Efficacy of Medical Therapy in Women and Men With Angina and Myocardial Bridging

Phase 2

Terminated

Conditions: Myocardial Bridging

Interventions: Other: Placebo
Drug: Nebivolol
Drug: Diltiazem

Registration Number: NCT04130438

Lead Sponsor: Stanford University

Brief Summary: The proposed clinical trial is relevant to public health because it is expected to expand the differential diagnosis and provide an evidence--based therapy for the large population of patients with angina in the absence of obstructive CAD who currently remain undiagnosed and untreated. It, therefore, upholds an important part of the mission of the The National Heart, Lung, and Blood Institute (NHLBI), which is to promote the treatment of heart disease and enhance the health of all individuals so that they can live longer and more fulfilling lives.

Detailed Description: Angina in the absence of obstructive coronary artery disease (CAD) affects millions, resulting in a reduced quality of life and a burden on the health care system. Previous work has focused on endothelial and microvascular dysfunction as causes of angina in these patients, but even when these etiologies are tested for, nearly half of patients remain undiagnosed, and proven therapies are lacking. The long--term goal of this research proposal is to improve the lives of patients with angina in the absence of obstructive CAD. These patients have been found to have a disproportionate prevalence of myocardial bridges (MBs) (60% vs. 30% in the general population).

MBs are known to cause angina, and the mechanism by which they do so is also known, but MBs have not been actively studied in the context of patients with angina in the absence of obstructive CAD. Medical therapies for symptomatic MBs, including beta blockers and calcium channel blocker have been suggested, but have never been appropriately tested, and may not be better than placebo. The overall objective of this research proposal is to demonstrate that MBs are an important and treatable cause of angina in patients with non--obstructive CAD.

The investigator will conduct the first--ever randomized, double--blind, placebo--controlled trial of medical therapy in patients with angina and an MB. The rationale is that a proven treatment would significantly expand the paradigm by which patients with angina in the absence of obstructive CAD are evaluated and treated. Our central hypothesis is that beta blockers and calcium channel blockers are effective treatments for reducing angina in patients with an MB compared with placebo. Guided by strong preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) Determine the efficacy of beta blockers and calcium channel blockers in treating patients with angina and an MB and 2) Identify predictors of efficacy of beta blockers and calcium channel blockers in treating patients with angina and an MB. For Aim #1, the investigator will randomize a total of 360 adult patients with angina and an MB into one of three treatment arms: beta blocker (nebivolol), calcium channel blocker (diltiazem), or placebo (1:1:1).

Efficacy will be determined after 30 days on the study drug by a change in angina, as assessed by the Seattle Angina Questionnaire (SAQ). The investigator will also evaluate changes in exercise capacity, as well as drug adherence and side effects. For Aim #2, the investigator will evaluate MB muscle index (MMI, a product of MB length x depth) by coronary computed tomography angiography, as well as male sex, as predictors of efficacy. Randomization will be stratified on sex, ensuring a balance of women and men in each arm. The proposed research is innovative because it shifts the current clinical perspective on angina in the absence of obstructive CAD by considering myocardial bridging as a potential etiology.

It is also significant because it will substantially increase the number of patients with angina in the absence of obstructive CAD that clinicians are able to diagnose and treat, ultimately leading to improvements in quality of life and a reduction in health care costs.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 5

Inclusion Criteria

Not provided

Exclusion Criteria

Asymptomatic
Status--post heart transplant
Presence of another likely explanation of chest pain, such as pulmonary hypertension, hypertrophic obstructive cardiomyopathy, or aortic stenosis
Presence of an acute coronary syndrome (unstable angina, NSTEMI, or STEMI), Tako--tsubo, or cardiogenic shock
An abnormal left ventricular ejection fraction (EF<55%)
History of a severe adverse reaction to beta blockers or calcium channel blockers (prior minor intolerance or ineffectiveness not exclusion)
Use of existing medication that has an unsafe drug--drug interaction with beta blockers or calcium channel blockers
Refusal to take beta blockers or calcium channel blockers
Resting systolic blood pressure <100 mmHg or heart rate <50 beats per minute
Inability to provide an informed consent, including an inability to speak, read, or understand English or Spanish
A hearing impairment that won't allow for a typical verbal conversation or a visual impairment that won't allow for reading of the written consent
A potentially vulnerable subject (including pregnant women, prisoners, economically and educationally disadvantaged, decisionally impaired, and institutionalized individuals)

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	-
Beta Blocker (nebivolol)	Nebivolol	-
Calcium Channel Blocker (diltiazem)	Diltiazem	-

Primary Outcome Measures

Name	Time	Method
Change in Angina Score Assessed by the Seattle Angina Questionnaire (SAQ)	baseline and 30 days	Effectiveness of beta blockers and calcium channel blockers for reducing angina in patients with a Myocardial Bridge (MB) compared to placebo determined after 30 days on the study drug by a change in angina, as assessed by the Seattle Angina Questionnaire (SAQ). The SAQ assesses 5 domains: physical limitation, angina stability angina frequency, treatment satisfaction, and quality of life. Each domain score is normalized to a range of 0 to 100, with higher scores corresponding to better outcomes.

Secondary Outcome Measures

Name	Time	Method
Duke Treadmill Score by Risk Category	baseline, 30 days	Changes in exercise capacity will be measured by difference in exercise time increment between the groups. The Duke treadmill score is calculated as exercise time × (5 × ST-segment deviation) - (4 × exercise angina), with 0 = no angina, 1 = non-limiting angina, and 2 = exercise-limiting angina. Possible scores range from -25 (highest risk) to +15 (lowest risk). Scores are reported by the number of participants in each risk category: low risk (≥+5), moderate risk (-10 to +4) and high risk (≤-11) (Shaw, et al, 1998).
Duke Treadmill Score	baseline, 30 days	The Duke treadmill score is calculated as exercise time × (5 × ST-segment deviation) - (4 × exercise angina), with 0 = no angina, 1 = non-limiting angina, and 2 = exercise-limiting angina. Possible scores range from -25 (highest risk) to +15 (lowest risk).
Number of Participants With Cardiac Events	30 days, 6 months	Major adverse cardiovascular events include death, heart attack, coronary stent or bypass surgery, and stroke.
Drug Adherence.	30 days	Percentage of drug taken by participants, measured by pill count at the end of 30 days.
Number of Participants With Side Effects	30 days	Patient self-reported side effects recorded in a diary to be turned in at 30 days. In addition, patients are requested to contact us regarding any serious side effects during the study. Finally, patients are asked about any side effects they experienced during their 30-day follow-up to ensure that symptoms are captured.
Treatment Course	6 months	Number of participants who stayed on the study drug at the initial dose, stayed on the study drug at a different dose, switched to an alternate therapy, and/or underwent further cardiac testing.