Official Title: “Randomized, Controlled, Parallel Arm, PROBE Study to Evaluate Different Effects of Imidapril and Candesartan on Fibrinolysis and Insulin-Sensitivity in Patients With Mild to Moderate Hypertension”

BACKGROUND The effects of ACE-inhibitors on fibrinolysis are well documented. Experimental and clinical studies have shown that ACE inhibitors induce a reduction in plasma PAI-1 levels in many cardiovascular diseases, like hypertension, coronary heart disease, and heart failure. Their effects on t-PA are more controversial, due to the fact that t-PA exists in several forms, including free and bound to PAI-1. Indeed an increase in t-PA activity has been observed in humans and it seems related to bradykinin increase which is known to stimulate endothelial t-PA synthesis. These favourable effects on fibrinolysis could be related not only to the Angiotensin II reduction and the bradykinin increase but also to the improvement in insulin sensitivity, as insulin has been suggested as one of the main regulators of fibrinolytic activity.

To date conflicting results have been reported about the effects of ARBs on fibrinolysis.

Some studies have reported small improvements, others no significant effect. These conflicting results may be due to possible methodological bias but a possible pathophysiological explanation might be that receptor subtypes other than AT1 mediate the effect of Angiotensin-II on endothelial PAI-1 expression, i.e. the AT4 receptors, and during AT1 receptor blockade there is an important increase not only of Angiotensin-II, but also of all its catabolites including Angiotensin IV. The dissimilar effects on of ACE Is and ARBs may also depend on their different action on the RAS and their different effect on insulin sensitivity: ACE-Is improve insulin sensitivity, while the majority of ARBs have been reported to have a neutral effect. Moreover, unlike ACE-Is, ARBs do not affect the metabolism of bradykinin, which is known to stimulate t-PA synthesis and release.

AIM OF THE STUDY The aim of this study is to verify the effect of imidapril compared to candesartan on insulin sensitivity, evaluated through the euglycemic hyperinsulinemic clamp, and on fibrinolysis, evaluated through the plasma PAI-1 and t-PA activity, in mild to moderate hypertensive patients.

Study Type: Interventional

Study Design: Treatment, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: March 2008

Intervention(s) in this Clinical Trial

• Drug: Imidapril
  • tablets; 5, 10, 15, 20 mg; od; 12 weeks
• Drug: Candesartan
  • tablets; 8, 16, 24, and 32 mg; od; 12 weeks

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 2
  • Imidapril
• Active Comparator: 1
  • Candesartan

Primary Measures

• PAI-1 level and t-PA activity time course changes
  • Time Frame: Desmopressin and Clamp venous blood samples will be taken for all patients between 08.00 and 09.00 at 0 and 12 weeks; week 0, 1, 2, 4, 8, and 12 for the others
    Safety Issue?: Yes
• t-PA activity at the desmopressin test
  • Time Frame: Desmopressin and Clamp venous blood samples will be taken for all patients between 08.00 and 09.00 at 0 and 12 weeks; week 0, 1, 2, 4, 8, and 12 for the others
    Safety Issue?: Yes
• Insulin sensitivity state through euglycemic hyperinsulinemic clamp method
  • Time Frame: Desmopressin and Clamp venous blood samples will be taken for all patients between 08.00 and 09.00 at 0 and 12 weeks; week 0, 1, 2, 4, 8, and 12 for the others
    Safety Issue?: Yes

Secondary Measures

• Blood pressure changes
  • Time Frame: At 0, 1, 2, 4, 8, and 12 weeks
    Safety Issue?: Yes

Inclusion Criteria:

• Age 18-65 years
• DBP ≥ 90 < 110 mmHg and SBP ≥ 140 < 180 mmHg
• Normal Body Mass Index (BMI) (≤ 25 Kg/m2)
• Normal kidney function (Creatinine Clearance > 80 ml/min)
• Normocholesterolemia (TC < 250 mg/dl)
• At least one of the following risk factor:
• age (M > 55 years)
• smoking
• family history of premature CV disease
• echocardiographic LVH
• carotid wall thickening (IMT > 0.9 mm)
• ankle/brachial BP < 0.9

Exclusion Criteria:

• Secondary hypertension
• Overweight or obese state (BMI ≥ 25 Kg/m2)
• Suspected history of allergy to the ARBs, or ACEs
• Malignancy
• Renal, hepatic, endocrine, or gastrointestinal disease
• Women who are pregnant and lactating
• Women child-bearing potential
• Heart failure
• AMI and/or stroke in the previous 6 months
• CHD
• Diabetes mellitus

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 65 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Pavia

Overall Clinical Trial Officials and Contacts

Giuseppe Derosa, MD Principal Investigator University of Pavia  

Overall Contact: Giuseppe Derosa, MD +39 0382 502614 giuseppe.derosa@unipv.it

Information obtained from ClinicalTrials.gov on October 10, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00644475

Study ID Number: UNIPV001DIM2008

ClinicalTrials.gov Identifier: NCT00644475

Health Authority: Italy: National Monitoring Centre for Clinical Trials - Ministry of Health