An Active-controlled, Clinical Trial to Assess Central Hemodynamic Effects of Bisoprolol in Hypertensive Patients (Central Hemodynamic Assessment Measured in Patient With HypertensION [CHAMPION])

A Prospective, Multi-center, Randomized, Open-label, Clinical Trial to Compare the Aortic Pulse Pressure Effects of Bisoprolol and Atenolol in 12 Weeks Treatment of Hypertension

Antihypertensive drugs aim to reduce blood pressure (BP) either through decrease of the total peripheral resistance through vasodilatation at the level of arterioles (microcirculation) or by decreasing the cardiac output through reduction of the stroke volume or heart rate or both. On the other hand, all antihypertensive drugs might potentially decrease arterial stiffness passively with the reduction of the distending pressure or with the resynchronization of the reflected pressure wave. With theses potential mechanisms, it is also expected that these drugs might exert a favorable effect on pulse pressure amplification between central and peripheral arteries.

However, there is solid evidence that the widely applied antihypertensive drugs have differential effect on brachial and central BP. Several reports in the past have confirmed the potential hypothesis that beta blockers decrease central BP less than the observed reduction at the level of the brachial artery. It has been hypothesized that deceleration of heart rate and the re synchronizing the reflected pressure wave earlier in the systolic phase seems to be the leading cause of non-favorable effect of beta blockers on central BP, these effects might be partially counterbalanced in beta blockers with high beta-1 selectivity resulting in less peripheral vasoconstriction properties.

Study Overview

• Status: Completed
• Conditions: Hypertension
• Intervention / Treatment: Drug: Bisoprolol; Drug: Atenolol

Detailed Description

Central pulse pressure is a better predictor of left ventricular mass and carotid intima thickness, and the conventional peripheral BP does not seem to be an accurate reflection of central arterial BP. The pulse pressure amplification between peripheral and central arteries reflects the left ventricular afterload, subendothelial viability, and the intensity of cyclic stress imposed to the renal and cerebral micro- and macro vessels. As central hemodynamic parameters are independently associated with organ damage and are closely related to important cardiovascular outcome, it is suggested that the new clinical trials on antihypertensive drug treatment should compare simultaneously the chronic effect of drugs on both peripheral and central BP.

OBJECTIVES

Primary objective:

• To assess the effect of bisoprolol versus atenolol on the aortic pulse pressure as a central hemodynamic index in subjects with hypertension

Secondary objectives:

• To assess the effect of bisoprolol versus atenolol on the aortic BP as a central hemodynamic index in subjects with hypertension
• To assess the effect of bisoprolol versus atenolol on the AIx and cfPWV as arterial stiffness indexes in subjects with hypertension
• To assess the effect of bisoprolol versus atenolol on the aortic pulse pressure as a central hemodynamic index at interim visit (Visit 4)
• To assess the effect of bisoprolol versus atenolol on the lipid profile and serum glucose as metabolism indexes
• To assess the effect of bisoprolol versus atenolol on the brachial BP as a peripheral BP index in subjects with hypertension
• To assess the safety and tolerability of bisoprolol versus atenolol in subjects with hypertension

The present study will be approximately of 14 weeks duration comprising of 1 week screening, followed by a 12 weeks treatment period and a 2 weeks post study follow up contact conducted via telephone to monitor additional serious adverse experiences.

There will be 4 scheduled visits (at Day -7, Day 0, Week 4 and Week 12). After screening period in which eligibility criteria were confirmed, subjects with hypertension will be randomized in a 1:1 ratio to receive treatment with either bisoprolol or atenolol. Hemodynamic measurements will be made at baseline, Week 4, Week 12 and biochemical measurements will be made at baseline (Day 0) and at Week 12.

• Study Type: Interventional
• Enrollment (Actual): 209
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of
    • Severance Hosptial, 250, Seongsanno, Seodaemungu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 71 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• An antihypertensive-naive subject or a subject who has not been taking the previously administered antihypertensive agent for at least 4 weeks prior to screening
• Subjects aged between 20 and 75 years, inclusive
• Subjects with systolic blood pressure (SBP) greater than or equal to 140 millimeter of mercury (mmHg) and less than 180 mmHg or diastolic blood pressure (DBP) greater than or equal to 90 mmHg and less than 110 mmHg

Exclusion Criteria:

