pharmaceutics Review The Road to Better Management in Resistant Hypertension—Diagnostic and Therapeutic Insights 1,2 1,2, 1,2 1,2 1,2 Elisabeta Bădilă , Cristina Japie *, Emma Weiss , Ana-Maria Balahura , Daniela Bartos, and 1,3 Alexandru Scafa Udris, te 1 Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy Bucharest, 050474 Bucharest, Romania; [email protected] (E.B.); [email protected] (E.W.); [email protected] (A.-M.B.); [email protected] (D.B.); [email protected] (A.S.U.) 2 Department of Internal Medicine, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania 3 Department of Cardiology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania * Correspondence: [email protected] Abstract: Resistant hypertension (R-HTN) implies a higher mortality and morbidity compared to non-R-HTN due to increased cardiovascular risk and associated adverse outcomes—greater risk of developing chronic kidney disease, heart failure, stroke and myocardial infarction. R-HTN is considered when failing to lower blood pressure below 140/90 mmHg despite adequate lifestyle measures and optimal treatment with at least three medications, including a diuretic, and usually a blocker of the renin-angiotensin system and a calcium channel blocker, at maximally tolerated doses. Hereby, we discuss the diagnostic and therapeutic approach to a better management of R- HTN. Excluding pseudoresistance, secondary hypertension, white-coat hypertension and medication non-adherence is an important step when diagnosing R-HTN. Most recently different phenotypes associated to R-HTN have been described, specifically refractory and controlled R-HTN and masked Citation: B˘adil˘a,E.; Japie, C.; Weiss, uncontrolled hypertension. Optimizing the three-drug regimen, including the diuretic treatment, E.; Balahura, A.-M.; Bartos, , D.; Scafa β Udris, te, A. The Road to Better adding a mineralocorticoid receptor antagonist as the fourth drug, a -blocker as the fifth drug Management in Resistant and an α1-blocker or a peripheral vasodilator as a final option when failing to achieve target blood Hypertension—Diagnostic and pressure values are current recommendations regarding the correct management of R-HTN. Therapeutic Insights. Pharmaceutics 2021, 13, 714. https://doi.org/ Keywords: resistant hypertension; pseudoresistance; adherence; diuretic; mineralocorticoid receptor 10.3390/pharmaceutics13050714 antagonist; lifestyle measure Academic Editor: Tihomir Tomašiˇc Received: 21 April 2021 1. Introduction Accepted: 7 May 2021 Published: 13 May 2021 Arterial hypertension (HTN), defined as office systolic blood pressure (BP) values ≥ 140 mmHg and/or diastolic BP values ≥ 90 mmHg, is known as the most Publisher’s Note: MDPI stays neutral important risk factor for cardiovascular (CV) diseases. Nowadays, the prevalence of HTN with regard to jurisdictional claims in amounts to 1.13 billion people, or around 30–45% of the global population [1,2]. The World published maps and institutional affil- Health Organization concluded that HTN is the third cause of death worldwide (one in iations. eight deaths being attributed to high BP) and this proportion is expected to increase over time [3]. Thus, the high prevalence of HTN and its subsequent complications are becoming a major problem for health systems across the world. Resistant hypertension (R-HTN), a severe form of HTN, has been intensively studied since the early 1960s, when it was first defined. R-HTN is considered when failing to lower Copyright: © 2021 by the authors. BP below 140/90 mmHg despite adequate lifestyle measures and optimal treatment with at Licensee MDPI, Basel, Switzerland. This article is an open access article least three antihypertensive medications of different classes, including a diuretic, typically distributed under the terms and a blocker of the renin-angiotensin system (angiotensin converting enzyme inhibitor or an- conditions of the Creative Commons giotensin receptor blocker) and a long-acting calcium channel blocker (CCB), at maximum Attribution (CC BY) license (https:// or maximally tolerated daily doses administered at the appropriate dosing interval [4]. creativecommons.org/licenses/by/ The 2018 European Society of Hypertension and European Society of Cardiology 4.0/). (ESH/ESC) Guidelines’ definition for R-HTN requires inadequate control of BP to be Pharmaceutics 2021, 13, 714. https://doi.org/10.3390/pharmaceutics13050714 https://www.mdpi.com/journal/pharmaceutics Pharmaceutics 2021, 13, x 2 of 16 or angiotensin receptor blocker) and a long-acting calcium channel blocker (CCB), at max- imum or maximally tolerated daily doses administered at the appropriate dosing interval [4]. Pharmaceutics 2021, 13, 714 The 2018 European Society of Hypertension and