Optimal Medical Treatment of Difficult-to-treat Hypertension

The purpose of this study is to evaluate best medical management to achieve the BP goals of ESC/ESH (120-129 / 70-79 mmHg) in HT patients who are \<65 years old and ineffectively treated (BP ≥ 130/80 mg) with 3 or more antihypertensive drugs

Purpose: To evaluate best medical management to achieve the ESC/ESH 2018 BP goals of 120-129 / 70-79 mmHg in HT patients aged \< 65 y not controlled on 3 or more antihypertensive drugs.

Study design:

Phase A (Active screening) (n = 2500) 7 days Confirmation of the true ineffectiveness of antihypertensive therapy based on 3 or more antihypertensive drugs (single or dual drug preparations) using ABPM and home BP measurements.

Phase B (Open-label, non-randomized) (n = 1250) 12 weeks Replacement of ineffective antihypertensive treatment based on 3 or more antihypertensive drugs (single or dual drug preparations) with a triple single pill combination (SPC) based on optimally combined antihypertensive drugs: perindopril + indapamide + amlodipine (P+I+A) or olmesartan + hydrocholothiazide + amlodipine (O+H+A).

Phase C (Double blind, randomized, parallel-group) (n = 480) 24 weeks

Comparison of antihypertensive efficacy and tolerability profile:

* spironolactone
* eplerenone
* torasemide attached as an antihypertensive drug of 4th choice.

Eligibility Criteria:
Inclusion Criteria:

* documented history of HT
* HT treated for at least six months,
* office BP ≥ 130 and / or ≥80 mm Hg (average seated BP at Visit 1)
* use of 3 or more antihypertensive drugs, including an ACEi/ARB and a thiazide/thiazide-like diuretic or loop diuretic (single drugs or double SPCs)
* stable antihypertensive treatment regimen - no changes in antihypertensive treatment strategy at least for 4 weeks
* able and willing to comply with all study procedures and able to attend one of the study centers

Exclusion Criteria:

* inability to give informed consent
* SBP ≥180 mm Hg and/or DBP ≥110 mm Hg and/or DBP \<60 mm Hg
* BMI ≥40 kg/m2
* eGFR of \<45 mL/min/1.73 m2
* potassium serum concentration \> 4.8 mmol/L or \< 3.5 mmol/L
* persistent hyponatremia or history of hyponatremia related to TD/TLD treatment (sodium concentration \<135 mmol/L)
* secondary hypertension (not including sleep apnea)
* chronic oral glucocorticoid therapy
* myocardial infarction or cerebrovascular event (e.g. stroke, transient ischemic event, cerebrovascular accident) in the year prior to study inclusion
* heart failure requiring treatment with diuretic or aldosterone antagonists
* cardiomyopathy exluding LVH related to HT
* severe valvular disease
* ascending aortic aneurysm ≥5 cm
* prescribed to any standard antihypertensive of cardiovascular medication (e.g. beta blockers) for other chronic conditions (e.g. chronic coronary syndromes, arytmia) such that discontinuation might pose serious risk to health
* primary pulmonary hypertension
* decompensated hyperthyroidism or hypothyroidism
* severe liver dysfunction (alanine aminotransferase and/or asparagine aminotransferase activity ≥3 times the upper limit of normal value),
* documented contraindication or allergy to studied drugs
* limited life expectancy of \< 1 year at the discretion of the Investigator
* any known, unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions, or for any reason in the opinion of the investigator, would be unlikely or unable to comply with study protocol requirements
* all women of child bearing potential; women of child bearing potential can be included in the study ONLY after providing documentation of effective contraception (intrauterine device);
* concurrent enrollment in any other investigational drug or device trial
* anticipated change of medical status during the trial (e.g., surgical intervention requiring \>2 weeks convalescence)
* current therapy for cancer