Cardiology / Primary Care

The Efficacy of Spironolactone for the Treatment of Drug-resistant Hypertension

By Harold L. Karpman, MD, FACC, FACP

Clinical Professor of Medicine, David Geffen School of Medicine, UCLA, Cardiovascular Medical Group

SYNOPSIS: Spironolactone was compared to other hypotensive drugs and determined to be the most effective additive therapy for drug-resistant hypertension patients who had previously not controlled their blood pressure through the traditional three hypotensive therapy classifications.

SOURCE: Williams B, MacDonald TM, Morant S, et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): A randomized, double-blind, crossover trial. Lancet 2015;386:2059-2063.

When blood pressure elevation remains uncontrolled despite the administration of three recommended hypotensive agents at their maximum tolerated dose, it is deemed drug-resistant hypertension. As this form of hypertension cannot be controlled by the three traditional hypertension-relieving drug categories (angiotensin converting enzyme [ACE] inhibitors, angiotensin II receptor blockers [ARB] in conjunction with a calcium channel blocker [CCB], and diuretics like thiazide), many researchers have attempted to discover an efficacious fourth-line alternative treatment.

Following speculation that the primary cause of drug-resistant hypertension is sodium retention and evidence suggesting positive effects from select diuretics on blood pressure stabilization, the authors elected to test the diuretic spironolactone to discern its effects on drug resistant hypertension. Williams et al enacted a year-long, double-blind and placebo controlled crossover trial, enrolling patients from 14 healthcare centers around the United Kingdom. Participants that were included needed to present with blood pressure readings greater than or equal to 140 mmHg (or, for diabetic patients, greater than or equal to 135 mmHg) consistently, despite treatment for at least three months with the maximum tolerated dosage of the three hypertension reducing drug groups — ACE, ARB with CCN, and diuretics — thus demonstrating sufficient drug resistance. Patients included cycled through four once-a-day oral therapy treatments of doxazosin, bisoprolol, spironolactone, and placebo. Home blood pressure measurements were used to eliminate the effect of white coat syndrome or placebo effect. The study results showed that spironolactone significantly increased the likelihood that a patient achieved blood pressure control compared to doxazosin or bisoprolol. Nearly 60% of drug-resistant hypertension patients that underwent spironolactone therapy achieved blood pressure control within the first three months of receiving the treatment.