In patients with resistant hypertension (uncontrolled on 3 drugs including a diuretic at optimal doses), which of the following options is MOST supported by current evidence as add-on fourth-line antihypertensive therapy?
- A Alpha-1 blocker (doxazosin) as preferred fourth-line agent
- B Spironolactone 25–50 mg once daily ✓
- C Renal denervation procedure as pharmacological equivalent
- D Adding a second diuretic (e.g., eplerenone to furosemide)
Explanation
The PATHWAY-2 trial (Lancet 2015) demonstrated that spironolactone (25–50 mg) was the most effective add-on for resistant hypertension, lowering home systolic BP by a mean of 8.7 mmHg more than placebo — superior to doxazosin, bisoprolol, or placebo. This is consistent with the hypothesis that aldosterone excess (primary hyperaldosteronism or relative excess) underlies many resistant hypertension cases. Spironolactone is recommended as first-choice fourth-line agent in NICE 2023 and AHA/ACC 2023 guidelines. Renal denervation (SPYRAL trial) has supportive evidence but is not yet standard pharmacological therapy.
Reference: Harrison's Principles of Internal Medicine, 21st ed.
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