Effect of ACE-Inhibition on Microvascular Function in Women With Assessed Microvascular Dysfunction and No Obstructive Coronary Artery Disease
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 63
- 试验地点
- 1
- 主要终点
- Change from baseline in coronary flow reserve to after intervention
研究概览
简要总结
The aim of this study is to explore effects of long term treatment with ACE-inhibitor on the small vessel function assessed by coronary flow reserve (CFR) by transthoracic echocardiography and flow mediated dilation in normotensive patients with small vessel disease (CFR<2.2) and Angina Pectoris but no obstructive coronary artery disease.
详细描述
BACKGROUND Microvascular angina is proposed to be myocardial ischemia caused by microvascular dysfunction. When the microvasculature is dysfunctioning, blood flow in the coronary vessels does not increase sufficiently to meet oxygen demand leading to ischemia and pain. In the absence of stenosis of major coronary arteries, coronary flow reserve (CFR) reflects coronary microcirculation. Up to 50% of patients with angina and no obstructive coronary artery disease (CAD) have impaired CFR, which is a strong predictor of poor cardiovascular prognosis. Furthermore CFR has been shown to be associated with conventional risk factors; among these hypertension.
ACE-inhibitor treatment of patients with Angina Pectoris and/or essential hypertension and no stenosis on coronary angiogram improves CFR measured invasively by Doppler Guidewire or gas chromotography suggesting an effect of ACE inhibition on the microvasculature. Studies assessing the effect of ACE-inhibition in hypertensive and mild coronary artery disease patients with CFR assessed by positron emission tomography (PET) showed divergent results. One study showed an improvement on both resting and hyperaemic myocardial blood flow , another showed an increased myocardial perfusion reserve post treatment and a third failed to show any significant effect. If the effect seen on CFR is indirectly mediated via treatment of hypertension or if ACE-inhibition has a direct effect on the microvasculature continues to be uncertain in patients with microvascular angina. Some studies show an effect on CFR in both normotensive and hypertensive patients with microvascular angina whereas other studies only show an effect in hypertensive patients and not in normotensive. Treating patients with diabetes and a CFR>2.0 with ACE-inhibitor has also proven efficient in increasing CFR measured by transthoracic Doppler echocardiography (TTDE) supporting the theory that ACE-inhibition could have a direct effect on the microvasculature. In animal studies ACE-inhibition has shown capability of preventing adverse vascular remodelling dissociated to its blood pressure lowering effect. ACE inhibitor treatment is thought to be associated with vascular changes in CAD patients. However Clinical trials have shown discrepant results regarding reduction of hard endpoints with ACE inhibition in high-risk CAD patients. It remains unclear if ACE-inhibition has a direct effect on the microvasculature in normotensive patients with microvascular angina.
Endothelial dysfunction assessed by Flow-dependent endothelium-mediated dilation (FMD) is associated with cardiovascular risk factors and more prominent in women. FMD predicts long term cardiovascular events in healthy subjects. Treatment with most types of ACE-inhibitors improves FMD shown in studies with patients with syndrome X, coronary artery disease, and hypertension and in healthy elderly. However Enalapril treatment did not show an affect on FMD.
AIM The aim of this study is to explore effects of long term treatment with ACE-inhibitor on the microvasculature and endothelial function assessed by coronary flow reserve (CFR) by transthoracic echocardiography and flow mediated dilation (FMD) in normotensive patients with microvascular dysfunction (CFR<2.2) and Angina Pectoris but NO-CAD.
HYPOTHESIS ACE inhibitor treatment reverts microvascular remodelling and endothelial dysfunction in patients with microvascular dysfunction and Angina Pectoris but NO-CAD thereby improving microvascular function and reducing symptoms.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 86 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Patients from an established cohort of patients with non obstructive coronary artery disease
- •Microvascular dysfunction defined as a transthoracic echocardiography measured coronary flow reserve (CFR) < 2.2
- •A good quality (quality index > 3) examination
- •A blood pressure ≤ 150 at last visit in iPower
- •Patients who are not in treatment for documented hypertension
排除标准
- •Current treatment with ACE-inhibitors or Angiotensin II-antagonists
- •Atrial fibrillation
- •Pace-maker
- •Allergy towards Ace-inhibitor, Ramipril ® or tool-medicine: Dipyridamole/adenosine, Nitro-glycerine or rescue medicine: Theophylline
- •Baseline CFR >2.5 when entering ACIM-study.
