Effect of ACE-Inhibition on Microvascular Function in Women With Assessed Microvascular Dysfunction
Condition: Microvascular Angina
MeSH terms: Microvascular Angina
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Ramipril (ACE-inhibitor); placebo
Intervention type(s): Drug; Drug
Intervention description(s): up to 10 mg; up to 10 mg
Other intervention name(s): Ramipril
Intervention MeSH terms: Ramipril; Angiotensin-Converting Enzyme Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Microvascular Angina; therapy