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Comprehensive Treatment of Angina in Women With Microvascular Dysfunction (CORA)

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. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02910154
Recruitment Status : Unknown
Verified February 2017 by Eva Prescott, Bispebjerg Hospital.
Recruitment status was:  Recruiting
First Posted : September 21, 2016
Last Update Posted : February 14, 2017
Sponsor:
Collaborators:
University Hospital Bispebjerg and Frederiksberg
Cambridge Weight Plan Limited
Information provided by (Responsible Party):
Eva Prescott, Bispebjerg Hospital

Brief Summary:

Angina is the most common symptom of coronary heart disease among women but unlike men most women do not have stenosis of the coronary arteries. In a large proportion of these women, coronary microvascular dysfunction (CMD) is thought to be the cause of angina. However, CMD is also demonstrable in the asymptomatic population, and may merely be an innocent bystander related to the presence of cardiovascular risk factors rather than a cause of angina symptoms.

The aim of this study is to determine whether comprehensive intervention is feasible and results in improvement in both angina and microvascular function in these patients.


Condition or disease Intervention/treatment Phase
Angina Pectoris Coronary Microvascular Disease Dietary Supplement: Diet Behavioral: Training Drug: Medication (with statin and ACE-inhibition) Not Applicable

Detailed Description:

Coronary microvascular dysfunction is found to be associated with a significant adverse prognosis. The condition is strongly associated with increased future risk of major cardiovascular events, frequent hospital readmission, continued angina and loss of quality of life compared to the general population.

Pathophysiology of microvessel disease:

In the heart 95% of the blood flow is controlled by the microcirculation. When oxygen demand is increased the normal response of the microvessels is to reduce resistance in order to increase flow. When microvessels are dysfunctional the blood flow in the larger coronary vessels does not increase sufficiently to meet oxygen demand, thus leading to ischemia and pain. The main causes are thought to be dysfunction of endothelium and structural changes such as perivascular fibrosis and changes in vascular smooth muscle cells. In addition to vasodilation the endothelium plays a central role in the atherosclerotic process by generating vasoactive and anticoagulant factors that are important mediators of thrombosis. Coronary microvessel dysfunction (CMD) has been shown to be a strong predictor of poor cardiovascular prognosis in a wide group of cardiac patients.

Rationale for intervention:

In women with angina and no obstructive stenosis of the coronary vessels cardiovascular risk factors are common. Among 3000 Danish women with angina and open arteries, 12% had diabetes, 48% hypertension, 20% were smokers and the mean body mass index was 27 kg/m2. In a randomized trial among overweight patients with coronary artery disease both a large weight loss and intensive exercise training have shown to significantly improve coronary flow velocity reserve (CFVR). Small studies addressing risk factors individually suggest an effect on peripheral vascular function of exercise training, statin therapy, and weight loss. Pre-diabetes is found in eighty percent of these patients and is strongly associated to microvessel disease. Lifestyle intervention significantly reduces risk of developing diabetes. Medical treatment targeting microvessel dysfunction in patients with angina has not been systematically tested but small studies indicate an effect of beta-blockers and Angiotensin Converting Enzyme (ACE)-inhibition on coronary microvessel function. Small studies indicate effect of individual interventions but mainly on the function of peripheral vessels. A comprehensive intervention simultaneously targeting CMD and angina has not previously been attempted.

The rationale for this present intervention is to test this concept in women with angina and CMD.The study is a pilot study which, if successful, will be expanded to a multicentre, intervention trial with prognostic outcome. A large study showing improved prognosis is of crucial importance for treatment of this patient group to become part of guidelines.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Comprehensive Treatment of Angina in Women With Microvascular Dysfunction - a Proof of Concept Study of the iPower Cohort
Study Start Date : December 2016
Estimated Primary Completion Date : September 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Angina

Arm Intervention/treatment
Experimental: Weight loss, training, medication

The intervention program consists of a comprehensive 24-week treatment period of: 1) Body weight loss without significant loss of muscle mass, through low energy diet combined with 2) Exercise training based on interval training and resistance exercise and 3) Optimal medical treatment for hypertension and hypercholesterolemia (with statin and ACE-inhibition). Further, participants in this allocation group receive nutrition counselling.

The diet products are sponsored by Cambridge Weight Plan. No persons with interest in Cambridge Weight Plan will take part in the intervention phase, analyzing phase, data processing, or publication of data in this study.

