Optimal Heart Failure Therapy for Heart Failure

(COPILOT-HF Trial)

Overseen By Alexander Blood, MD, MSc

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Brigham and Women's Hospital

Must be taking: ARNi, SGLT2i

Must not be taking: Pulmonary hypertension therapies

Disqualifiers: Low blood pressure, Aortic stenosis, Amyloid heart disease, 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to find the best way to manage heart failure through remote care. It compares two strategies: one begins with immediate medication and education, while the other starts with education and adds medication management after three months. The treatments being tested include medications like ARNI (a combination of Sacubitril and Valsartan), beta blockers, and SGLT2 inhibitors, which help control heart failure symptoms. People diagnosed with heart failure who have seen a Mass General Brigham doctor in the last two years might be a good fit. This trial is especially relevant for those seeking to manage heart failure from home with medical guidance. As a Phase 4 trial, the treatment is already FDA-approved and proven effective, aiming to understand how it benefits more patients.

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, it seems to focus on optimizing heart failure treatments, so it's possible that adjustments to your medications might be part of the study.

What is the safety track record for these treatments?

Research shows that the treatments tested in this trial are generally safe for people with heart failure. Here's a breakdown:

1. **ARNI (sacubitril/valsartan)**: Studies have found this medication to be safe and well-tolerated in people with heart failure. It lowers the risk of death and hospital visits without causing major side effects.

2. **Beta Blockers**: Commonly used for heart problems, these are FDA-approved for heart failure. They might cause side effects like tiredness and dizziness but are generally safe.

3. **MRA (mineralocorticoid receptor antagonists)**: Used for heart failure for a long time, these drugs help reduce hospital visits and the risk of death. Some side effects can occur, but the benefits usually outweigh the risks.

4. **MTD (methadone)**: Although not typically used for heart failure, methadone is included here. It can cause heart-related side effects, so careful monitoring is important.

5. **SGLT2i (sodium-glucose transport 2 inhibitors)**: These drugs have shown benefits for heart failure patients, reducing the risk of hospitalization and heart problems, with a good safety record.

Overall, these treatments have a history of being safe and effective for heart failure, but each has its own side effects to watch for. Discuss any concerns with a healthcare provider. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about this trial because it explores a new approach to managing heart failure by integrating a remote, pharmacist-driven heart failure clinic. Unlike standard treatments that often rely on in-person visits and separate medication adjustments, this trial emphasizes a streamlined, remote monitoring system that uses a standardized medical algorithm to guide medication management. This could lead to more personalized and timely adjustments in treatment, potentially improving patient outcomes and convenience. Additionally, the trial examines the impact of starting with comprehensive patient and provider education, aiming to enhance understanding and engagement in heart failure management.

What evidence suggests that this trial's treatments could be effective for heart failure?

This trial will compare different treatment strategies for heart failure. Studies have shown that each treatment in this trial can benefit people with heart failure. Sacubitril/valsartan, a type of medication, reduces the risk of death from heart problems or hospitalization by about 20% compared to enalapril. Beta blockers lower the risk of hospital visits and death due to heart failure. MRAs (mineralocorticoid receptor antagonists) also reduce the risk of death from heart issues and hospital visits for heart failure. Medication-assisted treatments (MTD) can decrease hospital stays for those with both heart failure and opioid use disorder. SGLT2 inhibitors lower the risk of heart failure events and deaths related to heart problems. Each treatment has shown promise in improving outcomes for heart failure patients. Participants in this trial will be assigned to either a "Medication & Education-First" arm or an "Education-First" arm to evaluate the effectiveness of these approaches. ^{2 6 7 8 9}

Are You a Good Fit for This Trial?

This trial is for heart failure patients who have seen a Mass General Brigham provider in the last 2 years, with an EF assessment in the past 24 months, and speak English or Spanish. It's not for those with severe blood pressure issues, certain heart diseases like amyloidosis or pulmonary hypertension, very low kidney function, active chemotherapy treatment, end-of-life care recipients, transplant-related cases or those on specific heart support treatments.

Inclusion Criteria

Your heart function was checked in the last 24 months.

I have been diagnosed with heart failure.

Seen Mass General Brigham provider within the last 24 months

Exclusion Criteria

My kidney function is severely reduced.

You are receiving care for a terminal illness or are in hospice.

I have a severe narrowing or leakage of the aortic valve in my heart.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Education

Participants receive curated patient education and provider education, followed by an alert to providers

3 months

Remote education sessions

Remote Clinic Management

Participants begin participation in a remote, pharmacist-driven heart failure clinic for medication initiation and titration

3 months

Remote clinic visits

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 months

What Are the Treatments Tested in This Trial?

Interventions

• ARNI
• beta blocker
• Education-First
• MRA
• MTD
• SGLT2i

Trial Overview The COPILOT-HF trial tests two remote care strategies to optimize prescriptions of guideline-directed medical therapies (like SGLT2i inhibitors and ARNI) for heart failure patients. The study randomly assigns participants to different treatment approaches and monitors them remotely within the healthcare system.

How Is the Trial Designed?

