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.

Insights on β‐blockers for the treatment of hypertension: A survey of health care practitioners

“…In 2014, approximately 73 000 deaths in the United States were attributed to hypertension, an increase of 34.1% since 2004 . While many efficacious options for pharmacologically lowering blood pressure (BP) are available—including angiotensin‐converting enzyme inhibitors (ACEI), angiotensin II receptors blockers (ARBs), calcium channel blockers (CCBs), diuretics, aldosterone antagonists, and β‐blockers—hypertension remains uncontrolled in nearly 50% of hypertensive adults, and the prevalence of resistant hypertension is rising …”