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Williams B, 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. Lancet. 2015;386:2059–2068. PMID 26414968

One-paragraph summary

PATHWAY-2 tested fourth-line therapy in patients whose hypertension remained uncontrolled despite maximally tolerated ACE inhibitor or ARB, calcium-channel blocker, and thiazide-like diuretic therapy. In a randomized double-blind crossover comparison, spironolactone lowered home systolic BP 8.70 mm Hg more than placebo (95% CI 7.69–9.72) and 4.26 mm Hg more than the mean of bisoprolol and doxazosin (3.38–5.13). The treatment gradient across renin supported sodium retention as a common mechanism of resistant hypertension.

Design

Element Detail
Population Adults with resistant hypertension on standardized triple therapy
Treatments Spironolactone, bisoprolol, doxazosin, placebo
Sequence Randomized double-blind crossover
Primary measurement Home systolic BP
Main clinical question Best empiric fourth-line drug

Key findings

  • Spironolactone versus placebo: −8.70 mm Hg home systolic BP (95% CI −9.72 to −7.69).
  • Spironolactone versus mean active comparators: −4.26 mm Hg (95% CI −5.13 to −3.38).
  • Home BP reduced white-coat distortion and increased repeated-measure precision.
  • Low-renin participants showed the clearest spironolactone response, supporting volume/aldosterone biology.
  • The trial strengthened the case for mineralocorticoid-receptor antagonism after true resistance is confirmed.

Limitations

  • Participants passed a structured trial pathway; routine-care apparent resistance often reflects adherence, measurement, or under-dosing.
  • Follow-up periods were short and the outcome was BP, not cardiovascular events or HHD regression.
  • Hyperkalemia and renal-function constraints limit use, especially in CKD.
  • Primary aldosteronism was not equivalent to the low-renin phenotype.
  • The result does not remove the need to investigate secondary hypertension.

Why it matters

Resistant hypertension accelerates HHD and is a common point at which clinicians either intensify treatment or mislabel pseudo-resistance. PATHWAY-2 supplies a high-quality therapeutic answer once measurement, adherence, regimen quality, and secondary causes have been addressed.

Cited by wiki pages

  • overview
  • pharmacologic prevention and regression
  • secondary hypertension and modifiers
  • guidelines