The Effect of Nebivolol in Hypertensive Patients With Coronary Arterial Spasm

The correlation between endothelial dysfunction and the risk of coronary heart disease is well known through previous studies. The degradation of the function of nitric oxide acting on the endothelium of blood vessels is mainly explained by reduction of synthesis, loss due to oxidative stress, and decreased sensitivity to vascular dilatation action. In particular, patients with high blood pressure have been known to have impaired vascular endothelial function through animal experiments and several clinical studies, mainly due to increased biomechanical friction in the blood vessels and decreased biological availability of nitric oxide, which in turn causes incongruity in the production of nitric monoxide and changes in normal vascular dilatation. There have also been reports recently that early diagnosis and treatment may improve endothelial dysfunction and prevent the progression of coronary artery disease. However, the reality is that the drugs available in vasospastic angina patients with endothelial dysfunction are very limited. Until recently, beta-blockers were reported to inhibit vascular dilatation of adrenaline stimuli, a drug corresponding to relative contraindications in vasospastic angina patients, with one study reporting that propranolol cannot, but rather exacerbates, vasospastic angina. However, a series of reports on the vascular dilatation of the recently developed third-generation beta-blockers have reinvented the role of beta-blockers in vasospastic angina, especially nebivolol (selective, continuous beta-blockers) is known to act on β-1 adrenaline receptor blockings and endothelium to create vascular dilatation, and also to stimulate β-3 adrenaline receptors to cause nitric oxide generation and antioxidant effects in the endothelium of blood vessels. Therefore, this clinical trial seeks to find whether nebivolol will inhibit vascular contraction in hypertensive patients and will work in angiospastic angina patients.

Study Overview

• Status: Completed
• Conditions: Coronary Vasospasm
• Intervention / Treatment: Drug: Nebivolol; Drug: Diltiazem; Drug: Nebivolol+Diltiazem

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 02841
    • Korea University Anam Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 20 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• hypertension (stage I-2: Systolic blood pressure 140-179mmHg and diastolic blood pressure 90-109mmHg)
• 20 to 80 years old
• diagnosed with vasospastic angina through coronary angiography and provocation test
• available to outpatient treatment
• voluntarily signed a written consent to participate in the clinical trial

Exclusion Criteria:

1. Previous history of hypersensitivity to beta blockers or calcium channel blockers
2. History of dementia or accompanying psychiatric illness or history of drug abuse
3. Those who participated in other clinical trials within 1 month before screening
4. A person who is unable to perform compliance with the plan and procedures, or who has been judged by the tester to be in a medical condition inappropriate for participation
5. Study subjects who are taking drugs that can affect the study drug efficacy evaluation (ACE inhibitors, angiotensin blockers, beta blockers other than clinical trial drugs, calcium antagonists other than clinical trial drugs, diuretics other than indapamide). These subjects are allowed to participate after a wash-out period of at least 2 weeks
6. Malignant hypertension (with retinal hemorrhage or papilledema) or known moderate or severe retinopathy (retinal hemorrhage within the last 6 months, visual disturbance, retinal microaneurysm)
7. A history of secondary hypertension and all suspected secondary hypertension: coarctation of the aorta, hyperaldosteronism, renal artery stenosis, Cushing's disease, chromatin-positive cell tumor, polycystic kidney disease, etc.
8. Patients with orthostatic hypotension with symptoms
9. Patients with severe heart disease (heart failure New York Heart Association class 3 and 4), recent 6-month ischemic heart disease (angina pectoris, myocardial infarction), percutaneous coronary intervention, or coronary artery bypass surgery)
10. Patients with severe cerebrovascular disease (stroke, cerebral infarction, cerebral hemorrhage within the last 6 months)
11. Patients with anuria or severe renal failure (creatinine clearance <30 mL / min)
12. Severe liver failure or AST or ALT> 3 times the upper limit of normal, biliary obstruction, biliary cirrhosis, cholestasis
13. Gastrointestinal diseases and surgery patients that may affect the absorption, distribution, metabolism, and excretion of drugs, current active gastritis and gastrointestinal / rectal bleeding that the tester considers clinically significant, active inflammatory bowel syndrome within the last 12 months
14. Pregnant and lactating women, those who have a pregnancy plan during the trial and do not agree with the appropriate method of contraception

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Nebivolol group; Oral Nebivolol 5mg / day (2 weeks) -> 10mg / day (10 weeks)	Drug: Nebivolol; Patients are randomly assigned to a ratio of 1: 1: 1, divided into 3 groups.
Placebo Comparator: Diltiazem group; Oral Diltiazem 90mg / day (2 weeks) -> 180mg / day (10 weeks)	Drug: Diltiazem; Patients are randomly assigned to a ratio of 1: 1: 1, divided into 3 groups.
Placebo Comparator: Nebivolol+Diltiazem group; Oral Nebivolol 2.5mg / day + Oral Diltiazem 45mg / day (2 weeks) -> Oral Nebivolol 5mg / day + Oral Diltiazem 90mg / day (10 weeks)	Drug: Nebivolol+Diltiazem; Patients are randomly assigned to a ratio of 1: 1: 1, divided into 3 groups.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in coronary spasm	The descriptive statistics (mean subject number, standard deviation, median value, minimum value, and maximum value) of changes in the baseline and 12-week outcomes will be presented for each treatment group, and the comparison between the three groups for ANOVA or ANOVA Kruskal-Wallis test. Changes in each group will be analyzed using Paired t-test or Wilcoxon signed rank test. An ANCOVA analysis will be performed when there are more influencing factors.	Baseline to 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Quality of Life	Changes in Quality of Life based on Seattle Angina Questionnaire	Baseline to 12 weeks
Changes in mean sitting systolic blood pressure and mean sitting diastolic blood pressure	Changes in mean sitting systolic blood pressure and mean sitting diastolic blood pressure	Baseline to 6, 12 weeks
Percentage of target blood pressure reached	Percentage of target blood pressure reached from baseline to 6, 12 weeks	Baseline to 6, 12 weeks

Collaborators and Investigators

• Sponsor: Korea University Anam Hospital
• Collaborators: Korea University Guro Hospital; Severance Hospital; Korea University Ansan Hospital

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2018
• Primary Completion (Actual): March 31, 2019
• Study Completion (Actual): March 31, 2019

Study Registration Dates

• First Submitted: April 24, 2019
• First Submitted That Met QC Criteria: April 25, 2019
• First Posted (Actual): April 29, 2019

Study Record Updates

• Last Update Posted (Actual): March 10, 2020
• Last Update Submitted That Met QC Criteria: March 8, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Nebivolol
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Coronary Disease; Coronary Vasospasm; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Adrenergic Agonists; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Adrenergic beta-Agonists; Adrenergic beta-1 Receptor Agonists; Nebivolol; Diltiazem
• Other Study ID Numbers: NevibololSpasm

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No