et al.[2020]

A new ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for accurately quantifying direct oral anticoagulants (DOACs) like dabigatran, rivaroxaban, and apixaban, showing high precision and stability.

Different coagulation assays were evaluated for their effectiveness in measuring DOAC levels, with the LD diluted thrombin time test being the most accurate for dabigatran, while anti-factor Xa assays were superior for rivaroxaban and apixaban, highlighting the importance of using a reference method for accurate quantification.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants. Schmitz, EM., Boonen, K., van den Heuvel, DJ., et al.[2023]

A study analyzing 521 adverse drug reaction reports found that direct oral anticoagulants (DOACs) were associated with a higher incidence of gastrointestinal disorders, particularly gastrointestinal bleeding, compared to vitamin K antagonists (VKAs).

Dabigatran etexilate was the most frequently reported DOAC linked to gastrointestinal issues, emphasizing the need for careful prescribing and monitoring for potential drug interactions, especially with antithrombotic agents and proton-pump inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse drug reactions with oral anticoagulants: data from sicilian spontaneous reporting system database. Barbieri, MA., Cutroneo, PM., Baratelli, C., et al.[2021]

A meta-analysis of 37 randomized control trials found that apixaban has the lowest risk of major gastrointestinal (GI) bleeding among standard-dose direct oral anticoagulants (DOACs).

The study also revealed that a low dose of edoxaban (30 mg daily) has a lower risk of major GI bleeding compared to rivaroxaban (10 mg daily), indicating that different DOACs have varying safety profiles regarding GI bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative differences in the risk of major gastrointestinal bleeding among different direct oral anticoagulants: An updated traditional and Bayesian network meta-analysis. Chen, X., Wang, L., Li, H., et al.[2023]

Direct oral anticoagulants (DOACs) like dabigatran, rivaroxaban, apixaban, and edoxaban offer rapid action and do not require routine monitoring, but they may increase the risk of gastrointestinal bleeding compared to traditional vitamin K antagonists (VKAs).

Management of bleeding in patients on DOACs involves assessing renal function and the timing of the last dose, with specific reversal agents like idarucizumab and andexanet available for severe cases, highlighting the need for a multidisciplinary approach in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct oral anticoagulants and digestive bleeding: therapeutic management and preventive measures. Deutsch, D., Boustière, C., Ferrari, E., et al.[2022]

Direct oral anticoagulants (DOACs) are increasingly popular for anticoagulation but carry a higher risk of gastrointestinal bleeding (GIB) compared to warfarin, necessitating careful management by healthcare providers.

The review emphasizes the importance of understanding high-risk patient groups for DOAC-related GIB and outlines strategies for managing bleeding, including the use of reversal agents and careful periendoscopic management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gastrointestinal bleeding secondary to the new anticoagulants. Abraham, NS., Horsley-Silva, JL.[2018]

References

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

Review Article: Gastrointestinal Bleeding Risk with Direct Oral Anticoagulants. [2022]

2. Canada pubmed.ncbi.nlm.nih.gov

Rates of rebleeding, thrombosis and mortality associated with resumption of anticoagulant therapy after anticoagulant-related bleeding. [2021]

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

Severity of Gastrointestinal Bleeding in Patients Treated with Direct-Acting Oral Anticoagulants. [2022]

4. Switzerland pubmed.ncbi.nlm.nih.gov

No Association between Gastrointestinal Rebleeding and DOAC Therapy Resumption: A Systematic Review and Meta-Analysis. [2023]

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

Safety of direct oral anticoagulants in patients with liver disease: a systematic review and meta-analysis. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Bleeding complications from the direct oral anticoagulants. [2020]

7. England pubmed.ncbi.nlm.nih.gov

Determination of dabigatran, rivaroxaban and apixaban by ultra-performance liquid chromatography - tandem mass spectrometry (UPLC-MS/MS) and coagulation assays for therapy monitoring of novel direct oral anticoagulants. [2023]

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

Adverse drug reactions with oral anticoagulants: data from sicilian spontaneous reporting system database. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Comparative differences in the risk of major gastrointestinal bleeding among different direct oral anticoagulants: An updated traditional and Bayesian network meta-analysis. [2023]

10. England pubmed.ncbi.nlm.nih.gov

Direct oral anticoagulants and digestive bleeding: therapeutic management and preventive measures. [2022]

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

Gastrointestinal bleeding secondary to the new anticoagulants. [2018]