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

September 24, 2015

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

  1. Allan S. Brett, MD

In a randomized trial, spironolactone was the winner.

  1. Allan S. Brett, MD

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.


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


Reader Comments (5)

Wajahat Humayun, M.D Resident, Internal Medicine, Abington Memorial Hospital

Great Study. Can you please elaborate how frequently you were monitoring plasma potassium in patients who were on maximal ACEi and Max Spirinolactone?

Carlos Alberto Scarampi Physician, Cardiology, Argentina

Eplerenone would be a good choice, since it has less side effects

Marie Grenon Physician, Geriatrics, Quebec, St-Francois d'Assise Hospital

Very interessing! Thanks!

enoch orugun Physician, Internal Medicine, North Cumbria University Hospitals NHS Trust

An interesting study that would change practice. It would be nice to know how these combination drugs affected the quality of life of patients as intake of these drugs are going to be life-long. What is the drop out rate and how was concordance to medication managed?

GAURANGA DHAR Physician, Family Medicine/General Practice

This is a fantastic study, just the reflection of my daily practice. If spironolactone started with very low dose and titrate gradually, hyperkalemia is not a problem, although we need to follow electrolytes time to time.

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