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

August 9, 2012
April 3, 2014
April 2013
December 2014   (final data collection date for primary outcome measure)
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.

Same as current
Complete list of historical versions of study NCT01665508 on ClinicalTrials.gov Archive Site
  • 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)
  • 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
  • peripheral arterial tone and pulse wave analysis [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Peripheral arterial tone ( PAT) and pulse wave analysis to determine whether or not nebivolol leads to changes in vascular relaxation and stiffness among women with microvascular ischemia ( if additional funding can be obtained)
  • circulating metabolites [ Time Frame: 3 months ] [ Designated as safety issue: No ]
    Blood samples will be collected into the edta tubes pre and post exercise at baseline and after 3 months of nebivolol treatment and stored at -80C. The list of metabolites assayed have been previously published by the investigators of this application. In brief, we have established a Lc-MS-based metabolomics platform that analysis approximately 300 human metabolites in a targeted manner. A metabolite can be identified by its parent mass and dominant daughter mass on a high resolution mass spectrometer in combination with its retention time on an appropriate LC column. The present platform can acquire the data for 300 metabolites in approximately 60 minutes from < 200ul of plasma.
Not Provided
Not Provided
 
Study to Evaluate Effect of Nebivolol on Angina in Women With Microvascular Disease
Nebivolol for the Relief of Microvascular Angina in Women

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.

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.

Interventional
Phase 4
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Microvascular Angina
Drug: Nebivolol
Patient to start nebivolol and have repeat testing in 3 months
Other Name: Bystolic
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.
Intervention: Drug: Nebivolol
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
70
December 2014
December 2014   (final data collection date for primary outcome measure)

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
Female
40 Years to 80 Years
No
Contact: Nandita S Scott, MD 617 724 1739 nsscott@partners.org
Contact: Malissa J Wood, MD 617 724 1986 mjwood@partners.org
United States
 
NCT01665508
BYS-IT-75
Yes
Nandita Scott, Massachusetts General Hospital
Massachusetts General Hospital
Forest Laboratories
Principal Investigator: Nandita S Scott, MD Massachusetts General Hospital
Principal Investigator: Malissa J Wood, MD Massachusetts General Hospital
Massachusetts General Hospital
April 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP