Antiplatelet Therapy for Cardiac Vasculopathy Post-Heart Transplant

Recruiting at 2 trial locations

Overseen By Heather Ross

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Ottawa Heart Institute Research Corporation

Must not be taking: Anticoagulants

Disqualifiers: Bleeding disorder, Low platelet count, others

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

Compensation: Varies

Number of Visits: 2

Duration: 3 years

135 Participants Needed

Trial Summary

What is the purpose of this trial?

Cardiac allograft vasculopathy is a common complication affecting heart transplant patients. This condition causes narrowing of the heart arteries leading to graft dysfunction. The research team is investigating whether early antiplatelet therapy post heart transplant can prevent the development of CAV. This study will determine the feasibility of a large multicenter randomized placebo-controlled trial to answer this question.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on antiplatelet therapy for non-cardiac reasons, you may not be eligible to participate.

What data supports the effectiveness of this drug for cardiac vasculopathy after a heart transplant?

Research suggests that early use of aspirin (ASA) after a heart transplant is linked to lower rates of cardiac allograft vasculopathy (CAV), a condition affecting the heart's blood vessels. However, the effectiveness of aspirin and other antiplatelet drugs like clopidogrel in preventing CAV progression is still not fully understood, as some studies show mixed results. ^{1 2 3 4 5}

Is antiplatelet therapy with aspirin and clopidogrel safe for humans?

Aspirin and clopidogrel are commonly used antiplatelet medications and are generally considered safe for humans, but they can cause side effects like bleeding, especially when used together. They are widely used in heart-related treatments and have a good safety profile, though monitoring for bleeding is important. ^{2 6 7 8 9}

How is the drug combination of Aspirin and Clopidogrel unique for treating cardiac vasculopathy after a heart transplant?

This drug combination is unique because it targets platelet aggregation (clumping together of blood cells) which is a key factor in cardiac allograft vasculopathy (CAV) progression. While aspirin is commonly used, its effectiveness can vary, and combining it with clopidogrel may offer a more comprehensive approach to reducing platelet activity and potentially slowing CAV progression. ^{1 3 4 5 10}

Research Team

Sharon Chih

Principal Investigator

Ottawa Heart Institute Research Corporation

Eligibility Criteria

The AERIAL Trial is for adults who've had a heart transplant and can give informed consent. It's not for those with allergies to aspirin or clopidogrel, recent intracranial hemorrhage, bleeding disorders, very low platelet counts, past aspirin-related stomach issues, need for antiplatelets due to other conditions, allergy to iodine contrast agents, or poor kidney function preventing coronary angiography.

Inclusion Criteria

I am 18 years old or older.

I have had a heart transplant.

Able to provide informed consent

Exclusion Criteria

I have a bleeding disorder.

I cannot have a heart artery test due to low kidney function and I'm not on dialysis.

I have been on blood thinners for more than 3 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Evaluation

Baseline clinical evaluation and data collection for heart transplant patients

1 week

Treatment

Participants are randomized to receive either placebo, aspirin, or clopidogrel daily

3 years

Visits at 2 months, 1 year, and 2 years post-transplant for invasive coronary studies and platelet function testing

Follow-up

Participants are monitored for safety and effectiveness after treatment, including angiography at 24 months and according to institutional protocol

3 years

Treatment Details

Interventions

• Aspirin
• Clopidogrel
• Placebo

Trial Overview This trial tests if early use of antiplatelet drugs like aspirin or clopidogrel can prevent artery narrowing after heart transplants compared to a placebo. The goal is to see if this approach could work in a larger study across multiple centers.

Participant Groups

Group I: aspirin Active Control 1 Intervention

Group II: clopidogrel Active Control 1 Intervention

Group III: placebo Placebo Group 1 Intervention

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?

Ottawa Heart Institute Research Corporation

Lead Sponsor

Trials

200

Recruited

95,800+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Findings from Research

In a study of 120 heart transplant patients, early use of aspirin (ASA) for more than 6 months was linked to significantly lower rates of moderate to severe cardiac allograft vasculopathy (CAV) in patients who experienced acute cellular rejection or antibody-mediated rejection.

However, ASA use did not show a protective effect against CAV in patients without any rejection episodes, suggesting that its benefits may be most pronounced in those facing rejection after transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early aspirin use, allograft rejection, and cardiac allograft vasculopathy in heart transplantation. Bergmark, BA., Zelniker, TA., Kim, M., et al.[2022]

In a study of 197 patients undergoing coronary artery bypass grafting (CABG), both clopidogrel alone and the combination of clopidogrel with aspirin maintained high graft patency rates at 1 and 12 months post-surgery.

There were no significant differences in graft patency between the two treatment groups, indicating that either antiplatelet therapy is effective for preventing graft failure after CABG.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clopidogrel and aspirin versus clopidogrel alone on graft patency after coronary artery bypass grafting. Gao, C., Ren, C., Li, D., et al.[2022]

Heart transplant patients with cardiac allograft vasculopathy (CAV) showed significantly higher platelet aggregation compared to both healthy controls and heart transplant patients without CAV, indicating a potential risk factor for complications.