Dietary Supplement: Diet
Weight loss achieved by following an evidence-based low energy diet of 800-1200 kcal/day for 12 weeks (Cambridge Weight Plan). Hereafter follow 12 weeks of 'weight maintenance' with consumption of normal heart healthy diet. Goal: total weight loss of at least 10% without significant loss of muscle mass. Monitored and supervised by a dietician
Other Name: Low Energy Diet

Behavioral: Training
Aerobic interval training and resistance exercise in group sessions twice weekly throughout the 24-week intervention. Training intensity individually adapted to the restricted calorie intake. Goal: Improved VO2 peak (at least 10%). Monitored by a physiotherapist.
Other Name: Aerobic Exercise Training

Drug: Medication (with statin and ACE-inhibition)
Medical treatment for hypertension and/or hypercholesterolemia if systolic blood pressure > 130 and/or low density lipoprotein (LDL) > 2.0.
Other Name: Medical treatment for hypertension and hypercholesterolemia

No Intervention: Control
The control group receives 24 weeks of usual care according to guidelines of Danish Cardiology Society. Treatment of angina pectoris in absence of coronary artery disease is normally provided by the patient's general practitioner and does not comprise intensive lifestyle intervention or medical treatment. If control group participants in this study need medical therapy for hypertension or hypercholesterolemia, this will be effectuated by the researcher, MD. Then, control participants will be monitored with blood pressure and LDL blood samples and receive medicine adjustments according to National Prevention Guidelines during the full study period.



Primary Outcome Measures :
  1. Changes in coronary microvascular function [ Time Frame: Up to 24 months ]
    Coronary microvascular function will be assessed by transthoracic Doppler stress echocardiography (TTDSE) and measured as Coronary Flow Velocity Reserve (CFVR). CFVR is a measure of microvascular dysfunction in the absence of upstream coronary stenosis. CFVR is the ratio of flow during stress and flow during rest and will be measured with TTDSE of the left anterior descending artery before and during infusion of high dose adenosine (0.14 mg/kg/min).


Secondary Outcome Measures :
  1. Changes in symptom burden assessed by the Seattle Angina Questionnaire (SAQ) [ Time Frame: Up to 24 months ]

    The SAQ is a reliable, predictive tool that has been validated in 175 women with a confirmed diagnosis of stable coronary artery disease and angina pectoris. It is a 19-item health-related quality-of-life measure for patients with coronary artery disease. The answers given by the patients in the SAQ's questions are used to calculate scores in five scales: 1. Anginal Stability, 2. Anginal Frequency, 3. Physical Limitation, 4. Treatment Satisfaction and 5) Quality of Life.

    Scale scores are transformed to a 0-100 range by subtracting the lowest possible scale score, dividing by the range of the scale and multiplying by 100. Higher scores indicate less symptom burden. Because each scale monitors a unique dimension of coronary artery disease, no summary score is generated. A score change of 10 points is clinically perceptible to patients and is considered a clinically relevant difference, while a substantial change is considered to be a change of 20 points.


  2. Changes in peripheral endothelial function assessed by brachial flow mediated (vaso)dilation (FMD) [ Time Frame: Up to 24 months ]
    The method is based upon measurement of the change in diameter of the brachial artery following short term occlusion of blood supply that causes a hyperemic flow response that stimulates dilation of the artery via nitric oxide (NO) released as a response to shear stress on the endothelium. Brachial artery 2-dimensional and pulsed Doppler flow velocity signals will be obtained above the antecubital crease with a linear array transducer, using a cardiovascular ultrasound system (GE healthcare vivid E9). Hyperemia is induced by inflating a blood pressure cuff on the proximal portion of the arm to 300 mmHg occluding arterial flow for 5 minutes. Pulsed Doppler recordings and 2-dimensional images will be obtained 60 seconds after cuff deflation (endothelial dependent dilation). After 15 minutes of rest to allow restoration of baseline conditions, non-endothelium-dependent brachial artery dilation will be assessed before and after administration of 0.4 mg sublingual nitroglycerine.

