Sacubitril-Valsartan for High Blood Pressure

(PRECISION-BP Trial)

Overseen By Pankaj Arora, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: University of Alabama at Birmingham

Must not be taking: Hypertension medications

Disqualifiers: Cardiovascular disease, Diabetes, Stroke, 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: 28

Duration: 4 weeks

160 Participants Needed

Trial Summary

What is the purpose of this trial?

Obese individuals have a higher prevalence of nocturnal hypertension and non-dipping blood pressure (BP). These conditions are associated with an increased risk of cardiovascular (CV) events and death. Natriuretic Peptides (NPs) are hormones produced by the heart which directly regulate BP by causing dilation of blood vessels and by removing sodium and water from the body. NPs have a 24-hour day-night rhythm and this controls the day-night rhythm of BP as well. The NP-BP rhythm relationship is broken down in obese individuals. Obese individuals also have lower circulating NP levels. Lower circulating levels of NPs and elevated renin hormone (a part of the Renin-Angiotensin-Aldosterone System \[RAAS\]) at nighttime may contribute to the high nocturnal blood pressure in obese individuals which puts them at a higher risk of developing CV events. This current study seeks to determine the biological implications of chronopharmacology for synchronizing NP-RAAS-based blood pressure therapy with the physiological diurnal rhythms to restore the normal diurnal rhythm of blood pressure in obese individuals.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking three or more classes of hypertension medications at the maximum dose or have resistant hypertension, you are not eligible to participate.

What data supports the effectiveness of the drug Sacubitril-Valsartan for high blood pressure?

Sacubitril-Valsartan (Entresto) has been shown to be effective in reducing the risk of death and hospitalization in patients with heart failure, which is related to high blood pressure. It was found to be more effective than enalapril, a common heart failure medication, in large studies. ^{1 2 3 4 5}

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, and low sodium levels. It should not be used during pregnancy, breastfeeding, or with certain other medications in people with diabetes. ^{1 2 6 7 8}

How is the drug Sacubitril-Valsartan unique for treating high blood pressure?

Sacubitril-Valsartan is unique because it combines two components: sacubitril, which inhibits neprilysin (an enzyme that breaks down certain proteins), and valsartan, an angiotensin receptor blocker (ARB). This dual action not only helps manage high blood pressure but also offers additional benefits for heart failure patients by reducing the risk of cardiovascular death and hospitalization. ^{1 2 4 9 10}

Research Team

Pankaj Arora, MD

Principal Investigator

University of Alabama at Birmingham

Eligibility Criteria

This trial is for adults over 18 with obesity (BMI between 30 to 45) and high blood pressure (systolic BP 130-160mmHg, diastolic BP 80-100mmHg). It's not for those under 18, on multiple max-dose hypertension meds, with certain kidney/liver issues, pregnant/breastfeeding women not using birth control, or anyone with a history of severe cardiovascular disease.

Inclusion Criteria

Blood pressure: Systolic BP more than or equal to 130mmHg and less than or equal to 160mmHg and diastolic blood pressure more than or equal to 80mmHg and less than or equal to 100mmHg. Individuals with hypertension as per the 2017 ACC/AHA Guidelines will be eligible for enrollment

You have a body mass index (BMI) between 30 and 45.

Exclusion Criteria

Anemia (men, Hct < 38%; women, Hct <36%)

Hepatic Transaminase (AST and ALT) levels >3x the upper limit of normal;

My BMI is either below 30 or above 45.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either sacubitril/valsartan or valsartan, administered once daily in the morning or evening for 28 days

4 weeks

Baseline and after 28 days of intervention

Follow-up

Participants are monitored for changes in blood pressure and hormone levels after treatment

4 weeks

Treatment Details

Interventions

• Sacubitril
• Standardized Study Diet
• Valsartan

Trial Overview The study tests if timing the administration of Sacubitril-Valsartan or Valsartan can synchronize NP-RAAS-based blood pressure therapy with natural body rhythms to normalize daily blood pressure variations in obese individuals.

Participant Groups

Group I: Sacubitril/Valsartan Morning Dose Experimental Treatment 1 Intervention

We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the morning and a placebo pill in the evening for 28 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 28 days of intervention.

Group II: Sacubitril/Valsartan Evening Dose Experimental Treatment 1 Intervention

We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the evening and a placebo pill in the morning for 28 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 28 days of intervention.

Group III: Valsartan Morning Dose Active Control 1 Intervention

We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the morning and a placebo pill in the evening for 28 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 28 days of intervention.

