Spironolactone may be effective as add-on treatment for drug-resistant hypertension

Spironolactone compared favorably to placebo, bisoprolol, and doxazosin as an add-on treatment for drug-resistant hypertension, a new trial indicates.

Researchers performed a double-blind, placebo-controlled, crossover trial at secondary and primary care sites in the United Kingdom. Participating patients were 18 to 79 years of age and had persistent hypertension despite at least 3 months of treatment with maximum doses of 3 drugs, such as an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, a calcium-channel blocker, and a thiazide or thiazide-like diuretic. To test their hypothesis that resistant hypertension is related to sodium retention and that a diuretic drug could be effective, the researchers rotated patients in a randomized, preassigned order through 12 weeks of treatment with once-daily spironolactone, 20 to 50 mg; bisoprolol, 5 to 10 mg; modified-release doxazosin, 4 to 8 mg; or placebo while regular antihypertensive medications were continued. After 6 weeks of each cycle, the add-on treatment dose was doubled. No washout period occurred between the 4 treatment cycles.

The study's primary end points were difference in average of home systolic blood pressure between spironolactone and placebo, difference in home systolic blood pressure between spironolactone and the average of the other 2 add-on drugs, and difference in home systolic blood pressure between spironolactone and each of the other 2 add-on drugs. The study results were published online Sept. 21 by Lancet.

A total of 335 patients were randomly assigned to treatment between May 15, 2009, and July 8, 2014, but 21 were later excluded because they had no follow-up data for any of the drugs. Overall, 285 patients received spironolactone, 282 received doxazosin, 285 received bisoprolol, and 274 received placebo. Two hundred thirty patients finished all of the treatment cycles, and all of the treatments were generally well tolerated. In their intention-to-treat analysis, the researchers found that spironolactone yielded an average reduction in home systolic blood pressure that was greater than placebo (difference, −8.70 mm Hg), the mean of doxazosin and bisoprolol (difference,−4.26 mm Hg), and doxazosin (difference,−4.03 mm Hg) and bisoprolol (difference,−4.48 mm Hg) individually (P<0.001 for all comparisons). Two hundred nineteen of 314 patients achieved a target home systolic blood pressure of 135 mm Hg, and 58% achieved control with spironolactone, superior to the other add-on treatments.

The authors noted that the trial was relatively short, that it did not include data on morbidity and mortality outcomes, and that their results may not apply to patients with kidney disease or to nonwhite populations, among other limitations. However, they concluded that spironolactone was the most effective add-on treatment in this study for resistant hypertension and suggested that their findings should have global influence on treatment guidelines and clinical practice, including the possibility that patients should receive a course of spironolactone in addition to other treatments before resistant hypertension is diagnosed. “A longer-term question is whether the antecedent to resistant hypertension is under treatment or wrong treatment, with the resistance to conventional drugs marking a subpopulation in whom spironolactone should be used at an earlier stage,” the authors wrote.