Fluid retention, aldosterone excess, and treatment of resistant hypertension

Abstract

In 2015, Bryan Williams and colleagues1Williams B MacDonald TM Morant S et al.Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.Lancet. 2015; 386: 2059-2068Summary Full Text Full Text PDF PubMed Scopus (676) Google Scholar published the findings of the landmark PATHWAY-2 trial, which clearly established spironolactone as superior to other classes of antihypertensive drugs for treatment of resistant hypertension that is uncontrolled by a multidrug regimen comprised of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, thiazide-type diuretic, and a calcium channel blocker.1Williams B MacDonald TM Morant S et al.Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.Lancet. 2015; 386: 2059-2068Summary Full Text Full Text PDF PubMed Scopus (676) Google Scholar Importantly from a clinical perspective, spironolactone provided antihypertensive benefit irrespective of baseline plasma renin concentrations, but was especially effective in patients with low renin concentrations. As renin release is progressively suppressed by increasing fluid retention, the observed inverse relation between renin concentration and the antihypertensive benefit of spironolactone provided indirect evidence that blocking the mineralocorticoid receptor treats resistant hypertension by overcoming, or at least diminishing, excess fluid retention. In The Lancet Diabetes & Endocrinology, Williams and colleagues2Williams B MacDonald TM Morant SV et al.Endocrine and haemodynamic changes in resitant hypertension, and its response to spironolactone or amiloride: the PATHWAY-2 mechanims substudies.Lancet Diabetes Endocrinol. 2018; (published online April 11.)http://dx.doi.org/10.1016/S2213-8587(18)30071-8Summary Full Text Full Text PDF PubMed Scopus (134) Google Scholar now report the results of several PATHWAY-2 substudies that extend the main study findings, including by confirming that the antihypertensive benefit of spironolactone when treating resistant hypertension is largely related to its natriuretic and diuretic effects.2Williams B MacDonald TM Morant SV et al.Endocrine and haemodynamic changes in resitant hypertension, and its response to spironolactone or amiloride: the PATHWAY-2 mechanims substudies.Lancet Diabetes Endocrinol. 2018; (published online April 11.)http://dx.doi.org/10.1016/S2213-8587(18)30071-8Summary Full Text Full Text PDF PubMed Scopus (134) Google Scholar Such an effect is consistent with resistant hypertension being broadly attributable to persistent fluid retention secondary to varying degrees of aldosterone excess. Additionally, in an optional, open-label, run-out phase substudy, the investigators further demonstrate that amiloride is an effective alternative to spironolactone for treating resistant hypertension. These new findings are important both for advancing our understanding of the mechanisms of resistant hypertension, and also in providing important clinical guidance for choice of drugs for more effective treatment of resistant hypertension. Findings from previous studies have suggested that resistant hypertension is largely volume dependent—ie, attributable to inappropriate fluid retention that persists despite use of multiple drug combinations, including conventional thiazide diuretics. Taler and colleagues3Taler SJ Textor SC Augustine JE Resistant hypertension: comparing hemodynamic management to specialist care.Hypertension. 2002; 39: 982-988Crossref PubMed Scopus (243) Google Scholar reported that antihypertensive treatment resistance was often related to occult volume expansion as shown by increased thoracic fluid content measured by bioimpedance. When noted, the higher thoracic fluid content facilitated enhanced blood pressure control through intensification of diuretic therapy.3Taler SJ Textor SC Augustine JE Resistant hypertension: comparing hemodynamic management to specialist care.Hypertension. 2002; 39: 982-988Crossref PubMed Scopus (243) Google Scholar Gaddam and colleagues4Gaddam K Corros C Pimenta E et al.Rapid reversal of left ventricular hypertrophy and intracardiac volume overload in patients with resistant hypertension and hyperaldosteronism: a prospective clinical study.Hypertension. 2010; 55: 1137-1142Crossref PubMed Scopus (111) Google Scholar, 5Gaddam KK Nishizaka MK Pratt-Ubunama MN et al.Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion.Arch Intern Med. 2008; 168: 1159-1164Crossref PubMed Scopus (243) Google Scholar reported that resistant hypertension, despite treatment with multidrug regimens, including hydrochlorothiazide, is characterised by persistent excess intravascular fluid retention in relation to aldos