Prevention And Treatment of Hypertension With Algorithm based therapY-2 - PATHWAY 2


The goal of the trial was to evaluate treatment with spironolactone compared with doxazosin or bisoprolol or placebo among subjects with resistant hypertension.

Contribution to the Literature: The PATHWAY-2 trial showed that spironolactone was the most effective add-on treatment for resistant hypertension.

Study Design

  • Randomized
  • Parallel
  • Blinded
  • Crossover

Subjects with resistant hypertension were randomized to each of the four different add-on study medications, each for a 12-week period. Study medications included spironolactone 25-50 mg daily, doxazosin 4-8 mg daily, bisoprolol 5-10 mg daily, or placebo.

  • Total number of enrollees: 335
  • Mean patient age: 61 years
  • Percentage female: 31%
  • Percentage diabetics: 14%

Other salient features/characteristics:

  • Home blood pressure: 148/84 mm Hg
  • Clinic blood pressure: 157/90 mm Hg

Inclusion criteria:

  • Resistant hypertension defined as uncontrolled blood pressure despite three antihypertensive agents (angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker + calcium antagonist + thiazide diuretic)

Exclusion criteria:

  • Noncompliance as cause for resistant hypertension
  • White coat hypertension
  • Secondary hypertension

Principal Findings:

The primary outcome:

  • ∆ in home systolic blood pressure (SBP) between spironolactone and placebo: -8.70 mm Hg (p < 0.001)
  • ∆ in home SBP between spironolactone and bisoprolol/doxazosin: -4.26 mm Hg (p < 0.001)
  • ∆ in home SBP between spironolactone and doxazosin: -4.03 mm Hg (p < 0.001)
  • ∆ in home SBP between spironolactone and bisoprolol: -4.48 mm Hg (p < 0.001)

Secondary outcomes:

  • Home SBP with spironolactone: 135 mm Hg (-12.8 mm Hg ∆ from baseline)
  • Home SBP with doxazosin: 139 mm Hg (-8.7 mm Hg ∆ from baseline)
  • Home SBP with bisoprolol: 139 mm Hg (-8.3 mm Hg ∆ from baseline)
  • Home SBP with placebo: 144 mm Hg (-4.1 mm Hg ∆ from baseline)

Serious adverse events were 2.3% with spironolactone, 1.7% with doxazosin, 2.6% with bisoprolol, and 1.7% with placebo.


Among subjects with resistant hypertension, spironolactone was the most effective add-on agent for improved blood pressure control. Spironolactone resulted in a nearly 9 mm Hg reduction in SBP compared with placebo and an approximate 4 mm reduction compared with active antihypertensive agents. Spironolactone was well-tolerated with a low/similar frequency of serious adverse events. Spironolactone should be considered in the treatment algorithm for resistant hypertension.


Williams, B, MacDonald TM, Morant S., et al. Spironolactone Versus Placebo, Bisoprolol, and Doxazosin to Determine the Optimal Treatment for Drug-Resistant Hypertension (PATHWAY-2): a Randomised, Double-Blind, Crossover Trial. The Lancet 2015;386:2059-2068.

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

Clinical Topics: Diabetes and Cardiometabolic Disease, Prevention, Hypertension

Keywords: Algorithms, Antihypertensive Agents, Bisoprolol, Blood Pressure, Doxazosin, Hypertension, Metabolic Syndrome X, Primary Prevention, Sodium Chloride Symporter Inhibitors, Spironolactone, ESC Congress

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