Spironolactone was significantly more effective in controlling resistant hypertension compared with doxazosin or bisoprolol in the PATHWAY-2 study, and the combination of amiloride and hydrochlorothiazide (HCTZ) amplified the desirable effects of each drug on blood pressure (BP) lowering while neutralizing the undesirable changes in blood glucose and potassium levels in the PATHWAY-3 study. The study results were presented, respectively, by Bryan Williams, MD, University College London, London, United Kingdom, and Morris J. Brown, MD, University of Cambridge, Cambridge, United Kingdom.

PATHWAY-2 was a double-blind, randomized, placebo-controlled, crossover trial [Williams B et al. BMJ Open. 2015], with the hypothesis that resistant hypertension is a sodium-retaining state characterized by an inappropriately low plasma renin level despite treatment, and that further diuretic therapy with spironolactone would be more effective at lowering BP than treatments targeting different mechanisms. Although a recent meta-analysis suggested that spironolactone may be effective for resistant hypertension [Dahal K et al. Am J Hypertens. 2015], there is no clinical trial evidence comparing it with other BP-lowering drugs.

The primary end point was hierarchical, with the first measure being the difference in average home systolic BP (HSBP) between spironolactone and placebo; if significant, followed by the difference in HSBP with spironolactone vs the average of bisoprolol and doxazosin; if significant, the difference in HSBP with spironolactone vs bisoprolol and vs doxazosin.

A total of 314 patients were included in the intent-to-treat analysis: 285 randomized to spironolactone (25-50 mg OD), 282 to doxazosin (4-8 mg OD), 285 to bisoprolol (5-10 mg OD), and 274 to placebo. Their mean age was 61.4 years, and 68.7% were men; the mean home BP was 147.6/84.2 mm Hg and the mean clinic BP was 157.0/90.0 mm Hg.

In PATHWAY-2, spironolactone produced significantly greater reductions for the average of the HSBP measurements at 6 and 12 weeks for each component of the primary outcome (P < .001 for all 4 comparators).

Spironolactone also produced significantly greater seated clinic BP reductions compared with each of the other treatments: −9.92 mm Hg vs placebo, −4.42 mm Hg vs doxazosin, and −4.45 mm Hg vs bisoprolol, respectively (all P < .001). The rate of serious adverse events and withdrawals did not vary significantly between the treatment groups.

Prof Williams stated that the BP response to spironolactone was inversely related to plasma renin levels and unlike other active treatments the BP response was dose dependent, supporting the hypothesis that the dominant cause of resistant hypertension is sodium retention despite background treatment with a thiazide diuretic. He concluded that the results unequivocally favored spironolactone (25-50 mg daily) as the most effective treatment for resistant hypertension, and that patients should not be defined as having resistant hypertension unless their BP remains uncontrolled when spironolactone is added to the treatment regimen.

Prof Brown highlighted the need to determine the optimal diuretic treatment for hypertension, noting the apparent link between potassium-depletion with hypertension treatment and the increased risk of diabetes [Stears AJ et al. Hypertension. 2012], suggesting possible benefit with potassium-sparing diuretics.

PATHWAY-3 was a parallel-group, randomized, double-blind, multicenter trial, comparing HCTZ 25 to 50 mg, amiloride 10 to 20 mg, and the combination of both diuretics at half of these doses; forced titration occurred at 12 weeks and follow-up was 6 months [Brown MJ et al. BMJ Open. 2015]. The hypothesis was that the combination of half-maximal doses of these drugs would neutralize the undesired effects of HCTZ on glucose and potassium levels while potentiating the desired BP lowering.

The hierarchical primary end point was the difference in change from baseline in the 2-hour oral glucose tolerance test (OGTT) with amiloride and HCTZ at 12 and 24 weeks; if significant, the difference in change from baseline in the 2-hour OGTT between the half-dose combination of treatments and HCTZ.

A total of 399 patients were included in the analysis: 132 taking amiloride, 134 taking HCTZ, and 133 taking the combination treatment. The mean age of the patients was 62 years and 39% were women; the home BP was 149/87 mm Hg and the clinic BP was 154/91 mm Hg. At baseline, 44 (33%) patients had impaired glucose tolerance.

Both amiloride and the amiloride/HCTZ combination produced a significantly greater reduction in glucose compared with HCTZ. Amiloride and HCTZ alone produced similar BP reduction at both 12 and 24 weeks. However, the amiloride/HCTZ combination lowered BP by 3.4 mm Hg more than each drug alone (95% CI, 0.9 to 5.8; P = .007). The amiloride/HCTZ combination also produced a significantly greater increase in renin levels than HCTZ alone.

The rates of adverse events and withdrawals were comparable between the groups, with the exception of hyperkalemia, which occurred more frequently with amiloride and the combination treatment compared with HCTZ. However, Prof Brown noted there were no increases in potassium > 5.8 mmol/L.

The combination of amiloride and HCTZ did not adversely affect blood glucose and potassium but improved the BP-lowering effect of each drug, concluded Prof Brown. The PATHWAY-2 and PATHWAY-3 trials demonstrated that potassium-sparing diuretics are safe and effective and may be the preferred choice for the treatment of hypertension.