24 Hour Ambulatory Cardiac Oxygen Consumption (ACRPP)

Ambulatory 24-Hour Cardiac Oxygen Consumption and Blood Pressure-Heart Rate Variability: Effects of Nebivolol and Valsartan Alone and in Combination

A randomized,double-blind, active controlled,15 week study to evaluate the effects of nebivolol and valsartan alone and in combination on 24-hour ambulatory cardiac work and variability of heart rate-mean central systolic pressure product.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Nebivolol; Drug: Valsartan; Drug: Nebivolol/valsartan combination

Detailed Description

Subjects with hypertension (systolic blood pressure (SBP) >140 or diastolic blood pressure (DBP)>90, n=26) were studied using a double-blinded, forced-titration, sequence-controlled, crossover design with 3 experimental periods: Valsartan 320, nebivolol 40, and nebivolol/valsartan 320/40 mg daily. After 4 weeks of each drug, ambulatory pulse wave analysis (IEM MobilOGraph) was performed every 20 min for 24-hours. The primary hypothesis was that nebivolol/valsartan combination therapy would be superior to valsartan monotherapy in reducing mean 24-hour mean myocardial oxygen consumption determined by 24-hour ambulatory heart rate-central systolic pressure product [ACRPP]. A secondary hypothesis was that the combination would also reduce the variability of 24-hour myocardial oxygen consumption.

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14215
      • Erie County Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Subjects with chronic hypertension, treated or untreated

  • Males and females, 18 years or older
  • Seated clinic systolic BP 145-184 mmHg inclusive or
  • Seated clinic diastolic BP 92-119 mmHg, inclusive.

Exclusion Criteria:

• Subjects with any of the following conditions will be excluded:

  • Any acute or chronic medical condition that, in the judgment of the investigator, renders the subject unable to complete the study, would interfere with optimal participation in the study, or cause significant risk to the subject
  • Concomitant or probable need for treatment with other cardiovascular or antihypertensive drugs that may affect blood pressure or influence the effects of study drugs, (e.g. NSAIDs, beta-agonist inhalers therapy for bronchospastic asthma, diuretics); other stable chronic medications that have little effect on study drugs (e.g. diabetes medications, hormone replacements, chronic pain medications. osteoporosis drugs, vitamins, cholesterol drugs, etc.) are permitted if continued at stable doses throughout study.
  • History of clinically significant adverse events with beta-blocker or angiotensin-receptor blocker
  • Known or suspected secondary hypertension (e.g., renovascular hypertension, primary hyperaldosteronism, etc.)
  • Known ischemic heart disease requiring continuous beta-blocker therapy (includes angina, prior transmural myocardial infarction, coronary artery bypass graft surgery or percutaneous transluminal coronary angioplasty or stenting within 6 months prior to study entry).
  • Dilated cardiomyopathy (NYHA Functional Class III-IV)
  • Clinically significant valvular heart disease or obstructive hypertrophic cardiomyopathy
  • Presence of clinically significant ventricular or supraventricular arrhythmias (e.g. atrial fibrillation/flutter), pre-excitation syndrome, second or third degree atrioventricular block, other conduction defects necessitating the implantation of a permanent cardiac pacemaker, or sick sinus syndrome.
  • Chronic kidney disease (serum creatinine >2.5 mg/dL)
  • Uncontrolled diabetes mellitus (hemoglobin A1c > 10%)
  • History of alcohol or other drug abuse within 6 months prior to enrollment
  • Positive pregnancy test or failure to practice adequate contraception in women of child-bearing potential

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sequence 1: Nebivolol first, then valsartan, then combination of nebivolol/valsartan; Nebivolol, 20 mg daily for 1 week followed by 40 mg daily for 3 weeks, followed by 1 week down-titration to 20 mg daily; then Valsartan, 160 mg daily for 1 week followed by 320 mg daily for 3 weeks, followed by 1-week down-titration to 160 mg daily; then Combination of nebivolol/valsartan 20/160 mg daily for 1 week followed by 40/320 mg daily for 3 weeks, followed by 1-week down-titration to 20/160 mg daily	Drug: Nebivolol; Nebivolol 20 mg daily (1 week) followed by nebivolol 40 mg daily (3 weeks) followed by nebivolol 20 mg daily (1 week); Other Names: Bystolic; Drug: Valsartan; Valsartan 160 mg daily (1 week) followed by valsartan 320 mg daily (3 weeks) followed by valsartan 160 mg daily (1 week).; Other Names: Diovan; Drug: Nebivolol/valsartan combination; Valsartan/Nebivolol, 160/20 mg daily (1 week) followed by valsartan/nebivolol 320/40 mg daily (3 weeks) followed by valsartan/nebivolol 160/20 mg daily (1 week); Other Names: Diovan/Bystolic
Active Comparator: Sequence 2: Nebivolol first, then combination of nebivolol/valsartan; then valsartan; Nebivolol, 20 mg daily for 1 week followed by 40 mg daily for 3 weeks, followed by 1 week down-titration to 20 mg daily; then combination of nebivolol/valsartan 20/160 mg daily for 1 week followed by 40/320 mg daily for 3 weeks, followed by 1-week down-titration to 20/160 mg daily; then Valsartan, 160 mg daily for 1 week followed by 320 mg daily for 3 weeks, followed by 1-week down-titration to 160 mg daily	Drug: Nebivolol; Nebivolol 20 mg daily (1 week) followed by nebivolol 40 mg daily (3 weeks) followed by nebivolol 20 mg daily (1 week); Other Names: Bystolic; Drug: Valsartan; Valsartan 160 mg daily (1 week) followed by valsartan 320 mg daily (3 weeks) followed by valsartan 160 mg daily (1 week).; Other Names: Diovan; Drug: Nebivolol/valsartan combination; Valsartan/Nebivolol, 160/20 mg daily (1 week) followed by valsartan/nebivolol 320/40 mg daily (3 weeks) followed by valsartan/nebivolol 160/20 mg daily (1 week); Other Names: Diovan/Bystolic
Active Comparator: Sequence 3: Valsartan first, then Nebivolol, then combination of nebivolol/valsartan,; Valsartan, 160 mg daily for 1 week followed by 320 mg daily for 3 weeks, followed by 1-week down-titration to 160 mg daily; then Nebivolol, 20 mg daily for 1 week followed by 40 mg daily for 3 weeks, followed by 1 week down-titration to 20 mg daily; then combination of nebivolol/valsartan 20/160 mg daily for 1 week followed by 40/320 mg daily for 3 weeks, followed by 1-week down-titration to 20/160 mg daily;	Drug: Nebivolol; Nebivolol 20 mg daily (1 week) followed by nebivolol 40 mg daily (3 weeks) followed by nebivolol 20 mg daily (1 week); Other Names: Bystolic; Drug: Valsartan; Valsartan 160 mg daily (1 week) followed by valsartan 320 mg daily (3 weeks) followed by valsartan 160 mg daily (1 week).; Other Names: Diovan; Drug: Nebivolol/valsartan combination; Valsartan/Nebivolol, 160/20 mg daily (1 week) followed by valsartan/nebivolol 320/40 mg daily (3 weeks) followed by valsartan/nebivolol 160/20 mg daily (1 week); Other Names: Diovan/Bystolic