Low-dose aspirin treatment reduced platelet aggregation in heart transplant patients, but those with CAV still exhibited higher levels of aggregation on aspirin compared to those without CAV, suggesting that aspirin alone may not be sufficient for effective platelet inhibition in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Platelet aggregation and response to aspirin therapy in cardiac allograft vasculopathy. Bjerre, KP., Clemmensen, TS., Berg, K., et al.[2021]

Heart transplant recipients showed significantly increased platelet hyperaggregation compared to healthy individuals and nontransplant coronary patients, indicating a heightened risk for blood clotting issues.

Platelets from heart transplant recipients were resistant to the effects of aspirin, the main antiplatelet medication, which may contribute to the higher incidence of myocardial infarction in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Increased platelet aggregation after heart transplantation: influence of aspirin. de Lorgeril, M., Dureau, G., Boissonnat, P., et al.[2013]

In a study of 529 heart transplant recipients, early use of aspirin (ASA) within the first year significantly reduced the progression of cardiac allograft vasculopathy (CAV), as indicated by lower plaque volume and plaque index.

Patients who started ASA early also experienced lower all-cause mortality and no cardiac deaths, suggesting that early ASA treatment may improve survival and reduce the risk of graft dysfunction after heart transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Association of Aspirin Treatment With Cardiac Allograft Vasculopathy Progression and Adverse Outcomes After Heart Transplantation. Asleh, R., Briasoulis, A., Smith, B., et al.[2021]

Clopidogrel, when used alongside aspirin, is effective and safe as an antiplatelet agent in patients undergoing coronary stenting, including those with transplanted hearts.

In a reported case, direct coronary stenting in a transplanted heart was successful, with preserved vessel patency and no signs of restenosis observed during a 4-month follow-up angiography.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clopidogrel as an antiplatelet agent in transplant heart coronary stenting. Mahadevan, VS., Khan, MM., Adgey, JA.[2019]

In a study of 321 patients with HeartMate 3 LVADs, both usual-dose (325 mg) and low-dose (81 mg) aspirin showed similar rates of survival free from hemocompatibility-related adverse events (HRAEs) after 2 years, indicating that lower doses may be just as effective.

There were no significant differences in rates of bleeding or thrombotic events between the usual-dose and low-dose groups, suggesting that the optimal aspirin dose for patients with HM3 LVADs may not need to be high.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of aspirin dose on hemocompatibility-related outcomes with a magnetically levitated left ventricular assist device: An analysis from the MOMENTUM 3 study. Saeed, O., Colombo, PC., Mehra, MR., et al.[2021]

In a study of 3436 patients admitted for lower gastrointestinal bleeding (LGIB), it was found that while dual antiplatelet therapy (aspirin and clopidogrel) and other anticoagulants were common, they did not significantly increase the risk of severe LGIB requiring major interventions.

Among the 511 patients with confirmed LGIB, only 61 were on dual or multiple antithrombotic therapies, indicating that while these therapies may raise overall bleeding risk, they do not lead to more severe bleeding events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dual Antiplatelet Therapy and the Severity Risk of Lower Intestinal Bleeding. Carlin, N., Asslo, F., Sison, R., et al.[2020]

Aspirin remains the preferred antiplatelet agent for most patients with atherothrombotic disease due to its established efficacy, safety, and cost-effectiveness in preventing recurrent vascular events.

Clopidogrel can be beneficial for patients with peripheral arterial disease or those who cannot tolerate aspirin, providing an alternative treatment option when aspirin is ineffective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic benefit. Aspirin revisited in light of the introduction of clopidogrel. Gorelick, PB., Born, GV., D'Agostino, RB., et al.[2022]

Triple antithrombotic therapy, which includes acetylsalicylic acid, clopidogrel, and warfarin, is commonly used after coronary stent implantation to lower the risk of thrombosis, but it significantly increases the risk of bleeding complications.

To minimize bleeding risks while maintaining efficacy, strategies such as careful monitoring of INR, limiting the duration of triple therapy, and using radial access with bare metal stents are recommended.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Warfarin combined with blood platelet inhibition]. Vik-Mo, H.[2013]

References

1. Denmark pubmed.ncbi.nlm.nih.gov

Early aspirin use, allograft rejection, and cardiac allograft vasculopathy in heart transplantation. [2022]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Clopidogrel and aspirin versus clopidogrel alone on graft patency after coronary artery bypass grafting. [2022]

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

Platelet aggregation and response to aspirin therapy in cardiac allograft vasculopathy. [2021]

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

Increased platelet aggregation after heart transplantation: influence of aspirin. [2013]

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

Association of Aspirin Treatment With Cardiac Allograft Vasculopathy Progression and Adverse Outcomes After Heart Transplantation. [2021]

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

Clopidogrel as an antiplatelet agent in transplant heart coronary stenting. [2019]

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

Effect of aspirin dose on hemocompatibility-related outcomes with a magnetically levitated left ventricular assist device: An analysis from the MOMENTUM 3 study. [2021]

8. India pubmed.ncbi.nlm.nih.gov

Dual Antiplatelet Therapy and the Severity Risk of Lower Intestinal Bleeding. [2020]

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

Therapeutic benefit. Aspirin revisited in light of the introduction of clopidogrel. [2022]

10. Norway pubmed.ncbi.nlm.nih.gov

[Warfarin combined with blood platelet inhibition]. [2013]