Microvascular Angina Clinical Trial
Official title:
Effect of ACE-Inhibition on Microvascular Function in Women With Assessed Microvascular Dysfunction and No Obstructive Coronary Artery Disease
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.
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.
RESEARCH DESIGN The study is a randomised double-blinded interventional study. 72 patients
with microvascular dysfunction assessed by TTDE as a CFR<2.2 are recruited from the iPower
(ImProve diagnOsis and treatment of Women with angina pEctoris and micRovessel disease)
cohort (women with angina but no obstructive CAD examined with TTDE CFR), Region Zealand.
Patients with hypertension will be excluded from the study.
The patients will be randomised to group 1 or 2:
1. Group 1: Oral ACE-inhibitor for 6±1,5 months
2. Group 2: Oral matching placebo for 6±1,5 months Examinations and measurements will be
performed at baseline and after 6±1,5 months. There are furthermore 2 possible blood
pressure (BP)/kidney function control visits depending on how many up titrations of
treatment medicine are necessary for the individual patient. Compliance calls and
control of adverse events will be made every month and the patient can also contact us
with any concern.
Participation in the study is 6±1,5 months. 24 hours before final measurements Ramipril
treatment will be discontinued. Ramipril treatment will be add-on to usual treatment.
RANDOMIZATION PROCEDURE Patients will be randomized into 2 equal groups receiving either
Ramipril or placebo. Randomization is done by the pharmacy (Glostrup Apotek). ACIM (Effect
of ACE-Inhibition on Microvascular Function in Women with Assessed Microvascular
Dysfunction) Id-numbers (ACIM1-72) are allocated equally to either placebo or Ramipril
treatment using simple randomization.
Randomization is concealed in a document sealed in an opaque envelope and can only be
revealed at the end of the study. For individual patients in occurrence of a serious adverse
event the sponsor or investigator will contact the pharmacy to reveal medication type. The
sealed envelope will be locked in a cabinet at the office of the sponsor.
The sponsor, investigator, research assistant and patients will have no knowledge of which
randomization group the patients belong to Id-numbers (ACIM1-72) will be allocated to
patients in a consecutive order.
TRIAL MEDICINE AND BLINDING Study medication will be prepared by the pharmacy (Glostrup
Apotek) in a double-blinded manner. Medication will be delivered in bottles containing
50/100 x 5 mg placebo tablets or 5 mg Ramipril (Ramipril®, Hexal) and both bottle containers
and tablets are indistinguishable. Tablets are produced with a pressure sensitive score
notch and can be divided into equal halves. Bottle containers will be labelled with a study
id-number ACIM1-ACIM72 (identification number/treatment number), the batch and/or code
number to identify the contents and packaging operation, the name of the investigator Marie
Michelsen/research assistant and mobile number, pharmaceutical dosage form, route of
administration, quantity of dosage units, indication of use: "clinical trial", the storage
conditions, period of use (expiry date) and warning label: "keep out of reach of children".
The directions for use will be made to a leaflet according to individual dosage because of
different final dosage after up titrations.
In both the placebo and Ramipril group medication will start with either 2,5 mg (BP<130) or
5 mg (BP>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.
Blood pressure and kidney function will be controlled at each visit (see fig. 1). If
patients have symptoms of hypotension (dizziness, syncope or high pulse) treatment dose will
be reduced and/or other blood pressure lowering treatment discontinued or if necessary
Ramipril treatment discontinued.
If oral ACE-inhibitors are not tolerated treatment will be discontinued. Regarding exclusion
for treatment discontinuation please see "withdrawal criteria".
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 Patients will be up titrated in same manner
independent of which medication they are on. For each study id-number medication for up
titration is available. Patients will receive the appropriate amount of bottles
according to uptitrated dose level (annex 1).
Patients will be up titrated and monitored by a research assistant so the investigator
making the primary endpoint measure is unaware of the final treatment dose. In case of any
adverse events/reactions or serious events/reactions the research assistant will confer with
the sponsor or a project physician if necessary and not the investigator to avoid awareness
of medication type for person obtaining primary endpoint. Only in case of a suspected
serious reaction medication type will be unblinded by the sponsor or investigator by calling
the pharmacy, Døgnåbent Glostrup Apotek, with patients id/cpr-number. Regarding exclusion
for unblinding please see "withdrawal criteria".
Analysis of echocardiographic measurements for primary and secondary measurements will be
made minimum 1 month after baseline and final visit so the investigator is unaware of blood
pressure measurements during examinations.
Control of compliance will be made at visits and hereafter every month by patient structured
open questions interviews (visits and telephone) Furthermore patients will make a diary
every day of pill intake and any symptoms (potential adverse effects).
At the end of the study the patient will return used pill containers with remaining tablets
within. These will be counted again to ensure medication compliance and accuracy.
;
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