24 Hour Ambulatory Cardiac Oxygen Consumption

Study Overview
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Brief Summary
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A randomized,double-blind,double-dummy,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
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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.

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

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Valsartan
* Drug: Nebivolol
* Drug: Nebivolol/valsartan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Nebivolol<br>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<br>* 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<br>* Other names: Bystolic;|
| Active Comparator: Valsartan<br>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: Valsartan<br>* Valsartan 160 mg PO daily for 1 week followed by 320 mg daily for 3 weeks, followed by 1 week down-titration to 160 mg daily<br>* Other names: Diovan;|
| Active Comparator: Nebivolol/valsartan<br>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/valsartan<br>* Valsartan/Nebivolol, 160/20 mg daily for 1 week followed by 320/40 mg daily for 3 weeks, followed by 1 week down-titration to 160/20 mg daily<br>* Other names: Diovan/Bystolic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 24-hour myocardial oxygen consumption | Determined by 24-hour ambulatory heart rate-central systolic pressure product [ACRPP] at the end of each study phase (units) | 15 weeks | 
| Standard deviation of 24-hour myocardial oxygen consumption | Standard deviation of ACRPP | 15 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical peripheral systolic blood pressure | Seated office blood pressure (mmHg) | 15 weeks | 
| Clinical peripheral diastolic blood pressure | Seated brachial office blood pressure (mmHg) | 15 weeks | 
| Brachial heart rate-systolic pressure product | heart rate*systolic pressure (units) | 15 weeks | 
| 24-hour mean heart rate | Ambulatory heart rate averaged over 24 hours (bpm) | 15 weeks | 
| 24-hour central systolic pressure | Ambulatory pressure averaged over 24 hours (mmHg) | 15 weeks | 
| 24-hour central diastolic pressure | Ambulatory pressure averaged over 24 hours (mmHg) | 15 weeks | 
| 24-hour peripheral Systolic pressure | Ambulatory pressure averaged over 24 hours (mmHg) | 15 weeks | 
| 24-hour peripheral diastolic pressure | Ambulatory pressure averaged over 24 hours (mmHg) | 15 weeks | 
| 24-hour mean heart rate systolic pressure product | Ambulatory heart rate*systolic pressure averaged over 24 hours | 15 weeks | 
| Daytime myocardial oxygen consumption | Determined by ambulatory heart rate-central systolic pressure product (hours 6:00-21:59) at the end of each study phase (units) | 15 weeks | 
| Nighttime myocardial oxygen consumption | Determined by ambulatory heart rate-central systolic pressure product (hours 22:00-05:59) at the end of each study phase (units) | 15 weeks | 
| Daytime heart rate | Mean ambulatory heart rate (hours 6:00-21:59) (bpm) | 15 weeks | 
| Nighttime heart rate | Mean ambulatory heart rate (hours 22:00-05:59) (bpm) | 15 weeks | 
| Daytime central systolic pressure | Mean ambulatory central systolic pressure (hours 6:00-21:59) (mmHg) | 15 weeks | 
| Nighttime central systolic pressure | Mean ambulatory central systolic pressure (hours 22:00-05:59) (mmHg) | 15 weeks | 
| Daytime peripheral systolic pressure | Mean ambulatory peripheral systolic pressure (hours 6:00-21:59) (mmHg) | 15 weeks | 
| Nighttime peripheral systolic pressure | Mean ambulatory peripheral systolic pressure (hours 22:00-05:59) (mmHg) | 15 weeks | 
| Daytime central diastolic pressure | Mean ambulatory central diastolic pressure (hours 6:00-21:59) (mmHg) | 15 weeks | 
| Nighttime central diastolic pressure | Mean ambulatory central diastolic pressure (hours 22:00-05:59) (mmHg) | 15 weeks | 
| Daytime peripheral diastolic pressure | Mean ambulatory peripheral diastolic pressure (hours 6:00-21:59) (mmHg) | 15 weeks | 
| Nighttime peripheral diastolic pressure | Mean ambulatory peripheral diastolic pressure (hours 22:00-05:59) (mmHg) | 15 weeks | 
| Daytime heart rate systolic blood pressure product | Mean ambulatory heart rate systolic blood pressure product (hours 6:00-21:59) (units) | 15 weeks | 
| Nighttime heart rate systolic blood pressure product | Mean ambulatory heart rate systolic blood pressure product (hours 22:00-5:59) (units) | 15 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diastolic blood pressure, Myocardial oxygen consumption, Systolic blood pressure, Variability in hemodynamic indicators, Valsartan, Nebivolol, IEM ambulatory monitoring