Group I: Medication & Education-First Experimental Treatment 1 Intervention

Patient will immediately begin participation in a remote, pharmacist-driven heart failure clinic that will initiate and titrate medications according to a standardized medical algorithm.

Group II: Education-First Active Control 2 Interventions

Patient will first receive curated patient education, an alert to providers, and provider education, and then after 3 months begin participation in the remote heart failure clinic.

ARNI is already approved in United States, European Union for the following indications:

Approved in United States as Entresto for:

• Chronic heart failure with reduced ejection fraction (HFrEF) in NYHA class II, III, or IV

Approved in European Union as Entresto for:

• Chronic heart failure with reduced ejection fraction (HFrEF)

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

Boehringer Ingelheim

Industry Sponsor

Trials

2,566

Recruited

16,150,000+

Eli Lilly and Company

Industry Sponsor

Trials

2,708

Recruited

3,720,000+

Dr. Daniel Skovronsky

Eli Lilly and Company

Chief Medical Officer since 2018

MD from Harvard Medical School

David A. Ricks

Eli Lilly and Company

Chief Executive Officer since 2017

BSc from Purdue University, MBA from Indiana University

Published Research Related to This Trial

Mineralocorticoid-receptor antagonists (MRAs) are now recommended for nearly all patients with heart failure with reduced ejection fraction (HFrEF), indicating their broadening application in treatment.

New treatments like spironolactone and LCZ696 show potential for heart failure with preserved ejection fraction (HFpEF), addressing a significant unmet need in this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting the renin-angiotensin-aldosterone system in heart failure. Lang, CC., Struthers, AD.[2021]

Sacubitril-valsartan significantly reduces the risk of all-cause and cardiovascular mortality in patients with heart failure with reduced ejection fraction (HFrEF), as shown in a meta-analysis of six trials involving 14,959 patients.

While sacubitril-valsartan is associated with a higher risk of symptomatic hypotension, it has a lower risk of worsening renal function and serious hyperkalaemia compared to traditional treatments like enalapril or valsartan.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of sacubitril-valsartan in heart failure: a meta-analysis of randomized controlled trials. Zhang, H., Huang, T., Shen, W., et al.[2022]

Mineralocorticoid receptor antagonists (MRA) have been shown to reduce heart failure hospitalizations in patients with preserved ejection fraction, with moderate-quality evidence indicating a risk ratio of 0.82, suggesting a beneficial effect.

Beta-blockers, angiotensin converting enzyme inhibitors (ACEI), and angiotensin receptor blockers (ARB) showed little to no effect on mortality or quality of life in heart failure with preserved ejection fraction, highlighting the uncertainty of their efficacy in this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction. Martin, N., Manoharan, K., Thomas, J., et al.[2023]

Sacubitril/valsartan (Entresto®) is the first angiotensin receptor neprilysin inhibitor (ARNI) approved for heart failure patients with reduced ejection fraction, combining a neprilysin inhibitor and an angiotensin II receptor blocker.

A case report highlighted a probable instance of ARNI-induced hyponatremia in an elderly woman, suggesting a likely association between the drug and her low sodium levels, as assessed by the Naranjo Adverse Drug Reaction Assessment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan (Entresto®)-Induced Hyponatremia. Fuzaylova, I., Lam, C., Talreja, O., et al.[2021]

Entresto (Sacubitril/Valsartan) is a newly FDA-approved treatment for Heart Failure with Reduced Ejection Fraction (HFrEF), offering a novel mechanism of action by combining angiotensin receptor blockage and neprilysin inhibition.

This drug represents a significant advancement in heart failure management, providing an alternative to traditional treatments like ACE inhibitors and ARBs, and highlights the ongoing evolution of therapies available for heart failure patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Entresto, a New Panacea for Heart Failure? Khalil, P., Kabbach, G., Said, S., et al.[2021]

The combination of valsartan-sacubitril (an ARNI) and empagliflozin (a gliflozin) showed rapid improvement in heart function and clinical markers in an elderly female patient with congestive heart failure and type 2 diabetes, suggesting a beneficial cardio-reno-metabolic approach.

The PARADIGM-HF study demonstrated that valsartan-sacubitril significantly reduces cardiovascular events and mortality in heart failure patients, highlighting its efficacy compared to traditional treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Modification of the of the cardiometabolic profile using combined therapy of the angiotensin receptor-neprilysin inhibitor and empagliflozin in comorbid patients with Chronic Heart Failure and type 2 Diabetes Mellitus]. Tsygankova, OV., Veretyuk, VV., Mareev, VY.[2020]

SGLT2 inhibitors (SGLT2i) showed a trend towards reducing the risk of cardiovascular death or heart failure hospitalization compared to sacubitril/valsartan and vericiguat, indicating their potential effectiveness in heart failure treatment.

