Sacubitril-Valsartan for Hemodialysis Patients

Overseen By Finnian R Mc Causland, MBCCh, MMSc

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Brigham and Women's Hospital

Must not be taking: Sacubitril/valsartan, ACE inhibitors

Disqualifiers: Anuria, Angioedema, Hyperkalemia, ACS, others

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 16 weeks

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effects of sacubitril-valsartan on individuals who have recently begun hemodialysis, a treatment for kidney failure. Researchers aim to determine if the medication can help manage fluid levels, protect remaining kidney function, and ensure safety. Participants will receive either the actual medication or a placebo (a harmless pill with no active medicine) for comparison. This trial suits individuals who have started hemodialysis within the last 90 days and have stable blood pressure before dialysis sessions. As a Phase 2 trial, this research measures how well the treatment works in an initial, smaller group of people.

Will I have to stop taking my current medications?

The trial requires that you have not taken an ACE inhibitor for 36 hours before joining. If you are currently using sacubitril/valsartan, you must stop at least 30 days before participating. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

Is there any evidence suggesting that sacubitril-valsartan is likely to be safe for humans?

Research shows that sacubitril-valsartan is generally well-tolerated by patients. Earlier studies with people on hemodialysis noted some common side effects, such as high potassium levels and low blood pressure. However, these side effects were not severe enough to outweigh the treatment's potential benefits. Sacubitril-valsartan has also demonstrated positive effects, such as reducing hospital visits and lowering death rates in patients with heart failure and severe kidney disease.

While some risks exist, the available data suggest that sacubitril-valsartan is reasonably safe for people undergoing hemodialysis. Participants should discuss possible side effects with the trial team and closely monitor their health during the study. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Most treatments for patients on hemodialysis focus on managing symptoms and complications, like blood pressure, with medications such as ACE inhibitors or beta-blockers. However, sacubitril-valsartan offers a unique approach by combining two active ingredients that work together to enhance heart function. Sacubitril increases levels of beneficial peptides, while valsartan blocks harmful effects of angiotensin II. Researchers are excited because this dual-action could lead to better cardiovascular outcomes for hemodialysis patients, potentially improving their quality of life and reducing hospitalizations.

What evidence suggests that sacubitril-valsartan might be an effective treatment for hemodialysis patients?

Studies have shown that sacubitril-valsartan, which participants in this trial may receive, can reduce the risk of death and hospital visits for people with heart failure, especially when the heart doesn't pump well. This is particularly true for patients with severe kidney problems, who also experience improved heart function over time. Research indicates that even at low doses, this treatment can safely enhance heart health in patients undergoing hemodialysis, a process that cleans the blood when kidneys fail. Initial findings suggest it is well-tolerated, meaning most people can take it without major side effects. These results provide hope that sacubitril-valsartan could help manage fluid levels and protect kidney function in patients on hemodialysis. ^{2 4 6 7 8}

Who Is on the Research Team?

Finnian Mc Causland, MBBCh, MMSc

Principal Investigator

Brigham and Women's Hospital

Are You a Good Fit for This Trial?

Adults over 18 who recently started hemodialysis can join this trial. They must have stable blood pressure, not be on certain heart medications, and able to consent. Excluded are those with recent major heart issues, planned transplants, severe liver disease, untreated serious arrhythmias or cancer within the last year.

Inclusion Criteria

I am on a thrice-weekly hemodialysis schedule.

I am 18 or older and started hemodialysis within the last 90 days.

Informed consent

Exclusion Criteria

I am scheduled for a kidney transplant within the next 4 months.

Angioedema related to previous ACE inhibitor, ARB, or ARNI therapy

Serum potassium >5.5 mEq/L at screening (pre-HD if already on HD)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive sacubitril/valsartan or placebo, with dose titration over the first 4 weeks and maintenance for 12 weeks

16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Placebo
• Sacubitril-valsartan

Trial Overview The trial tests if sacubitril-valsartan is better than a placebo for managing fluid overload and preserving kidney function in new hemodialysis patients. It's randomized: participants won't choose which treatment they get.

How Is the Trial Designed?