  3. Changes in biomarkers including inflammatory markers and markers of metabolism [ Time Frame: Up to 24 months ]

    Several components in the inflammatory system may be associated with cardiovascular disease and atherosclerosis. A meta-analysis comprising 29 prospective studies associated interleukin-6 (IL6), tumor necrosis factor-alfa (TNF-alfa) and C-reactive protein (CRP) to increased cardiovascular risk independent of traditional risk factors in the healthy population.51

    Fasting blood samples will be collected at baseline and follow-up for assessment of:

    Lipids (total-, low density lipoprotein, very low density lipoprotein, high density lipoprotein, cholesterol and triglycerides), endocrine function (Hba1c, glucose, insulin, thyroid stimulating hormone), kidney function (creatinine, estimated glomerular filtration rate (eGFR)), haematology and inflammatory disease (high sensitive CRP, high sensitive troponin-T, orosomucoid, interleukin-6, tumor necrosis factor alfa (TNF-alfa), adiponectin)


  4. Changes in exercise capacity (VO2peak) [ Time Frame: Up to 24 months ]
    A cardiopulmonary exercise test (CPET) is performed using a bicycle ergometer with breath-by-breath gas exchange measurements (Jaeger, Vyntus CPX, Germany. Participants will be encouraged to continue until exhaustion. Criteria for VO2 peak are levelling off of VO2 despite increasing workload and peak respiratory exchange ratio (peak RER) > 1.10.38 VO2 peak and peak RER are determined at peak effort with 15-second average measurements. VO2 peak is expressed as: VO2 peak (mL/min), VO2 peak (mL/kg body weight/min) and VCO2 peak (mL/min). Predicted VO2 peak is calculated using the equation for sedentary, overweight individuals presented by Wassermann and Hansen. Measured VO2peak in percent of predicted is determined.

  5. Changes in body weight and fat distribution (DEXA scan) [ Time Frame: Up to 24 months ]

    To estimate body composition (body fat mass and fat free mass ) a whole body dual X-ray absorptiometry (DEXA) scan will be performed.

    Body composition will be measured in the morning after a 10-hour fast.


  6. Changes in level of anxiety and depression (HADS questionnaire) [ Time Frame: Up to 24 months ]
    HADS is a self-administered questionnaire consisting of 14 items (each scored 0-3), seven of which concern depression and seven anxiety symptoms. One of the main purposes of this instrument was to identify affective symptoms among somatically ill patients.Therefore, the items focuses on the non-somatic aspects of depression and anxiety, to avoid that symptoms from the somatic disease, such as fatigue, affected the measurements.Depression and anxiety items are summarized separately in two scales ranging from 0 to 21, where a higher score indicates more symptoms.

  7. Changes in systolic and diastolic heart function at rest and during stress including advanced imaging (eg. Strain-Echocardiography) [ Time Frame: Up to 24 months ]
    Diastolic heart function tends to be impaired in obesity and in diabetes, but whether this is also the case in microvessel dysfunction is unclear. Improvement in cardiac function following intervention may be subtle and is more likely measurable during stress. By using global longitudinal and radial 2D strain at rest and during dipyridamole or adenosine stress, we expect that we will be able to detect a smaller difference in myocardial function than by using change in left ventricular ejection fraction (LVEF) assessed by the Simpsons method.

  8. Changes in body weight [ Time Frame: Up to 24 months ]
    Weight in kilograms wil be measured in the morning after a 10-hour fast

  9. changes in hip- and waist circumference [ Time Frame: Up to 24 months ]
    hip and waist circumference will be measured in the morning after a 10-hour fast. Waist circumference is measured halfway between the lower rib and the iliac crest and hip circumference at the maximal gluteal protuberance and calculated as an average of two consecutive measurements.



Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

Patients will be recruited and included from the ongoing iPower study.(the acronym iPower stands for: improving diagnosis and treatment of women with angina pectoris and microvascular disease)

  • Female gender
  • 40-75 years of age
  • Referred to a cardiac centre for assessment with coronary angiography due to chest pain or other signs of ischemia leaving out ST-segment elevation myocardial Infarction (STEMI) or NSTEMI patients (elevated enzymes, electrocardiographic (ECG) changes/no ECG changes)
  • No significant stenotic lesions at the following coronary angiography defined as > 50% stenosis of epicardial vessels. Patients are included within 1 year after coronary angiography.

    • Angina with a symptom burden of symptoms > monthly
    • Impaired coronary microvascular function, defined as a Transthoracic Doppler Echocardiography measured CFVR < 2.5 with a good quality (quality index > 3)
    • BMI > 26 or BMI >= 25 combined with a waist hip ratio of >=0.8
    • Informed consent

Exclusion Criteria:

  • Previously verified myocardial infarction, verified in medical records: ST-elevation myocardial infarction, elevated coronary markers or Non ST-elevation myocardial infarction
  • Previous percutaneous coronary intervention or coronary artery bypass graft.
  • Left ventricular ejection fraction (LVEF) < 45% assessed by echocardiography within 6 months before inclusion
  • Any allergies to the content of the low energy diet (gluten/nuts), allergy to dipyridamole, adenosine, or theophyllamine
  • Significant valvular heart disease
  • Congenital heart disease
  • Severe asthma
  • Severe chronic obstructive pulmonary disease (COPD): forced expiratory volume in 1st second (FEV1) < 50% of predicted (age, height, ethnicity)
  • Severe comorbidity with limited life-expectancy < 1 year
  • Chest pain with a strongly suspected non-ischemic etiology (e.g. pericarditis, pneumonia)
  • Pregnancy
  • Active cancer
  • Renal (eGFR < 50) or severe hepatic comorbidity
  • Chronic alcohol abuse
  • Atrial flutter or fibrillation
  • Atrioventricular block > 1st degree
  • Diabetes Mellitus type I
  • Diabetes Mellitus type II patients in treatment with Sulphonylureas
  • Participation in other trials if relevant for the present study
  • Language- or other barrier to giving informed consent
  • Physical or mental disabilities contraindicating or hampering diet or exercise training
  • Travel distance to research hospital requiring more than 3 hours of travel, making it difficult for the patient to participate

Withdrawal criteria

  • Sudden unexpected serious adverse reaction or sustained side effects
  • Poor compliance will lead to withdrawal from the study at the mentioned time points: Low energy diet: No weight loss within the first 3 weeks of the intervention period. Medication: < 80% of the prescribed medicine taken within the first 3 weeks. Training: < 50% attendance to training sessions/home training within the first 5 weeks.

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): NCT02910154


Contacts
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Contact: Eva Prescott, MD, DMSc +45 40262134 Eva.Irene.Bossano.Prescott@regionh.dk
Contact: Kira Bové, MD +45 40355627 kira.bang.bove.01@regionh.dk

Locations
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Denmark
Bispebjerg Hospital, Dept. of Cardiology Y builing 67, 1.floor, Bispebjerg Bakke 23 Recruiting
Copenhagen, Denmark, 2400
Contact: Eva Prescott, MD, DMSc    +45 4026 2134    Eva.Irene.Bossano.Prescott@regionh.dk   
Contact: Kira Bové, MD    +45 4035 5627    kira.bang.bove.01@regionh.dk   
Frederiksberg Hospital, Dept. of Cardiology, Building 16, Y3, Nordre Fasanvej 57 Not yet recruiting
Frederiksberg, Denmark, 2000
Contact: Eva Prescott, MD, DMSc    +45 4026 2134    Eva.Irene.Bossano.Prescott@regionh.dk   
Contact: Kira Bové, MD    +45 4035 5627    kira.bang.bove.01@regionh.dk   
Sponsors and Collaborators
Bispebjerg Hospital
University Hospital Bispebjerg and Frederiksberg
Cambridge Weight Plan Limited
Investigators
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Principal Investigator: Eva Prescott, MD, DMSc Professor

Publications of Results:

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Responsible Party: Eva Prescott, Professor, MD, DMSc, Bispebjerg Hospital
ClinicalTrials.gov Identifier: NCT02910154    
Other Study ID Numbers: CORA
R144 A5460 ( Other Grant/Funding Number: Region Hovedstadens Forskningsfond til Sundhedsforskning )
H-16032518 ( Other Identifier: Approval by the National Committee on Health Research Ethics )
First Posted: September 21, 2016    Key Record Dates
Last Update Posted: February 14, 2017
Last Verified: February 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Additional relevant MeSH terms:
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Angina Pectoris
Myocardial Ischemia
Heart Diseases
Cardiovascular Diseases
Vascular Diseases
Chest Pain
Pain
Neurologic Manifestations
Signs and Symptoms
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Enzyme Inhibitors
Lipid Regulating Agents