BLOCKade of Calcium Channels and Beta Adrenergic Receptors for the Treatment of Hypertension in HFpEF

NCT04434664 | Completed Phase 4 Results FDA Drug

• 1 other identifier: 833517
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

Heart failure with preserved ejection fraction (HFpEF) is a critical public health problem. Heart failure (HF) affects over 5 million adults in the United States (US), and is a major source of morbidity, mortality, and impaired quality of life. Approximately half of individuals with HF have a preserved left ventricular (LV) ejection fraction (EF), termed HF with preserved EF (HFpEF). While there are several effective pharmacologic therapies for HF with reduced ejection fraction (HFrEF), none have been identified for HFpEF. Hypertension, which is present in approximately 80% of individuals with HFpEF, is the foremost modifiable risk factor for the development and progression of HFpEF. Despite the clinical importance of hypertension in HFpEF, there is limited information on how common antihypertensive agents, particularly calcium channel blockers (CCBs) and β-blockers, effect pathophysiologic mechanisms of HFpEF. This is a mechanistic investigation of the role of dihydropyridine CCBs compared to β-blockers (commonly used antihypertensive agents in clinical practice) in targeting key physiologic abnormalities in HFpEF.

Conditions

Heart Failure With Preserved Ejection Fraction; Hypertension

Keywords

Calcium channel blocker; Beta-blocker

Outcome Measures

Primary Outcomes (1)

• Difference in Home Systolic Blood Pressure

  The difference in home systolic blood pressure between treatments was determined using a single summary value per participant per intervention period, calculated as the mean of all available home systolic BP readings obtained during the final week of each intervention period. Home BP monitoring was performed using the same validated device model (Microlife BP 3MX1-4 WatchBP Home N), with three consecutive measurements taken in the morning and evening each day over the seven-day period.

  Measured during the last week of each of the two 4-week intervention phases

Secondary Outcomes (10)

• Difference in Home Diastolic Blood Pressure

  Measured during the last week of each of the two 4-week intervention phases

• Difference in Office Systolic Blood Pressure

  Measured at the end of each of the two 4-week intervention phases

• Difference in Office Diastolic Blood Pressure

  Measured at the end of each of the two 4-week intervention phases

• Difference in Peak Oxygen Consumption (VO2) During a Maximal Exercise Test

  Measured at the end of each of the two 4-week intervention phases

• Difference in Quality of Life

  Measured at the end of each of the two 4-week intervention phases

Study Arms (2)

Amlodipine besylate

ACTIVE COMPARATOR

Initial dose 5mg (1 capsule) daily, titrated up to 10mg (2 capsules) daily for a home systolic BP ≥135 mmHg and heart rate ≥50 bpm after the first week of use

Drug: Amlodipine Besylate

Metoprolol succinate

ACTIVE COMPARATOR

Initial dose 100mg (1 capsule) daily, titrated up to 200mg (2 capsules) daily for a home systolic BP ≥135 mmHg and heart rate ≥50 bpm after the first week of use

Drug: Metoprolol Succinate

Interventions

Amlodipine Besylate DRUG

The interventions will be implemented in random order in a crossover (AB-BA) design, separated by an approximately one-week washout period

Amlodipine besylate

Metoprolol Succinate DRUG

The interventions will be implemented in random order in a crossover (AB-BA) design, separated by an approximately one-week washout period

Metoprolol succinate

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adults age 18-90 years
• Diagnosis of hypertension defined by at least two of the following: A) ICD-9 (401.0-404.91) or ICD-10 (I10-I13) codes signifying hypertension; B) Treatment with antihypertensive medication other than a loop diuretic for at least two months; C) History of previous blood pressure readings ≥130/80 mmHg at two separate office visits
• Stable antihypertensive therapy; defined as no changes in antihypertensive medications in the preceding 30 days
• A diagnosis of heart failure
• LV ejection fraction \>50%
• Elevated filling pressures defined by at least one of the following criteria: A) Mitral E/e' ratio (lateral or septal) \>8 with low e' velocity (septal e' \<7 cm/s or lateral e' \<10 cm/s) and at least one of the following: a. Enlarged left atrium (LA volume index \>34 ml/m2); b. Chronic loop diuretic use for management of symptoms; c. Elevated natriuretic peptides (BNP levels \>100 ng/L or NT-proBNP levels \>300 ng/L); B) Mitral E/e' ratio (lateral or septal) \>14; C) Previously elevated invasively determined filling pressures based on one of the following criteria: a. Resting LVEDP \>16 mmHg; b. Mean PCWP \>12 mmHg; c. PCWP or LVEDP ≥25 mmHg with exercise; D) Previous acutely decompensated heart failure requiring IV diuretics;

