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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04130438
Recruitment Status : Not yet recruiting
First Posted : October 17, 2019
Last Update Posted : December 12, 2019
Sponsor:
Information provided by (Responsible Party):
Jennifer Ann Tremmel, 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.

Condition or disease Intervention/treatment Phase
Myocardial Bridging Drug: Nebivolol Drug: Diltiazem Other: Placebo Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 360 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Efficacy of Medical Therapy in Women and Men With Angina and Myocardial Bridging
Estimated Study Start Date : March 1, 2020
Estimated Primary Completion Date : September 1, 2020
Estimated Study Completion Date : September 1, 2025

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Angina

Arm Intervention/treatment
Active Comparator: Beta Blocker (nebivolol) Drug: Nebivolol
The intervention to be tested is oral beta blocker (nebivolol 2.5 mg) vs. calcium channel blocker (Diltiazem-SR 120 mg) vs. placebo. Once enrolled, baseline data will be gathered and subjects will be randomly assigned to a treatment arm. Subjects will be instructed to take their assigned study drug once a day for 30 days.

Active Comparator: Calcium Channel Blocker (diltiazem) Drug: Diltiazem
The intervention to be tested is oral beta blocker (nebivolol 2.5 mg) vs. calcium channel blocker (Diltiazem-SR 120 mg) vs. placebo. Once enrolled, baseline data will be gathered and subjects will be randomly assigned to a treatment arm. Subjects will be instructed to take their assigned study drug once a day for 30 days.

Placebo Comparator: Placebo Other: Placebo
The intervention to be tested is oral beta blocker (nebivolol 2.5 mg) vs. calcium channel blocker (Diltiazem-SR 120 mg) vs. placebo. Once enrolled, baseline data will be gathered and subjects will be randomly assigned to a treatment arm. Subjects will be instructed to take their assigned study drug once a day for 30 days.




Primary Outcome Measures :
  1. Effectiveness of beta blockers and calcium channel blockers for reducing angina in patients with a Myocardial Bridge (MB) compared to placebo [ Time Frame: 6 months ]
    The study 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).


Secondary Outcome Measures :
  1. Changes in exercise capacity. [ Time Frame: 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. Scores will be categorized as low risk (≥+5), moderate risk (-10 to +4) and high risk (≤-11).

    Ref: L.J. Shaw, E.D. Peterson, L.K. Shaw, K.L. Kesler, E.R. Delong, F.E. Harrell Jr., L.H. Muhlbaier, D.B. Mark. Use of a prognostic treadmill score in identifying diagnostic coronary disease subgroups. Circulation, 98 (1998), pp. 1622-1630


  2. Changes in exercise capacity. [ Time Frame: 30 days ]
    We will also calculate the Duke Treadmill Score for each patient and compare this between groups.


Other Outcome Measures:
  1. Drug adherence. [ Time Frame: 30 days ]
    This will be measured by pill count at the end of 30 days.

  2. Side effects. [ Time Frame: 30 days ]
    These will be 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, we will also ask the patient of any side effects during their 30-day follow-up to ensure that we've captured any symptoms.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age ≥18 years
  2. Stable angina (typical or atypical, based on Diamond criteria (35))
  3. Exercise stress echocardiogram showing focal septal buckling with apical sparing (suggestive of an MB) (must have been performed within 3 months of enrollment while not on a beta blocker or calcium channel blocker)
  4. CCTA confirming the presence of an MB
  5. Absence of obstructive CAD, as demonstrated by no ischemia

Exclusion Criteria:

  1. Asymptomatic
  2. Status--post heart transplant
  3. Presence of another likely explanation of chest pain, such as pulmonary hypertension, hypertrophic obstructive cardiomyopathy, or aortic stenosis
  4. Presence of an acute coronary syndrome (unstable angina, NSTEMI, or STEMI), Tako--tsubo, or cardiogenic shock
  5. An abnormal left ventricular ejection fraction (EF<55%)
  6. Currently taking a beta blocker or calcium channel blocker
  7. History of a severe adverse reaction to beta blockers or calcium channel blockers (prior minor intolerance or ineffectiveness not exclusion)
  8. Use of existing medication that has an unsafe drug--drug interaction with beta blockers or calcium channel blockers
  9. Refusal to take beta blockers or calcium channel blockers
  10. Resting systolic blood pressure <100 mmHg or heart rate <50 beats per minute
  11. Inability to provide an informed consent, including an inability to speak, read, or understand English or Spanish
  12. 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
  13. A potentially vulnerable subject (including pregnant women, prisoners, economically and educationally disadvantaged, decisionally impaired, and institutionalized individuals)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04130438


Locations
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United States, California
Stanford University
Palo Alto, California, United States, 94305
Contact: Jennifer Tremmel, MD    650-723-0180    jtremmel@stanford.edu   
Sponsors and Collaborators
Stanford University
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Responsible Party: Jennifer Ann Tremmel, Interventional cardiologist, Stanford University
ClinicalTrials.gov Identifier: NCT04130438    
Other Study ID Numbers: 47447
First Posted: October 17, 2019    Key Record Dates
Last Update Posted: December 12, 2019
Last Verified: December 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Myocardial Bridging
Coronary Vessel Anomalies
Heart Defects, Congenital
Cardiovascular Abnormalities
Cardiovascular Diseases
Heart Diseases
Congenital Abnormalities
Nebivolol
Diltiazem
Antihypertensive Agents
Vasodilator Agents
Adrenergic beta-1 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Calcium Channel Blockers
Membrane Transport Modulators
Calcium-Regulating Hormones and Agents