Group I: sacubitril/valsartan Experimental Treatment 1 Intervention

Participants will take sacubitril/valsartan, beginning dose of 24/26mg twice daily, with titration to target dose of 97/103 mg twice daily over the first four weeks. Patients will remain on the maximally tolerated dose for the remaining 12 weeks (total on-drug period of 16 weeks) before stopping drug and being followed for a further two weeks (total study time of 18 weeks).

Group II: placebo Placebo Group 2 Interventions

Participants will take equivalent placebo, beginning equivalent dose of 24/26mg twice daily, with titration to target equivalent dose of 97/103 mg twice daily over the first four weeks. Patients will remain on the maximally tolerated dose for the remaining 12 weeks (total on-drug period of 16 weeks) before stopping drug/placebo and being followed for a further two weeks (total study time of 18 weeks).

Sacubitril-valsartan is already approved in European Union, United States for the following indications:

Approved in European Union as Entresto for:

• Heart failure with reduced ejection fraction

Approved in United States as Entresto for:

• Chronic heart failure with reduced ejection fraction

Who Is Running the Clinical Trial?

Brigham and Women's Hospital

Lead Sponsor

Trials

1,694

Recruited

14,790,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

This case report describes the first instance of severe liver injury associated with sacubitril/valsartan (Entresto) in a 90-year-old female patient, highlighting a potential risk of hepatotoxicity despite the drug's established safety profile.

After discontinuing sacubitril/valsartan, the patient's liver function improved, suggesting that while liver injury from this medication is rare, clinicians should remain vigilant for signs of hepatotoxicity during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan-induced liver injury: A case report and literature review. Zhang, T., Cai, JL., Yu, J.[2023]

In a study of 5 hemodialysis patients, including those with heart failure, switching to sacubitril/valsartan led to significant improvements in blood pressure post-dialysis and heart function over a 6-month period, with no reported side effects.

NT-pro-BNP levels decreased significantly, indicating improved heart function, and echocardiography showed a reduction in left atrial size and an increase in left ventricular ejection fraction, demonstrating the efficacy of sacubitril/valsartan in managing hypertension and heart failure in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Functional changes in the heart after sacubitril/valsartan use in 5 hemodialysis patients with hypertension. Case report. Kuwae, N.[2023]

In a study of 40 patients undergoing peritoneal dialysis with hypertension or heart failure, sacubitril/valsartan (SV) significantly reduced mean sitting systolic blood pressure by 19.25 mmHg and diastolic blood pressure by 10.10 mmHg, demonstrating its efficacy in managing hypertension in this population.

The pharmacokinetics of LBQ657, a metabolite of sacubitril, showed that peritoneal dialysis had a minor impact on its elimination, and a dosage of 100 mg twice daily was found to be safe and effective for patients with hypertension or heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of sacubitril/valsartan in peritoneal dialysis patients. He, Y., Jin, Y., Xue, H., et al.[2023]

In a study of 65 chronic heart failure patients with end-stage renal disease on dialysis, treatment with sacubitril-valsartan (LCZ696) significantly reduced the rehospitalization rate for heart failure compared to the control group (43.28% vs. 73.47%).

LCZ696 was found to be safe, showing no significant impact on serum creatinine and potassium levels, while also providing a longer median survival time free from rehospitalization (139.0 days vs. 116.0 days) over a 1-year follow-up.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of sacubitril-valsartan in the treatment of chronic heart failure patients with end-stage renal disease undergoing dialysis. Liu, X., Huang, L., Tse, G., et al.[2023]

In a study of 66 chronic kidney disease (CKD) patients with systolic dysfunction, treatment with sacubitril/valsartan led to a significant improvement in left ventricular ejection fraction (LVEF) from 31% to 39% over 6 months, indicating enhanced heart function.

The treatment was also associated with an initial improvement in renal function after one month, with glomerular filtration rate (GFR) increasing to 53 mL/min/1.73 m², and stability in kidney function was maintained throughout the follow-up period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan in chronic kidney disease, the nephrologist point of view. Quiroga, B., de Santos, A., Sapiencia, D., et al.[2021]

Sacubitril/valsartan (Entresto) significantly reduces the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction, outperforming enalapril in clinical studies.

