Study to Evaluate Effect of Nebivolol on Angina in Women With Microvascular Disease (NIRVANA)

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Massachusetts General Hospital
Sponsor:
Collaborator:
Forest Laboratories
Information provided by (Responsible Party):
Nandita Scott, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT01665508
First received: August 9, 2012
Last updated: April 3, 2014
Last verified: April 2014
  Purpose

Women have less significant blockages of coronary arteries, however have greater symptoms and worse outcomes compared to their age-matched male counterparts. This paradox has led to the recognition and importance of the microvasculature ( small vessels) as a contributor to symptoms and outcomes. Nebivolol has unique antioxidant properties and dilates blood vessels and it is therefore proposed that treatment with nebivolol will reduce angina (chest symptoms) in women with microvascular disease as well as improve exercise capacity, reduce resource utilization and improve other measures of artery function.


Condition Intervention Phase
Microvascular Angina
Drug: Nebivolol
Phase 4

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Nebivolol for the Relief of Microvascular Angina in Women

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • Seattle Angina Questionnaire Score [ Time Frame: 3 months ] [ Designated as safety issue: No ]

    Seattle Angina Questionnaire (SAQ):

    The SAQ is a 5 part survey that is widely used and well validated tool to assess angina stability and angina frequency among patients with coronary artery disease.



Secondary Outcome Measures:
  • peak VO2 measured by cardiopulmonary exercise testing [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Assessment of exercise capacity (peak VO2) as determined by CPET, additional fitness parameters will include: VO2 at the anaerobic threshold, peak work-load, time-to-angina, aerobic efficiency and O2 pulse)

  • resource utilization questionnaire [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Resource utilization as determined by patient phone calls, office visits, emergency room visits, and number of hospitalizations, as well an index cost for any hospitalizations

  • SF36 [ Time Frame: baseline and 12 week follow-up ] [ Designated as safety issue: No ]
    widely used questionnaire used as a measure of health status will be obtained at baseline ( standardized care ) and follow-up ( 3 months on nebivolol)


Estimated Enrollment: 70
Study Start Date: April 2013
Estimated Study Completion Date: December 2014
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Nebivolol
Testing will be performed at baseline (SAQ questionnaire, cardiopulmonary testing, resource utilization, metabolomics and vascular testing). This will be repeated on the same group of patients after 3 months of nebivolol treatment.
Drug: Nebivolol
Patient to start nebivolol and have repeat testing in 3 months
Other Name: Bystolic

  Hide Detailed Description

Detailed Description:

Though women have less obstructive coronary artery disease (CAD) they continue to have a greater burden of symptoms, more myocardial ischemia, and a higher rate of adverse outcomes than their age-matched male counterparts. This ostensible paradox has led to the recognition of a distinct pathophysiology of ischemic heart disease, in part related to microvascular dysfunction, and abnormal coronary reactivity. The term primary microvascular angina, (MVA) is used to describe a syndrome among patients who have symptoms suggestive of cardiac ischemia, evidence of electrocardiographic abnormalities, abnormalities on stress imaging or a history of ACS, but no evidence of obstructive epicardial coronary disease. In this population, microvascular angina causes significant morbidity and in some may contribute to increased mortality.

The treatment of microvascular disease remains empirical due to lack of data regarding symptom alleviation, as well as ultimate mortality reduction. Women with ischemic heart disease and microvascular angina continue to report more frequent angina and worse quality of life. They frequently seek medical attention for the evaluation of cardiovascular symptoms including chest pain and shortness of breath. Consequently, these women incur greater healthcare costs, with more office visits, hospitalizations, and myocardial infarctions. In fact, more than one half of women without obstructive coronary disease continue to have ischemic symptoms that lead to further consumption of CAD resources, most often because of diagnostic uncertainty.

In the absence of robust outcomes data to drive the care of these women with microvascular ischemia, various approaches are taken, in addition to the fundamental management of baseline risk factors. Some physicians treat these women as they would treat patients with known obstructive CAD, while some, in the setting of "open" coronary arteries and persistent chest pain, opt for reassurance. Nevertheless, given that these women with microvascular ischemia continue to have higher morbidity and mortality, as well as increased resource consumption, there is a widely recognized need for effective therapeutic agents to reduce symptoms, improve quality of life, decrease resource consumption, and ultimately reduce mortality.

Nebivolol, due to its unique antioxidant and vasodilator properties, via its effect on NO bioactivity, and subsequent effects on the endothelium may be a potentially ideal therapeutic agent for the treatment of microvascular angina among women. For example, one previous study showed that nebivolol improved exercise parameters, as well as endothelial function, more effectively than other beta blockade with metoprolol, among patients with persistent angina and non-obstructive coronary disease.