Active Comparator: Sequence 4: Valsartan first, then combination of nebivolol/valsartan, then Nebivolol,; Valsartan, 160 mg daily for 1 week followed by 320 mg daily for 3 weeks, followed by 1-week down-titration to 160 mg daily; then combination of nebivolol/valsartan 20/160 mg daily for 1 week followed by 40/320 mg daily for 3 weeks, followed by 1-week down-titration to 20/160 mg daily; then Nebivolol, 20 mg daily for 1 week followed by 40 mg daily for 3 weeks, followed by 1 week down-titration to 20 mg daily;	Drug: Nebivolol; Nebivolol 20 mg daily (1 week) followed by nebivolol 40 mg daily (3 weeks) followed by nebivolol 20 mg daily (1 week); Other Names: Bystolic; Drug: Valsartan; Valsartan 160 mg daily (1 week) followed by valsartan 320 mg daily (3 weeks) followed by valsartan 160 mg daily (1 week).; Other Names: Diovan; Drug: Nebivolol/valsartan combination; Valsartan/Nebivolol, 160/20 mg daily (1 week) followed by valsartan/nebivolol 320/40 mg daily (3 weeks) followed by valsartan/nebivolol 160/20 mg daily (1 week); Other Names: Diovan/Bystolic
Active Comparator: Sequence 5: Combination of nebivolol/valsartan first, then Nebivolol, then Valsartan,; Combination of nebivolol/valsartan 20/160 mg daily for 1 week followed by 40/320 mg daily for 3 weeks, followed by 1-week down-titration to 20/160 mg daily; then Nebivolol, 20 mg daily for 1 week followed by 40 mg daily for 3 weeks, followed by 1 week down-titration to 20 mg daily; then Valsartan, 160 mg daily for 1 week followed by 320 mg daily for 3 weeks, followed by 1-week down-titration to 160 mg daily;	Drug: Nebivolol; Nebivolol 20 mg daily (1 week) followed by nebivolol 40 mg daily (3 weeks) followed by nebivolol 20 mg daily (1 week); Other Names: Bystolic; Drug: Valsartan; Valsartan 160 mg daily (1 week) followed by valsartan 320 mg daily (3 weeks) followed by valsartan 160 mg daily (1 week).; Other Names: Diovan; Drug: Nebivolol/valsartan combination; Valsartan/Nebivolol, 160/20 mg daily (1 week) followed by valsartan/nebivolol 320/40 mg daily (3 weeks) followed by valsartan/nebivolol 160/20 mg daily (1 week); Other Names: Diovan/Bystolic
Active Comparator: Sequence 6: Combination of nebivolol/valsartan first, then Valsartan, then Nebivolol, ,; Combination of nebivolol/valsartan 20/160 mg daily for 1 week followed by 40/320 mg daily for 3 weeks, followed by 1-week down-titration to 20/160 mg daily; then Valsartan, 160 mg daily for 1 week followed by 320 mg daily for 3 weeks, followed by 1-week down-titration to 160 mg daily; then Nebivolol, 20 mg daily for 1 week followed by 40 mg daily for 3 weeks, followed by 1 week down-titration to 20 mg daily; then	Drug: Nebivolol; Nebivolol 20 mg daily (1 week) followed by nebivolol 40 mg daily (3 weeks) followed by nebivolol 20 mg daily (1 week); Other Names: Bystolic; Drug: Valsartan; Valsartan 160 mg daily (1 week) followed by valsartan 320 mg daily (3 weeks) followed by valsartan 160 mg daily (1 week).; Other Names: Diovan; Drug: Nebivolol/valsartan combination; Valsartan/Nebivolol, 160/20 mg daily (1 week) followed by valsartan/nebivolol 320/40 mg daily (3 weeks) followed by valsartan/nebivolol 160/20 mg daily (1 week); Other Names: Diovan/Bystolic