European Society of Cardiology2 of 16 (ESH/ESC) Guidelines’ definition for R-HTN requires inadequate control of BP to be con- firmed by ambulatory BP monitoring (ABPM) or home BP monitoring (HBPM) and ad- herenceconfirmed to therapy by ambulatory to be validated BP monitoring [4]. After (ABPM) excluding or home pseudoresistance BP monitoring and (HBPM) secondary and formsadherence of HTN, to therapy the prevalence to be validated of R-HTN [4]. Afteris estimated excluding to be pseudoresistance less than 10% in and hypertensive secondary treatedforms of patients HTN, the[4]. prevalence The increased of R-HTN prevalence is estimated during to the be last less 30 than years, 10% despite in hypertensive the im- provementtreated patients of antihypertensive [4]. The increased regimens, prevalence may during be explained the last 30by years,the progressive despite the ageing improve- of thement population of antihypertensive and by the obesity regimens, pandemic. may be explained by the progressive ageing of the population and by the obesity pandemic. 2. Resistant Hypertension-Associated Phenotypes 2. Resistant Hypertension-Associated Phenotypes Different R-HTN-associated phenotypes have been described. The 2017 American CollegeDifferent of Cardiology/American R-HTN-associated phenotypesHeart Association have been (ACC/AHA) described. guideline The 2017 introduced American twoCollege new ofconcepts: Cardiology/American controlled R-HTN Heart and Associationrefractory R-HTN (ACC/AHA) [5]. Controlled guideline R-HTN introduced is con- sideredtwo new in concepts:patients receiving controlled at least R-HTN four and antihypertensive refractory R-HTN medications [5]. Controlled and achieving R-HTN an is adequateconsidered office in patients BP control. receiving Refractory at least R-HTN four antihypertensive (rfR-HTN) refers medications to patients andwith achieving elevated officean adequate BP values office while BP control. on trea Refractorytment with R-HTN five or (rfR-HTN)more antihypertensive refers to patients drugs, with including elevated aoffice long-acting BP values thiazide-type while on treatment diuretic, withsuch fiveas indapamide or more antihypertensive or chlorthalidone, drugs, or includinga mineral- a ocorticoidlong-acting receptor thiazide-type antagonist diuretic, (MRA), such such as indapamide as spironolactone or chlorthalidone, [5] (Figure or 1). a mineralocor-The preva- lenceticoid of receptor rfR-HTN antagonist has been (MRA), estimated such by as a spironolactonelimited number [ 5of] (Figurestudies.1 ).The The Spanish prevalence ABPM of rfR-HTN has been estimated by a limited number of studies. The Spanish ABPM Registry Registry database was initiated in 2004 and contained a total of 70,997 treated patients. A database was initiated in 2004 and contained a total of 70,997 treated patients. A total total of 11,972 patients fulfilled the standard criteria of R-HTN (16.9%) and 955 had rfR- of 11,972 patients fulfilled the standard criteria of R-HTN (16.9%) and 955 had rfR-HTN HTN (7.9% of the total number of patients with R-HTN and 1.4% of the entire treated (7.9% of the total number of patients with R-HTN and 1.4% of the entire treated group) [6]. group) [6]. Similarly, the prevalence of rfR-HTN among the participants included in the Similarly, the prevalence of rfR-HTN among the participants included in the REGARD REGARD (Reasons for Geographic And Racial Differences in Stroke) Study was 0.5% [7]. (Reasons for Geographic And Racial Differences in Stroke) Study was 0.5% [7]. Compared Compared with R-HTN, patients with rfR-HTN were younger, had a longer duration of with R-HTN, patients with rfR-HTN were younger, had a longer duration of HTN, a higher HTN, a higher prevalence of obesity, diabetes mellitus, dyslipidemia, chronic kidney dis- prevalence of obesity, diabetes mellitus, dyslipidemia, chronic kidney disease and target ease and target organ damage and previous history of CV events [6,7]. Thus, these patients organ damage and previous history of CV events [6,7]. Thus, these patients require a require a greater medical attention among all patients with R-HTN. greater medical attention among all patients with R-HTN. FigureFigure 1. 1. HypertensionHypertension classification classification based based on on blood blood pressure pressure control control and and number number of of antihyper- antihyperten- tensivesive medications. medications. MostMost recently, recently, a new R-HTN-associated phenotype phenotype was was described—masked described—masked uncon- uncon- trolledtrolled HTN, HTN, referring referring to to patients patients receiving receiving four four or more antihypertensive medications andand achieving achieving an an adequate adequate office office