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

Study Overview
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Brief Summary
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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.

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

Conditions
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Heart Failure With Preserved Ejection Fraction, Hypertension

Intervention / Treatment
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* Drug: Amlodipine Besylate
* Drug: Metoprolol Succinate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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; Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in home diastolic blood pressure | Mean systolic BP measured using home BP monitoring (Microlife BP 3MX1-4 WatchBP Home N). | Measured during the last week of each of the two 4-week intervention phases | 
| Change in office systolic and diastolic blood pressure | Blood pressure will be measured at rest with a validated oscillometric device (Omron 705IT; HEM-759-E). | Measured at the end of each of the two 4-week intervention phases | 
| Change 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 | 
| Change 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 | 
| Change 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 reduction in SVR during exercise, relative to SVR at rest ([rest SVR - peak exercise SVR] / rest SVR). | Measured at the end of each of the two 4-week intervention phases | 
| Change in arterial wave reflections | We will use a high-fidelity Millar applanation tonometer to record carotid pressure waveforms, which will be calibrated using brachial diastolic and mean pressures. | Measured at the end of each of the two 4-week intervention phases | 
| Change in large artery stiffness | We will use a tonometer to record large artery stiffness determined by carotid-femoral pulse wave velocity. | Measured at the end of each of the two 4-week intervention phases | 
| Change in left ventricular filling pressure | We will assess the ratio of early diastolic mitral inflow velocity to mitral annular tissue velocity (a surrogate of LV filling pressures) on echocardiography | Measured at the end of each of the two 4-week intervention phases | 
| Change in myocardial strain | Systolic function will be assessed via systolic myocardial strain using speckle tracking echocardiography | Measured at the end of each of the two 4-week intervention phases | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Calcium channel blocker, Beta-blocker