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

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.