Prevention And Treatment of Hypertension With Algorithm based therapY-3 - PATHWAY-3


The goal of the trial was to evaluate treatment with amiloride/hydrochlorothiazide (HCTZ) vs. amiloride vs. HCTZ among subjects with uncontrolled hypertension.

Contribution to the Literature: The PATHWAY-3 trial showed that combination amiloride/HCTZ was superior to either diuretic alone on favorable blood pressure and glycemic effects.

Study Design

  • Randomized
  • Parallel

Subjects with uncontrolled hypertension were randomized to amiloride (5-10 mg)/HCTZ 12.5-25 mg) versus amiloride (10-20 mg) versus HCTZ (25-50 mg). Forced up-titration occurred at 12 weeks.

Inclusion criteria:

  • Uncontrolled hypertension (systolic blood pressure [SBP] >140 mm Hg)
  • Eligible for diuretic therapy
  • At least one additional component of the metabolic syndrome
  • Total number of enrollees: 440
  • Duration of follow-up: 24 weeks
  • Mean patient age: 62 years
  • Percentage female: 39%
  • Blood pressure: 154/91 mm Hg

Principal Findings:

For the primary outcome: Average difference (12 and 24 weeks) from baseline in oral glucose tolerance test 2-hour glucose for amiloride versus HCTZ was -0.55 mmol/L (p = 0.009). Average difference (12 and 24 weeks) from baseline in oral glucose tolerance test 2-hour glucose for amiloride/HCTZ versus HCTZ was -0.42 mmol/L (p = 0.048).

For the secondary outcomes: Twenty-four week blood pressure was lowest in the amiloride/HCTZ group (p = 0.02 vs. HCTZ). Twenty-four week potassium was highest in the amiloride group (p < 0.001 vs. HCTZ), intermediate in the amiloride/HCTZ group (p < 0.001 vs. HCTZ), and lowest in the HCTZ group.


Among patients with uncontrolled hypertension, amiloride or combination amiloride/HCTZ (10/25 mg daily at 24 weeks) blunted adverse glycemic effects that occurred with HCTZ alone. Potassium was lowest in the HCTZ group, while SBP was lowest in the combination amiloride/HCTZ group. These results suggest that HCTZ should not be used as a single diuretic in treating hypertension (i.e., adverse glycemic effects and low potassium levels), but rather added to the potassium-sparing diuretic amiloride (i.e., neutral glycemia/potassium, lowest blood pressure levels).


Presented by Dr. Morris Brown at the European Society of Cardiology Congress, London, August 31, 2015.

Keywords: Amiloride, Blood Pressure, Diuretics, Diuretics, Potassium Sparing, Glucose Tolerance Test, Hydrochlorothiazide, Hypertension, Metabolic Syndrome, Potassium, Primary Prevention, ESC Congress

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