- Question
- In patients with resistant hypertension, is spironolactone more effective at lowering blood pressure than non-diuretic add-on drugs (bisoprolol and doxazosin) and placebo?
- Design
- Double-blind, placebo-controlled crossover trial conducted at 12 secondary and 2 primary care sites in the UK. A total of 335 patients were randomized and rotated in a preassigned order through four 12-week cycles; 230 completed all cycles. Analysis was by intention to treat.
- Population
- Adults aged 18-79 years with seated clinic systolic blood pressure of 140 mm Hg or higher (135 mm Hg or higher with diabetes) and home systolic blood pressure of 130 mm Hg or higher despite at least 3 months of treatment with three drugs at maximally tolerated doses.
- Intervention
- Once-daily spironolactone (25-50 mg) added to background antihypertensive treatment, with the dose doubled after 6 weeks of each cycle. The other active cycles were bisoprolol (5-10 mg) and modified-release doxazosin (4-8 mg).
- Control
- Placebo, bisoprolol and doxazosin, each given for 12 weeks in random order on top of background treatment.
- Primary outcome
- Hierarchical endpoints: difference in average home systolic blood pressure between spironolactone and placebo; then between spironolactone and the mean of the other two active drugs; and finally between spironolactone and each of them individually.
- Results
- Spironolactone lowered home systolic blood pressure more than placebo (-8.70 mm Hg; 95% CI -9.72 to -7.69; P<0.0001) and more than the mean of doxazosin and bisoprolol (-4.26; 95% CI -5.13 to -3.38; P<0.0001). It was also superior to doxazosin (-4.03; P<0.0001) and bisoprolol (-4.48; P<0.0001). It was the most effective drug across the whole distribution of baseline plasma renin, with a greater advantage at lower values.
- Safety
- All treatments were well tolerated. In 6 of the 285 patients receiving spironolactone, serum potassium exceeded 6.0 mmol/L on one occasion.
- Conclusion
- Spironolactone was the most effective add-on drug in resistant hypertension, supporting a central role of sodium retention in this condition.
- Why it matters
- It provided direct head-to-head evidence that positioned spironolactone as a preferred fourth-line option in resistant hypertension over non-diuretic alternatives.
Card generated automatically with AI from the abstract of the original publication and the trial registry; every figure was checked against those sources. It may contain errors: verify the data at the source before using it for clinical decisions.
Generated on October 14, 2026