REducing Blood Pressure Variability in Essential Hypertension With RAmipril vErsus Nifedipine GITS Trial

Study Overview
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Brief Summary
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The purpose of this study is to compare the effects of nifedipine GITS and ramipril on blood pressure variability in subjects with elevated blood pressure variability. to assess whether the degree of treatment-induced changes in blood pressure variability, is related to the degree of regression (or progression) of organ damage in heart, kidneys and carotid arteries.

Detailed Description
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Elevated blood pressure variability (BPV) is associated with adverse cardiovascular outcomes and organ damage in hypertensive subjects. An antihypertensive treatment able to reduce BPV independently of BP lowering effect might thus provide additional protection in terms of cardiovascular risk in subjects with elevated BPV, independently on its effect of BP itself. However, data on the effects of different classes of antihypertensive drugs on BPV are limited and inconsistent. Some studies have suggested a possible usefulness of calcium antagonists in this setting. Based on the above considerations the investigators hypothesize that a calcium channel blocker nifedipine GITS, will provide a greater BPV lowering effect, when compared with ramipril, independently from the reduction in mean BP level. Based on the above considerations, the primary objective of this study is to compare the effects of nifedipine GITS and ramipril on different estimates of BPV (24 h BPV, home BPV, and visit-to-visit BPV) in subjects with elevated BPV. The secondary objective is to assess whether the degree of treatment-induced changes in BPV, is related to the degree of regression (or progression) of organ damage, after accounting for mean BP reduction by treatment.

Official Title
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Short - Medium and Long Term Blood Pressure Variability in Essential Hypertensive Patients Treated With Nifedipine GITS or Ramipril - a Randomized Trial

Conditions
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Hypertension, High Blood Pressure Variability

Intervention / Treatment
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* Drug: Nifedipine GITS
* Drug: Ramipril


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects Age 35-75 years Clinic systolic BP ≥140 mmHg and/or diastolic BP ≥ 90 mmHg (under no antihypertensive treatment) Daytime BP on ambulatory BP monitoring (ABPM) ≥135 mmHg systolic and/or ≥85 mmHg diastolic (under no antihypertensive treatment) Home SBP standard deviation (SD) >7 mmHg and/or daytime ambulatory SBP SD >12 mmHg Patients may be included if untreated or, if treated with one antihypertensive drug or two drugs in low doses, after 2 weeks' washout period Written informed consent to participate in the study Exclusion Criteria: Subjects treated with ≥ 2 antihypertensive drugs (except those on two drugs in low doses) Treated subjects with on-treatment clinic BP ≥160 mmHg systolic and/or 100 mmHg diastolic Treated antihypertensive subjects in whom withdrawal of treatment is deemed unethical by the investigator (e.g. because of the existence of compelling indications other than hypertension for continuous use of previously used antihypertensive agent) Contraindications to study treatments as detailed in the relative Summaries of Medical Product Characteristics for ramipril (hypersensitivity to ramipril or any of the excipients or any other ACE inhibitor, history of angioneurotic oedema, extracorporeal treatments leading to contact of blood with negatively charged surfaces, significant bilateral renal artery stenosis or renal artery stenosis in a single functioning kidney, second and third trimesters of pregnancy, lactation, haemodynamically relevant renal artery stenosis, hypotensive or haemodynamically unstable patients) or nifedipine GITS (known hypersensitivity to nifedipine or to any of the excipients, pregnancy before week 20 and during breastfeeding, cardiovascular shock, concomitant treatment with rifampicin, patients with a Kock pouch) Cardiovascular diseases other than hypertension (coronary heart disease, heart failure or left ventricular systolic dysfunction of any degree, atrial fibrillation or frequent arrhythmias, valvular or congenital heart disease, cardiomyopathies, cerebrovascular disease, peripheral artery disease, aortic aneurysm) Chronic kidney disease Suspected or confirmed secondary hypertension Diabetes mellitus Subjects with conditions other than those mentioned above, where compelling indications for the use of any specific class of antihypertensive medication exist, according to current (e.g. European Society of Cardiology) guidelines Other conditions deemed relevant by the investigator (including respiratory disorders, liver disease, renal disease, thyroid disorders) BMI ≥35 kg/m2 Known severe obstructive sleep apnea (apnea-hypopnea index > 30 or use of CPAP) Premenopausal women not using effective contraceptive methods Elevated probability of noncompliance with the study procedures

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 75 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nifedipine GITS 30 mg slow release<br>Nifedipine GITS 30 mg slow release in tablets. | Drug: Nifedipine GITS<br>* Commercially available drug formulations are used. Study medication will be assumed in a single morning (7-10 a.m.) administration per os.<br>|
| Experimental: Ramipril 10 mg<br>Ramipril 10 mg in tablets. | Drug: Ramipril<br>* Commercially available drug formulations are used. Study medication will be assumed in a single morning (7-10 a.m.) administration per os.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variability (standard deviation) of home systolic blood pressure at final visit |  | After 10 weeks of study treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Variability (standard deviation) of home diastolic blood pressure measured at final visit |  | At baseline and after 10 weeks of study treatment | 
| Short term 24h variability of systolic blood pressure at final visit (24h weighted standard deviation) |  | At baseline and after 10 weeks of study treatment | 
| Short term 24h variability of diastolic blood pressure at final visit (24h weighted standard deviation) |  | At baseline and after 10 weeks of study treatment | 
| Visit-to-visit variability (standard deviation) of systolic blood pressure assessed over the three last visits |  | At baseline and after 6, 8 and 10 weeks of study treatment | 
| Visit-to-visit variability (standard deviation) of diastolic blood pressure assessed over the three last visits |  | At baseline and after 6, 8 and 10 weeks of study treatment | 
| Mean 24 hour systolic blood pressure at final visit |  | At baseline and after 10 weeks of study treatment | 
| Mean 24 hour diastolic blood pressure at final visit |  | At baseline and after 10 weeks of study treatment | 
| Sokolow index at the end of the extension study |  | At baseline and after 12 months of study treatment | 
| Cornell voltage duration index at the end of the extension study |  | At baseline and after 12 months of study treatment | 
| Left ventricular mass index at the end of the extension study |  | At baseline and after 12 months of study treatment | 
| Microalbuminuria (albumin-creatinine ratio) at the end of the extension study |  | At baseline and after 12 months of study treatment | 
| Estimated glomerular filtration rate (eGFR, by CKD-EPI formula) at the end of the extension study |  | At baseline and after 12 months of study treatment | 
| Carotid-femoral pulse wave velocity (cfPWV) at the end of the extension study |  | At baseline and after 12 months of study treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Blood pressure variability, Home systolic blood pressure, Organ damage, Ramipril, Hypertension, Nifedipine GITS