24 Hour Ambulatory Cardiac Oxygen Consumption

Phase 3

Completed

Conditions: Hypertension

Interventions: Drug: Nebivolol
Drug: Valsartan
Drug: Nebivolol/valsartan combination

Registration Number: NCT05170061

Lead Sponsor: State University of New York at Buffalo

Brief Summary: 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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 26

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Sequence 3: Valsartan first, then Nebivolol, then combination of nebivolol/valsartan,	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;
Sequence 3: Valsartan first, then Nebivolol, then combination of nebivolol/valsartan,	Nebivolol/valsartan combination	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;
Sequence 4: Valsartan first, then combination of nebivolol/valsartan, then Nebivolol,	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;
Sequence 5: Combination of nebivolol/valsartan first, then Nebivolol, then Valsartan,	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 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;
Sequence 4: Valsartan first, then combination of nebivolol/valsartan, then 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 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;
Sequence 4: Valsartan first, then combination of nebivolol/valsartan, then Nebivolol,	Nebivolol/valsartan combination	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;
Sequence 5: Combination of nebivolol/valsartan first, then Nebivolol, then Valsartan,	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;
Sequence 5: Combination of nebivolol/valsartan first, then Nebivolol, then Valsartan,	Nebivolol/valsartan combination	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;
Sequence 6: Combination of nebivolol/valsartan first, then Valsartan, then Nebivolol, ,	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
Sequence 6: Combination of nebivolol/valsartan first, then Valsartan, then Nebivolol, ,	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 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
Sequence 6: Combination of nebivolol/valsartan first, then Valsartan, then Nebivolol, ,	Nebivolol/valsartan combination	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
Sequence 1: Nebivolol first, then valsartan, then combination of nebivolol/valsartan	Nebivolol	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
Sequence 1: Nebivolol first, then valsartan, then combination of nebivolol/valsartan	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
Sequence 1: Nebivolol first, then valsartan, then combination of nebivolol/valsartan	Nebivolol/valsartan combination	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
Sequence 2: Nebivolol first, then combination of nebivolol/valsartan; then valsartan	Nebivolol	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
Sequence 2: Nebivolol first, then combination of nebivolol/valsartan; then valsartan	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
Sequence 2: Nebivolol first, then combination of nebivolol/valsartan; then valsartan	Nebivolol/valsartan combination	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
Sequence 3: Valsartan first, then Nebivolol, then combination of nebivolol/valsartan,	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 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;

Primary Outcome Measures

Name	Time	Method
ACRPP: 24-hour Ambulatory Central Rate-pressure Product (Also Called TTI, CTTI)	measurement after 4 weeks in each treatment arm	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).

Secondary Outcome Measures

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