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.

Tools for Practice

Tools for Practice articles in Canadian Family Physician (CFP) are adapted from articles published on the Alberta College of Family Physicians (ACFP) website, summarizing medical evidence with a focus on topical issues and practice-modifying information. The ACFP summaries and the series in CFP are coordinated by Dr G. Michael Allan, and the summaries are co-authored by at least 1 practising family physician and are peer reviewed. Feedback is welcome and can be sent to toolsforpractice@cfpc.ca. Archived articles are available on the ACFP website: www.acfp.ca.