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

Hypertension Clinical Trial

— BLOCK HFpEF  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04434664
• Other study ID #: 833517
• Status: Recruiting
• Phase: Phase 4
• Start date: May 1, 2021
• Est. completion date: October 1, 2024

Study information

• Verified date: August 2023
• Source: University of Pennsylvania
• Contact: Jordana Cohen, MD, MSCE
• Phone: 267-588-7914
• Email: jco[@]pennmedicine.upenn.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: October 1, 2024
• Est. primary completion date: October 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

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 ß-blocker, or =160 mmHg if already receiving a CCB and/or ß-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 ß-blocker therapy (e.g. use of non-dihydropyridine CCB [diltiazem or verapamil] or ß-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

Related Conditions & MeSH terms

• Heart Failure
• Heart Failure With Preserved Ejection Fraction
• Hypertension

Intervention

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

Locations

Country	Name	City	State
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania

Sponsors (3)

Lead Sponsor	Collaborator
University of Pennsylvania	Julio Chirinos, MD, PhD, Raymond Townsend, MD

Country where clinical trial is conducted

United States, 

References & Publications (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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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