Aspirin + Warfarin for Congestive Heart Failure

Overseen By Boaz Elad, MD

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Columbia University

Must be taking: Aspirin, VKA

Must not be taking: Antiplatelets

Disqualifiers: Pregnancy, Other clinical trials, 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

Compensation: Varies

Number of Visits: Unknown

Duration: 1 year

128 Participants Needed

Trial Summary

What is the purpose of this trial?

Heart failure is a world epidemic. LVADs are increasingly used as they have demonstrated improved survival rates compared to optimal medical management. Improving outcomes have been seen with the newer LVAD technology, the HeartMate 3 (Abbott, Chicago, IL), however, hemocompatibility related adverse events, including thrombosis and bleeding, are still a major cause of morbidity and mortality. The recent ARIES trial showed that in patients with advanced heart failure treated with a HeartMate3 LVAD, avoidance of aspirin as part of an antithrombotic regimen, which includes vitamin K antagonist (VKA), is not inferior to a regimen containing aspirin, does not increase thromboembolism risk, and is associated with a reduction in bleeding events. This clinical investigation is a prospective, randomized, controlled study of advanced heart failure patients supports with the HeartMate3 for more then 3 months with two different antithrombotic regimens: VKA with and without aspirin. The objective of this investigation is to study the safety and efficacy of an antithrombotic regimen without antiplatelet therapy.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it involves testing two different blood-thinning regimens, one with aspirin and one without. You should discuss your current medications with the trial team to see how they fit with the study requirements.

What data supports the effectiveness of the drug combination of aspirin and warfarin for congestive heart failure?

Research shows that combining aspirin and warfarin can reduce the risk of heart attacks and strokes more than aspirin alone, especially in patients with heart disease. However, this combination also increases the risk of bleeding, so it's important to weigh the benefits and risks. ^{1 2 3 4 5}

Is the combination of aspirin and warfarin generally safe for humans?

The combination of aspirin and warfarin can increase the risk of minor and major bleeding, but it does not increase the risk of bleeding in the brain. It may be beneficial for certain heart conditions if used carefully, but it should be monitored closely to manage bleeding risks. ^{2 5 6 7 8}

How does the drug combination of aspirin and warfarin differ from other treatments for congestive heart failure?

The combination of aspirin and warfarin for congestive heart failure is unique because it combines an antiplatelet agent (aspirin) and an anticoagulant (warfarin) to potentially reduce the risk of reinfarction and thromboembolic stroke more effectively than aspirin alone, although it may increase the risk of bleeding. ^{3 4 5 9 10}

Research Team

Nir Uriel, MD

Principal Investigator

Seymour, Paul, and Gloria Milstein Professor of Cardiology at Columbia University

Eligibility Criteria

This trial is for advanced heart failure patients who have been supported by the HeartMate3 device for over three months. It's not clear what specific exclusion criteria are, but typically, participants would need to be stable enough to follow the trial procedures and not have conditions that could interfere with the study or their safety.

Inclusion Criteria

Participant must provide written informed consent prior to any clinical investigation-related procedure

I have had a HeartMate3 LVAD implanted for over 3 months.

I am older than 18 years.

Exclusion Criteria

Participation in any other clinical investigation(s) involving an MCS device, or interventional investigation(s) likely to confound study results or affect study outcome

Presence of other anatomic or comorbid conditions, or other medical, social, or psychological conditions that, in the investigator's opinion, could limit the subject's ability to participate in the clinical investigation or to comply with follow-up requirements, or impact the scientific soundness of the clinical investigation results

I am not pregnant and am using birth control.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either Warfarin with or without Aspirin for the duration of the study

1 year

Follow-up

Participants are monitored for safety and effectiveness after treatment, including survival and hemocompatibility related adverse events

1 year

Extension

Participants may continue to be monitored for long-term outcomes and rehospitalizations

Long-term

Treatment Details

Interventions

• Aspirin
• Warfarin

Trial Overview The study is testing two blood-thinning strategies in heart failure patients using HeartMate3: one includes both warfarin (a vitamin K antagonist) and aspirin, while the other uses only warfarin. The goal is to see if dropping aspirin reduces bleeding without increasing clotting risks.

Participant Groups

Group I: Warfarin without Aspirin Experimental Treatment 1 Intervention

Participants will only take Warfarin.

Group II: Warfarin and Aspirin Active Control 2 Interventions

This is the control arm. Participants will take Warfarin and aspirin, which is the standard of care.

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

Approved in European Union as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in United States as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in Canada as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention
• Preeclampsia prevention

Approved in China as Aspirin for:

• Pain relief
• Fever reduction
• Inflammation
• Cardiovascular disease prevention

Who Is Running the Clinical Trial?

Columbia University

Lead Sponsor

Trials

1,529

Recruited

2,832,000+

Weill Medical College of Cornell University

Collaborator

Trials

1,103

Recruited

1,157,000+

Findings from Research

In a review of 4 randomized controlled trials involving 3663 patients, warfarin did not show a significant advantage over aspirin in preventing death or stroke in patients with heart failure and normal sinus rhythm.

While warfarin was associated with a lower risk of any stroke and ischemic stroke compared to aspirin, it also significantly increased the risk of major bleeding, suggesting that its use may not be justified in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk-benefit profile of warfarin versus aspirin in patients with heart failure and sinus rhythm: a meta-analysis. Lee, M., Saver, JL., Hong, KS., et al.[2022]

Combination antithrombotic therapy with aspirin plus warfarin significantly reduces the risk of death, reinfarction, and ischemic stroke by 29-45% in high-risk patients with atherosclerotic heart disease, provided that warfarin compliance is over 70% and the INR is maintained between 2.0-2.5.

