Mineralocorticoid Receptor Antagonists Treatment in Resistant Hypertension and HFpEF: Evidence and Courage

Mineralocorticoid Receptor Antagonists Treatment in Resistant Hypertension and HFpEF: Evidence... Heart failure is a complex syndrome and associated with a major health-economic burden due the high hospital readmission rate. During the last decade heart failure management has been more focused on heart failure with preserved ejection fraction (HFpEF).1 There are some limitations in the classification and recognizing the different phenotypes within HFpEF. Consequently, this may lead to more tailored therapy for heart failure. Hypertension, diabetes beyond age and gender play an important role in the development of HFpEF.2 Resistant hypertension increases the risk for development of HFpEF and may aggravate the HFpEF process. It is evident that resistant hypertension needs to be treated appropriately.3,4 A few studies like ASCOT and PATHWAY-2 have shown that mineralocorticoid receptor antagonists (MRA), especially spironolactone are very effective in blood pressure lowering.5,6 There is still therapeutic inertia in the treatment of resistant hypertension,7 which lead unfortunately to worsening of the heart failure condition. In this issue, Rossignol et al. described the results of a subanalysis of the Americas subgroup of The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial,8 in which they compared the effect of spironolactone vs. placebo in 403 participants with HFpEF with presence of resistant hypertension vs. HFpEF participants without resistant hypertension.9 In the resistant hypertension group spironolactone resulted in a significant decrease in median systolic blood pressure of 6.1 mm Hg and 2.9 mm Hg in diastolic blood pressure during the first 8 months. Blood pressure control was obtained after 4 weeks in 63% of patients receiving spironolactone vs. 46% receiving placebo with similar responses at 8 weeks, 4 and 8 months. Patients with resistant hypertension obtained similar overall benefit from spironolactone on the primary outcomes as those without resistant hypertension. An important finding based on a post-hoc analysis was observed that the better blood pressure control in the spironolactone group in the first 8 months did not significantly differ across the different subgroups defined based either on a pathophysiological or epidemiological basis. It was remarkable that the rates of any serious adverse events were similar between patients with and without resistant hypertension (63% vs. 65%). Several clinical studies have provided evidence that aldosterone and mineralocorticoid receptors play an important role in the pathogenesis of resistant hypertension.3,10,11 On the basis of a meta-analysis by Sinnott et al., MRAs reduce blood pressure more effectively than other fourth-line agents in resistant hypertension.12 The question remains regarding the time interval of the beneficial effect of spironolactone on left ventricular structure vs. function in hypertensive left ventricular hypertrophy. Gupta et al. studied the effect of spironolactone on the diastolic function in resistant hypertensive patients with left ventricular hypertrophy.13 They found a rapid reversal of left ventricular hypertrophy with 6 months of spironolactone therapy in patients with resistant hypertension, preserved left ventricular ejection fraction, and no history of heart failure. They also investigated the effect of spironolactone on preclinical diastolic dysfunction, which was prominent in these patients. Short-term spironolactone therapy did not lead to improvement in diastolic function despite rapid reversal of left ventricular hypertrophy. Spironolactone, the MRA prototype, has been developed nearly more than 50 years ago and is widely used. However, there are a large number of health care providers, who consider the MRA as a potassium sparing diuretic and are cautious in the utilization, while they underscore the cardiovascular protective effect.14 During the last half century, landmark studies with spironolactone have been performed in different pathologies as hypertension (resistant and nonresistant), systolic heart failure (RALES Study), HFpEF (TOPCAT Study), in which spironolactone was very successful in reducing significant CVD outcome events.14 Other MRAs have been developed. Eplerenone, a second generation of MRA is less potent than spironolactone with less side-effects but more expensive. Eplerenone has been studied less extensively studied in resistant hypertension and never compared with spironolactone in the same study.15 Currently, a new generation MRAs are in development—as potent as spironolactone, as selective as