High Blood Pressure
Conditions
Keywords
Nitric Oxide, Adrenergic beta-Antagonists, Antihypertensive Agents, Vasodilator Agents, Anti-Arrhythmia Agents, Sympatholytics, Vascular Resistance, Neurotransmitter Agents, Cardiovascular Diseases, Metoprolol succinate, Therapeutic Uses, Metoprolol, Vascular Diseases, Nebivolol, Cardiovascular Agents, Endothelium-Dependent Relaxing Factors
Brief summary
High blood pressure (hypertension) is called the silent killer because many people do not know they have it, and do not know when it is well controlled. Unfortunately, over time uncontrolled hypertension can cause irreversible organ damage that can lead to heart attack, stroke, heart failure, and kidney failure. If a person cannot control their blood pressure with diet and exercise, doctors often prescribe medications to help control the blood pressure. Nebivolol is a medication that has been recently approved by the FDA for the treatment of hypertension. Our study will investigate whether treatment with nebivolol, as compared to another medication called metoprolol, in African Americans with hypertension will be more effective in protecting blood vessels against the harmful effects of high blood pressure. Over time high blood pressure causes hardening of the arteries (atherosclerosis) which leads to narrowing of the blood vessels and reduces blood flow to our organs. Arteries also relax and contract naturally, which further changes the blood supply. When arteries are narrowed, exercise can bring on a condition in which the blood supply is inadequate, and this might result in the sensation of pain. Cells lining our blood vessels produce a variety of substances that normally cause arteries to relax. Two of these substances are called nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF). We are trying to determine the nature of these substances in African Americans with high blood pressure and how it is affected by nebivolol and metoprolol. One way to determine this is to inject drugs such as L-NMMA (N(G)-monomethyl-L-arginine) or TEA (tetraethylammonium chloride), which block the production of NO and EDHF respectively, and then study what happens to the blood flow at rest and during exercise. It is our thought that nebivolol, in comparison to metoprolol, will increase the substances that naturally cause arteries to relax and improve blood supply.
Interventions
DRUGNebivolol
Subjects will be randomized to either nebivolol or metoprolol xl, and remain on the study drug for 10 weeks. They will then cross over to take 10 weeks of the comparator drug.
DRUGMetoprolol XL
Subjects will be randomized to either nebivolol or metoprolol xl, and remain on the study drug for 10 weeks. They will then cross over to take 10 weeks of the comparator drug.
Sponsors
Forest Laboratories
Emory University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
21 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Male or post-menopausal females aged 18-80 years. * Subjects self-identified as black or African-American. * Diagnosis of hypertension. * Patients on current anti-hypertensive therapy that does not include beta blockade should have BP \>135/85. * Patients on anti-hypertensive therapy including beta blockers will have their beta blockers discontinued gradually over 2 weeks before enrolment. * Concomitant therapy: Patients will be allowed to be on concomitant therapy with aspirin, statins, thiazide diuretics, calcium antagonists (for treatment of hypertension), clonidine, or vasodilators. 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
* Initiation or change in dose of statin or other anti-hypertensive therapy within 2 months before the study * Inability to return to Emory for follow-up testing * Age \< 21 or \>80 years * Premenopausal females with potential for pregnancy * Acute infection in previous 2 weeks * On angiotensin antagonists (ACE inhibitors or ARBs) * History of substance abuse * Current neoplasm * Chronic renal failure \[creatinine \> 2.5 mg/dL\] or liver failure (liver enzymes \>2X normal) * Acute coronary syndrome, Class IV heart failure, CVA, coronary intervention within 2 months * Known aortic stenosis, hypertrophic cardiomyopathy. * Inability to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks | 12 weeks | Forearm blood flow measured by venous occlusion plethysmography at rest, after administration of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium chloride (TEA), after administration of L-NMMA, TEA, and acetylcholine, and after administration of L-NMMA, TEA, and exercise. Unit of Measure refers to volume of blood (mL) per 100 mL of forearm tissue per minute. |
| Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks | 24 weeks | Forearm blood flow measured by venous occlusion plethysmography at rest, after administration of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium chloride (TEA), after administration of L-NMMA, TEA, and acetylcholine, and after administration of L-NMMA, TEA, and exercise. Unit of Measure refers to volume of blood (mL) per 100 mL of forearm tissue per minute. |
Countries
United States
Participant flow
Recruitment details
Subjects recruited from the general medical clinics of The Emory Clinic, Emory University Hospital, and Grady Memorial Hospital between January 2010 through January 2012.
Pre-assignment details
91 subjects were enrolled but 47 subjects were withdrawn prior to group assignment due to various factors, which included eligibility criteria, lost to follow-up, and withdrawal by subject.
