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Spironolactone vs Clonidine: Which Is the Better Fourth Drug for Resistant HTN?

Information sourced from NEJM Journal Watch:

In Resistant Hypertension, Is Spironolactone or Clonidine a Better Choice for a Fourth Drug?

The two drugs performed similarly, but spironolactone might be an easier medication to add.

Resistant hypertension is an infrequent but difficult-to-manage clinical problem. After prescription of the common frontline drugs (diuretic, angiotensin-converting–enzyme inhibitor or angiotensin-receptor blocker, and calcium-channel blocker), the most suitable drug to add is uncertain. In the ReHOT study (Resistant Hypertension Optimal Treatment), researchers in Brazil compared spironolactone and clonidine as a fourth drug in patients with resistant hypertension.

n the two-phase study, 1597 hypertensive patients were treated with ≤3 drugs for 12 weeks, and 187 patients (11.7%) were identified as having resistant hypertension. Compared with the other patients, those with true resistant hypertension had higher incidences of stroke and diabetes and lower glomerular filtration rates. Of this group, 162 were randomized to spironolactone or clonidine; mean daily doses were 40 mg and 0.35 mg, respectively.

The primary combined endpoint of blood pressure (BP) control during office measurement (less than 140/90 mm Hg) and 24-hour ambulatory BP monitoring [less than 130/80 mm Hg] was not different between the two groups. Only 21% of patients achieved normal BP levels. On secondary endpoints, spironolactone was associated with greater decreases than clonidine in 24-hour systolic and diastolic BP and diastolic daytime ambulatory BP. Analyses limited to patients with greater than 80% adherence to drugs showed similar trends on the primary outcome. The rates of adverse effects were low for both drugs.


Joel M. Gore, MD

In this multicenter trial, more than 1 of 10 hypertension patients had resistant hypertension. Clonidine was not superior to spironolactone as a fourth-drug therapy. As the authors note, because spironolactone is taken once daily, it should be considered the better choice for patients with resistant hypertension who require a fourth drug.


Allan S. Brett, MD

Here’s another reason to avoid clonidine. In some patients considered to have resistant hypertension, the “resistance” actually reflects poor adherence to their medication regimens, sometimes for understandable reasons (e.g., financial constraints in uninsured, impoverished populations). Adding clonidine can be risky, given the severe rebound hypertension that can occur in such patients when clonidine is started or stopped abruptly and unpredictably.

Joel M. Gore, MD and Allan S. Brett, MD reviewing Krieger EM et al. Hypertension 2018 Apr.


Krieger EM et al. Spironolactone versus clonidine as a fourth-drug therapy for resistant hypertension: The ReHOT randomized study (Resistant Hypertension Optimal Treatment). Hypertension 2018 Apr; 71:681.

NEJM Journal Watch is produced by NEJM Group, a division of the Massachusetts Medical Society. Copyright ©2018 Massachusetts Medical Society. All rights reserved.

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