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This trial investigated which drug is best added to high blood pressure (hypertension) treatment if blood pressure has not come down to normal levels after taking three blood pressure lowering drugs. Such “resistant hypertension” accounts for around 10% of all people who have hypertension.

The study found that adding spironolactone to the existing three-drug regimen was the most effective treatment and was well-tolerated by patients.

Spironolactone is currently recommended by NICE at this fourth stage of treatment, but at half the dose used in this study. The higher dose will increase the cost of prescribing slightly.

Potassium levels need to be monitored when using spironolactone as there is a risk they can rise. High levels were detected in only around 2% of the study participants given spironolactone, which is reassuring.

Why was this study needed?

One in four adults in England has hypertension with a blood pressure of 140/90mmHg or more. Hypertension puts strain on the blood vessels and heart and can lead to a range of health conditions including heart attacks, kidney disease, stroke and vascular dementia. Treatment includes lifestyle measures such as reducing salt intake and maintaining a healthy weight. NICE guidelines suggest that drug treatments are used in a “stepped” manner, with other drugs added to the regimen if initial treatment is not adequate. The NIHR funded this study, called PATHWAY-2, to investigate which of the add-on drugs currently recommended for resistant hypertension was most effective.

What did this study do?

The PATHWAY-2 trial recruited 335 participants and began with a month-long “run in” where each received a placebo treatment. This was in addition to the three types of blood pressure lowering drugs they were already taking (ACE inhibitor, calcium channel blocker and thiazide/thiazide-like diuretic). After, participants were randomised to receive each of the fourth line treatment one after the other: spironolactone, doxazosin, bisoprolol and placebo (see Definitions for more information). Participants started on a lower dose for the first six weeks, which was doubled in the final six weeks of each treatment cycle. There was no “wash out” period between treatments (to allow drugs to leave the person’s system) but the treatments were delivered in different orders to ensure that the sequence in which drugs were received did not affect outcomes. The full treatment cycles were completed by 230 participants.

What did it find?

  • Adding spironolactone to existing treatment resulted in a greater reduction in home-measured systolic blood pressure when compared with placebo (‑8.70mm Hg, 95% confidence interval [CI] ‑9.72 to ‑7.69), doxazosin (‑4.03 mm Hg, 95% CI ‑5.04 to ‑3.02) or bisoprolol (‑4.48 mm Hg, 95% CI ‑5.50 to ‑3.36).
  • Average blood pressure readings taken at home and in the clinic were comparable, although readings were slightly higher when taken in the clinic, which is known as the “white coat effect”.
  • Potassium levels were slightly raised in people receiving spironolactone and bisoprolol, but this was not deemed clinically significant. Two per cent of the 285 people taking spironolactone had a high serum potassium level (6.0 to 6.5 mmol/L) on a single occasion, normal serum potassium level is 3.5 to 5.5 mmol/L.

What does current guidance say on this issue?

The 2011 NICE hypertension guideline recommends drug treatment for hypertension using an angiotensin-converting-enzyme (ACE) inhibitor or an angiotensin-II receptor blocker first. If either of these “first line” treatments do not work, calcium-channel blockers are added. If first and second line treatment is not effective then a thiazide-like diuretic is added to the other drugs. NICE recommends that people with “resistant hypertension” who do not adequately respond to first, second and third line treatments are prescribed 25 mg of spironolactone. If this is not tolerated, then an alpha or beta-blocker is advised.

What are the implications?

The findings of this study reinforce NICE’s 2011 recommendation that people with resistant hypertension be offered spironolactone in addition to their current treatments. However, the final six weeks of this 12 week drug trial used a daily spironolactone dose (50 mg) twice that recommended by NICE (25 mg). The cost of monitoring potassium levels in those receiving spironolactone should be factored into implementation costs. The trial included primarily white patients, so it is unclear whether this treatment would be as effective in other ethnic groups. People of African or Caribbean descent are at increased risk of developing hypertension and may respond better to diuretics. This group makes up 3% of the UK population.


Williams B, MacDonald TM, Morant S, et al; British Hypertension Society's PATHWAY Studies Group. 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. [Epub ahead of print]

This study was funded by a special project grant from the British Heart Foundation (number SP/08/002). Further funding was provided by the National Institute for Health Research (NIHR) Comprehensive Local Research Networks.


NHS Choices. Doxazosin (Doxazosin 1mg tablets). London: NHS Choices; 2015.

NHS Choices. High blood pressure (hypertension). London: NHS Choices; 2014.

NHS Choices. Spironolactone (Spironolactone 100mg tablets). London: NHS Choices; 2015.

NICE. Hypertension: Clinical management of primary hypertension in adults. CG127. London: National Institute for Health and Care Excellence; 2011.

ONS. Ethnicity and National Identity in England and Wales 2011. Newport: Office for National Statistics; 2012.

Produced by the University of Southampton and Bazian on behalf of NIHR through the NIHR Dissemination Centre


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The exact physical cause of resistant hypertension is not fully understood and available treatments target different parts of the body to try to reduce it.

Spironolactone is an aldosterone receptor antagonist. It causes the kidneys to excrete more sodium and water which reduces the blood pressure.


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