Spironolactone Add-On Therapy Superior for Resistant Hypertension

The drug was more effective at lowering blood pressure than placebo, doxazosin, and bisoprolol.
The drug was more effective at lowering blood pressure than placebo, doxazosin, and bisoprolol.

Spironolactone effectively lowers blood pressure in patients with resistant hypertension and is superior to other non-diuretic add-on drugs, a new study finds.

“Spironolactone substantially increases the likelihood of achieving blood pressure control relative to bisoprolol or doxasosin, with almost 60% achieving blood pressure control within 3 months of starting treatment,” lead researcher professor Bryan Williams, MD, FRCP, of the National Institute for Health Research in London, and colleagues wrote in The Lancet.

The finding challenges the concept that resistant hypertension cannot be managed adequately with existing drug therapies, they noted.

For the double-blind, crossover study, the investigators randomly assigned 230 patients with persistently high systolic pressure (despite treatment for 3 or more months with maximum doses of 3 antihypertensive medications: an ACE inhibitor or an angiontensin II receptor blocker as well as a calcium channel blocker and a thiazide-like diuretic) to fourth-line therapies. Participants rotated through 12-week cycles of add-on treatment with spironolactone (25–50 mg), bisoprolol (5–10 mg), doxazosin (4–8 mg), and placebo; doses of each drug were doubled after 6 weeks. Patients with advanced kidney disease (estimated glomerular filtration rate less than 45 mL/min/1.73 m2) were excluded.

Spironolactone proved superior to placebo, doxazosin, bisoprolol, and the average of the 2 active medications, lowering systolic pressure by an extra 8.70, 4.03, 4.48, and 4.26 mm Hg, respectively, according to results published in The Lancet.

Furthermore, the investigators found evidence to support the hypothesis that resistant hypertension is caused by excessive sodium retention. Spironolactone, an aldosterone receptor antagonist, was the most-effective add-on drug to lower blood pressure throughout the distribution of plasma renin, a biomarker inversely related to sodium status, but it was particularly impactful at lower levels of renin.  

Previous research indicates that spironolactone works by reducing serum sodium and increasing potassium. Over the 3-month treatment in this study, only 6 patients taking spironolactone experienced an episode of hyperkalemia (serum potassium above 6 mmol/L).

The highest dose of spironolactone used in the study, 50 mg, is not the maximum dose possible in the range. Raising the dose might control blood pressure even better in some patients, according to the researchers.

Regarding study strengths, the investigators noted that they minimized the placebo effect and white coat hypertension by relying on average home blood pressure measurements rather than clinical readings. They also took steps to reinforce medication adherence. Limitations included the relatively short treatment period, absence of drug washout, and the homogeneous population (mostly Caucasian).

Editorialists praised the study, but pointed to some outstanding questions: “Would similar results be achieved in an African-American…cohort? Can these results be applied to patients with advanced kidney disease at risk for hyperkalemia? Would people with much lower sodium intake…still require addition of spironolactone? Additionally, would a longer acting thiazide diuretic such as chlorthalidone or indapamide reduce the need for spironolactone?” Future studies need to address these issues.

Whether undertreatment or the wrong treatment is responsible for resistant hypertension is still an open question, the researchers acknowledged.

Sources

  1. Williams, B; MacDonald, TM; Morant, S; et al. The Lancet; doi: 10.1016/S0140-6736(15)00257-3.
  2. Sternlicht, H and Bakris, GL. The Lancet; doi: 10.1016/S0140-6736(15)00264-0.
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