While effective, sacubitril/valsartan can cause side effects such as low blood pressure, angioedema, and impaired kidney function, and it is contraindicated in pregnant or breastfeeding women and patients with severe liver impairment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Angiotensin-receptor- and neprilysin-inhibition: a new option against heart failure]. Bruhn, C.[2021]

In a study involving male Sprague-Dawley rats with chronic kidney disease, treatment with LCZ696 (sacubitril/valsartan) significantly improved cardiovascular health compared to valsartan alone, showing better outcomes in heart weight, kidney function, and markers of heart stress and inflammation.

LCZ696 was more effective than valsartan in reducing cardiac hypertrophy, fibrosis, and oxidative stress, indicating its potential as a superior treatment for cardiovascular issues associated with chronic kidney disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

LCZ696 (Sacubitril/Valsartan), an Angiotensin-Receptor Neprilysin Inhibitor, Attenuates Cardiac Hypertrophy, Fibrosis, and Vasculopathy in a Rat Model of Chronic Kidney Disease. Suematsu, Y., Jing, W., Nunes, A., 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]

In a case study of a 67-year-old man with severe heart failure and renal insufficiency undergoing hemodialysis, treatment with sacubitril/valsartan was found to be feasible and safe, even with low blood pressure.

The patient experienced symptomatic improvement and a significant reduction in NT-proBNP levels, indicating better heart function and decreased filling pressures after starting the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan in heart failure and end-stage renal insufficiency. Heyse, A., Manhaeghe, L., Mahieu, E., et al.[2021]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39163041/

Sacubitril-Valsartan in Patients Requiring Hemodialysis Importance: Randomized clinical trials have shown that sacubitril-valsartan reduces the risks of mortality and hospitalization in patients with ...

2. jamanetwork.com jamanetwork.com/journals/jamanetworkopen/fullarticle/2822448

Sacubitril-Valsartan in Patients Requiring Hemodialysis Sacubitril-valsartan reduces the risks of mortality and hospitalization in patients with heart failure with reduced ejection fraction (HFrEF).

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9276171/

Low dose sacubitril/valsartan is effective and safe in ... Low does ARNI treatment could effectively improve cardiac function in HD patients with heart failure and hypotension. It was also safe and well tolerated.

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04572724?term=NCT02554890%20NCT02754518%20NCT02787798%20NCT02874794%20NCT02887183%20NCT02900378%20NCT02970669%20NCT03005184%20NCT03066804%20NCT03119623%20NCT03168568%20NCT03300427%20NCT03552575%20NCT03785405%20NCT03988634%20NCT04103554%20NCT04128891%20NCT04572724%20NCT04688294%20NCT05164653%20NCT05194111%20NCT05243199%20NCT05487261%20NCT05881720&rank=7

The Effect of Sacubitril/Valsartan on Cardiovascular Events ... Sacubitril/Valsartan was reported the different effectiveness in HFrEF and HF with preserved ejection fraction (HFpEF), and the clinical trials' results are ...

5. ascpt.onlinelibrary.wiley.com ascpt.onlinelibrary.wiley.com/doi/10.1002/cpt.3315

Long‐Term Outcomes of Sacubitril/Valsartan in Heart Failure ... Sacubitril/valsartan treatment demonstrated significantly lower 5-year mortality rates and greater LVEF improvement in HFrEF patients with coexisting ESRD.

6. jacc.org jacc.org/doi/10.1016/j.jacc.2024.03.392

Effects of Sacubitril/Valsartan Across the Spectrum ... Patients in the highest KDIGO risk categories experienced the highest rates of the primary composite outcome (7.6 per 100 person-years [95% CI: 6.5-9.0 per 100 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12410819/

Efficacy and safety of sacubitril-valsartan in Maintenance ... Hypertension is associated with elevated mortality rates among individuals on maintenance hemodialysis (MHD). However, there is limited ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11337068/

Sacubitril-Valsartan in Patients Requiring Hemodialysis Sacubitril-valsartan therapy was associated with beneficial effects in all-cause mortality and all-cause hospitalization.