Comprehensive Treatment of Angina in Women With Microvascular Dysfunction

Not Applicable

Completed

• Conditions: Angina Pectoris; Coronary Microvascular Disease
• Interventions: Dietary Supplement: Diet; Behavioral: Training; Drug: Medication (with statin and ACE-inhibition)

• Registration Number: NCT02910154
• Lead Sponsor: 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.

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.

Study Timeline

• Study First Submitted: 2016-09-13
• Study First Submitted QC: 2016-09-20
• Study First Posted: 2016-09-21
• Study Start: 2016-12
• Primary Completion: 2018-10-01
• Study Completion: 2018-10-01
• Status Verified: 2020-06
• Last Update Submitted: 2020-06-21
• Last Update Posted: 2020-06-23

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Female
• Target Recruitment: 62

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 < 30) or severe hepatic comorbidity
• Chronic alcohol abuse
• Atrial flutter or fibrillation
• Atrioventricular block > 1st degree
• 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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Weight loss, training, medication	Training	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.
Weight loss, training, medication	Diet	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.
Weight loss, training, medication	Medication (with statin and ACE-inhibition)	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.

Primary Outcome Measures

Name	Time	Method
Changes in coronary microvascular function	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

Name	Time	Method
Changes in biomarkers including inflammatory markers and markers of metabolism	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)
Changes in exercise capacity (VO2peak)	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.
Changes in level of anxiety and depression (HADS questionnaire)	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.
Changes in symptom burden assessed by the Seattle Angina Questionnaire (SAQ)	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.
changes in hip- and waist circumference	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.
Changes in body weight and fat distribution (DEXA scan)	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.
Changes in systolic and diastolic heart function at rest and during stress including advanced imaging (eg. Strain-Echocardiography)	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.
Changes in body weight	Up to 24 months	Weight in kilograms wil be measured in the morning after a 10-hour fast

Trial Locations

Locations (2)

Bispebjerg Hospital, Dept. of Cardiology Y builing 67, 1.floor, Bispebjerg Bakke 23; 🇩🇰 Copenhagen, Denmark

Frederiksberg Hospital, Dept. of Cardiology, Building 16, Y3, Nordre Fasanvej 57; 🇩🇰 Frederiksberg, Denmark