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 randomized placebo-controlled clinical trial will evaluate the effect of sacubitril/valsartan (compared with placebo) on echocardiographic measures of hypervolemia, preservation of residual renal function, and key safety parameters in incident hemodialysis patients.

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 sacubitril-valsartan safe for humans?

Sacubitril-valsartan (Entresto) is generally safe for humans but can cause side effects like low blood pressure, swelling (angioedema), kidney problems, high potassium levels, low sodium levels, and in rare cases, liver injury. It should not be used during pregnancy, breastfeeding, or with certain other medications in people with diabetes. ^{1 2 3 4 5}

How is the drug sacubitril-valsartan unique for hemodialysis patients?

Sacubitril-valsartan is unique because it combines two components that work together to improve heart function and reduce blood pressure in hemodialysis patients, showing better results than using valsartan alone. It has been shown to improve heart function and reduce symptoms in patients with heart failure and hypertension undergoing dialysis, without causing common side effects like high potassium levels. ^{2 5 6 7 8}

What data supports the effectiveness of the drug sacubitril-valsartan for hemodialysis patients?

Research shows that sacubitril-valsartan can improve heart function and reduce blood pressure in hemodialysis patients with heart failure, as seen in improvements in heart measurements and symptoms over a 6-month period. ^{2 5 6 8 9}

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

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]

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]

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 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 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]

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]

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]

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 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]

Citations

1. United States 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. [2023]

2. Spain pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan in chronic kidney disease, the nephrologist point of view. [2021]

3. Japan pubmed.ncbi.nlm.nih.gov

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

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

Effects of sacubitril-valsartan in the treatment of chronic heart failure patients with end-stage renal disease undergoing dialysis. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan in heart failure and end-stage renal insufficiency. [2021]

6. Germany pubmed.ncbi.nlm.nih.gov

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

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

Sacubitril/Valsartan (Entresto®)-Induced Hyponatremia. [2021]

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

Sacubitril/valsartan-induced liver injury: A case report and literature review. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and pharmacodynamics of sacubitril/valsartan in peritoneal dialysis patients. [2023]