Fluid retention, aldosterone excess, and treatment of resistant hypertension
Authors: David A Calhoun
Journal: The Lancet Diabetes & Endocrinology (2018)

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 aldosterone concentrations, as indicated by high intracardiac volumes measured by MRI, as well as higher natriuretic peptide concentrations than patients with more easily controlled hypertension. The high intracardiac volumes and increased natriuretic peptide concentrations could be reversed by treatment with spironolactone in association with large reductions in blood pressure, suggesting that persistent intravascular volume expansion contributes to antihypertensive treatment resistance. On the basis of their substudies done concomitant with the main PATHWAY-2 trial, 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 provide rigorous confirmation that resistant hypertension is broadly volume dependent, attributable to relative degrees of aldosterone excess. In addition to the blood pressure reduction induced by spironolactone being inversely related to renin concentrations (r2=0·11, p=0·00024), the investigators further report that the reduction in blood pressure by spironolactone is likewise predicted by the baseline aldosterone-to-renin ratio, with higher ratios portending larger blood pressure reductions (r2=0·13, p<0·0001). Additionally, the spironolactone-related blood pressure reductions were associated with significant decreases in thoracic fluid content—spironolactone reduced thoracic fluid index by about 7%—consistent with reductions in intravascular volume. By contrast, changes in vascular resistance were small and largely the same for the other treatment groups, including placebo. Taken together, the main PATHWAY-2 results and new substudy findings strongly implicate inappropriate aldosterone-induced fluid retention as an important cause of resistant hypertension, which, in turn, is best overcome by spironolactone. Some clinical aspects of the PATHWAY-2 findings should be highlighted. First, the magnitude of systolic blood pressure reduction achieved with spironolactone in patients with the lowest plasma renin concentrations exceeded 20 mm Hg on average. Such a degree of blood pressure reduction is extraordinary, and certainly greater than would be anticipated with other classes of antihypertensive drugs. Second, being able to anticipate this degree of blood pressure reduction on the basis of an easily measured biochemical marker is quite unique. Efficacy of other classes of antihypertensive drugs cannot be predicted by laboratory tests, even in specific situations. Thus, to be able to predict efficacy for spironolactone highlights an improved understanding of a common cause of resistant hypertension and the potential for preferentially prescribing spironolactone to treat it. Although its superiority as fourth-line treatment for resistant hypertension is now firmly established, use of spironolactone is often limited by tolerability. Particularly at higher doses and especially in men, the use of spironolactone can be precluded by development of gynaecomastia, breast tenderness, or sexual dysfunction. Eplerenone, a more selective mineralocorticoid receptor antagonist, is one alternative, but is well known to be less potent than spironolactone and its cost is often prohibitive.6Roush GC Sica DA Diuretics for hypertension: a review and update.Am J Hypertens. 2016; 29: 1130-1137Crossref PubMed Scopus (89) Google Scholar, 7Sica DA Mineralocorticoid receptor antagonists for treatment of hypertension and heart failure.Methodist Debakey Cardiovasc J. 2015; 11: 235-239Crossref PubMed Scopus (21) Google Scholar Therefore, the finding by 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 that amiloride was as effective as spironolactone as a fourth drug for treating resistant hypertension (6 weeks of treatment with amiloride 10 mg once daily reduced clinic systolic blood pressure by 20·4 mm Hg [95% CI 18·3–22·5] compared with a reduction of 18·3 mm Hg (16·2–20·5) with spironolactone 25 mg once daily) is clinically important. Their findings are based on an open-label extension in a subgroup of patients as opposed to the more rigorous, double-blind, randomised design of the main study, but they do provide a compelling reason to consider amiloride as a viable substitute for spironolactone when spironolactone is not tolerated. I declare no competing interests. Endocrine and haemodynamic changes in resistant hypertension, and blood pressure responses to spironolactone or amiloride: the PATHWAY-2 mechanisms substudiesOur results suggest that resistant hypertension is commonly a salt-retaining state, most likely due to inappropriate aldosterone secretion. Mineralocorticoid receptor blockade by spironolactone overcomes the salt retention and resistance of hypertension to treatment. Amiloride seems to be as effective an antihypertensive as spironolactone, offering a substitute treatment for resistant hypertension. Full-Text PDF Open Access