While this combination therapy is effective, it does increase the risk of minor bleeding and slightly raises the risk of major bleeding, although it does not increase the risk of intracranial bleeding.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combination antithrombotic therapy with antiplatelet agents and anticoagulants for patients with atherosclerotic heart disease. Arjomand, H., Cohen, M., Ezekowitz, MD.[2013]

In a study of 42 patients with reduced left ventricular ejection fraction (LVEF) after an acute myocardial infarction, overall LVEF improved significantly from a median of 35% to 39% over three months (P<0.001).

The study found no significant differences in LVEF or biochemical markers between patients treated with low-dose aspirin and those treated with warfarin, indicating that low-dose aspirin does not negatively interact with angiotensin-converting enzyme inhibitors (ACE-I) in this context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin does not influence the effect of angiotensin-converting enzyme inhibition on left ventricular ejection fraction 3 months after acute myocardial infarction. Hurlen, M., Hole, T., Seljeflot, I., et al.[2019]

In the WARIS II study involving patients post-myocardial infarction, combining warfarin with aspirin reduced the risk of reinfarction and thromboembolic stroke by 29% compared to aspirin alone, while warfarin alone reduced the risk by 19%.

However, the use of warfarin, whether alone or in combination with aspirin, was associated with a higher incidence of major and minor bleeding events compared to aspirin alone, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Warfarin and aspirin give more benefit than aspirin alone but also more bleeding after myocardial infarction. Doggrell, SA.[2019]

Aspirin (ASA) use in patients with congestive heart failure (CHF) is associated with a significant reduction in all-cause mortality, based on a meta-analysis of 14 studies involving 64,550 patients.

While ASA did not significantly affect the frequency of hospitalization for heart failure, its benefits on mortality were enhanced in patients also taking nitrates and oral anticoagulants.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Survival Benefit of Aspirin in Patients With Congestive Heart Failure: A Meta-Analysis. Jiwani, S., Mustafa, U., Desai, S., et al.[2022]

In a study of 7352 heart failure patients, aspirin use did not increase the risk of death or heart failure readmission, even among those without coronary disease or with renal dysfunction.

Patients using ACE inhibitors had a lower risk of death or heart failure readmission, and aspirin did not interfere with the benefits of ACE inhibitors, suggesting that aspirin can be safely used in heart failure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aspirin use and outcomes in a community-based cohort of 7352 patients discharged after first hospitalization for heart failure. McAlister, FA., Ghali, WA., Gong, Y., et al.[2013]

Aspirin is widely used for secondary prevention of cardiovascular diseases in patients with a history of heart attacks or strokes, demonstrating strong efficacy in clinical trials.

The combination of aspirin with a proton pump inhibitor in the polypill PA32540 has shown promising safety and efficacy in Phase I and Phase III trials, potentially reducing the risk of gastrointestinal side effects associated with aspirin.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PA32540 for the secondary prevention of cardiovascular disease in patients at risk for aspirin-associated gastric ulcers. Duffy, D., Rooney, B., Adams, S., et al.[2021]

Combination therapy with warfarin and acetylsalicylic acid (ASA) may be beneficial for patients with prosthetic heart valves at high risk of thromboembolism, compared to using warfarin alone, based on a review of 16 studies.

However, this combination therapy is not recommended for patients with established ischemic heart disease or other conditions, as it increases the risk of bleeding, and the maximum safe dose of ASA with warfarin is 100 mg daily.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of combination warfarin and ASA therapy: a systematic review of the literature and update of guidelines. Loewen, P., Sunderji, R., Gin, K.[2018]

There is currently no prospective study that has evaluated the combined effects of ACE inhibitors and aspirin on clinical outcomes in patients with congestive heart failure (CHF), indicating a gap in research.

Most existing studies have only looked at short-term effects on hemodynamic parameters, so ongoing trials are needed to clarify the efficacy and safety of using both medications together in CHF patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined aspirin/ACE inhibitor treatment for CHF. Olson, KL.[2017]

The WATCH trial aimed to determine the best antithrombotic treatment for chronic heart failure patients, comparing warfarin to antiplatelet therapies (aspirin and clopidogrel) in a study of 1587 symptomatic heart failure patients with reduced ejection fractions.

Although the trial was cut short due to low enrollment, it is expected to provide valuable insights into the safety and efficacy of anticoagulation versus antiplatelet therapy in managing heart failure, particularly regarding the prevention of serious vascular events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Warfarin and Antiplatelet Therapy in Heart Failure trial (WATCH): rationale, design, and baseline patient characteristics. Massie, BM., Krol, WF., Ammon, SE., et al.[2019]

References

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

Risk-benefit profile of warfarin versus aspirin in patients with heart failure and sinus rhythm: a meta-analysis. [2022]

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

Combination antithrombotic therapy with antiplatelet agents and anticoagulants for patients with atherosclerotic heart disease. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Aspirin does not influence the effect of angiotensin-converting enzyme inhibition on left ventricular ejection fraction 3 months after acute myocardial infarction. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Warfarin and aspirin give more benefit than aspirin alone but also more bleeding after myocardial infarction. [2019]

5. Canada pubmed.ncbi.nlm.nih.gov

Survival Benefit of Aspirin in Patients With Congestive Heart Failure: A Meta-Analysis. [2022]

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

Aspirin use and outcomes in a community-based cohort of 7352 patients discharged after first hospitalization for heart failure. [2013]

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

PA32540 for the secondary prevention of cardiovascular disease in patients at risk for aspirin-associated gastric ulcers. [2021]

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

The efficacy and safety of combination warfarin and ASA therapy: a systematic review of the literature and update of guidelines. [2018]

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

Combined aspirin/ACE inhibitor treatment for CHF. [2017]

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

The Warfarin and Antiplatelet Therapy in Heart Failure trial (WATCH): rationale, design, and baseline patient characteristics. [2019]