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#165 Three drugs and still hypertensive: What’s Left?

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

Spironolactone provides the largest BP reduction for “4th line therapy” in resistant hypertension (10/4 mmHg), causing an additional one in every three patients treated to reach target.  Potassium rises on average ~0.4 mmol/L (and should be monitored), causing around 2% to stop due to hyperkalemia (≥5.5 mmol/L)Hard outcome data is lacking.  

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  • Only data on BP (not hard outcomes).   
    • High-quality cross-over Randomized Controlled Trial (RCT)1 of 348 patients with resistant hypertension. Each patient cycled through six weeks low-dose and six weeks high-dose of spironolactone 25-50 mg, doxazosin 4-8 mg, bisoprolol  5-10 mg, and placebo. 
      • Over both doses, average reduction in office BP versus placeboSpironolactone 10/4 mmHg, bisoprolol 5/5 mmHg, or doxazosin 5/3 mmHg. 
        • High dose decreased systolic BP more than low dose: Spironolactone  5 mmHg, bisoprolol 2 mmHg, or doxazosin 1 mmHg. 
      • Patients achieving target home systolic BP (<135 mmHg): Spironolactone 58%, bisoprolol 44%, doxazosin 42%, placebo 24%. 
        • Number Needed to Treat (NNT) versus placebo: Spironolactone NNT=3, bisoprolol or doxazosin NNT=6. 
      • Serum K >6.0 in 2% of patients with spironolactone. 
      • Notes: Excluded patients with abnormal serum K or eGFR <45 mL/min. 
    • Three systematic reviews2-4 missed studies and pooled inappropriately (heterogeneity ≥90%). 
    • Five remaining spironolactone (generally 25 mg/day) RCTs (17-167 patients, 4-16 weeks):5-9 
      • Two smallest trials (Iran and Cameroon) with randomization concerns had largest BP changes (19-21/10-17 mmHg): Likely unreliable.8,9   
      • Three remaining RCTS: Spironolactone reduced BP 10-16/3-7 mmHg.5-7  
      • Serum K increases ~0.3-0.4 mmol/L5-9 and ~2% stop due to hyperkalemia  (K >5.5 mmol/L).5,7
  • Resistant hypertension is defined as office BP >140/90 mmHg while receiving (and adherent to) >BP-lowering drugs of different classes at optimal doses.10,11 
    • Thiazides, ACE/ARB, and dihydropyridine calcium channel blockers all have evidence for reducing cardiovascular endpoints.   
  • Prevalence of resistant hypertension is likely around 13% or less.12 
  • Lower baseline potassium may be associated with better response to spironolactone.7,13  

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  • G. Michael Allan MD CCFP
  • Ricky D. Turgeon BSc(Pharm) ACPR PharmD

1. Williams B, MacDonald TM, Morant S, et al. Lancet. 2015; 386:2059-68.

2. Dahal K, Kunwar S, Rijal J, et al. Am J Hypertens. 2015; 28:1376-86.

3. Liu G, Zheng XX, Xu YL, et al. J Hum Hypertens. 2015; 29:159-66.

4. Guo H, Xiao Q. Int J Clin Exp Med. 2015; 8:7270-8.

5. Bobrie G, Frank M, Azizi M, et al. J Hypertens. 2012; 30:1656-64.

6. Oxlund CS, Henriksen JE, Tarnow L, et al. J Hypertens. 2013; 31:2094-102.

7. Václavík J, Sedlák R, Jarkovský J, et al. Medicine (Baltimore). 2014; 93:e162.

8. Djoumessi RN, Noubiap JJ, Kaze FF, et al. BMC Res Notes. 2016; 9:187.

9. Abolghasmi R, Taziki O. Saudi J Kidney Dis Transpl. 2011; 22:75-8.

10. Calhoun DA, Jones D, Textor S, et al. Circulation. 2008; 117:e510-e526.

11. Krause T, Lovibond K, Caulfield M, et al. BMJ. 2011; 343:d4891.

12. Achelrod D, Wenzel U, Frey S. Am J Hypertens. 2015; 28:355-61.

13. Shlomai G, Sella T, Sharabi Y, et al. Hypertens Res. 2014; 37:1037-41.

Authors do not have any conflicts to disclose.