Imidapril and Candesartan on Fibrinolysis and Insulin-Sensitivity in Patients With Mild to Moderate Hypertension

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Essential Hypertension

Intervention / Treatment
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* Drug: Imidapril
* Drug: Candesartan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 2<br>Imidapril | Drug: Imidapril<br>* tablets; 5, 10, 15, 20 mg; od; 12 weeks<br>* Other names: Not yet registered in Italy;|
| Active Comparator: 1<br>Candesartan | Drug: Candesartan<br>* tablets; 8, 16, 24, and 32 mg; od; 12 weeks<br>* Other names: Registered in Italy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PAI-1 level and t-PA activity time course changes |  | 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 | 
| t-PA activity at the desmopressin test |  | 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 | 
| Insulin sensitivity state through euglycemic hyperinsulinemic clamp method |  | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood pressure changes |  | At 0, 1, 2, 4, 8, and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hypertension, Insulin sensitivity, Fibrinolysis