- •No episodes of chest pain within 6 months before inclusion
- •Coronary angiography with significant stenotic lesions (>/=50%)
- •Other cause of chest discomfort deemed highly likely
- •Left ventricular ejection fraction below 45% assessed by echocardiography at baseline measurement
- •Significant valvular heart disease (Definition: Verified in medical records after echocardiography. If the echocardiographer in this study suspects valvular heart disease, the patient is referred for expert evaluation and excluded from the study until valvular disease has been excluded. All definitions are taken from the guidelines of the Danish Society of Cardiology (DCS).
- •Haemodynamic significant Aortic Stenosis: Valve area < 1 cm2 or <0.6 cm2/m2 body surface area.
- •Severe aorta Regurgitation (AR): Vena contracta > 6 mm, Moderate/severe left ventricle (LV) volume load, ERO > 0.3 cm².
- •Mitral Stenosis (MS): Valve area < 2.5 cm
- •Severe Mitral Regurgitation (MR): effective regurgitant orifice > 0.4 cm², Moderate/severe LV-load, Vena contracta > 6 mm.
- •Congenital heart disease or cardiomyopathy verified in medical records
- •Significant co-morbidity with < 1 year expected survival: decision made by the person responsible for inclusion based on the patient interview and/or medical records.
- •Severe chronic obstructive pulmonary disease with forced expiratory volume in 1 second (FEV1)<50% of predicted
- •Severe asthma defined as asthma which requires treatment with high dose inhaled corticosteroids (ICS) plus a second controller (long acting β2 agonist (LABA), leukotriene modifier, theophylline or systemic corticosteroids) to prevent it from becoming uncontrolled or which remains uncontrolled despite this therapy."
- •Previous verified myocardial infarction (Definition: verified in medical records, ST segment elevation myocardial infarction (STEMI) (ST segment elevation, elevated enzymes) or non-ST-segment elevation myocardial infarction (NSTEMI) (elevated enzymes, ECG changes/no ECG changes).
- •Previous revascularization (Percutaneous Coronary Intervention or coronary artery bypass grafting)
- •Elevated cardiac biomarkers: Troponin > 50 ng/l (high sensitive) or > 0.03 μg/l (
- •generation), creatinin kinase myoglobin (CKMB) > 4.0 μg/l (women).
- •ECG with verified ST-segment elevation
- •Language- or other barrier to giving informed consent (for example mental ability to understand project)
- •Travel distance: a distance to research hospital requiring more than 3 hours of travel
- •Patient unwilling to participate (Low burden of symptoms, other illnesses, "Lack of energy", transport problems, anxiety because of the examination, other).
- •No signed informed consent.
- •Other (Pregnancy, significant psychiatric disorder)
- •glomerular filtration rate < 50 mL/min/1,73 m2
研究组 & 干预措施
ACE-inhibitor
In both the placebo and Ramipril group medication will start with either 2,5 mg (Blood Pressure<130) or 5 mg (Blood Pressure>130) daily. After 2-3 weeks the dose is doubled to 5 mg or 10 mg unless blood pressure is below 115 mmHg. If blood pressure continues to be higher than 115 mmHg for patients up titrated to 5 mg treatment dose will be doubled to 10 mg at the third visit.
Patients taking a dose of
- 2,5 mg will take a half tablet a day
- 5 mg will take one whole tablet a day
- 10 mg will take two tablets a day
干预措施: Ramipril (ACE-inhibitor) (Drug)
Placebo
In both the placebo and Ramipril group medication will start with either 2,5 mg (Blood Pressure<130) or 5 mg (Blood Pressure>130) daily. After 2-3 weeks the dose is doubled to 5 mg or 10 mg unless blood pressure is below 115 mmHg. If blood pressure continues to be higher than 115 mmHg for patients up titrated to 5 mg treatment dose will be doubled to 10 mg at the third visit.
Patients taking a dose of
- 2,5 mg will take a half tablet a day
- 5 mg will take one whole tablet a day
- 10 mg will take two tablets a day
干预措施: placebo (Drug)
结局指标
主要结局
Change from baseline in coronary flow reserve to after intervention
时间窗: Patients are followed on average 6 months
Coronary flow reserve is assessed by non-invasive Trans-Thoracic Doppler Echocardiography (TTDE)
次要结局
- Change from baseline in Endothelial function to after intervention(Patients are followed on average 6 months)
- Change from baseline in Roses questionnaire to after intervention(Patients are followed on average 6 months)
- Change from baseline in International physical activity questionnaire (IPAQ) questionnaire to after intervention(Patients are followed on average 6 months)
- Change from baseline in Systolic function by speckle tracking strain to after intervention(Patients are followed on average 6 months)
- Change from baseline in Seattle Angina Questionnaire to after intervention(Patients are followed on average 6 months)
- Change from baseline in Vital exhaustion questionnaire to after intervention(Patients are followed on average 6 months)
研究者
Marie Mide Michelsen
Medical Doctor
Bispebjerg Hospital