title: Preferred Fourth-Line Pharmacotherapy for Resistant Hypertension: Are We There Yet?
abstract: Resistant hypertension (RH) is defined as blood pressure (BP) that remains above target levels despite adherence to at least three different antihypertensive medications, typically including a diuretic. Epidemiological studies estimate that RH is increasing in prevalence, and is associated with detrimental health outcomes. The pathophysiology underlying RH is complex, involving multiple, overlapping contributors including activation of the renin-angiotensin aldosterone system and the sympathetic nervous system, volume overload, endothelial dysfunction, behavioural and lifestyle factors. Hypertension guidelines currently recommend specific pharmacotherapy for 1st, 2nd and 3rd-line treatment, however no specific fourth-line pharmacotherapy is provided for those with RH. Rather, five different antihypertensive drug classes are generally suggested as possible alternatives, including: mineralocorticoid receptor antagonists, α1-adrenergic antagonists, α2-adrenergic agonists, β-blockers, and peripheral vasodilators. Each of these drug classes vary in their efficacy, tolerability and safety profile. This review summarises the available data on each of these drug classes as a potential fourth-line drug and reveals a lack of robust clinical evidence for preferred use of most of these classes in the setting of RH. Moreover, there is a lack of direct comparative trials that could assist in identifying a preferred fourth-line pharmacologic approach and in providing evidence for hypertensive guidelines for adequate treatment of RH.
authors.affiliation: Dobney Hypertension Centre, Faculty of Health and Medical Sciences, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.
authors.forename: Hamish Cg
authors.initials: HC
authors.lastname: Prosser
authors.affiliation: Dobney Hypertension Centre, Faculty of Health and Medical Sciences, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.|Department of Cardiology, Royal Perth Hospital, Perth, Australia.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gregory
authors.affiliation: Dobney Hypertension Centre, Faculty of Health and Medical Sciences, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.
authors.forename: Dagmara
authors.initials: D
authors.lastname: Hering
authors.affiliation: Dobney Hypertension Centre, Faculty of Health and Medical Sciences, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.|Department of Cardiology, Royal Perth Hospital, Perth, Australia.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Hillis
authors.affiliation: Department of Nephrology, Royal Perth Hospital, Perth, Australia.
authors.forename: Greg
authors.initials: G
authors.lastname: Perry
authors.affiliation: Dobney Hypertension Centre, Faculty of Health and Medical Sciences, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.|Department of Nephrology, Royal Perth Hospital, Perth, Australia.
authors.forename: Johan
authors.initials: J
authors.lastname: Rosman
authors.affiliation: Dobney Hypertension Centre, Faculty of Health and Medical Sciences, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.|Department of Cardiology, Royal Perth Hospital, Perth, Australia.
authors.forename: Carl
authors.initials: C
authors.lastname: Schultz
authors.affiliation: Department of Nephrology, Royal Perth Hospital, Perth, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Dobney Hypertension Centre, Faculty of Health and Medical Sciences, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, Australia.|Department of Cardiology, Royal Perth Hospital, Perth, Australia.
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Watts
authors.affiliation: Dobney Hypertension Centre, Faculty of Health and Medical Sciences, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, Australia. markus.schlaich@uwa.edu.au.|Department of Cardiology, Royal Perth Hospital, Perth, Australia. markus.schlaich@uwa.edu.au.|Department of Nephrology, Royal Perth Hospital, Perth, Australia. markus.schlaich@uwa.edu.au.|Dobney Chair in Clinical Research, School of Medicine and Pharmacology - Royal Perth Hospital Unit, The University of Western Australia, Level 3, MRF Building, Rear 50 Murray St, Perth, WA, 6000, Australia. markus.schlaich@uwa.edu.au.
authors.forename: Markus P
authors.initials: MP
authors.lastname: Schlaich
mesh_terms: D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D004232:Diuretics / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D012084:Renin-Angiotensin System
chemical_list: D000959:Antihypertensive Agents; D004232:Diuretics
keywords: Antihypertensive medications; Fourth-line therapy; Pharmacotherapy; Resistant hypertension