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Two older diuretics ‘work best’ for drug-resistant hypertension

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Two older diuretic drugs have been found to be the most effective treatment for drug-resistant hypertension, based on salt retention being the main culprit behind it, according to UK researchers.

They noted that as many as 10% patients with high blood pressure have “resistant hypertension”, meaning it was not controlled despite treatment with a diuretic and at least two other drugs.

“Either of these two well-established diuretics will achieve excellent blood pressure control in the majority of these patients”

Bryan Williams

Initial results from the PATHWAY-2 study, reported two years ago in The Lancet, showed spironolactone was significantly more effective than other drugs at lowering blood pressure in the resistant population.

The drug is a diuretic that has been around for more than 50 years, but has rarely been used to treat hypertension, said the researchers.

Now, new analyses from the same study has revealed why spironolactone works best, and that another older diuretic, called amiloride, works equally well.

The findings, presented today, would “change clinical practice across the world and will help improve the blood pressure and outcomes of our patients with resistant hypertension”, said study investigator Dr Bryan Williams, chair of medicine at University College London.

“We now have two new treatments based on old drugs,” he said. “Our study provides strong evidence that either of these two well-established diuretics will achieve excellent blood pressure control in the majority of these patients.”

PATHWAY-2 was a phase 4 study that compared four additional interventions in 314 patients with resistant hypertension.

“This has been a wonderful story of using sophisticated modern methods to solve an old problem”

Morris Brown

At baseline, all patients were receiving best tolerated doses of the “A+C+D treatment strategy”, which is standard treatment based on three medications.

This strategy includes an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB), plus a calcium-channel blocker (CCB), and a diuretic.

Patients remained on this baseline treatment and were then rotated through four 12-week cycles of each of the investigational treatments as add-on therapy.

The add-on treatments included placebo, bisoprolol, doxazosin – both commonly used blood pressure-lowering drugs – or spironolactone.

Using sophisticated, non-invasive measurements of cardiac output, vascular resistance and total body water volume, the researchers also confirmed amiloride’s similar efficacy to spironolactone.

The reason why both drugs work so well in resistant hypertension is because salt-retention in this population is due to over-production of the salt-retaining hormone aldosterone, said Dr Williams.

University College London

Two older diuretics ‘work best’ for drug-resistant hypertension

Bryan Williams

“Both spironolactone and amiloride block the effects of aldosterone, which is probably why they are especially effective in resistant hypertension,” he said.

“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,” he added.

Dr Morris Brown, chief investigator for the PATHWAY studies from Queen Mary University, London, said: “This has been a wonderful story of using sophisticated modern methods to solve an old problem – why some patients have seemingly intractable hypertension.

“The discovery of salt overload as the underlying cause has enabled us to target the hormone which drives this, and to treat or cure most of the patients,” he noted.

The latest findings were presented today at the European Society of Cardiology’s annual congress in Barcelona.

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