SGLT2i demonstrated the greatest reduction in heart failure hospitalization rates compared to standard care and vericiguat, suggesting they may be the most effective therapy among the treatments analyzed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relative Efficacy of Sacubitril-Valsartan, Vericiguat, and SGLT2 Inhibitors in Heart Failure with Reduced Ejection Fraction: a Systematic Review and Network Meta-Analysis. Aimo, A., Pateras, K., Stamatelopoulos, K., et al.[2022]

Aldosterone receptor antagonists, such as spironolactone and eplerenone, are recommended for many heart failure patients to improve treatment outcomes when used alongside ACE inhibitors or ARBs and beta-blockers.

The combination of these medications can enhance heart function and reduce symptoms in heart failure patients, highlighting the importance of a multi-drug approach in managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Aldosterone receptor antagonists for heart failure: current status, future indications. Pitt, B., Rajagopalan, S.[2019]

In a study of 120 patients with heart failure and reduced ejection fraction (HFrEF) in Pakistan, Sacubitril/Valsartan was found to be safe and well-tolerated, with 80.6% of patients able to continue the prescribed dose over 12 weeks.

The treatment led to significant improvements in functional class, with 75% of patients improving to class I, although hyperkalemia (21.3% incidence) and hypotension (19.4% incidence) were noted as safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and tolerability of Sacubitril/Valsartan in heart failure patient with reduced ejection fraction. Khan, MN., Soomro, NA., Naseeb, K., et al.[2023]

A historical review of mortality trials shows that ACE inhibitors and angiotensin II receptor antagonists have been the standard treatment for chronic heart failure, demonstrating their efficacy in improving patient outcomes.

The new dual inhibitor valsartan + neprilysin (LCZ 696) shows promise as a future treatment option, while other approaches like direct renin blockers and dual blockers have proven ineffective.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Inhibition of renin-angiotensin-aldosterone system in heart failure, or from CONSENSUS to PARADIGM-HF]. Vítovec, J., Špinar, J., Špinarová, L.[2018]

Comprehensive therapy using a combination of ARNI, β blockers, MRAs, and SGLT2 inhibitors significantly reduces the risk of cardiovascular death and hospital admissions for heart failure compared to conventional therapy, with a hazard ratio of 0.38 for the primary endpoint.

Patients receiving comprehensive therapy can expect substantial gains in event-free survival, with estimates of 2.7 to 8.3 additional years free from cardiovascular events and 1.4 to 6.3 additional years of overall survival, depending on age.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Vaduganathan, M., Claggett, BL., Jhund, PS., et al.[2023]

Sacubitril/valsartan (Entresto) significantly reduces the risk of cardiovascular death and hospitalization for heart failure by 20% compared to the standard treatment enalapril, based on data from the PARADIGM-HF trial and other studies.

While sacubitril/valsartan is effective for patients with heart failure with reduced ejection fraction, it does carry a risk of hypotension and nonserious angioedema, necessitating careful monitoring by healthcare providers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A New Mechanism of Action in Heart Failure: Angiotensin-Receptor Neprilysin Inhibition. Richardson, J., David, T., Grace, Y., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10259398/

Efficacy and safety of sacubitril/valsartan in heart failure ... In comparison to enalapril, sacubitril/valsartan reduced the occurrence of the primary outcome (cardiovascular death or hospitalisation for HF) by 20% and ...

2. annfammed.org annfammed.org/content/23/Supplement_1/8199

Efficacy and safety of Sacubitril/Valsartan in the treatment ... Conclusions In patients with HFrHF, Sacubitril/Valsartan reduces all-cause mortality and hospitalisations and confers an improvement in quality ...

3. ahajournals.org ahajournals.org/doi/10.1161/JAHA.121.021459

Clinical Effectiveness of Sacubitril/Valsartan Among ... Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF).

4. mayoclinicproceedings.org mayoclinicproceedings.org/article/S0025-6196(23)00358-0/fulltext

Efficacy of Sacubitril-Valsartan on Survival and Cardiac ... Hypotensive/ARNi users had lower ARNi initiation doses than nonhypotensive/ARNi users. We observed significantly lower mortality, composite ...

5. entrestohcp.com entrestohcp.com/hfref/clinical-trial-biomarker-data

Clinical Trial and Biomarker Data PIONEER-HF: Starting early counts—in-hospital initiation of ENTRESTO reduced heart failure biomarkers and improved outcomes in stabilized patients7,8.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9773772/

Sacubitril/valsartan in heart failure: efficacy and safety in and ... The critical analysis of the worldwide safety data has revealed that the overall benefit–risk profile remains favourable and the benefit–risk balance of S/V ...

7. ahajournals.org ahajournals.org/doi/10.1161/JAHA.124.038249

Comprehensive Analysis of the Effects of Sacubitril ... Sacubitril/valsartan was safe and well‐tolerated in both women and men with heart failure with reduced ejection fraction. •. The change in ...

8. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/38030039/

The real-world safety of sacubitril / valsartan among older ... In this postmarking study, none of the prespecified adverse events was reported more frequently in older adults.

9. entrestohcp.com entrestohcp.com/hfref/hospitalization-and-initiation

Hospital Data | ENTRESTO® (sacubitril/valsartan) | HCP ENTRESTO reduced 15-day heart failure readmissions vs enalapril. ENTRESTO demonstrated fewer 15-day heart failure readmissions in a post hoc analysis.