Which Add-On Drug Is Best for Three-Drug–Resistant Hypertension?

[Argirios Argiriou]

September 24, 2015

Which Add-On Drug Is Best for Three-Drug–Resistant Hypertension?

Allan S. Brett, MD reviewing Williams B et al. Lancet 2015 Sep 20.

In a randomized trial, spironolactone was the winner.

For patients whose blood pressure (BP) is not optimal despite treatment with three drugs (i.e., “resistant hypertension”), no consensus exists on the most effective add-on drug. To clarify this issue, U.K. researchers conducted a randomized, placebo-controlled, crossover trial that involved 314 patients (age range, 18–79) with clinic systolic BP ≥140 mm Hg despite treatment with angiotensin-converting–enzyme inhibitors or angiotensin-receptor blockers, diuretics, and calcium-channel blockers. On these baseline three-drug regimens, mean home BP was 148/82 mm Hg, and mean clinic BP was 157/90 mm Hg. Patients with glomerular filtration rate <45 mL/minute/1.73 m2 and patients with recent stroke or myocardial infarction were excluded.

All patients received each of four add-on drugs, assigned in random order: spironolactone (25 mg and 50 mg), doxazosin (4 mg and 8 mg), bisoprolol (5 mg and 10 mg), and placebo. For each drug cycle, patients received the lower dose for 6 weeks, followed by the higher dose for 6 weeks. The average of multiple home BP readings during the last few days of each 6-week cycle was calculated, and the averages were compared; outcomes were as follows:

With each drug's higher dose compared with placebo, mean systolic BP was lowered by 10 mm Hg with spironolactone, 5 mm Hg with doxazosin, and 4 mm Hg with bisoprolol; the difference between spironolactone and the other two drugs was significant.

With spironolactone, mean systolic BP was significantly lower — by 4 mm Hg — with 50-mg than with 25-mg doses.

Although spironolactone appeared to be effective across the spectrum of baseline plasma renin activity (PRA), efficacy was best when PRA was lowest.

Six spironolactone recipients developed asymptomatic serum potassium levels >6 mmol/L, with no serious clinical consequences.

COMMENT

Spironolactone was the clear “winner” in this valuable study of resistant hypertension; the inverse relation with baseline PRA suggests that its efficacy is related, at least in part, to enhanced natriuresis. BPs of these study participants at enrollment were elevated only moderately; knowing whether the results apply to resistant-hypertensive patients with substantially higher BPs would be useful. A final caveat: This study doesn't provide direct evidence that spironolactone-containing four-drug regimens improve long-term cardiovascular and renal outcomes compared with alternative regimens.

EDITOR DISCLOSURES AT TIME OF PUBLICATION

Disclosures for Allan S. Brett, MD at time of publication
Nothing to disclose

CITATION(S):

Williams B et al. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): A randomised, double-blind, crossover trial. Lancet 2015 Sep 20; [e-pub]. (Δεν είναι ορατοί οι σύνδεσμοι (links). Εγγραφή ή Είσοδος)

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