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

Phase 4

Completed

• Conditions: Heart Failure with Preserved Ejection Fraction; Hypertension
• Interventions: Drug: Metoprolol Succinate; Drug: Amlodipine Besylate

• Registration Number: NCT04434664
• Lead Sponsor: University of Pennsylvania

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-06-10
• Study First Submitted QC: 2020-06-12
• Study First Posted: 2020-06-17
• Study Start: 2021-12-01
• Primary Completion: 2024-12-03
• Study Completion: 2024-12-20
• Status Verified: 2025-01
• Last Update Submitted: 2025-01-07
• Last Update Posted: 2025-01-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 50

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Metoprolol succinate	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
Amlodipine besylate	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

Primary Outcome Measures

Name	Time	Method
Change in home systolic blood pressure	Measured during the last week of each of the two 4-week intervention phases	Mean systolic BP measured using home BP monitoring (Microlife BP 3MX1-4 WatchBP Home N)

Secondary Outcome Measures

Name	Time	Method
Change in home diastolic blood pressure	Measured during the last week of each of the two 4-week intervention phases	Mean systolic BP measured using home BP monitoring (Microlife BP 3MX1-4 WatchBP Home N).
Change in office systolic blood pressure	Measured at the end of each of the two 4-week intervention phases	Blood pressure will be measured at rest with a validated oscillometric device (Uscom BP+/UM-211).
Change in office diastolic blood pressure	Measured at the end of each of the two 4-week intervention phases	Blood pressure will be measured at rest with a validated oscillometric device (Uscom BP+/UM-211).
Change in peak oxygen consumption (VO2) during a maximal exercise test	Measured at the end of each of the two 4-week intervention phases	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.
Change in quality of life	Measured at the end of each of the two 4-week intervention phases	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.
Change in systemic vasodilatory response to exercise	Measured at the end of each of the two 4-week intervention phases	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 reduction in SVR during exercise, relative to SVR at rest (\[rest SVR - peak exercise SVR\] / rest SVR).
Change in arterial wave reflections	Measured at the end of each of the two 4-week intervention phases	We will use a high-fidelity Millar applanation tonometer to record carotid pressure waveforms, which will be calibrated using brachial diastolic and mean pressures.
Change in large artery stiffness	Measured at the end of each of the two 4-week intervention phases	We will use a tonometer to record large artery stiffness determined by carotid-femoral pulse wave velocity.
Change in left ventricular filling pressure	Measured at the end of each of the two 4-week intervention phases	We will assess the ratio of early diastolic mitral inflow velocity to mitral annular tissue velocity (a surrogate of LV filling pressures) on echocardiography
Change in myocardial strain	Measured at the end of each of the two 4-week intervention phases	Systolic function will be assessed via systolic myocardial strain using speckle tracking echocardiography

Trial Locations

Locations (1)

Hospital of the University of Pennsylvania; 🇺🇸 Philadelphia, Pennsylvania, United States