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

• ClinicalTrials.gov Identifier: NCT00424801
• Recruitment Status: Terminated
• First Posted: January 22, 2007
• Last Update Posted: May 6, 2009
• Sponsor: University of Aarhus
• Collaborators: Danish Cardiovascular Research Academy; Danish Heart Foundation; Novartis
• Information provided by: University of Aarhus

Tracking Information

• First Submitted Date: January 19, 2007
• First Posted Date: January 22, 2007
• Last Update Posted Date: May 6, 2009
• Study Start Date: January 2007
• Estimated Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: February 11, 2008): Minimal coronary resistance [ Time Frame: 8 months ]
• Original Primary Outcome Measures (submitted: January 19, 2007): Minimal coronary resistance
• Change History: Complete list of historical versions of study NCT00424801 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: February 11, 2008)

• Peripheral vascular resistance [ Time Frame: 8 months ]
• Work capacity [ Time Frame: 8 months ]
• Ischemia threshold [ Time Frame: 8 months ]

Original Secondary Outcome Measures (submitted: January 19, 2007)

• Peripheral vascular resistance
• Work capacity
• Ischemia threshold

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effects of Intensive Long-Term Vasodilation in Hypertensive Patients With Microvascular Angina Pectoris
• Official Title: Intensive Non-Sympathetic Activating Vasodilatory Treatment in Hypertensive Patients With Microvascular Angina Pectoris
• Brief Summary: 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

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.

• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Microvascular Angina
• Hypertension

Intervention

• Drug: Lercanidipine
  Individual titration, max. dose 20 mg OD for 8 months
  Other Name: Zanidip
• Drug: Valsartan
  Individual titration, max. dose 160 mg OD for 8 months
  Other Name: Diovan
• Drug: Nicorandil
  Individual titration, max. dose 20 mg BD for 8 months
  Other Name: Angicor
• Drug: Doxazosin
  Individual titration, max. dose 4 mg OD for 8 months
  Other Name: Doxazosin "Stada"
• Drug: Moxonidin
  Possible add-on therapy in case target blood pressure can not be reached with a combination of the other drugs in the Vasodilatory arm. Individual titration, max. dose 0,2 mg OD for 8 months
  Other Name: Moxonidin "Alpharma"
• Drug: Pindolol
  Possible add-on therapy in case target blood pressure can not be reached with a combination of the other drugs in the Vasodilatory arm. Individual titration, max. dose 10 mg OD for 8 months
  Other Name: Visken
• Drug: Amiloride, hydrochlorothiazide
  Possible add-on therapy in case target blood pressure can not be reached with a combination of the other drugs in the Vasodilatory arm. Individual titration, max. dose 1 tbl. OD for 8 months
  Other Name: Sparkal

Study Arms

Experimental: Vasodilatory

Patients in this arm will receive intensive vasodilatory treatment to lower blood pressure

Interventions:

• Drug: Lercanidipine
• Drug: Valsartan
• Drug: Nicorandil
• Drug: Doxazosin
• Drug: Moxonidin
• Drug: Pindolol
• Drug: Amiloride, hydrochlorothiazide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: May 5, 2009): 10
• Original Enrollment (submitted: January 19, 2007): 100
• Estimated Study Completion Date: December 2008
• Estimated Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Denmark

Administrative Information

• NCT Number: NCT00424801
• Other Study ID Numbers: Vasointense
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Kent Lodberg Christensen, DMSc, Aarhus Hospital
• Study Sponsor: University of Aarhus

Collaborators

• Danish Cardiovascular Research Academy
• Danish Heart Foundation
• Novartis

Investigators

• Principal Investigator: Michael N Præstholm, MD; University of Aarhus
• Study Director: Kent L Christensen, MD, DrMSc; Aarhus Hospital, medical-cardiologic dept. A
• Study Director: Won Yong Kim, MD, DrMSc; Skejby Hospital, cardiologic dept. B
• Study Director: Hans Erik Bøtker, MD, DrMSc; Skejby Hospital, cardiologic dept. B

• PRS Account: University of Aarhus
• Verification Date: May 2009