Optimal Medical Treatment of Difficult-to-treat Hypertension

National Institute of Cardiology, Warsaw, Poland2,500 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

2,500

Conditions

Hypertension

Interventions

Phase C: EplerenoneDRUG

Participants randomly assigned to this arm take Eplerenone and placebos of Spironolactone and Torasemide

Phase C: SpironolactoneDRUG

Participants randomly assigned to this arm take Spironolactone and placebos of Eplerenone and Torasemide

Phase C: TorasemideDRUG

Participants randomly assigned to this arm take Torasemide and placebos of Eplerenone and Spironolactone

Eligibility

Sex: ALLMin age: 18 YearsMax age: 65 Years

Medical Language ↔ Plain English

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

Locations (1)

National Institute of Cardiology

Warsaw, Masovian Voivodeship, Poland

RECRUITING

Outcomes

Primary Outcomes

Patients with uncontrolled BP on ABPM

Percentage of patients with uncontrolled BP confirmed on ABPM (24h mean, SBP ≥125 mm Hg or DBP ≥80 mm Hg)

Time frame: First week of the patients' participation in the study

Patients with controlled BP after 12 weeks on triple SPC

Percentage of patients with controlled BP after 12 weeks of treatment with triple SPC, confirmed on ABPM (24h mean, SBP \<125 mm Hg and DBP \<80 mm Hg) - as the efficacy of the treatment strategy (switching ineffective treatment to triple SPC) - the whole group and P+I+A and E+H+A groups separetly.

Time frame: Next 12 weeks of the patients' participation in the study

Systolic BP reduction on 4th antihypertensive drug

Magnitude of reduction of SBP on ABPM (24h mean) after 12 weeks of treatment - comparison of eplerenone vs spironolactone and torasemide vs spironolactone.

Time frame: Last 24 weeks of the patients' participation in the study

Secondary Outcomes

Percentage of patients with BP controlled confirmed by HBPM

Percentage of patients with BP controlled confirmed by HBPM (mean over the period of 6 days, SBP ≥130 mm Hg or DBP ≥80 mm Hg)

Time frame: First week of the patients' participation in the study

Consistency of the rate of uncontrolled BP

Consistency of the rate of uncontrolled BP between ABPM and HBPM

Time frame: First week of the patients' participation in the study

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by OBPM

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by OBPM (SBP \<130 mm Hg and DBP \<80 mm Hg).

Central Contacts

Piotr Dobrowolski, Professor

CONTACT

(+48) 228156556 pdobrowolski@ikard.pl

Aleksander Prejbisz, Professor

CONTACT

aprejbisz@ikard.pl

Data from ClinicalTrials.gov

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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 A: Confirmation of uncontrolled hypertensionDIAGNOSTIC_TEST

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.

Time frame: Next 12 weeks of the patients' participation in the study

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by HBPM

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by HBPM (mean over 6 days, SBP \<130 mm Hg and DBP \<80 mm Hg).

Time frame: Next 12 weeks of the patients' participation in the study

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by ABPM

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by ABPM in daytime (SBP \<135 mm Hg and DBP \<85 mm Hg) and nighttime (SBP \<120 mm Hg and DBP \<70 mm Hg) reading.

Time frame: Next 12 weeks of the patients' participation in the study

Percentage of patients requiring an increase in the dose

Percentage of patients requiring an increase in the dose of drugs used in the whole group and in the patients treated with P+I+A and O+H+A separately.

Time frame: Next 12 weeks of the patients' participation in the study

Consistency of the rate of uncontrolled BP

Consistency of the rate of uncontrolled BP between ABPM, HBPM and OBPM.

Time frame: Next 12 weeks of the patients' participation in the study

The magnitude of the decrease in SBP and DBP on OBPM, ABPM and HBPM after 12 weeks

The magnitude of the decrease in SBP and DBP on OBPM, ABPM and HBPM after 12 weeks of treatment in the whole group and in the patients treated with P+I+A and O+H+A separately.

Time frame: Next 12 weeks of the patients' participation in the study

The magnitude of changes in HBPM and ABPM derived indices after 12 weeks

The magnitude of changes in HBPM and ABPM derived indices after 12 weeks of treatment in the whole group and in the patients treated with P+I+A and O+H+A separately.

Time frame: Next 12 weeks of the patients' participation in the study

Phase C

* Changes of SBP on ABPM (24h mean) after 12 weeks of treatment in patients receiving spironolactone, eplerenone or torasemide as compared against baseline. * Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by OBPM (SBP \<130 mm Hg and DBP \<80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group. * Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by HBPM (mean over 6 days, SBP \<130 mm Hg and DBP \<80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group. * Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by ABPM, in 24h mean (SBP \<125 mm Hg and DBP \<80 mm Hg), daytime (SBP \<135 mm Hg and DBP \<85 mm Hg) and nighttime (SBP \<120 mm Hg and DBP \<70 mm Hg) readings - comparison of eplerenone / torasemide groups against the spironolactone group.

