Effects of Intensive Long-Term Vasodilation in Hypertensive Patients With Microvascular Angina Pectoris

Condition(s) targeted: Microvascular Angina; Hypertension

Intervention: Lercanidipine (Drug); Valsartan (Drug); Nicorandil (Drug); Doxazosin (Drug); Moxonidin (Drug); Pindolol (Drug); Amiloride, hydrochlorothiazide (Drug); Metoprolol (Drug); Diltiazem (Drug); Isosorbidemononitrate (Drug); Bendroflumethiazide (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: University of Aarhus

Official(s) and/or principal investigator(s):
Michael N Præstholm, MD, Principal Investigator, Affiliation: Aarhus University
Kent L Christensen, MD, DrMSc, Study Director, Affiliation: Aarhus Hospital, medical-cardiologic dept. A
Won Yong Kim, MD, DrMSc, Study Director, Affiliation: Skejby Hospital, cardiologic dept. B
Hans Erik Bøtker, MD, DrMSc, Study Director, Affiliation: Skejby Hospital, cardiologic dept. B

Overall contact:
Michael N Præstholm, MD, Phone: +45 8942 1710, Email: praestholm@ki.au.dk

The purpose of this study is to determine if long-term vasodilatory treatment is more effective than the standard treatment in hypertensive patients with microvascular angina pectoris

Official title: Intensive Non-Sympathetic Activating Vasodilatory Treatment in Hypertensive Patients With Microvascular Angina Pectoris

Study design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Efficacy Study

Primary outcome: Minimal coronary resistance

Secondary outcome:

Peripheral vascular resistance

Work capacity

Ischemia threshold

Detailed description: Patients with hypertension frequently develop angina pectoris. This can be caused by either epicardial stenotic disease or, equally frequent, by increased resistance in small resistance

vessels - microvascular dysfunction. This increased resistance is caused by a process called

remodelling, where the existing material in the vessel wall is rearranged around a smaller lumen, whereas the sensitivity of the smooth muscle cells to agonist stimuli is unchanged. Under resting conditions the resistance is determined by both the tone in the smooth muscle cells in the vessel walls and the structure of the vessels themselves (RREST). Under hyperemic conditions the muscles relax and the resistance is determined only by vessel structure (RMIN).

A literature survey of the various studies on this subject has shown that structural changes relates to tone rather than blood pressure. This suggests that resistance vessel structure will be normalized only by an antihypertensive treatment which normalizes RREST i. e. rely on vasodilatation as a cause of the antihypertensive effect more than reduction of cardiac output.

The main hypothesis is, that it is possible to reverse the structural changes in the resistance vessels by vasodilatory treatment for eight months, thereby achieving lower coronary and peripheral minimal resistance (as determined by MRI and plethysmography, respectively), higher work capacity on exercise-ECG and less tendency to angina in these patients.

We will include 80 patients with essential hypertension, angina pectoris CCS class II-III and signs of ischemia on exercise-ECG or myocardial SPECT, but without significant stenosis in angiography. The patients are randomised, in a parallel, open-label design, to either vasodilatory (lercanidipine, valsartan, doxazosin and nicorandil) or standard treatment (metoprolol, diltiazem and isosorbide mononitrate). The aim of treatment in both arms is BP below 120/80 and the protocol allows further add-on therapy to reach this goal. The patients will be followed for eight months with a titration period of two months. MRI, plethysmography, exercise-ECG and echocardiography will be performed before and after the study period. The primary endpoint is minimal coronary resistance as determined by MRI; secondary endpoints are peripheral vascular resistance as determined by plethysmography, work capacity and ischemia threshold on exercise-ECG or myocardial SPECT.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- hypertension

- angina pectoris CCS class II-IV

- objective signs of ischemia on exercise-ECG or myocardial SPECT

- no significant stenosis on angiography (minimal lumen diameter >50% of relevant

reference segment)

Exclusion Criteria:

- known allergy to any study medication

- abnormal lab tests of clinical significance

- valvular disease of haemodynamic significance

- known secondary hypertension

- atrial fibrillation or other significant arrythmias

- myocardial infarction < 30 days before inclusion

- resting angina < one week before inclusion

- known endocrine disease, nephropathy or hepatic disease

- present malignant disease

- pregnancy

- fertile women not using safe contraceptives > 6 months before inclusion. Use of

contraceptives must continue 1 month after completion or retraction from the study

- body mass index > 30

- significant chronic obstructive lung disease (FEV1 < 1. 5 l)

- participant in another study including test medicine

- present treatment with dipyridamole

- present treatment with phosphodiesterase-5-inhibitors that the patient does not want

to discontinue during the study period

- heart transplanted patients

- patients with magnetizable metallic implants

Michael N Præstholm, MD, Phone: +45 8942 1710, Email: praestholm@ki.au.dk

Aarhus Hospital, Aarhus 8000, Denmark; Recruiting

Starting date: January 2007
Ending date: December 2008
Last updated: August 11, 2008