Clinical trial NCT03476616: Antihypertensive Pharmacological Therapy With Mineralocorticoid Receptor Antagonists in Obese Hypertensive Patients
Official title: HYpertension Therapy With Valsartan Versus EpleRenone for Obese Patients: A Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Hypertension
Obesity
Keywords: Hypertension
Obesity
Ambulatory Blood Pressure
Eplerenone
Valsartan
Mineralocorticoid Receptor Antagonists
Angiotensin II Receptor Blockers
Lead sponsor: Hippocration General Hospital
Sponsor class: OTHER
First posted: 2018-03-26
Enrollment: 330
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Obesity is a complex metabolic state at which many pathophysiological pathways seem to interfere, like imbalance of autonomic nervous system, as well as renin-angiotensin-aldosterone system (RAAS) activation. Latest studies have shown that the increase of peripheral fat in obese patients, alongside with the increase of P-450 aromatase leads to hyper-aldosteronism, which results to increased sodium intake and rise of blood pressure. The present study aims to investigate the potential superiority of an aldosterone antagonist based therapy (eplerenone) over the renin-angiotensin antagonists (ARBs) (valsartan) based therapy in hypertensive obese patients regarding reduction of blood pressure (office, home and ambulatory) over a 24-week period.

Detailed description: The present study plans to enroll obese patients (BMI= 30-40 kg/m2) of 30-75 years of age, with untreated or never-treated essential hypertension to either eplerenone-based or valsartan-based therapy Patients visiting hypertension center(s), eligible to participate in the study and meeting study's inclusion criteria, will at first thoroughly be informed of study's protocol rationale, including scheduled follow-up visits. There will be a period of 2-4 weeks, at which medical history will be taken, as well as somatometrics, including height, weight, BMI and waist circumference. Moreover, a thorough clinical examination will take place, including office blood pressure, ECG, heart-echo, renal ultrasound, blood and urine ultrasound. All women of gestational age should have pregnancy test.

At randomization visit, patients still meeting inclusion/exclusion criteria will be randomized (1:1) to either eplerenone (E) 25mg bd or valsartan (V) 160mg od for 8 weeks. At 8, 16 and 24 weeks, patients at both arms will be evaluated with ambulatory BP measurements primary, as well as home and office BP measurements. At week 8, patients with controlled hypertension (mean ambulatory blood pressure measurement (ABPM) \<130/80mmHg), will continue in monotherapy with eplerenone or valsartan and patients with uncontrolled hypertension (mean 24-h ambulatory≥130/80mmHg) will continue with the addition of calcium-channel blocker, amlodipine (C) 5 mg od. At week 16, patients achieving BP control will continue in either monotherapy (E), (V) or dual therapy (E+C), (V+C). However, in patients not achieving blood pressure target, a third drug, thiazide-like-diuretic will be added \[indapamide (D) 1.25 mg od\]. All groups at both arms will be finally evaluated at 24 weeks.

Eligibility criteria: Inclusion Criteria:

1. 30-75 years of age
2. Written consent
3. Untreated or never-treated arterial hypertension with office systolic blood pressure of 140-180 mmHg and/or diastolic blood pressure of 90-120 mmHg, confirmed by 24-hour ambulatory blood pressure measurements of mean ambulatory systolic blood pressure over 130 mmHg and/or mean ambulatory diastolic blood pressure over 80 mmHg
4. Obesity, confirmed estimated by Body Mass Index (BMI) of 30-40 kg/m2

Exclusion Criteria

1. Age \<30 or \>75
2. Inability to give informed consent
3. Participation in a clinical study involving an investigational drug or device within 4 weeks of screening
4. Secondary hypertension
5. Recent (\<6 months) cardiovascular event requiring hospitalization (eg. myocardial infarction or stroke)
6. Type 1 diabetes
7. Chronic kidney disease assessed by Estimated Glomerular Filtration Rate (eGFR) \<45 mL/min
8. Bilateral renal arteries stenosis
9. Addison's disease
10. Hemodynamically significant valvular heart disease
11. Plasma potassium outside of normal range on two successive measurements during screening
12. Pregnancy, planning to conceive or women of childbearing potential, that is, not using effective contraception
13. Scheduled surgery or cardiovascular surgery over the next 6 months
14. Absolute contra-indication to study drugs (eg. asthma) or previous intolerance of trial therapy
15. History of sustained atrial fibrillation
16. Requirement for study drug for reason other than to treat hypertension, (eg, β-blockers for angina or aldosterone antagonists for heart failure)
17. Neoplasm under treatment (radiotherapy / chemotherapy / immunotherapy)
18. Any concomitant condition that, in the opinion of the investigator, may adversely affect the safety and/or efficacy of the study drug or
19. severely limit that patients' life-span or ability to complete the study (eg, alcohol or drug abuse, disabling or terminal illness, mental
20. disorders)
21. Contemporary systemic disease with life expectancy shorter than the end of the study
22. Treatment with any of the following medications:

    * Oral corticosteroids within 3 months of screening. Treatment with systemic corticosteroids is also prohibited during study participation
    * Chronic stable use, or unstable use of NSAIDs (other than low dose aspirin) is prohibited. Chronic use is defined as \>3 consecutive or non-consecutive days of treatment per week. In addition, intermittent use of NSAIDs is strongly discouraged throughout the study and NSAIDs if required, must not be used for more than a total of 2 days. For those requiring analgesics during the study, paracetamol is recommended.
    * The use of short-acting nitrates (eg, sublingual nitroglycerin) is permitted.
    * The use of sympathomimetic decongestants is permitted, however, not within 1 day prior to any study visit/BP assessment
    * The use of theophylline is permitted but the dose must be stable for at least 4 weeks prior to screening and throughout the study;
    * The use of phosphodiesterase type V inhibitors is permitted; however, study participants must refrain from taking these medications for at least 1 day prior to screening or any subsequent study visits
    * The use of α-blockers is not permitted, with the exception of alfuzosin and tamsulosin for prostatic symptoms

Primary outcomes:
measure: Difference in change of ABPM from baseline, in the eplerenone arm versus the valsartan arm as monotherapy at 8 weeks, as combined dual treatment with amlodipine at 16 weeks and as combined triple treatment with amlodipine and indapamide at 24 weeks.
timeFrame: 8, 16 and 24 weeks
Secondary outcomes:
measure: Difference in change of office BP from baseline, in the eplerenone arm versus the valsartan arm as monotherapy at 8 weeks, as combined dual treatment with amlodipine at 16 weeks and as combined triple treatment with amlodipine and indapamide at 24 weeks.
timeFrame: 8, 16 and 24 weeks
Other outcomes:
measure: Difference in frequency of controlled hypertension (mean ABPM < 130/80 mm Hg) between the study arms at 8, 16 and 24 weeks.
timeFrame: 8, 16 and 24 weeks
Locations:
city: Athens
country: Greece
facility: Hypertension Unit, First Cardiology Clinic, Hippocration General Hospital, University of Athens, Athens, Greece
Study officials:
affiliation: Hypertension Unit, First Cardiology Clinic, Hippocration General Hospital, University of Athens, Greece
name: Konstantinos P Tsioufis, Ass. Prof.
role: PRINCIPAL_INVESTIGATOR
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