Group IV: Valsartan Evening Dose Active Control 1 Intervention

We will enroll 40 adult obese individuals. Each participant will take the assigned dose of medication once in the evening and a placebo pill in the morning for 28 days. We evaluate Natriuretic Peptide-Renin-Angiotensin-Aldosterone System Rhythm Axis and Nocturnal Blood Pressure at baseline and after 28 days of intervention.

Sacubitril is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Entresto for:

• Heart failure with reduced ejection fraction

Approved in United States as Entresto for:

• Heart failure with reduced ejection fraction

Approved in Canada as Entresto for:

• Heart failure with reduced ejection fraction

Approved in Japan as Entresto for:

• Heart failure with reduced ejection fraction

Who Is Running the Clinical Trial?

University of Alabama at Birmingham

Lead Sponsor

Trials

1,677

Recruited

2,458,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

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]

In a study of 224 patients with heart failure and reduced ejection fraction, approximately 38.4% were eligible for sacubitril/valsartan treatment after being on optimized guideline-directed medical therapy.

The analysis revealed that many patients remained symptomatic despite optimal treatment, highlighting the potential need for additional therapies like sacubitril/valsartan in managing chronic heart failure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-Life Indications to Sacubitril/Valsartan Treatment in Patients With Chronic Systolic Heart Failure. Pinto, G., Tondi, L., Gemma, M., et al.[2021]

In the PARADIGM-HF trial, sacubitril/valsartan significantly reduced the risk of death from cardiovascular causes or hospitalization for worsening heart failure compared to the ACE inhibitor enalapril, demonstrating its efficacy in treating chronic heart failure with reduced ejection fraction (HFrEF).

Sacubitril/valsartan was generally well tolerated, with no increase in life-threatening adverse events, although it did have a higher incidence of symptomatic hypotension compared to enalapril, indicating it is a safer and more effective alternative for managing HFrEF.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction. McCormack, PL.[2021]

In a retrospective study of heart failure patients, sacubitril/valsartan significantly reduced mortality to 6.8% compared to 34% in those receiving conventional therapy, demonstrating its superior efficacy in preventing all-cause death.

The hospitalization rate for heart failure was only 4.5% in the sacubitril/valsartan group versus 59% in the control group, indicating a strong protective effect against heart failure hospitalizations, although there was a higher incidence of hypotension in the sacubitril/valsartan group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan for heart failure with reduced left ventricular ejection fraction : A retrospective cohort study. De Vecchis, R., Ariano, C., Di Biase, G., et al.[2022]

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]

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]

The PIONEER-HF trial is a 12-week study involving 882 patients with heart failure and reduced ejection fraction, assessing the safety and efficacy of starting sacubitril/valsartan in the hospital compared to enalapril.

Sacubitril/valsartan, a new angiotensin receptor-neprilysin inhibitor, aims to improve outcomes for patients stabilized after acute heart failure, with the primary goal of measuring changes in specific heart failure biomarkers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial. Velazquez, EJ., Morrow, DA., DeVore, AD., et al.[2021]

A study analyzing 80,316 reports from the FDA Adverse Event Reporting System found no significant increase in dementia-related adverse events associated with sacubitril/valsartan in heart failure patients, suggesting it is safe in this regard.

The statistical analysis showed that neither narrow nor broad dementia-related complications were over-reported in patients taking sacubitril/valsartan, indicating that long-term use may not adversely affect cognition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated insights on dementia-related risk of sacubitril/valsartan: A real-world pharmacovigilance analysis. Chen, C., Ding, L., Fu, F., et al.[2023]

Sacubitril valsartan (Entresto) is an oral medication approved for treating adults with symptomatic chronic heart failure and reduced ejection fraction, combining a neprilysin inhibitor and an angiotensin II receptor antagonist to enhance heart function.

The drug's mechanism of action involves inhibiting neprilysin, which helps to increase levels of beneficial peptides that promote vasodilation and reduce heart strain, making it a significant option in heart failure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

▼ Sacubitril valsartan for heart failure. [2021]

References

1. Germany pubmed.ncbi.nlm.nih.gov

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

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

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

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

Real-Life Indications to Sacubitril/Valsartan Treatment in Patients With Chronic Systolic Heart Failure. [2021]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Sacubitril/Valsartan: A Review in Chronic Heart Failure with Reduced Ejection Fraction. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Sacubitril/valsartan for heart failure with reduced left ventricular ejection fraction : A retrospective cohort study. [2022]

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

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

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

Efficacy and safety of sacubitril-valsartan in heart failure: a meta-analysis of randomized controlled trials. [2022]

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

Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial. [2021]

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

Updated insights on dementia-related risk of sacubitril/valsartan: A real-world pharmacovigilance analysis. [2023]

10. England pubmed.ncbi.nlm.nih.gov

▼ Sacubitril valsartan for heart failure. [2021]