• Subjects with secondary hypertension
• Subjects with renal impairment (Creatinine greater than 150 micromoles/liter [mcmol/L] or Creatinine greater than 1.7 mg/deciliter [dL])
• Subjects with severe hypertension (Stage III) SBP greater than or equal to 180 mmHg or DBP greater than or equal to 110 mmHg
• Subjects with congestive heart failure, acute myocardial infarction, unstable angina
• Subjects with moderate bronchial asthma, chronic obstructive pulmonary disease
• Subjects with symptomatic bradycardia, radial artery injury, second degree or third degree atrioventricular (AV) block, atrial fibrillation, atrial flutter, left bundle branch block (LBBB)
• Subjects with a history of hypersensitivity to bisoprolol and atenolol products
• Pregnancy or breastfeeding women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Bisoprolol	Drug: Bisoprolol; Bisoprolol tablet will be administered orally at a dose of 5 milligram (mg) once daily in the morning for 12 weeks.; Other Names: CONCOR®
Active Comparator: Atenolol	Drug: Atenolol; Atenolol tablet will be administered orally at a dose of 50 mg once daily in the morning for 12 weeks.; Other Names: TENORMIN®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Aortic Pulse Pressure (APP) in Intention to Treat (ITT) Population at Week 12	The APP was calculated as aortic systolic pressure minus aortic diastolic pressure. The change in APP at Week 12 was calculated as APP at Week 12 minus APP at baseline.	Baseline and Week 12
Change From Baseline in Aortic Pulse Pressure (APP) in Per Protocol (PP) Population at Week 12	The APP was calculated as aortic systolic pressure minus aortic diastolic pressure. The change in APP at Week 12 was calculated as APP at Week 12 minus APP at baseline.	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Aortic Blood Pressure (BP) at Week 4 and Week 12	The change in aortic BP (aortic systolic blood pressure [SBP], aortic diastolic blood pressure [DBP] and aortic mean blood pressure [BP]) at Week 4 and Week 12 was calculated as aortic BP (aortic SBP, aortic DBP and aortic mean BP) at Week 4 and Week 12 minus aortic BP (aortic SBP, aortic DBP and aortic mean BP) at baseline.	Baseline, Week 4 and Week 12
Change From Baseline in Aortic Augmentation Index (AIx) at Week 4 and Week 12	Augmentation index is a composite measure of wave reflection and systemic arterial stiffness which was calculated as the difference between the second and first systolic peaks. The change in AIx at Week 4 and Week 12 was calculated as AIx at Week 4 and Week 12 minus AIx at baseline.	Baseline, Week 4 and Week 12
Change From Baseline in Carotid-femoral Pulse Wave Velocity (cfPWV) at Week 4 and Week 12	Pulse wave velocity (PWV) is used as a measure of arterial stiffness, which is a measure of the cushioning functioning of major vessels like the aorta. The velocity of the Pulse wave (PW) along an artery is dependent on the stiffness of that artery. The change in cfPWV at Week 4 and Week 12 was calculated as cfPWV at Week 4 and Week 12 minus cfPWV at baseline.	Baseline, Week 4 and Week 12
Change From Baseline in Heart Rate at Week 4 and Week 12	The change in heart rate at Week 4 and Week 12 was calculated as heart rate at Week 4 and Week 12 minus heart rate at baseline.	Baseline, Week 4 and Week 12
Change From Baseline in Aortic Pulse Pressure (APP) at Week 4	The APP was calculated as aortic systolic pressure minus aortic diastolic pressure. The change in APP at Week 4 was calculated as APP at Week 4 minus APP at baseline.	Baseline and Week 4
Change From Baseline in Lipid Levels at Week 12	The lipid levels evaluated were total cholesterol, low density lipoprotein (LDL) cholesterol, and high density lipoprotein (HDL) cholesterol blood concentrations. The change in lipid levels at Week 12 was calculated as lipid levels at Week 12 minus lipid levels at baseline.	Baseline and Week 12
Change From Baseline in Blood Glucose Levels at Week 12	The change in blood glucose level at Week 12 was calculated as blood glucose level at Week 12 minus blood glucose level at baseline.	Baseline and Week 12
Change From Baseline in Brachial Blood Pressure (BP) at Week 4 and Week 12	The change in brachial BP (brachial SBP, brachial DBP and brachial mean BP) at Week 4 and Week 12 was calculated as brachial BP (brachial SBP, brachial DBP and brachial mean BP) at Week 4 and Week 12 minus brachial BP (brachial SBP, brachial DBP and brachial mean BP) at baseline.	Baseline, Week 4 and Week 12
Number of Participants With Adverse Events (AEs)	An adverse event (AE) was defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline during a clinical study with an Investigational Medicinal Product (IMP), regardless of causal relationship and even if no IMP has been administered.	Baseline up to Week 14 (follow-up visit)

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Collaborators: Merck Ltd.
• Investigators: Study Director: Medical Responsible, Merck Ltd., Korea, an affiliate of Merck KGaA, Darmstadt, Germany

Publications and helpful links

General Publications

• Park S, Rhee MY, Lee SY, Park SW, Jeon D, Kim BW, Kwan J, Choi D. A prospective, randomized, open-label, active-controlled, clinical trial to assess central haemodynamic effects of bisoprolol and atenolol in hypertensive patients. J Hypertens. 2013 Apr;31(4):813-9. doi: 10.1097/HJH.0b013e32835e8f5b.

Study record dates

Study Major Dates

• Study Start: December 1, 2009
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): October 1, 2011

Study Registration Dates

• First Submitted: March 2, 2010
• First Submitted That Met QC Criteria: March 2, 2010
• First Posted (Estimate): March 3, 2010

Study Record Updates

• Last Update Posted (Estimate): February 13, 2014
• Last Update Submitted That Met QC Criteria: January 20, 2014
• Last Verified: January 1, 2014

More Information

Terms related to this study

• Keywords: Hypertension; Blood pressure; Bisoprolol; Atenolol
• 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; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Bisoprolol; Atenolol
• Other Study ID Numbers: EMD 084000-505