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

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

The purpose of this study is

1. to compare the effects of nifedipine GITS and ramipril on blood pressure variability in subjects with elevated blood pressure variability.
2. 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.

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.

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