You may not qualify if:

• Systolic BP meeting any of the following criteria: A) Current office systolic BP \<100 mmHg; B) Current office systolic BP 100-119 mmHg if not receiving treatment with an antihypertensive agent or if holding antihypertensive medication prior to randomization would be clinically contraindicated, as per the investigator's clinical judgement; C) Current office systolic BP ≥180 mmHg if not receiving treatment with a CCB or β-blocker, or ≥160 mmHg if already receiving a CCB and/or β-blocker prior to the pre-randomization wash-out period; D) Orthostatic hypotension defined as \>20 mmHg decline in office systolic BP 3-5 minutes following the transition from sitting to standing position
• Resting heart rate \<50 or \>100 bpm
• Contraindication to withholding CCB or β-blocker therapy (e.g. use of non-dihydropyridine CCB \[diltiazem or verapamil\] or β-blocker for rate control for atrial fibrillation) as per the investigator's clinical judgement
• Children, fetuses, neonates, prisoners, and pregnant women (women of childbearing age will undergo a pregnancy test during the screening visit) are not included in this research study.
• Inability/unwillingness to exercise
• Any the following echocardiographic findings: A) LV ejection fraction \<45% on any prior echocardiogram, unless it was in the setting of uncontrolled atrial fibrillation; B) Hypertrophic, infiltrative, or inflammatory cardiomyopathy; C) Clinically significant pericardial disease, as per investigator judgment; D) Moderate or greater left-sided valvular disease, any degree of mitral stenosis, or prosthetic mitral valve; E) Severe right-sided valvular disease; F) Severe right ventricular dysfunction
• Active coronary artery disease, defined as any of the following: A) Acute coronary syndrome or coronary intervention in the past 2 months; B) Ischemia on stress testing without either subsequent revascularization or a subsequent angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgement
• Clinically significant lung disease, defined as any of the following: A) Chronic Obstructive Pulmonary Disease meeting GOLD criteria stage III or greater; B) Treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease; C) The use of daytime supplemental oxygen
• Primary pulmonary arteriopathy
• eGFR \<30 mL/min/1.73m2
• Any medical condition that, under the investigator's discretion, will interfere with safe completion of the study or validity of the endpoint assessments
• Known history of an allergy or clinically significant sensitivity (as determined by the investigator) to either amlodipine besylate or metoprolol succinate

Sponsors & Collaborators

• University of Pennsylvania: lead

Study Sites (1)

Hospital of the University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Related Publications (8)

• Cohen JB, Schrauben SJ, Zhao L, Basso MD, Cvijic ME, Li Z, Yarde M, Wang Z, Bhattacharya PT, Chirinos DA, Prenner S, Zamani P, Seiffert DA, Car BD, Gordon DA, Margulies K, Cappola T, Chirinos JA. Clinical Phenogroups in Heart Failure With Preserved Ejection Fraction: Detailed Phenotypes, Prognosis, and Response to Spironolactone. JACC Heart Fail. 2020 Mar;8(3):172-184. doi: 10.1016/j.jchf.2019.09.009. Epub 2020 Jan 8.

  PMID: 31926856 BACKGROUND

• Chirinos JA, Kips JG, Jacobs DR Jr, Brumback L, Duprez DA, Kronmal R, Bluemke DA, Townsend RR, Vermeersch S, Segers P. Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis). J Am Coll Cardiol. 2012 Nov 20;60(21):2170-7. doi: 10.1016/j.jacc.2012.07.054. Epub 2012 Oct 24.

