Three drugs and still hypertensive: what’s left?

Clinical question

Which drug lowers blood pressure (BP) best in patients with resistant hypertension?

Bottom line

Spironolactone causes the largest BP reduction (10/4 mm Hg) for “fourth-line therapy” in resistant hypertension; an additional 1 in 3 patients will reach target. Potassium (K) levels rise on average 0.4 mmol/L and should be monitored; about 2% of patients stop use owing to hyperkalemia. Hard outcome data are lacking.

Best evidence

There are only data on BP, not hard outcomes.

• In a high-quality crossover RCT¹ of resistant hypertension (N = 348), each patient cycled through 6 weeks of low-dose and 6 weeks of high-dose spironolactone (25–50 mg), doxazosin (4–8 mg), bisoprolol (5–10 mg), and placebo. The reduction in office BP (vs placebo) averaged over both doses was 10/4 mm Hg for spironolactone, 5/5 mm Hg for bisoprolol, and 5/3 mm Hg for doxazosin.

  • -High doses decreased systolic BP more than low doses did: spironolactone by 5 mm Hg, bisoprolol by 2 mm Hg, and doxazosin by 1 mm Hg more.

  • -Patients achieving target home systolic BP (< 135 mm Hg): spironolactone, 58%; bisoprolol, 44%; doxazosin 42%; placebo, 24%. Number needed to treat (vs placebo): spironolactone, 3; bisoprolol or doxazosin, 6.

  • -Serum K levels were greater than 6.0 mmol/L in 2% of patients using spironolactone. (Patients with baseline abnormal serum K levels or an estimated glomerular filtration rate less than 45 mL/min were excluded.)

• Three systematic reviews^2–4 missed studies and pooled inappropriately (heterogeneity was ≥ 90%).

• In 5 remaining RCTs (17–167 patients, 4–16 weeks) of spironolactone (generally 25 mg/d),^5–9 the 2 smallest trials had randomization concerns and the largest BP changes (19–21/10–17 mm Hg); the results are likely unreliable.^8,9 In the 3 remaining RCTs, spironolactone reduced BP by 10–16/3–7 mm Hg.^5–7

  • -Serum K levels increased about 0.3 to 0.4 mmol/L,^5–9 and about 2% of patients stopped use owing to hyperkalemia (K > 5.5 mmol/L).^5,7

Context

• Resistant hypertension is office BP above 140/90 mm Hg while receiving (and adherent to) 3 or more BP-lowering drugs from different classes at optimal doses.^10,11

  • -Thiazides, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and dihydropyridine calcium channel blockers all have evidence for reducing cardiovascular end points.

• Prevalence of resistant hypertension is likely 13% or less.¹⁰

• Lower baseline K might be associated with better response to spironolactone.^7,12

Implementation

Consider potential contributors to resistant hypertension (eg, incorrect BP readings, noncompliance, secondary causes like endocrine disorders, causative medications like nonsteroidal anti-inflammatory drugs, lifestyle factors like excessive alcohol or salt, renal impairment requiring loop diuretics).¹¹ However, some resistant hypertension arises because initial BP was very high (and more medications are required) or some patients do not respond as well to some agents. If a fourth medication is needed and spironolactone is selected, low doses should be tried and K levels should be monitored regularly, particularly on initiation.