Effect of Nebivolol on Oxidative Stress and Endothelial Progenitor Cells

Effect of Nebivolol on Oxidative Stress and Endothelial Progenitor Cells in Subjects With Hypertension

Hypertension, or high blood pressure, is a common disease that affects many Americans, and can lead to devastating consequences such as heart attack, stroke, and death if not treated. Nebivolol is a medication that has been recently approved by the FDA for the treatment of hypertension. Nebivolol has an unusual profile compared to other medications, in that its effects may be related to release of a substance called nitric oxide. Nitric oxide is released from the cells lining the blood vessels, and nebivolol may stimulate these cells to release more nitric oxide. Our study will investigate whether treatment with nebivolol, as compared to another medication called metoprolol, in hypertensive subjects will be more effective in protecting blood vessels against the harmful effects of high blood pressure. The mechanisms we will investigate include oxidative stress markers and circulating levels of endothelial progenitor cells.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Nebivolol; Drug: Metoprolol succinate

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males or post-menopausal females aged 21-80 years.
2. Hypertensive patients (BP >135/85) will be eligible to participate.
3. Patients on current anti-hypertensive therapy that does not include beta blockade should have BP >135/85.
4. Patients on anti-hypertensive therapy including beta blockade will have their beta blockers discontinued gradually over 2 weeks before enrolment.
5. Concomitant therapy: Patients will be allowed to be on comcomitant therapy with aspirin, statins, thiazide diuretics, calcium antagonists (for treatment of hypertension), clonidine, vasodilators, or angiotensin antagonists. Patients will be on stable medical therapy for at least 2 months before recruitment. Patients with previous treatment with beta adrenergic blockers (metoprolol, propranolol, atenolol, and labetalol) will also be eligible to participate, but will be randomized to the study beta blocker.

Exclusion Criteria:

1. Age < 21 or >80 years
2. Initiation or change in dose of statin or anti-hypertensive therapy within 2 months before the study
3. Premenopausal females with potential for pregnancy
4. Acute infection in previous 2 weeks
5. History of substance abuse
6. Current neoplasm
7. Chronic renal failure [creatinine > 2.5 mg/dL] or liver failure (Liver enzymes >2X normal)
8. Acute coronary syndrome, Class IV heart failure, CVA, coronary intervention within 2 months
9. Known aortic stenosis, hypertrophic cardiomyopathy.
10. Inability to give informed consent
11. Inability to return to Emory for follow-up testing

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Nebivolol/ Metoprolol; Subjects were randomized to nebivolol for 3 months. They "crossed over" to take 3 months of metoprolol succinate. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.	Drug: Nebivolol; Nebivolol 5 mg PO qday for 2 weeks, titrated up to Nebivolol 10 mg PO qday if BP is >125/80 for the 2 more weeks, and then titrated up to Nebivolol 20 mg PO qday if BP is >125/80 for the remaining 8 weeks; Other Names: Bystolic; Drug: Metoprolol succinate; Metoprolol 50 mg PO qday for 2 weeks, titrated up to Metoprolol 100 mg PO qday if BP is >125/80 for the 2 more weeks, and then titrated up to Metoprolol 200 mg PO qday if BP is >125/80 for the remaining 8 weeks; Other Names: Toprol XL
ACTIVE_COMPARATOR: Metoprolol/Nebivolol; Subjects were randomized to metoprolol succinate for 3 months. They "crossed over" to take 3 months of nebivolol. The initial 5 mg daily dose of nebivolol was titrated to 10 mg daily after 2 weeks if their BP remained >125/80, and subsequently titrated to 20 mg daily after another 2 weeks if the BP remained >125/80. Similarly, the initial 50 mg daily dose of metoprolol succinate was titrated to 100 mg daily after 2 weeks if BP remained >125/80, and further increased to 200 mg after 2 weeks if BP remained >125/80.	Drug: Nebivolol; Nebivolol 5 mg PO qday for 2 weeks, titrated up to Nebivolol 10 mg PO qday if BP is >125/80 for the 2 more weeks, and then titrated up to Nebivolol 20 mg PO qday if BP is >125/80 for the remaining 8 weeks; Other Names: Bystolic; Drug: Metoprolol succinate; Metoprolol 50 mg PO qday for 2 weeks, titrated up to Metoprolol 100 mg PO qday if BP is >125/80 for the 2 more weeks, and then titrated up to Metoprolol 200 mg PO qday if BP is >125/80 for the remaining 8 weeks; Other Names: Toprol XL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pulse Wave Velocity (Measure of Arterial Stiffness)	The pulse wave velocity (PWV) system measured the velocity of the blood pressure waveform between the carotid and femoral arteries using a single-lead electrocardiogram and tonometer to measure the pressure pulse waveform sequentially at the two peripheral artery sites. PWV is calculated as PWV=distance (d)/time (t) and the unit of measure is reported as meters per second (m/s).	Baseline
Pulse Wave Velocity (Measure of Arterial Stiffness)	The pulse wave velocity (PWV) system measured the velocity of the blood pressure waveform between the carotid and femoral arteries using a single-lead electrocardiogram and tonometer to measure the pressure pulse waveform sequentially at the two peripheral artery sites. PWV is calculated as PWV=distance (d)/time (t) and the unit of measure is reported as meters per second (m/s).	3 months
Pulse Wave Velocity (Measure of Arterial Stiffness)	The pulse wave velocity (PWV) system measured the velocity of the blood pressure waveform between the carotid and femoral arteries using a single-lead electrocardiogram and tonometer to measure the pressure pulse waveform sequentially at the two peripheral artery sites. PWV is calculated as PWV=distance (d)/time (t) and the unit of measure is reported as meters per second (m/s).	6 months

Collaborators and Investigators

• Sponsor: Emory University
• Collaborators: Forest Laboratories

Publications and helpful links

General Publications

• Hayek SS, Poole JC, Neuman R, Morris AA, Khayata M, Kavtaradze N, Topel ML, Binongo JG, Li Q, Jones DP, Waller EK, Quyyumi AA. Differential effects of nebivolol and metoprolol on arterial stiffness, circulating progenitor cells, and oxidative stress. J Am Soc Hypertens. 2015 Mar;9(3):206-13. doi: 10.1016/j.jash.2014.12.013. Epub 2014 Dec 31.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (ACTUAL): December 1, 2013
• Study Completion (ACTUAL): December 1, 2013

Study Registration Dates

• First Submitted: December 29, 2009
• First Submitted That Met QC Criteria: December 30, 2009
• First Posted (ESTIMATE): December 31, 2009

Study Record Updates

• Last Update Posted (ESTIMATE): December 19, 2014
• Last Update Submitted That Met QC Criteria: December 12, 2014
• Last Verified: December 1, 2014

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic Agonists; Adrenergic beta-Agonists; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Adrenergic beta-1 Receptor Agonists; Nebivolol; Metoprolol
• Other Study ID Numbers: IRB00013262; BYD-MD-20 (OTHER: Other)