LONDON – The combination of two old diuretics – amiloride and hydrochlorothiazide – at half-doses provides synergistic blood pressure lowering beyond the full doses of either drug alone while neutralizing the thiazide diuretic’s blood glucose– and uric acid–raising side effects, according to the results of the PATHWAY-3 trial.
“We think this combination of amiloride and hydrochlorothiazide at equipotent doses is a ‘win win,’ ” Dr. Morris J. Brown said in presenting the study findings at the annual congress of the European Society of Cardiology.
Bruce Jancin/Frontline Medical News
Dr. Morris J. Brown
“Since unlocking the data, we’ve scarcely been able to contain our excitement at the results. I believe these results will return potassium-sparing diuretics to prominence,” said Dr. Brown, professor of clinical pharmacology at the University of Cambridge (England).
The thiazide diuretics as a group have fallen out of favor because of their adverse metabolic effects, including increased risks of diabetes and gout. But the PATHWAY-3 trial demonstrates that, with the half-dose combination approach, amiloride cancels those side effects, while hydrochlorothiazide (HCTZ) neutralizes amiloride’s tendency to boost serum potassium, he explained.
PATHWAY-3 was a 13-center, 24-week randomized trial involving 399 hypertensive patients with at least one additional component of the metabolic syndrome. They were assigned to 12 weeks of amiloride at 10 mg/day, HCTZ at 25 mg/day, or the combination at half-doses, followed by another 12 weeks at twice the dose in all three groups.
The primary outcome was a safety endpoint: the change from baseline in 2-hour oral glucose tolerance tests conducted at 12 and 24 weeks. Blood glucose levels rose in patients on HCTZ and fell significantly in patients on amiloride or the combination. At 24 weeks, the 2-hour blood glucose level was 0.71 mmol/L lower in the amiloride group and 0.58 mmol/L lower in the combination group than in the HCTZ group.
A key secondary endpoint was change in home systolic blood pressure levels. Averaged over 24 weeks, systolic blood pressure was reduced from baseline by 14.7 mm Hg with amiloride monotherapy, by 14.0 mm Hg with HCTZ, and by 17.5 mm Hg with half-dose combination therapy.
Serum potassium levels rose over time with amiloride, fell with HCTZ, and remained unchanged with combination therapy. But full-dose amiloride monotherapy was well tolerated, with no instances of hyperkalemia as defined by a level above 5.8 mmol/L, even though virtually all patients were on background therapy with an ACE inhibitor or angiotensin receptor blocker, Dr. Brown reported.
He noted that the amiloride-HCTZ combination is the only diuretic that has demonstrated superiority in terms of morbidity and mortality in long-term clinical trials versus a calcium channel blocker in the INSIGHT trial (Lancet. 2000 Jul 29;356[9227]:366-72) and versus beta blocker therapy in the MRC-Elderly trial (BMJ. 1992 Feb 15;304:405-12).
PATHWAY-3 is part of an ongoing program developed by the British Heart Foundation to reexamine old, inexpensive drugs that have been pushed aside by newer and far costlier alternatives.
“The continuing famine of new small molecules makes reappraisal and repurposing of old drugs even more important,” Dr. Brown noted.
Discussant Dr. Antonio Coca found the PATHWAY-3 results compelling.
“On the basis of PATHWAY-3, the combination of amiloride and hydrochlorothiazide in equivalent doses becomes the preferred choice for diuretic treatment in patients with insulin resistance, such as obese hypertensives or those with elevated fasting plasma glucose. These findings together with previous morbidity and mortality data from INSIGHT and MRC-Elderly support its first-line use in patients requiring diuretic therapy for hypertension, alone or in combination with other antihypertensive drugs,” said Dr. Coca of the University of Barcelona.
In an interview, Dr. Elliott M. Antmann, immediate past president of the American Heart Association, said he found the PATHWAY-3 study “very impressive.”
“I personally am going to be prescribing more amiloride, which I haven’t prescribed in years,” said Dr. Antmann of Harvard Medical School, Boston.
Dr. Brown reported no financial conflicts regarding the PATHWAY-3 trial, funded by the British Heart Foundation and the National Institute for Health Research.