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
ACRPP: 24-hour Ambulatory Central Rate-pressure Product (Also Called TTI, CTTI)	ACRPP is the product of estimated aortic mean systolic pressure (mean aortic pressure estimated using a transfer function applied to brachial cuff blood pressure) during the systolic time interval adjusted for heart rate. Units are (mmHg*beats/min).	measurement after 4 weeks in each treatment arm

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cuff SBP	Seated office cuff systolic blood pressure (mmHg)	After 4 weeks in each treatment arm
Cuff DBP	Seated office cuff diastolic blood pressure (mmHg)	After 4 weeks in each treatment arm
Ambulatory Brachial Double Product	24-hour mean heart rate x 24-hour mean systolic BP	After 4 weeks in each treatment arm
Ambulatory Mean Heart Rate	Mean heart rate over 24 hours	After 4 weeks in each treatment arm
Ambulatory Mean Central Diastolic BP	Mean ambulatory aortic (central) diastolic pressure over 24 hours	After 4 weeks in each treatment arm
24-hour Brachial Systolic BP	Mean 24-hour ambulatory systolic BP	4 weeks
24-hour Brachial Diastolic BP	Mean 24-hour ambulatory cuff diastolic BP	After 4 weeks in each treatment arm
Daytime ACRPP (Ambulatory Central Rate-Pressure Product (Also Called TTI, CTTI)	Determined by ambulatory heart rate-central systolic pressure product during self-reported waking hours at the end of each study phase	After 4 weeks in each treatment arm
Nighttime ACRPP	Determined by ambulatory heart rate-central systolic pressure product during self-reported sleeping hours	After 4 weeks in each treatment arm
Daytime Heart Rate	Mean ambulatory heart rate during self-reported waking hours	After 4 weeks in each treatment arm
Nighttime Heart Rate	Mean ambulatory heart rate during self-reported sleeping hours	4 weeks
Daytime Central Systolic Pressure	Mean ambulatory central systolic pressure during self-reported waking hours	After 4 weeks in each treatment arm
Nighttime Central Systolic Pressure	Mean ambulatory central systolic pressure during self-reported sleeping hours	4 weeks
Daytime Brachial Systolic Pressure	Mean ambulatory brachial systolic pressure during self-reported waking hours	After 4 weeks in each treatment arm
Nighttime Brachial Systolic Pressure	Mean ambulatory brachial systolic pressure during self-reported sleeping hours	4 weeks
Daytime Central Diastolic Pressure	Mean ambulatory central diastolic pressure during self-reported waking hours	4 weeks
Nighttime Central Diastolic Pressure	Mean ambulatory central diastolic pressure during self-reported sleeping hours	After 4 weeks in each treatment arm
Daytime Brachial Diastolic Pressure	Mean ambulatory brachial diastolic pressure during self-reported waking hours	4 weeks
Nighttime Brachial Diastolic Pressure	Mean ambulatory brachial diastolic pressure during self-reported sleeping hours	After 4 weeks in each treatment arm
Ambulatory Daytime Brachial Rate-pressure Product	Mean ambulatory heart rate x brachial systolic blood pressure product during self-reported waking hours	After 4 weeks in each treatment arm
Ambulatory Nighttime Brachial Rate-pressure Product	Mean ambulatory heart rate x brachial systolic blood pressure product during self-reported sleeping hours	After 4 weeks in each treatment arm

Collaborators and Investigators

• Sponsor: State University of New York at Buffalo
• Investigators: Principal Investigator: Joseph L Izzo, MD, SUNY Buffalo

Publications and helpful links

General Publications

• Izzo JL Jr, Khan SU, Saleem O, Osmond PJ. Ambulatory 24-hour cardiac oxygen consumption and blood pressure-heart rate variability: effects of nebivolol and valsartan alone and in combination. J Am Soc Hypertens. 2015 Jul;9(7):526-35. doi: 10.1016/j.jash.2015.03.009. Epub 2015 Mar 28.

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): December 1, 2014

Study Registration Dates

• First Submitted: December 22, 2014
• First Submitted That Met QC Criteria: December 21, 2021
• First Posted (Actual): December 27, 2021

Study Record Updates

• Last Update Posted (Actual): June 8, 2025
• Last Update Submitted That Met QC Criteria: May 21, 2025
• Last Verified: May 1, 2025

More Information

Terms related to this study

• Keywords: Systolic blood pressure; Nebivolol; Valsartan; Diastolic blood pressure; Myocardial oxygen consumption; Variability in hemodynamic indicators; IEM ambulatory monitoring
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Adrenergic Agonists; Adrenergic Agents; Adrenergic beta-Agonists; Vasodilator Agents; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Adrenergic beta-1 Receptor Agonists; Valsartan; Nebivolol
• Other Study ID Numbers: BYS-IT-76