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

BLOCKade of Calcium Channels and Beta Adrenergic Receptors for the Treatment of Hypertension in Heart Failure With Preserved Ejection Fraction (BLOCK HFpEF) Trial

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.

Study Overview

• Status: Completed
• Conditions: Hypertension; Heart Failure With Preserved Ejection Fraction
• Intervention / Treatment: Drug: Amlodipine Besylate; Drug: Metoprolol Succinate

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of the University of Pennsylvania

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adults age 18-90 years
2. 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
3. Stable antihypertensive therapy; defined as no changes in antihypertensive medications in the preceding 30 days
4. A diagnosis of heart failure
5. LV ejection fraction >50%
6. 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;

Exclusion Criteria:

1. 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
2. Resting heart rate <50 or >100 bpm
3. 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
4. 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.
5. Inability/unwillingness to exercise
6. 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
7. 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
8. 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
9. Primary pulmonary arteriopathy
10. eGFR <30 mL/min/1.73m2
11. Any medical condition that, under the investigator's discretion, will interfere with safe completion of the study or validity of the endpoint assessments
12. Known history of an allergy or clinically significant sensitivity (as determined by the investigator) to either amlodipine besylate or metoprolol succinate

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Amlodipine besylate; 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; The interventions will be implemented in random order in a crossover (AB-BA) design, separated by an approximately one-week washout period
Active Comparator: Metoprolol succinate; 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; The interventions will be implemented in random order in a crossover (AB-BA) design, separated by an approximately one-week washout period

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Difference in Home Diastolic Blood Pressure	The difference in home diastolic blood pressure between treatments was determined using a single summary value per participant per intervention period, calculated as the mean of all available home diastolic 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
Difference in Office Systolic Blood Pressure	Blood pressure will be measured at rest with a validated oscillometric device (Uscom BP+/UM-211).	Measured at the end of each of the two 4-week intervention phases
Difference in Office Diastolic Blood Pressure	Blood pressure will be measured at rest with a validated oscillometric device (Uscom BP+/UM-211).	Measured at the end of each of the two 4-week intervention phases
Difference in Peak Oxygen Consumption (VO2) During a Maximal Exercise Test	We will use a supine cycle ergometer in conjunction with expired gas analysis to assess oxygen consumption (VO2) during exercise. Subjects will perform a maximal exertion-limited exercise test using a graded-exercise protocol.	Measured at the end of each of the two 4-week intervention phases
Difference in Quality of Life	Quality of life will be assessed with the Kansas City Cardiomyopathy Questionnaire. The responses are categorized under 3 subscales (symptom burden, physical limitation and quality of life) with a range of possible subscale scores from 0 to 100. The total score will be calculated as the mean of the three subscale scores. A mean score of 100 represents the least symptoms and 0 represents the worst symptoms.	Measured at the end of each of the two 4-week intervention phases
Difference in Systemic Vasodilatory Response to Exercise	Systemic vascular resistance (SVR) will be calculated at rest and at peak exercise as mean arterial pressure / cardiac output. Systemic vasodilatory reserve will be measured as the percentage reduction in SVR during exercise, relative to SVR at rest ([rest SVR - peak exercise SVR] / rest SVR) x 100%.	Measured at the end of each of the two 4-week intervention phases
Difference in Arterial Wave Reflections	Arterial wave reflections will be assessed using radial artery pressure waveforms obtained with a high-fidelity applanation tonometer. Waveforms will be calibrated using brachial mean and diastolic blood pressure. Forward and backward pressure wave components will be derived using wave separation analysis, and arterial wave reflection magnitude will be quantified as the ratio of backward to forward pressure wave amplitudes (unitless ratio). Change from baseline will be reported.	Measured at the end of each of the two 4-week intervention phases
Difference in Large Artery Stiffness	Large artery stiffness will be assessed by measuring carotid-femoral pulse wave velocity using arterial applanation tonometry. Pulse wave velocity will be calculated as the distance between the carotid and femoral recording sites divided by the transit time of the arterial pressure waveform.	Measured at the end of each of the two 4-week intervention phases
Difference in Left Ventricular Filling Pressure	We will assess the ratio of early diastolic mitral inflow velocity (E) to mitral annular tissue velocity (e'; a surrogate of LV filling pressures) on echocardiography	Measured at the end of each of the two 4-week intervention phases
Difference in Myocardial Strain	Left ventricular systolic function will be assessed by global longitudinal myocardial strain measured using two-dimensional speckle-tracking echocardiography. Strain will be calculated as the peak systolic percentage change in myocardial length from end-diastole to end-systole, expressed as a percentage.	Measured at the end of each of the two 4-week intervention phases

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Collaborators: Julio Chirinos, MD, PhD; Raymond Townsend, MD

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2021
• Primary Completion (Actual): December 3, 2024
• Study Completion (Actual): December 20, 2024

Study Registration Dates

• First Submitted: June 10, 2020
• First Submitted That Met QC Criteria: June 12, 2020
• First Posted (Actual): June 17, 2020

Study Record Updates

• Last Update Posted (Actual): January 30, 2026
• Last Update Submitted That Met QC Criteria: January 20, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Calcium channel blocker; Beta-blocker
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Hypertension; Organic Chemicals; Pyridines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Amines; Alcohols; Phenoxypropanolamines; Propanolamines; Amino Alcohols; Propanols; Dihydropyridines; Metoprolol; Amlodipine
• Other Study ID Numbers: 833517

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes