Spironolactone for resistant hypertension—hard to resist?
Authors: Hillel Sternlicht, George L Bakris
Journal: The Lancet (2015)

Resistant hypertension is characterised by failure to achieve a blood pressure of less than 140/90 mm Hg while on maximum tolerated doses of three different classes of antihypertensive drugs, including a diuretic appropriate for kidney function.1Calhoun DA Jones D Textor S et al.Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research.Hypertension. 2008; 51: 1403-1419Crossref PubMed Scopus (1235) Google Scholar While often ascribed to medication non-adherence,2Jung O Gechter JL Wunder C et al.Resistant hypertension? Assessment of adherence by toxicological urine analysis.J Hypertens. 2013; 31: 766-774Crossref PubMed Scopus (358) Google Scholar true resistant cases of hypertension are linked to non-adherence to lifestyle modifications to control blood pressure, including low sodium diet, reduced alcohol ingestion, and weight reduction.3Sarafidis PA Georgianos P Bakris GL Resistant hypertension—its identification and epidemiology.Nat Rev Nephrol. 2013; 9: 51-58Crossref PubMed Scopus (125) Google Scholar Several pharmacological regimens to treat such patients have inconsistent outcomes. It has been posited that the sympathetic nervous system and excess sodium intake are the principal drivers of resistant hypertension.4Iliescu R Lohmeier TE Tudorancea I Laffin L Bakris GL Renal denervation for the treatment of resistant hypertension.Am J Physiol Renal Physiol. 2015; (published online July 29.)https://doi.org/10.1152/ajprenal.00246.2015Crossref PubMed Scopus (36) Google Scholar Despite this, targeted therapies, based on both pharmacological approaches (ie, α–β blockers) and devices (ie, renal denervation), have generated disappointing results.4Iliescu R Lohmeier TE Tudorancea I Laffin L Bakris GL Renal denervation for the treatment of resistant hypertension.Am J Physiol Renal Physiol. 2015; (published online July 29.)https://doi.org/10.1152/ajprenal.00246.2015Crossref PubMed Scopus (36) Google Scholar Other adjuvant therapies include aldosterone antagonists such as spironolactone.5Dahal K Kunwar S Rijal J et al.The effects of aldosterone antagonists in patients with resistant hypertension: a meta-analysis of randomized and nonrandomized studies.Am J Hypertens. 2015; (published online March 23.)https://doi.org/10.1093/ajh/hpv031Crossref PubMed Scopus (79) Google Scholar These drugs have a plausible physiological basis because the prevalence of hyperaldosteronism is higher than previously appreciated and the phenomenon of aldosterone so-called escape exists after long-term renin–angiotensin system blockade.6Bakris GL Siomos M Richardson D et al.for the VAL-K Study GroupACE inhibition or angiotensin receptor blockade: impact on potassium in renal failure.Kidney Int. 2000; 58: 2084-2092Summary Full Text Full Text PDF PubMed Google Scholar Although spironolactone has proven superior to renal denervation in some treatment studies, head-to-head trials are lacking.7Azizi M Sapoval M Gosse P et al.Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial.Lancet. 2015; 385: 1957-1965Summary Full Text Full Text PDF PubMed Scopus (388) Google Scholar, 8Fadl Elmula FE Hoffmann P Fossum E et al.Renal sympathetic denervation in patients with treatment-resistant hypertension after witnessed intake of medication before qualifying ambulatory blood pressure.Hypertension. 2013; 62: 526-532Crossref PubMed Scopus (104) Google Scholar In The Lancet, Bryan Williams and colleagues9Williams B MacDonald TM Morant S et al.for The British Hypertension Society's PATHWAY Studies GroupSpironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.Lancet. 2015; (published online Sept 21.)http://dx.doi.org/10.1016/S0140-6736(15)00257-3Google Scholar report on the PATHWAY-2 study that investigates the effect of spironolactone versus placebo, and two other drugs, bisoprolol and doxazosin, in a randomised, double-blind, crossover trial to determine which drug produced the greatest reduction in blood pressure when added to a pre-existing three-drug regimen. The authors hypothesised that resistant hypertension, driven by sodium retention, would be best managed by adjuvant diuretic therapy—ie, spironolactone. To this end a surrogate for sodium status, plasma renin, was assessed in an attempt to predict those most responsive to spironolactone-based therapies. After confirmation of the presence of systolic blood pressures in excess of 130 mm Hg at home and 140 mm Hg in the clinic, and exclusion of those patients with advanced kidney disease, 335 individuals were randomised to a sequence comprising spironolactone (final dose 50 mg, n=285), bisoprolol (final dose 10 mg, n=285), doxazosin (final dose 8 mg, n=282), or placebo (n=274) for 12 weeks. After each treatment cycle, patients were treated sequentially with the remaining drugs, each for an additional 12-week period, with doses force-titrated (doubled) at 6 weeks. 230 patients received both doses of all treatments. The trial's primary endpoint was the difference in average home systolic blood pressure between spironolactone and placebo, followed if significant by differences in home systolic blood pressure between spironolactone and the mean of the other two drugs, followed by the other two drugs individually. In terms of difference in average home systolic blood pressure, spironolactone was superior to placebo (–8·70 mm Hg [95% CI −9·72 to −7·69]), to the mean of doxazosin and bisoprolol (–4·26 [–5·13 to −3·38]), and to doxazosin (–4·03 [–5·04 to −3·02]) and bisoprolol (–4·48 [–5·50 to −3·46]) individually. Upon study termination, 58% of spironolactone treated patients achieved blood pressure control versus about 42% of doxazosin, and 43% of bisoprolol patients. There was an inverse and linear relationship between renin and blood pressure response to spironolactone, a finding not seen with bisoprolol or doxazosin. Serious adverse event rates, including hyperkalaemia, were less than 3% in each group. Williams and colleagues9Williams B MacDonald TM Morant S et al.for The British Hypertension Society's PATHWAY Studies GroupSpironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.Lancet. 2015; (published online Sept 21.)http://dx.doi.org/10.1016/S0140-6736(15)00257-3Google Scholar provide the strongest support yet for the antihypertensive efficacy of spironolactone in cases of resistant hypertension. The mandatory use of pretrial diuretics and the assessment of clinic and home blood pressures allow the authors to exclude patients with so-called white coat hypertension. The implementation of renin profiling, previously shown to predict responsiveness to diuretics,10Egan BM Basile JN Rehman SU et al.Plasma renin test-guided drug treatment algorithm for correcting patients with treated but uncontrolled hypertension: a randomized controlled trial.Am J Hypertens. 2009; 22: 792-801Crossref PubMed Scopus (104) Google Scholar was an accurate predictor of spironolactone response. Despite these promising results, there are limitations to extrapolation of the results of PATHWAY-2 to the general population. The study design does not exclude a carry-over effect, because there were no interval washout periods between drugs, but the authors noted almost identical differences between drugs when only the first cycle treatments were compared in a parallel group fashion (appendix p 16).9Williams B MacDonald TM Morant S et al.for The British Hypertension Society's PATHWAY Studies GroupSpironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.Lancet. 2015; (published online Sept 21.)http://dx.doi.org/10.1016/S0140-6736(15)00257-3Google Scholar In view of the duration of spironolactone activity, this extended effect would be advantageous to the comparator drugs; however, treatment with spironolactone yielded about a 6 mm Hg greater reduction in systolic blood pressure compared with bisoprolol or doxazosin at 12 weeks. Additionally, there was a 4 mm Hg difference favouring spironolactone in the primary comparisons of average systolic blood pressure on low and high doses. Would similar results be achieved in an African-American or Afro-Caribbean cohort? Can these results be applied to patients with advanced kidney disease at risk for hyperkalaemia? Would people with much lower sodium intake than those participating in this study, in whom 24-h urine sodium was about 137 mmol/L (8 g), still require addition of spironolactone? Additionally, would a longer acting thiazide diuretic such as chlorthalidone or indapamide reduce the need for spironolactone? Lastly, the average weight of participants in Williams and colleagues' cohort was around 94 kg, generally less than that in some areas of the world. Future studies need to address these issues. PATHWAY-29Williams B MacDonald TM Morant S et al.for The British Hypertension Society's PATHWAY Studies GroupSpironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.Lancet. 2015; (published online Sept 21.)http://dx.doi.org/10.1016/S0140-6736(15)00257-3Google Scholar makes the addition of spironolactone to a three-drug regimen hard to resist in cases of resistant hypertension among overweight patients with stages 1 and 2 kidney disease. Newer aldosterone antagonists such as finerenone with less risk of hyperkalaemia11Bakris GL Agarwal R Chan JC et al.Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial.JAMA. 2015; 314: 884-894Crossref PubMed Scopus (410) Google Scholar and potassium binders, such as patiromer,12Bakris GL Pitt B Weir MR et al.Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST-DN randomized clinical trial.JAMA. 2015; 314: 151-161Crossref PubMed Scopus (306) Google Scholar will be available soon, to aid in reducing the risk of hyperkalaemia in the subset of resistant hypertensive patients with stage 3B or higher kidney disease. PATHWAY-2 provides strong evidence for an approach to conquer the problem of resistant hypertension in the general population. We declare no competing interests. Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trialSpironolactone was the most effective add-on drug for the treatment of resistant hypertension. The superiority of spironolactone supports a primary role of sodium retention in this condition. Full-Text PDF Open Access