PATHWAY-3: Amiloride-hydrochlorothiazide combination superior to either alone for uncontrolled hypertension

LONDON — A combination of half doses of amiloride and hydrochlorothiazide was superior to full doses of either treatment alone in patients with uncontrolled hypertension, according to the results of the PATHWAY-3 trial.

Perspective from Steen Dalby Kristensen, MD, DMSc, FESC

Researchers hypothesized that adding amiloride, a potassium-sparing diuretic, to a thiazide diuretic would control BP and decrease diabetes risk in patients with uncontrolled hypertension (defined as systolic BP > 140 mm Hg) and at least one other component of the metabolic syndrome who were not previously taking a diuretic.

Morris Brown

For the PATHWAY-3 study, Morris Brown, MD, MSc, FRCP, FAHA, FMedSci, and colleagues randomly assigned 440 patients to receive amiloride 10 to 20 mg/day, hydrochlorothiazide 25 to 50 mg/day or amiloride 5 to 10 mg/day plus hydrochlorothiazide 12.5 to 25 mg/day. Brown presented the findings at the European Society of Cardiology Congress.

The primary outcome was difference from baseline in 2-hour glucose, as indicated by an oral glucose tolerance test administered at 12 weeks and 24 weeks, with difference in home systolic BP at 12 and 24 weeks as the principal secondary outcome.

At 24 weeks, compared with hydrochlorothiazide alone, the adjusted means for change from baseline in 2-hour glucose was 0.71 mmol/L (95% CI, 0.21-1.21; P = .005) for amiloride and 0.58 mmol/L (95% CI, 0.08-1.06; P = .024) for amiloride plus hydrochlorothiazide, Brown, professor of clinical pharmacology at the University of Cambridge, said at a press conference.

At 12 weeks among those on low doses and 24 weeks for those on high doses, the amiloride plus hydrochlorothiazide group exhibited a larger decrease in systolic BP than the hydrochlorothiazide group alone (3.4 mm Hg; 95% CI, 0.9-5.8; P = .007) or the amiloride group alone, he said.

Importantly, the amiloride-hydrochlorothiazide combination had neutral effects on glucose and serum potassium, whole amiloride alone was associated with higher potassium and lower glucose levels, and hydrochlorothiazide alone was associated with lower potassium and higher glucose levels (P < .01 for both), Brown said. He noted that despite its effect on potassium, amiloride was well-tolerated and that no patient, including those on background ACE inhibitors or angiotensin receptor blockers, exceeded serum potassium levels of 5.8 mmol/L.

“The half doses combined are more effective than either on their own,” Brown said at the press conference. “We think this combination is what you may call a ‘win-win’ vs. the individual drugs at equipotent doses, amplifying the desirable effects of each on BP and neutralizing the undesirable, namely blood glucose and potassium.”

Brown told Cardiology Today that diuretic combinations could become an integral part of management of patients with high BP. “The release of the SPRINT study results will perhaps enhance the value of learning that diuretic combinations are more effective than a single diuretic in lowering BP,” he said. – by Erik Swain

Reference:

Brown M, et al. Hot Line IV: Hypertension. Presented at: European Society of Cardiology Congress; Aug. 29-Sept. 2, 2015; London.

Disclosure: Brown reports no relevant financial disclosures.

Perspective

Steen Dalby Kristensen, MD, DMSc, FESC

This trial showed that amiloride, a potassium-saving drug that has been around for a long time, seemed to have very interesting effects on glucose control. That’s an important new message. What we heard at this session about older drugs such as amiloride and spironolactone has the potential to change therapy for our patients with elevated BP.

Steen Dalby Kristensen, MD, DMSc, FESC

Professor of cardiology and consultant cardiologist

Aarhus University Hospital, Aarhus, Denmark

Disclosures: Kristensen reports no relevant financial disclosures.