Cardiopulmonary exercise testing is an ideal diagnostic test in this study as it will provide unique information on how microvascular ischemia influences functional capacity as measured through sensitive gas exchange parameters. Because it is known that a distinct pathophysiology contributes to microvascular angina among this subset of women, these parameters provided by CPET may provide essential information regarding the mechanism of symptom mitigation should nebivolol confer therapeutic value.

Furthermore, because exercise tolerance is often significantly impaired, objective measures of gas exchange that reflect submaximum and maximum fitness among these women will be useful both at baseline and on nebivolol.

Peripheral arterial tone and pulse wave analysis will also be performed. PAT signal technology provides a widely validated measurement of endothelium-mediated changes in vascular tone, using non-invasive bio-sensors on the fingertips that are elicited by creating a down-stream hyperemic response. This parameter correlates well with endothelial dysfunction in coronary arteries. We will perform endothelial function testing at baseline and after 3 months.

Metabolomics is an emerging field that offers the possibility of using the body's metabolites to both phenotype a disease as well as track its response to isolated perturbations, such as administration of a drug. In this study we will utilize metabolomics to define signatures of microvascular ischemia as well as nebivolol-mediated changes in metabolic profiles. Baseline metabolic profiling, as well as metabolic profiling after 3 months of nebivolol treatment will be performed in this study.

This type of assessment is an ideal complement to the clinical parameters delineated above as it combines targeted mass spectrometry to measures small molecules related to nitric oxide metabolism (ie: arginine, arginosuccinate, citrulline, ornithine, cGMP, ADMA) as well as more unbiased screening of metabolites that are not known to be associated with either nebivolol exposure or microvascular angina.

  Eligibility

Ages Eligible for Study:   40 Years to 80 Years
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • women between the ages of 40-80
  • with evidence of coronary microvascular dysfunction as determined by the presence of rest and or exertional chest tightness and a history of either an elevated troponin level or positive stress test ( EKG criteria or imaging) , as well as non-obstructive coronary artery disease (<50% epicardial obstruction) by either diagnostic catheterization with coronary angiography or CT angiography.

Exclusion Criteria:

  • Women who cannot tolerate a beta blocker.
  • Women receiving Hormone Replacement Therapy
  • Women of child-bearing age who are not on a birth-control method.
  • Women with inability to exercise.
  • Women with left ventricular systolic dysfunction (LVEF less than 40%)
  • Women who have a medical condition that, in the Investigator's opinion, would expose them to an increased risk of a significant adverse event or interfere with assessments of safety and efficacy during the course of the trial.
  • Women with any current malignancy, or any clinically significant hematological, endocrine, cardiovascular, renal, hepatic, gastrointestinal or neurological disease. If there is a history of such disease but the condition has been stable for at least the past year and is judged by the investigator not to interfere with the patient's participation in the study, the patient may be included.
  • Women who are unable to speak, read, and understand English and are judged by the investigator to be unable or unlikely to follow the study protocol and complete all scheduled visits.
  • Women with any contraindications to beta blocker therapy
  • Women with myocardial bridging
  • Women with Prinzmetal's angina
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01665508

Contacts
Contact: Nandita S Scott, MD 617 724 1739 nsscott@partners.org
Contact: Malissa J Wood, MD 617 724 1986 mjwood@partners.org

Locations
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Nandita S Scott, MD    617-724-1739    nsscott@partners.org   
Sub-Investigator: Aaron Baggish, MD         
Principal Investigator: Malissa J Wood, MD         
Principal Investigator: Nandita S Scott, MD         
Sub-Investigator: Gregory Lewis, MD         
Sponsors and Collaborators
Massachusetts General Hospital
Forest Laboratories
Investigators
Principal Investigator: Nandita S Scott, MD Massachusetts General Hospital
Principal Investigator: Malissa J Wood, MD Massachusetts General Hospital
  More Information

No publications provided

Responsible Party: Nandita Scott, Co-Director Corrigan Women's Heart Health Program, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01665508     History of Changes
Other Study ID Numbers: BYS-IT-75
Study First Received: August 9, 2012
Last Updated: April 3, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Massachusetts General Hospital:
angina
cardiopulmonary testing
metabolomics
nebivolol

Additional relevant MeSH terms:
Angina Pectoris
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Chest Pain
Pain
Signs and Symptoms
Nebivolol
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Vasodilator Agents
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 18, 2014