eplerenone, nonsteroidal, but renal tubule sparing (less chance of hyperkalemia) or otherwise tissue-selective. Finenerone, a third generation MRA, is now studied in heart failure, diabetes mellitus type II, and chronic kidney disease. Finenerone seems to have less problems with hyperkalemia. In conclusion, MRAs, especially spironolactone, are promising in the treatment of systolic heart failure (HFrEF) and HFpEF with or without resistant hypertension. The evidence of the beneficial effect of spironolactone in relation to cardiovascular morbidity and mortality in these heart failure conditions has been clearly shown. We only need the courage to start spironolactone in these conditions in our daily practice with careful monitoring of renal function and potassium to reduce further the burden of the heart failure and improve the quality of life in these patients. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Fonarow GC. Refining classification of heart failure based on ejection fraction. JACC Heart Fail  2017; 5: 808– 809. Google Scholar CrossRef Search ADS PubMed  2. Lourenço AP, Leite-Moreira AF, Balligand JL, Bauersachs J, Dawson D, de Boer RA, de Windt LJ, Falcão-Pires I, Fontes-Carvalho R, Franz S, Giacca M, Hilfiker-Kleiner D, Hirsch E, Maack C, Mayr M, Pieske B, Thum T, Tocchetti CG, Brutsaert DL, Heymans S. An integrative translational approach to study heart failure with preserved ejection fraction: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology. Eur J Heart Fail . 2017 [Epub ahead of print]. 3. Epstein M, Duprez DA. Resistant hypertension and the pivotal role for mineralocorticoid receptor antagonists: a clinical update 2016. Am J Med  2016; 129: 661– 666. Google Scholar CrossRef Search ADS PubMed  4. Achelrod D, Wenzel U, Frey S. Systematic review and meta-analysis of the prevalence of resistant hypertension in treated hypertensive populations. Am J Hypertens  2015; 28: 355– 361. Google Scholar CrossRef Search ADS PubMed  5. Dudenbostel T, Calhoun DA. Use of aldosterone antagonists for treatment of uncontrolled resistant hypertension. Am J Hypertens  2017; 30: 103– 109. Google Scholar CrossRef Search ADS PubMed  6. Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ; British Hypertension Society’s PATHWAY Studies Group. 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– 2068. Google Scholar CrossRef Search ADS PubMed  7. Solini A, Ruilope LM. How can resistant hypertension be identified and prevented? Nat Rev Cardiol  2013; 10: 293– 296. Google Scholar CrossRef Search ADS PubMed  8. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O’Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med  2014; 370: 1383– 1392. Google Scholar CrossRef Search ADS PubMed  9. Rossignol P, Claggett B, Liu J, Vardeny O, Pitt B, Zannad F, Solomon S. Spironolactone and resistant hypertension in heart failure with preserved ejection fraction. Am J Hypertens  2017; 31: 407– 414. Google Scholar CrossRef Search ADS   10. Duprez DA. Aldosterone and the vasculature: mechanisms mediating resistant hypertension. J Clin Hypertens (Greenwich)  2007; 9: 13– 18. Google Scholar CrossRef Search ADS PubMed  11. Calhoun DA. Hyperaldosteronism as a common cause of resistant hypertension. Annu Rev Med  2013; 64: 233– 247. Google Scholar CrossRef Search ADS PubMed  12. Sinnott SJ, Tomlinson LA, Root AA, Mathur R, Mansfield KE, Smeeth L, Douglas IJ. Comparative effectiveness of fourth-line anti-hypertensive agents in resistant hypertension: a systematic review and meta-analysis. Eur J Prev Cardiol  2017; 24: 228– 238. Google Scholar CrossRef Search ADS PubMed  13. Gupta A, Schiros CG, Gaddam KK, Aban I, Denney TS, Lloyd SG, Oparil S, Dell’Italia LJ, Calhoun DA, Gupta H. Effect of spironolactone on diastolic function in hypertensive left ventricular hypertrophy. J Hum Hypertens  2015; 29: 241– 246. Google Scholar CrossRef Search ADS PubMed  14. Funder JW. Spironolactone in cardiovascular disease: an expanding universe? F1000Res  2017; 6: 1738. Google Scholar CrossRef Search ADS PubMed  15. Flatt DM, Brown MC, Mizeracki AM, King BJ, Weber KT. Mineralocorticoid receptor antagonists in the management of heart failure and resistant hypertension: a review. JAMA Cardiol  2016; 1: 607– 612. Google Scholar CrossRef Search ADS PubMed  © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png American Journal of Hypertension Oxford University Press

Mineralocorticoid Receptor Antagonists Treatment in Resistant Hypertension and HFpEF: Evidence and Courage

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Publisher
Oxford University Press
Copyright
© American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com
ISSN
0895-7061
eISSN
1941-7225
D.O.I.
