Can Nebivolol Reverse Inappropriate Left Ventricular Mass in Hypertensive Patients? (Inapprop)

The purpose of this study is to evaluate if a drug called nebivolol can reverse inappropriate left ventricular mass (LVM) when compared to the standard of care drug metoprolol.

Study Overview

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

Detailed Description

In response to chronic pressure overload by arterial hypertension, the cardiac left ventricle undergoes hypertrophy, that is, increases its wall thickness and, therefore, its mass, to sustain the elevated workload. Such anatomical remodeling can be considered adaptive or appropriate. However, in a considerable number of patients with arterial hypertension, the increase in the left ventricular mass is excessive and, thus, inappropriate.

Ventricular mass is inappropriate when its amount surpasses the physical need of the ventricle to sustain the elevated workload. Therefore, ventricular mass can be inappropriate even in patients without arterial hypertension or without hypertrophy identified by echocardiography (echo). We can mathematically predict an appropriate amount of mass and observe the actual mass in individual patients based on ventricular workload and wall thickness, respectively, noninvasively evaluated by echo. By comparing the observed ventricular mass to the predicted one, we determine whether its amount is inappropriate. It follows that by therapeutically normalizing blood pressure in hypertension and thus eliminating the elevated workload, then any ventricular hypertrophy represents an inappropriate mass.

Inappropriate ventricular mass is proven to have a detrimental effect on long-term cardiovascular event-free survival, and ventricular hypertrophy is increasingly recognized as a potent risk factor of cardiovascular morbidity and mortality, and all-cause mortality. Ventricular performance is altered in hypertension with inappropriate mass, but this alteration can be subtle enough to escape detection using current echocardiography measures. Hence, patients with hypertension, who have inappropriate left ventricular mass, need to be specifically identified by analysis of the predicted and observed ventricular mass, and the therapeutic goal must include management of elevated blood pressure as well as reversal of the excessive ventricular mass.

In this double-blind prospective study, patients with hypertension and inappropriate ventricular mass will be randomized to therapy with nebivolol or metoprolol to find out whether nebivolol could reverse inappropriate left ventricular mass, thus providing a benefit beyond what is achieved by mere blood pressure reduction alone. If confirmed, this will represent a significant ancillary ability of nebivolol and be a key step towards therapy of inappropriate ventricular mass, which is a so far unmanaged cardiovascular risk and a poor event-free prognostic factor.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Scottsdale, Arizona, United States, 85259
      • Mayo Clinic Arizona

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 30 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

All candidates must have previously untreated hypertension. The candidates will be picked from patients with stage-1 hypertension (systolic BP 140-159 mm Hg or diastolic BP 90-99 mm Hg) and those with stage-2 hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥100), based on the seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines (JNC-7).

Inclusion Criteria:

• Presence of inappropriate LVM.
• Presence of phenotype of inappropriate LVM.

Exclusion Criteria:

The criteria will assure that only patients with hypertension are enrolled, that is, excluded will be subjects with systolic BP < 140 or diastolic BP < 90 (ie, prehypertension or normal BP), but without complications or any indication (or suspicion) of end-organ damage based on a physical exam, clinical history, or laboratory tests.

Specific exclusion criteria are:

• Reactive airways disease including asthma.
• Diabetes mellitus or hypoglycemia; thyrotoxicosis.
• LV dysfunction (ejection fraction < 50%) or heart failure.
• Present or previously documented coronary heart disease or angina.
• Acute myocardial infarction, or history of myocardial infarction.
• Severe bradycardia, heart block greater than first degree or sick sinus syndrome (unless a permanent pacemaker is in place).
• Hepatic insufficiency or history of cirrhosis.
• Chronic renal failure or renovascular dysfunction.
• Cerebrovascular dysfunction.
• Peripheral vascular disease.
• Pregnant or nursing women; women of childbearing age will be required to take a pregnancy test at the time of enrollment and use an acceptable method of birth control.
• Poor echo image quality.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Nebivolol; Subjects randomized to this arm will receive Nebivolol 2.5 mg once daily.	Drug: Nebivolol; Nebivolol 2.5 mg once daily; Other Names: Bystolic
OTHER: Metoprolol succinate; Subjects randomized to this arm will receive metoprolol succinate 50 mg once daily.	Drug: Metoprolol succinate; Metoprolol succinate 50 mg once daily; Other Names: Toprol XL

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Inappropriate Left Ventricular Mass (LVM)	LVM will be measured by echocardiography exam. LVM is inappropriate when observed LVM (oLVM) exceeds predicted LVM (pLVM) by more than 28%, that is, 100×(oLVM/pLVM) >128%.	baseline, 6 months

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Collaborators: Forest Laboratories
• Investigators: Principal Investigator: Marek Belohlavek, MD, PhD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start: June 1, 2012
• Primary Completion (ACTUAL): March 1, 2013
• Study Completion (ACTUAL): March 1, 2013

Study Registration Dates

• First Submitted: May 22, 2012
• First Submitted That Met QC Criteria: May 23, 2012
• First Posted (ESTIMATE): May 24, 2012

Study Record Updates

• Last Update Posted (ESTIMATE): May 19, 2014
• Last Update Submitted That Met QC Criteria: May 8, 2014
• Last Verified: May 1, 2014

More Information

Terms related to this study

• Keywords: Hypertension, Left Ventricular Mass
• 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: 11-007035