Preferred Fourth-Line Pharmacotherapy for Resistant Hypertension: Are We There Yet?

  • Hamish CG Prosser
  • Cynthia Gregory
  • Dagmara Hering
  • Graham S Hillis
  • Greg Perry
  • Johan Rosman
  • Carl Schultz
  • Mark Thomas
  • Gerald F Watts
  • Markus P Schlaich
Resistant Hypertension (E Pimenta, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Resistant Hypertension


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.


Resistant hypertension Pharmacotherapy Fourth-line therapy Antihypertensive medications 


Compliance with Ethics Standards

Conflict of Interest

Drs. Prosser, Gregory, Hering, Hillis, Perry, Rosman, Schultz, Thomas, Watts, and Schlaich declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Hamish CG Prosser
    • 1
  • Cynthia Gregory
    • 1
    • 2
  • Dagmara Hering
    • 1
  • Graham S Hillis
    • 1
    • 2
  • Greg Perry
    • 3
  • Johan Rosman
    • 1
    • 3
  • Carl Schultz
    • 1
    • 2
  • Mark Thomas
    • 3
  • Gerald F Watts
    • 1
    • 2
  • Markus P Schlaich
    • 1
    • 2
    • 3
    • 4
  1. 1.Dobney Hypertension Centre, Faculty of Health and Medical Sciences, School of Medicine-Royal Perth Hospital UnitUniversity of Western AustraliaPerthAustralia
  2. 2.Department of CardiologyRoyal Perth HospitalPerthAustralia
  3. 3.Department of NephrologyRoyal Perth HospitalPerthAustralia
  4. 4.Dobney Chair in Clinical Research, School of Medicine and Pharmacology - Royal Perth Hospital UnitThe University of Western AustraliaPerthAustralia

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