  PMID: 23103044 BACKGROUND

• Chirinos JA, Segers P. Noninvasive evaluation of left ventricular afterload: part 1: pressure and flow measurements and basic principles of wave conduction and reflection. Hypertension. 2010 Oct;56(4):555-62. doi: 10.1161/HYPERTENSIONAHA.110.157321. Epub 2010 Aug 23.

  PMID: 20733089 BACKGROUND

• Chirinos JA, Segers P. Noninvasive evaluation of left ventricular afterload: part 2: arterial pressure-flow and pressure-volume relations in humans. Hypertension. 2010 Oct;56(4):563-70. doi: 10.1161/HYPERTENSIONAHA.110.157339. Epub 2010 Aug 23.

  PMID: 20733088 BACKGROUND

• Zamani P, Rawat D, Shiva-Kumar P, Geraci S, Bhuva R, Konda P, Doulias PT, Ischiropoulos H, Townsend RR, Margulies KB, Cappola TP, Poole DC, Chirinos JA. Effect of inorganic nitrate on exercise capacity in heart failure with preserved ejection fraction. Circulation. 2015 Jan 27;131(4):371-80; discussion 380. doi: 10.1161/CIRCULATIONAHA.114.012957. Epub 2014 Dec 22.

  PMID: 25533966 BACKGROUND

• Zamani P, Tan V, Soto-Calderon H, Beraun M, Brandimarto JA, Trieu L, Varakantam S, Doulias PT, Townsend RR, Chittams J, Margulies KB, Cappola TP, Poole DC, Ischiropoulos H, Chirinos JA. Pharmacokinetics and Pharmacodynamics of Inorganic Nitrate in Heart Failure With Preserved Ejection Fraction. Circ Res. 2017 Mar 31;120(7):1151-1161. doi: 10.1161/CIRCRESAHA.116.309832. Epub 2016 Dec 7.

  PMID: 27927683 BACKGROUND

• Muntner P, Shimbo D, Carey RM, Charleston JB, Gaillard T, Misra S, Myers MG, Ogedegbe G, Schwartz JE, Townsend RR, Urbina EM, Viera AJ, White WB, Wright JT Jr. Measurement of Blood Pressure in Humans: A Scientific Statement From the American Heart Association. Hypertension. 2019 May;73(5):e35-e66. doi: 10.1161/HYP.0000000000000087.

  PMID: 30827125 BACKGROUND

• White WB, Krishnan S, Giacco S, Mallareddy M. Effects of metoprolol succinate extended release vs. amlodipine besylate on the blood pressure, heart rate, and the rate-pressure product in patients with hypertension. J Am Soc Hypertens. 2008 Sep-Oct;2(5):378-84. doi: 10.1016/j.jash.2008.03.002. Epub 2008 Jun 5.

  PMID: 20409919 BACKGROUND

MeSH Terms

Conditions

Hypertension

Interventions

Amlodipine; Metoprolol

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Dihydropyridines; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines

Limitations and Caveats

Sample size; while the study was adequately powered for the primary outcome, the small sample size yielded imbalance in some baseline characteristics and limits the ability to draw conclusions from the secondary outcomes.

Results Point of Contact

• Title: Jordana Cohen, MD, MSCE
• Organization: University of Pennsylvania

jco@pennmedicine.upenn.edu

215-573-6074

Publication Agreements

• PI is Sponsor Employee: Yes
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: For blinding, tablets are placed into oral gelatin capsules with an inert filler (lactose monohydrate). Blinding is performed and maintained by the University of Pennsylvania Investigational Drug Service.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Medicine and Epidemiology

Study Record Dates

• First Submitted: June 10, 2020
• First Posted: June 17, 2020
• Study Start: December 1, 2021
• Primary Completion: December 3, 2024
• Study Completion: December 20, 2024
• Last Updated: January 30, 2026
• Results First Posted: January 30, 2026

Record last verified: 2026-01

Locations

US (1)