Reference: Lancet 2015 Nov 21;386(10008):2059 (level 3 [lacking direct] evidence)
In the United States, 70 million adults (1 in 3) have hypertension and nearly 50% have not met their blood pressure treatment goal (NCHS Data Brief 2013 Oct;(133):1). According to the American Heart Association (AHA), “resistant hypertension” is defined as uncontrolled hypertension despite the use of three antihypertensive agents of differing drug classes, requiring the addition of a fourth drug (Hypertension 2008 Jun;51(6):1403). Spironolactone, a diuretic which blocks the mineralocorticoid receptor, has shown significant blood pressure reduction in observational and randomized studies in patients with resistant hypertension. The PATHWAY-2 randomized crossover trial compared the efficacy of spironolactone to other non-diuretic drugs and placebo.
335 patients aged 18-79 years with seated resting clinic systolic blood pressure 140 mm Hg or greater (or ≥ 135 mm Hg for patients with diabetes) and home systolic blood pressure 130 mm Hg or greater, despite at least 3 months of treatment, were enrolled. All had been treated with the maximum tolerated doses of three first-line antihypertensive agents (an angiotensin-converting enzyme [ACE] inhibitor or angiotensin receptor blocker [ARB], a calcium channel blocker, and a thiazide or thiazide-like diuretic). The patients were randomized by treatment order to complete all four possible add-on agents once daily for 12 weeks each, with no washout period between treatments. The add-ons to the standard regimen were spironolactone 25 mg/day titrated to 50 mg/day, bisoprolol (a beta-blocker) 5 mg/day titrated to 10 mg/day, doxazosin modified release (an alpha blocker) 4 mg/day titrated to 8 mg/day, and placebo. Only 230 patients (68.7%) completed all four treatment cycles, and 6.3% of patients without follow-up measurements were excluded from the analysis; both situations weaken the reliability of the outcomes. Additionally, the trial excluded patients with estimated glomerular filtration rate < 45 ml/min, and only 14% had diabetes, limiting the generalizability of the findings. The primary outcome was average home systolic blood pressure which was measured 3 times in the morning and the evening for 4 consecutive days prior to study visits.
Spironolactone reduced home systolic blood pressure not only significantly more than placebo (mean difference [MD] –8.7 mm Hg, 95% CI –9.7 to –7.7 mm Hg), but also more than doxazosin (MD –4.0 mm Hg, 95% CI –5.0 to –3.0 mm Hg) and bisoprolol (MD –4.5 mm Hg, 95% CI –5.5 to –3.5 mm Hg). Spironolactone also significantly reduced clinic blood pressure compared to placebo, doxazosin and bisoprolol (p < 0.001 for each). Overall 68.9% of patients achieved the target home systolic blood pressure of < 135 mm Hg. This was also significantly more likely to occur with spironolactone compared to placebo (odds ratio [OR] 0.23, 95% CI 0.16-0.33), doxazosin (OR 0.52, 95% CI 0.37-0.73), and bisoprolol (OR 0.55, 95% CI 0.39-0.78). Adverse events among all agents were generally mild and infrequent. Spironolactone was associated with a significant increase in serum potassium from baseline (mean increase of 0.42 mmol/L, p < 0.001). In 6 patients, serum potassium was raised > 6 mmol/L on single occasions but no cases of clinically serious hyperkalemia were reported.
PATHWAY-2 demonstrates that spironolactone may be more effective than placebo, doxazosin or bisoprolol in patients with resistant hypertension to further reduce blood pressure and achieve blood pressure treatment goal. Given the disease-oriented nature of the blood pressure outcome in this study, further trials are needed to evaluate the effect of this regimen on clinical events. Although adverse events were mild and infrequent in this trial, serum electrolytes and renal function should be carefully monitored when adding spironolactone to any regimen. This trial may influence any updated guideline for treatment of hypertension. At present, only one major guideline currently recommends spironolactone for resistant hypertension (Eur Heart J 2013 Jul;34(28):2159); however, this trial was published subsequent to the development of most relevant guidelines.
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