title: Dose doubling, relative potency, and dose equivalence of potassium-sparing diuretics affecting blood pressure and serum potassium: systematic review and meta-analyses.
abstract: BACKGROUND
  Potassium-sparing diuretics (PSDs) are valuable antihypertensives with additional benefits unrelated to control of systolic blood pressure (SBP). However, their key parameters affecting SBP and serum potassium are poorly defined, fostering underutilization.
  
  
  METHODS
  Consequently, we conducted systematic reviews and meta-analyses, yielding 3668 articles and ultimately 84 randomized comparisons.
  
  
  RESULTS
  For office SBP, overall placebo-adjusted changes were triamterene -1.9 (low dose only), amiloride -9.9, spironolactone -13.2, and eplerenone -9.2. Differences in antihypertensive effect were due to potency rather than efficacy. Doubling amiloride, eplerenone, and spironolactone doses reduced SBP (95% confidence limits) on average by -2.3 (-3.1, -1.5). Relative antihypertensive potencies were spironolactone>amiloride>eplerenone. Spironolactone had significantly greater antihypertensive potency than amiloride, -4.0 (-7.4, -0.6), and eplerenone, -5.5 (-7.4, -3.6). Dose equivalencies were eplerenone-spironolactone 4.5-to-1 (e.g., eplerenone 125∼spironolactone 25), amiloride-spironolactone 3.3-to-1, and eplerenone-amiloride 1.4-to-1. Increases in serum potassium from amiloride and spironolactone at commonly used doses averaged 0.14-0.29 mEq/l; the dose doubling effect was 0.16 (0.10, 0.22). Spironolactone caused greater hyperkalemia than amiloride across their dose ranges: 0.14, P = 0.043. Seven features make important bias unlikely: a comprehensive literature search, adjustment for covariates, all models explaining 95-100% of the between-study variability, similar dose doubling effects among PSDs, two different methods giving the same potency sequence, similar results from double blind comparisons, and similar results for eplerenone versus spironolactone from analysing direct comparison data (i.e., no meta-regression) for office and 24-h SBP.
  
  
  CONCLUSIONS
  This synthesis accomplishes for PSDs what has already been achieved for thiazide-type diuretics and other antihypertensives and can guide the application of these underutilized medicines.
authors.affiliation: aUCONN School of Medicine and St. Vincent's Medical Center, Department of Medicine, Bridgeport, Connecticut, bUniversity of Iowa Hospital and Clinics, Department of Family Medicine, Iowa City, Iowa, cCardiovascular Institute, Rutgers-Robert Wood Johnson Medical School, Chairman, Department of Medicine, New Brunswick, New Jersey, dDepartment of Medicine and Pharmacology, Virginia Commonwealth University, Richmond, Virginia, USA.
authors.forename: George C
authors.initials: GC
authors.lastname: Roush
authors.forename: Michael E
authors.initials: ME
authors.lastname: Ernst
authors.forename: John B
authors.initials: JB
authors.lastname: Kostis
authors.forename: Shamima
authors.initials: S
authors.lastname: Yeasmin
authors.forename: Domenic A
authors.initials: DA
authors.lastname: Sica
mesh_terms: D000584:Amiloride / Q000008:administration & dosage; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D000077545:Eplerenone; D006801:Humans; D006947:Hyperkalemia / Q000139:chemically induced; D011188:Potassium / Q000097:blood*; D049993:Sodium Chloride Symporter Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use; D013148:Spironolactone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D013810:Therapeutic Equivalency; D014223:Triamterene / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D000959:Antihypertensive Agents; D049993:Sodium Chloride Symporter Inhibitors; D013148:Spironolactone; D000077545:Eplerenone; D000584:Amiloride; D011188:Potassium; D014223:Triamterene