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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the optimal timing for restarting blood thinners known as DOACs (direct oral anticoagulants) after a serious stomach or intestinal bleed. It aims to determine if a structured plan for resuming these medications is safe for individuals who need them to prevent blood clots. The trial includes two groups: one for those at high risk of clotting and another for those at moderate risk. Suitable candidates for this trial have experienced a major GI bleed while on blood thinners and still require long-term treatment for conditions like atrial fibrillation (an irregular heartbeat) or a history of blood clots. As an unphased trial, this study provides a unique opportunity to contribute to important research that could enhance safety guidelines for restarting blood thinners.

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.

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

Research has shown that direct oral anticoagulants (DOACs), a type of blood thinner, can increase the risk of bleeding in the stomach and intestines. One study found that during the first year of taking DOACs, 9 to 13 cases of this type of bleeding occurred for every 100 people. Despite this risk, DOACs are considered safer and more effective than other blood thinners, such as Vitamin K antagonists (VKAs), for preventing strokes and bleeding in people with certain heart conditions.

Since DOACs are already used for other health issues, some knowledge about their safety exists. However, more safety information is needed when restarting DOACs after a stomach or intestinal bleed. This need makes studies like the one under consideration important. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it's exploring the optimal timing for restarting DOACs, or direct oral anticoagulants, after a gastrointestinal bleed. Unlike the standard practice, which often lacks precise guidelines on when to safely resume these medications, this study aims to provide clearer directions based on thrombotic risk levels. By tailoring the restart timing to either within 7 days for high-risk patients or between 7 and 14 days for moderate-risk patients, the trial seeks to balance the need to prevent blood clots while minimizing the risk of further bleeding. This could lead to more personalized and safer management strategies for patients who have experienced gastrointestinal bleeding.

What evidence suggests that this trial's treatments could be effective for resuming DOACs after GI bleeding?

This trial will compare different timings for restarting direct oral anticoagulants (DOACs) after gastrointestinal bleeding. Research has shown that resuming DOACs after bleeding in the stomach or intestines does not greatly increase the risk of rebleeding. One study found that patients who resumed DOACs within 7 to 40 days did not experience higher rebleeding rates compared to those who waited longer. Another study found that restarting DOACs soon, even after serious bleeding, was associated with a lower risk of stroke. However, major bleeding related to DOACs can still lead to a high risk of death within 30 days. These findings suggest that while restarting DOACs carries risks, it may reduce the chance of stroke for those at risk of blood clots. In this trial, participants at high thrombotic risk will resume DOACs within 7 days of clinical hemostasis, while those at moderate thrombotic risk will resume between 7 and 14 days. ^{6 7 8 9 10}

Who Is on the Research Team?

Deborah Siegal, MD

Principal Investigator

Ottawa Hospital Research Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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) 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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10329066/

Management of Gastrointestinal Bleeding and Resumption ... The aim of this review is to provide a multidisciplinary critical discussion of the optimal management of GI bleeding in patients with AF receiving oral ...

2. accpjournals.onlinelibrary.wiley.com accpjournals.onlinelibrary.wiley.com/doi/10.1002/phar.70055

Restarting Oral Anticoagulation in Patients With Atrial ... Overall, 4,389 patients resumed oral anticoagulation, with 3016 (68.7%) on warfarin and 1373 (31.3%) on DOACs, within 90 days of hospital ...

3. academic.oup.com academic.oup.com/pmj/advance-article/doi/10.1093/postmj/qgaf090/8196324

Risk of gastrointestinal rebleeding in direct oral anticoagulant ... Timing of DOAC resumption varied between 7 and 40 days from index bleeding. There were no statistically significant rates of rebleeding between ...

4. heart.bmj.com heart.bmj.com/content/early/2025/07/16/heartjnl-2024-325343

Timing of anticoagulation restart after serious bleeding in ... In a nationwide cohort, early DOAC restart (within 60 days) after serious bleeding was associated with a lower stroke risk, but the CI included the possibility ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0049384825001021

All-cause mortality after major gastrointestinal bleeding ... DOAC-related major GI bleeding appears to be associated with significant 30-day all-cause mortality. Further research is needed regarding the causes and ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/28043907/

Gastrointestinal Safety of Direct Oral Anticoagulants Direct oral anticoagulant (DOAC) agents increase the risk of gastrointestinal (GI) bleeding. We investigated which DOAC had the most favorable GI safety ...

7. gastrojournal.org gastrojournal.org/article/S0016-5085(16)35532-9/fulltext

Gastrointestinal Safety of Direct Oral Anticoagulants Direct oral anticoagulant (DOAC) agents increase the risk of gastrointestinal (GI) bleeding. We investigated which DOAC had the most favorable GI safety ...

8. sciencedirect.com sciencedirect.com/science/article/pii/S0049384823002906

Gastrointestinal bleeding with direct oral anticoagulants in ... Event rates of GI-bleeding in first year of DOAC therapy in anaemic AF-patients ranged between 9-13 per 100 patient years. •. In anaemic AF-patients, ...

9. journals.plos.org journals.plos.org/plosone/article?id=10.1371/journal.pone.0310322

Comparative safety and effectiveness of oral anticoagulants in ... DOACs had improved safety and effectiveness from bleeding and stroke/SE, respectively, versus VKAs among patients with NVAF at high risk for GIB.

10. frontiersin.org frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.1049283/full

Comparative differences in the risk of major gastrointestinal ... This meta-analysis includes the latest studies and aims to compare GI bleeding risk associated with the use of various DOACs.