10.1093/ajh/hpy003
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Abstract

Heart failure is a complex syndrome and associated with a major health-economic burden due the high hospital readmission rate. During the last decade heart failure management has been more focused on heart failure with preserved ejection fraction (HFpEF).1 There are some limitations in the classification and recognizing the different phenotypes within HFpEF. Consequently, this may lead to more tailored therapy for heart failure. Hypertension, diabetes beyond age and gender play an important role in the development of HFpEF.2 Resistant hypertension increases the risk for development of HFpEF and may aggravate the HFpEF process. It is evident that resistant hypertension needs to be treated appropriately.3,4 A few studies like ASCOT and PATHWAY-2 have shown that mineralocorticoid receptor antagonists (MRA), especially spironolactone are very effective in blood pressure lowering.5,6 There is still therapeutic inertia in the treatment of resistant hypertension,7 which lead unfortunately to worsening of the heart failure condition. In this issue, Rossignol et al. described the results of a subanalysis of the Americas subgroup of The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial,8 in which they compared the effect of spironolactone vs. placebo in 403 participants with HFpEF with presence of resistant hypertension vs. HFpEF participants without resistant hypertension.9 In the resistant hypertension group spironolactone resulted in a significant decrease in median systolic blood pressure of 6.1 mm Hg and 2.9 mm Hg in diastolic blood pressure during the first 8 months. Blood pressure control was obtained after 4 weeks in 63% of patients receiving spironolactone vs. 46% receiving placebo with similar responses at 8 weeks, 4 and 8 months. Patients with resistant hypertension obtained similar overall benefit from spironolactone on the primary outcomes as those without resistant hypertension. An important finding based on a post-hoc analysis was observed that the better blood pressure control in the spironolactone group in the first 8 months did not significantly differ across the different subgroups defined based either on a pathophysiological or epidemiological basis. It was remarkable that the rates of any serious adverse events were similar between patients with and without resistant hypertension (63% vs. 65%). Several clinical studies have provided evidence that aldosterone and mineralocorticoid receptors play an important role in the pathogenesis of resistant hypertension.3,10,11 On the basis of a meta-analysis by Sinnott et al., MRAs reduce blood pressure more effectively than other fourth-line agents in resistant hypertension.12 The question remains regarding the time interval of the beneficial effect of spironolactone on left ventricular structure vs. function in hypertensive left ventricular hypertrophy. Gupta et al. studied the effect of spironolactone on the diastolic function in resistant hypertensive patients with left ventricular hypertrophy.13 They found a rapid reversal of left ventricular hypertrophy with 6 months of spironolactone therapy in patients with resistant hypertension, preserved left ventricular ejection fraction, and no history of heart failure. They also investigated the effect of spironolactone on preclinical diastolic dysfunction, which was prominent in these patients. Short-term spironolactone therapy did not lead to improvement in diastolic function despite rapid reversal of left ventricular hypertrophy. Spironolactone, the MRA prototype, has been developed nearly more than 50 years ago and is widely used. However, there are a large number of health care providers, who consider the MRA as a potassium sparing diuretic and are cautious in the utilization, while they underscore the cardiovascular protective effect.14 During the last half century, landmark studies with spironolactone have been performed in different pathologies as hypertension (resistant and nonresistant), systolic heart failure (RALES Study), HFpEF (TOPCAT Study), in which spironolactone was very successful in reducing significant CVD outcome events.14 Other MRAs have been developed. Eplerenone, a second generation of MRA is less potent than spironolactone with less side-effects but more expensive. Eplerenone has been studied less extensively studied in resistant hypertension and never compared with spironolactone in the same study.15 Currently, a new generation MRAs are in development—as potent as spironolactone, as selective as eplerenone, nonsteroidal, but renal tubule sparing (less chance of hyperkalemia) or otherwise tissue-selective. Finenerone, a third generation MRA, is now studied in heart failure, diabetes mellitus type II, and chronic kidney disease. Finenerone seems to have less problems with hyperkalemia. In conclusion, MRAs, especially spironolactone, are promising in the treatment of systolic heart failure (HFrEF) and HFpEF with or without resistant hypertension. The evidence of the beneficial effect of spironolactone in relation to cardiovascular morbidity and mortality in these heart failure conditions has been clearly shown. We only need the courage to start spironolactone in these conditions in our daily practice with careful monitoring of renal function and potassium to reduce further the burden of the heart failure and improve the quality of life in these patients. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Fonarow GC. Refining classification of heart failure based on ejection fraction. JACC Heart Fail  2017; 5: 808– 809. Google Scholar CrossRef Search ADS PubMed  2. Lourenço AP, Leite-Moreira AF, Balligand JL, Bauersachs J, Dawson D, de Boer RA, de Windt LJ, Falcão-Pires I, Fontes-Carvalho R, Franz S, Giacca M, Hilfiker-Kleiner D, Hirsch E, Maack C, Mayr M, Pieske B, Thum T, Tocchetti CG, Brutsaert DL, Heymans S. An integrative translational approach to study heart failure with preserved ejection fraction: a position paper from the Working Group on Myocardial Function of the European Society of Cardiology. Eur J Heart Fail . 2017 [Epub ahead of print]. 3. Epstein M, Duprez DA. Resistant hypertension and the pivotal role for mineralocorticoid receptor antagonists: a clinical update 2016. Am J Med  2016; 129: 661– 666. Google Scholar CrossRef Search ADS PubMed  4. Achelrod D, Wenzel U, Frey S. Systematic review and meta-analysis of the prevalence of resistant hypertension in treated hypertensive populations. Am J Hypertens  2015; 28: 355– 361. Google Scholar CrossRef Search ADS PubMed  5. Dudenbostel T, Calhoun DA. Use of aldosterone antagonists for treatment of uncontrolled resistant hypertension. Am J Hypertens  2017; 30: 103– 109. Google Scholar CrossRef Search ADS PubMed  6. Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G, Ford I, Cruickshank JK, Caulfield MJ, Salsbury J, Mackenzie I, Padmanabhan S, Brown MJ; British Hypertension Society’s PATHWAY Studies Group. 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– 2068. Google Scholar CrossRef Search ADS PubMed  7. