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Angina PectorisCORANCT02910154

Comprehensive Treatment of Angina in Women With Microvascular Dysfunction

A study testing Diet, Training and Medication (with statin and ACE-inhibition) in people with Angina Pectoris and Coronary Microvascular Disease, run by Bispebjerg Hospital at 2 sites in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Ages 40 to 75 years, women only
What is being tested?
Diet, Training and Medication (with statin and ACE-inhibition)
Could I receive a placebo?
No, everyone receives an active treatment
How many people
62 participants
Where
2 sitesDenmark
Study dates
Dec 2016to 1 Oct 2018
Phase
Interventional
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 40 to 75 years
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 9Show fewer
  • 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

Who cannot join

  • 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
Show all 24Show fewer
  • 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.

Trial locations and contacts

2 sites in 1 country.

Denmark2 sites

  • Bispebjerg Hospital, Dept. of Cardiology Y builing 67, 1.floor, Bispebjerg Bakke 23

    Copenhagen, 2400

  • Frederiksberg Hospital, Dept. of Cardiology, Building 16, Y3, Nordre Fasanvej 57

    Frederiksberg, 2000

Other trials in Denmark

About this study

Official title: Comprehensive Treatment of Angina in Women With Microvascular Dysfunction - a Proof of Concept Study of the iPower Cohort

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.

Read the 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.

Being tested
Diet, Training, Medication (with statin and ACE-inhibition)
Medical subject headings
Angina Pectoris, Microvascular Angina

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DietDietary supplement

    Also called Low Energy 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

  • TrainingBehavioural

    Also called Aerobic Exercise 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.

  • Medication (with statin and ACE-inhibition)Drug

    Also called Medical treatment for hypertension and hypercholesterolemia

    Medical treatment for hypertension and/or hypercholesterolemia if systolic blood pressure > 130 and/or low density lipoprotein (LDL) > 2.0.

Study groups in NCT02910154
Study groupRoleWhat they receive
Weight loss, training, medicationExperimentalThe 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.
Receives: Dietary Supplement: Diet; Behavioral: Training; Drug: Medication (with statin and ACE-inhibition)
ControlNo interventionThe 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.

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Changes in coronary microvascular function

    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).

    Measured: Up to 24 months

Secondary outcomes (8)

  1. Changes in symptom burden assessed by the Seattle Angina Questionnaire (SAQ)

    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.

    Measured: Up to 24 months

  2. Changes in biomarkers including inflammatory markers and markers of metabolism

    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)

    Measured: Up to 24 months

  3. Changes in exercise capacity (VO2peak)

    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.

    Measured: Up to 24 months

  4. Changes in body weight and fat distribution (DEXA scan)

    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.

    Measured: Up to 24 months

  5. Changes in level of anxiety and depression (HADS questionnaire)

    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.

    Measured: Up to 24 months

  6. Changes in systolic and diastolic heart function at rest and during stress including advanced imaging (eg. Strain-Echocardiography)

    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.

    Measured: Up to 24 months

  7. Changes in body weight

    Weight in kilograms wil be measured in the morning after a 10-hour fast

    Measured: Up to 24 months

  8. changes in hip- and waist circumference

    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.

    Measured: Up to 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Sep 2016 (estimated)
  2. Study startDec 2016
  3. Primary completion1 Oct 2018
  4. Study completion1 Oct 2018

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase N/A
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
Single blind
Who is masked
Outcomes assessor
Enrolment
62 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02910154
Sponsor's protocol ID
CORA
Other IDs
R144 A5460, H-16032518
Acronym
CORA
Status last verified
Jun 2020
First submitted
13 Sep 2016
Last updated
23 Jun 2020
Results posted
No
Data monitoring committee
Yes
Individual data sharing
No

Publications

  • Bairey Merz CN, Shaw LJ, Reis SE, Bittner V, Kelsey SF, Olson M, Johnson BD, Pepine CJ, Mankad S, Sharaf BL, Rogers WJ, Pohost GM, Lerman A, Quyyumi AA, Sopko G; WISE Investigators. Insights from the NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE) Study: Part II: gender differences in presentation, diagnosis, and outcome with regard to gender-based pathophysiology of atherosclerosis and macrovascular and microvascular coronary disease. J Am Coll Cardiol. 2006 Feb 7;47(3 Suppl):S21-9. doi: 10.1016/j.jacc.2004.12.084.

    PubMed 16458167

  • Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol. 2009 Oct 20;54(17):1561-75. doi: 10.1016/j.jacc.2009.04.098.

    PubMed 19833255

  • Patel MR, Peterson ED, Dai D, Brennan JM, Redberg RF, Anderson HV, Brindis RG, Douglas PS. Low diagnostic yield of elective coronary angiography. N Engl J Med. 2010 Mar 11;362(10):886-95. doi: 10.1056/NEJMoa0907272.

    PubMed 20220183

  • Jespersen L, Hvelplund A, Abildstrom SZ, Pedersen F, Galatius S, Madsen JK, Jorgensen E, Kelbaek H, Prescott E. Stable angina pectoris with no obstructive coronary artery disease is associated with increased risks of major adverse cardiovascular events. Eur Heart J. 2012 Mar;33(6):734-44. doi: 10.1093/eurheartj/ehr331. Epub 2011 Sep 11.

    PubMed 21911339

  • Gulati M, Cooper-DeHoff RM, McClure C, Johnson BD, Shaw LJ, Handberg EM, Zineh I, Kelsey SF, Arnsdorf MF, Black HR, Pepine CJ, Merz CN. Adverse cardiovascular outcomes in women with nonobstructive coronary artery disease: a report from the Women's Ischemia Syndrome Evaluation Study and the St James Women Take Heart Project. Arch Intern Med. 2009 May 11;169(9):843-50. doi: 10.1001/archinternmed.2009.50.

    PubMed 19433695

  • Jespersen L, Abildstrom SZ, Hvelplund A, Galatius S, Madsen JK, Pedersen F, Hojberg S, Prescott E. Symptoms of angina pectoris increase the probability of disability pension and premature exit from the workforce even in the absence of obstructive coronary artery disease. Eur Heart J. 2013 Nov;34(42):3294-303. doi: 10.1093/eurheartj/eht395. Epub 2013 Sep 26.

    PubMed 24071763

  • Jespersen L, Abildstrom SZ, Hvelplund A, Prescott E. Persistent angina: highly prevalent and associated with long-term anxiety, depression, low physical functioning, and quality of life in stable angina pectoris. Clin Res Cardiol. 2013 Aug;102(8):571-81. doi: 10.1007/s00392-013-0568-z. Epub 2013 May 1.

    PubMed 23636227

  • Shaw LJ, Merz CN, Pepine CJ, Reis SE, Bittner V, Kip KE, Kelsey SF, Olson M, Johnson BD, Mankad S, Sharaf BL, Rogers WJ, Pohost GM, Sopko G; Women's Ischemia Syndrome Evaluation (WISE) Investigators. The economic burden of angina in women with suspected ischemic heart disease: results from the National Institutes of Health--National Heart, Lung, and Blood Institute--sponsored Women's Ischemia Syndrome Evaluation. Circulation. 2006 Aug 29;114(9):894-904. doi: 10.1161/CIRCULATIONAHA.105.609990. Epub 2006 Aug 21.

    PubMed 16923752

  • Crea F, Lanza GA. Angina pectoris and normal coronary arteries: cardiac syndrome X. Heart. 2004 Apr;90(4):457-63. doi: 10.1136/hrt.2003.020594. No abstract available.

    PubMed 15020531

  • Bugiardini R, Bairey Merz CN. Angina with "normal" coronary arteries: a changing philosophy. JAMA. 2005 Jan 26;293(4):477-84. doi: 10.1001/jama.293.4.477.

    PubMed 15671433

  • Phan A, Shufelt C, Merz CN. Persistent chest pain and no obstructive coronary artery disease. JAMA. 2009 Apr 8;301(14):1468-74. doi: 10.1001/jama.2009.425.

    PubMed 19351944

  • Cannon RO 3rd. Microvascular angina and the continuing dilemma of chest pain with normal coronary angiograms. J Am Coll Cardiol. 2009 Sep 1;54(10):877-85. doi: 10.1016/j.jacc.2009.03.080.

    PubMed 19712795

  • Sicari R, Rigo F, Cortigiani L, Gherardi S, Galderisi M, Picano E. Additive prognostic value of coronary flow reserve in patients with chest pain syndrome and normal or near-normal coronary arteries. Am J Cardiol. 2009 Mar 1;103(5):626-31. doi: 10.1016/j.amjcard.2008.10.033. Epub 2008 Dec 26.

    PubMed 19231324

  • Pepine CJ, Anderson RD, Sharaf BL, Reis SE, Smith KM, Handberg EM, Johnson BD, Sopko G, Bairey Merz CN. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, Lung and Blood Institute WISE (Women's Ischemia Syndrome Evaluation) study. J Am Coll Cardiol. 2010 Jun 22;55(25):2825-32. doi: 10.1016/j.jacc.2010.01.054.

    PubMed 20579539

  • Rigo F, Cortigiani L, Pasanisi E, Richieri M, Cutaia V, Celestre M, Raviele A, Picano E. The additional prognostic value of coronary flow reserve on left anterior descending artery in patients with negative stress echo by wall motion criteria. A Transthoracic Vasodilator Stress Echocardiography Study. Am Heart J. 2006 Jan;151(1):124-30. doi: 10.1016/j.ahj.2005.03.008.

    PubMed 16368303

Questions about this trial

What is this clinical trial studying?

A study testing Diet, Training and Medication (with statin and ACE-inhibition) in people with Angina Pectoris and Coronary Microvascular Disease, run by Bispebjerg Hospital at 2 sites in Denmark.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 23 Jun 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in Denmark. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Changes in coronary microvascular function (time frame: Up to 24 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02910154, which also lists 49 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 23 Jun 2020.

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