Inhibition aldosterone effects lowers blood pressure by decreasing salt retention in resistant hypertension patients

ESC 2017 - Barcelona

News - Aug. 27, 2017

PATHWAY-2 uncovers main cause of drug-resistant hypertension, finds old drugs work best

Presented at the ESC congress 2017 by: Bryan Williams (London, UK)


Initial results of the PATHWAY-2 study (314 patients) showed that spironolactone, an older diuretic medication but rarely used for hypertension, was significantly more effective than other drugs at lowering blood pressure in patients with resistant hypertension (no controlled blood pressure despite diuretic treatment and at least two other blood pressure medications). Spironolactone is a diuretic that specifically antagonizes the action of the body’s salt-retaining hormone aldosterone. In PATHWAY-2, after a 4-week run-in, patients were with cycles of low dose spironolactone (best tolerated), doxazosin, bisoprolol or placebo for 6-weeks, followed by a 6-week treatment of twice the dose of these agents.

Today, new analyses of three substudies that were embedded in the PATHWAY-2 study were presented at the ESC, about the mechanisms that may be involved in the superiority of blood pressure-lowering by spironolactone above other diuretics and whether alternative diuretics with a similar mechanism of action (eg. amiloride) would show similar benefits. For this, amiloride was given at 10-20 mg uptitration once a day for 12 weeks in an open-label phase after the initial 12-week PATHWAY-2 trial.

Main results

  • While neither placebo, nor doxazosin and bisoprolol showed a significant relation with renin or aldosterone levels or aldosterone/renin ratio, spironolactone did (renin mass: r2=0.108, P<0.0002, aldosterone r2=0.025, P=0.0524, aldosterone/renin ratio r2=0.130, P=0.0001).
  • Spironolactone was the only treatment that reduced fluid volume at the end of each treatment cycle, as measured by the thoracic fluid index (P<0.002 compared to baseline).
  • It was most effective in patients with a hormonal pattern that reflected most salt retention, which supports the hypothesis that the underlying problem in resistant hypertension is salt and water retention.
  • This was supported by the finding that around 25% of patients had excessive levels of aldosterone.
  • Blood pressure reduction from baseline on amiloride correlated with this with spironolactone (r=0.64, P<0.0001).


Resistant hypertension was characterized by salt and water excess. Most effective treatment was spironolactone that reduced this volume excess by antagonizing the effect of the salt-retaining hormone aldosterone. This effect was also achieved by amiloride. This diuretic has a similar mechanism but acts on a different pathway.

In a press release Williams stated: “It is remarkable when so many advances in medicine depend on expensive innovation, that we have been able to revisit the use of drugs developed over half a century ago and show that for this difficult-to-treat population of patients, they work really well”.

During the press conference, it was asked why Williams is so sure to extrapolate these results to the general population. He said that his confidence is supported by the data that show this drug works very effectively.

In addition, he stressed that these patients did not consume excessive amounts of salt what could have resulted in salt-retention.

- Our reporting is based on the information provided at the ESC congress -

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