Time frame: Last 24 weeks of the patients' participation in the study

Changes of SBP on ABPM (24h mean) after 12 weeks of treatment

Changes of SBP on ABPM (24h mean) after 12 weeks of treatment in patients receiving spironolactone, eplerenone or torasemide as compared against baseline.

Time frame: Last 24 weeks of the patients' participation in the study

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by OBPM

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by OBPM (SBP \<130 mm Hg and DBP \<80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group.

Time frame: Last 24 weeks of the patients' participation in the study

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by HBPM

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by HBPM (mean over 6 days, SBP \<130 mm Hg and DBP \<80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group.

Time frame: Last 24 weeks of the patients' participation in the study

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by ABPM

Percentage of patients with controlled BP after 12 weeks of treatment, confirmed by ABPM, in 24h mean (SBP \<125 mm Hg and DBP \<80 mm Hg), daytime (SBP \<135 mm Hg and DBP \<85 mm Hg) and nighttime (SBP \<120 mm Hg and DBP \<70 mm Hg) readings - comparison of eplerenone / torasemide groups against the spironolactone group.

Time frame: Last 24 weeks of the patients' participation in the study

Phase C continuation

Consistency of the rate of controlled BP between ABPM, HBPM and OBPM (after 12 weeks of treatment).

Time frame: Last 24 weeks of the patients' participation in the study

Phase C continuation

Changes in SBP and DBP on OBPM, ABPM and HBPM after 12 weeks of treatment - comparison of eplerenone / torasemide groups against the spironolactone group and comparison of each of the studied drug groups against baseline.

Time frame: Last 24 weeks of the patients' participation in the study

Changes in HBPM and ABPM derived indices after 12 weeks - comparison of treatment groups

Changes in HBPM and ABPM derived indices after 12 weeks of treatment - comparison of eplerenone / torasemide groups against the spironolactone group and comparison of each of the studied drug groups against baseline

Time frame: Last 24 weeks of the patients' participation in the study

Changes of SBP on ABPM (24h mean) after 24 weeks of treatment compared against spironolactone

Changes of SBP on ABPM (24h mean) after 24 weeks of treatment in patients receiving eplerenone or torasemide as compared against spironolactone.

Time frame: Last 24 weeks of the patients' participation in the study

Changes of SBP on ABPM (24h mean) after 24 weeks of treatment compared against baseline

Changes of SBP on ABPM (24h mean) after 24 weeks of treatment in patients receiving spironolactone, eplerenone or torasemide as compared against baseline.

Time frame: Last 24 weeks of the patients' participation in the study

Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by OBPM - comparison between groups

Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by OBPM (SBP \<130 mm Hg and DBP \<80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group.

Time frame: Last 24 weeks of the patients' participation in the study

Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by HBPM - comparison between groups

Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by HBPM (mean over 6 days, SBP \<130 mm Hg and DBP \<80 mm Hg) - comparison of eplerenone / torasemide groups against the spironolactone group.

Time frame: Last 24 weeks of the patients' participation in the study

Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by ABPM - comparison between groups

Percentage of patients with controlled BP after 24 weeks of treatment, confirmed by ABPM, in 24h mean (SBP \<125 mm Hg and DBP \<80 mm Hg), daytime (SBP \<135 mm Hg and DBP \<85 mm Hg) and nighttime (SBP \<120 mm Hg and DBP \<70 mm Hg) readings - comparison of eplerenone / torasemide groups against the spironolactone group.

Time frame: Last 24 weeks of the patients' participation in the study

Consistency of the rate of controlled BP between ABPM, HBPM and OBPM after 24 weeks

Consistency of the rate of controlled BP between ABPM, HBPM and OBPM after 24 weeks of treatment

Time frame: Last 24 weeks of the patients' participation in the study

Changes in SBP and DBP on OBPM, ABPM and HBPM after 24 weeks of treatment - comparison between groups

Changes in SBP and DBP on OBPM, ABPM and HBPM after 24 weeks of treatment - comparison of eplerenone / torasemide groups against the spironolactone group and comparison of each of the studied drug groups against baseline.

Time frame: Last 24 weeks of the patients' participation in the study

Changes in HBPM and ABPM derived indices after 24 weeks of treatment - - comparison between groups

Changes in HBPM and ABPM derived indices after 24 weeks of treatment - comparison of eplerenone / torasemide groups against the spironolactone group and comparison of each of the studied drug groups against baseline

Time frame: Last 24 weeks of the patients' participation in the study

Percentage of patients requiring an increase in the dose of drugs used after 6 and 12 weeks - comparison between groups

Percentage of patients requiring an increase in the dose of drugs used after 6 and 12 weeks - comparison of eplerenone / torasemide groups against the spironolactone.

Time frame: Last 24 weeks of the patients' participation in the study