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NIHR Signal Spironolactone is effective for treating resistant hypertension

Published on 1 December 2015

doi: 10.3310/signal-000152

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.

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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.

Citation

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.

Bibliography

EMC. Bisoprolol 2.5mg/5mg/10mg film coated tablet. electronic Medicines Compendium;

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.

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.

Citation

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.

Bibliography

EMC. Bisoprolol 2.5mg/5mg/10mg film coated tablet. electronic Medicines Compendium;

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.

Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial

Published on 20 September 2015

Prof Bryan Williams, Prof Thomas M MacDonald, Steve Morant, Prof David J Webb, Prof Peter Sever, Prof Gordon McInnes, Prof Ian Ford, Prof J Kennedy Cruickshank, Prof Mark J Caulfield, Prof Jackie Salsbury, Isla Mackenzie, Sandosh Padmanabhan, Prof Morris J Brown

The Lancet , 2015

Background Optimal drug treatment for patients with resistant hypertension is undefined. We aimed to test the hypotheses that resistant hypertension is most often caused by excessive sodium retention, and that spironolactone would therefore be superior to non-diuretic add-on drugs at lowering blood pressure. Methods In this double-blind, placebo-controlled, crossover trial, we enrolled patients aged 18–79 years with seated clinic systolic blood pressure 140 mm Hg or greater (or ≥135 mm Hg for patients with diabetes) and home systolic blood pressure (18 readings over 4 days) 130 mm Hg or greater, despite treatment for at least 3 months with maximally tolerated doses of three drugs, from 12 secondary and two primary care sites in the UK. Patients rotated, in a preassigned, randomised order, through 12 weeks of once daily treatment with each of spironolactone (25–50 mg), bisoprolol (5–10 mg), doxazosin modified release (4–8 mg), and placebo, in addition to their baseline blood pressure drugs. Random assignment was done via a central computer system. Investigators and patients were masked to the identity of drugs, and to their sequence allocation. The dose was doubled after 6 weeks of each cycle. The hierarchical primary endpoints were the difference in averaged home systolic blood pressure between spironolactone and placebo, followed (if significant) by the difference in home systolic blood pressure between spironolactone and the average of the other two active drugs, followed by the difference in home systolic blood pressure between spironolactone and each of the other two drugs. Analysis was by intention to treat. The trial is registered with EudraCT number 2008-007149-30, and ClinicalTrials.gov number, NCT02369081. Findings Between May 15, 2009, and July 8, 2014, we screened 436 patients, of whom 335 were randomly assigned. After 21 were excluded, 285 patients received spironolactone, 282 doxazosin, 285 bisoprolol, and 274 placebo; 230 patients completed all treatment cycles. The average reduction in home systolic blood pressure by spironolactone was superior to placebo (–8·70 mm Hg [95% CI −9·72 to −7·69]; p<0·0001), superior to the mean of the other two active treatments (doxazosin and bisoprolol; −4·26 [–5·13 to −3·38]; p<0·0001), and superior when compared with the individual treatments; versus doxazosin (–4·03 [–5·04 to −3·02]; p<0·0001) and versus bisoprolol (–4·48 [–5·50 to −3·46]; p<0·0001). Spironolactone was the most effective blood pressure-lowering treatment, throughout the distribution of baseline plasma renin; but its margin of superiority and likelihood of being the best drug for the individual patient were many-fold greater in the lower than higher ends of the distribution. All treatments were well tolerated. In six of the 285 patients who received spironolactone, serum potassium exceeded 6·0 mmol/L on one occasion. Interpretation Spironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. Funding The British Heart Foundation and National Institute for Health Research.

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.

Expert commentary

Doctors often have difficulty in selecting a fourth antihypertensive drug in patients who are established on three agents and have yet to achieve an acceptable target of blood pressure control. This study gives unequivocal support to the use of spironolactone in this regard. It was superior to doxazosin and bisoprolol in terms of blood pressure lowering efficacy. Often doctors are concerned that introducing this agent will lead to unacceptably high serum potassium levels but this was only observed in a very small minority of the patients in this trial. The practice point from these data is that if one is faced with a patient apparently refractory to antihypertensive medication, the fourth agent of choice should be an aldosterone antagonist such as spironolactone.

Professor Tony Heagerty, Professor of Medicine and Cardiac Centre Lead, The University of Manchester