Participants by arm
| Arm | Count |
|---|---|
| Nebivolol/Metoprolol XL Subjects were randomized to Nebivolol 5mg and titrated to Nebivolol 10mg two weeks after drug initiation. Ten weeks after titration, subjects crossed over to Metoprolol XL 50mg and titrated to Metoprolol XL 100mg two weeks after cross over. | 11 |
| Metoprolol XL/Nebivolol Subjects were randomized to Metoprolol XL 50mg and titrated to Metoprolol XL 100mg two weeks after drug initiation. Ten weeks after titration, subjects crossed over to Nebivolol 5mg and titrated to Nebivolol 10mg two weeks after cross over. | 8 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Treatment Period 1 (12 Weeks) | Lost to Follow-up | 0 | 1 |
| Treatment Period 1 (12 Weeks) | Protocol Violation | 2 | 2 |
| Treatment Period 2 (12 Weeks) | Lost to Follow-up | 2 | 3 |
| Treatment Period 2 (12 Weeks) | Protocol Violation | 8 | 7 |
Baseline characteristics
| Characteristic | Nebivolol/Metoprolol XL | Metoprolol XL/Nebivolol | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 8 Participants | 19 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 7 Participants | 6 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 23 | 0 / 21 |
| serious Total, serious adverse events | 0 / 23 | 0 / 21 |
Outcome results
Primary
Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks
Forearm blood flow measured by venous occlusion plethysmography at rest, after administration of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium chloride (TEA), after administration of L-NMMA, TEA, and acetylcholine, and after administration of L-NMMA, TEA, and exercise. Unit of Measure refers to volume of blood (mL) per 100 mL of forearm tissue per minute.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nebivolol/Metoprolol XL | Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks | At rest | 2.739 mL/100 mL/min | Standard Deviation 1.365 |
| Nebivolol/Metoprolol XL | Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks | L-NMMA+TEA | 1.963 mL/100 mL/min | Standard Deviation 0.968 |
| Nebivolol/Metoprolol XL | Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks | L-NMMA+TEA+ACh | 5.376 mL/100 mL/min | Standard Deviation 3.362 |
| Nebivolol/Metoprolol XL | Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks | L-NMMA+TEA+exercise | 7.377 mL/100 mL/min | Standard Deviation 2.754 |
| Metoprolol XL/Nebivolol | Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks | L-NMMA+TEA+exercise | 11.574 mL/100 mL/min | Standard Deviation 4.716 |
| Metoprolol XL/Nebivolol | Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks | At rest | 2.679 mL/100 mL/min | Standard Deviation 0.0901 |
| Metoprolol XL/Nebivolol | Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks | L-NMMA+TEA+ACh | 7.562 mL/100 mL/min | Standard Deviation 4.358 |
| Metoprolol XL/Nebivolol | Endothelial Function Measured by Forearm Blood Flow (FBF) at 12 Weeks | L-NMMA+TEA | 2.221 mL/100 mL/min | Standard Deviation 0.63 |
Primary
Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks
Forearm blood flow measured by venous occlusion plethysmography at rest, after administration of N(G)-monomethyl-L-arginine (L-NMMA) and tetraethylammonium chloride (TEA), after administration of L-NMMA, TEA, and acetylcholine, and after administration of L-NMMA, TEA, and exercise. Unit of Measure refers to volume of blood (mL) per 100 mL of forearm tissue per minute.
Time frame: 24 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nebivolol/Metoprolol XL | Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks | At rest | 3.066 mL/100 mL/min | Standard Deviation 1.469 |
| Nebivolol/Metoprolol XL | Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks | L-NMMA+TEA+ACh | 7.158 mL/100 mL/min | Standard Deviation 4.875 |
| Nebivolol/Metoprolol XL | Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks | L-NMMA+TEA+exercise | 9.589 mL/100 mL/min | Standard Deviation 3.55 |
| Nebivolol/Metoprolol XL | Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks | L-NMMA+TEA | 2.457 mL/100 mL/min | Standard Deviation 1.549 |
| Metoprolol XL/Nebivolol | Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks | L-NMMA+TEA+exercise | 10.395 mL/100 mL/min | Standard Deviation 2.687 |
| Metoprolol XL/Nebivolol | Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks | At rest | 2.968 mL/100 mL/min | Standard Deviation 1.164 |
| Metoprolol XL/Nebivolol | Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks | L-NMMA+TEA | 2.287 mL/100 mL/min | Standard Deviation 0.693 |
| Metoprolol XL/Nebivolol | Endothelial Function Measured by Forearm Blood Flow (FBF) at 24 Weeks | L-NMMA+TEA+ACh | 7.534 mL/100 mL/min | Standard Deviation 4.523 |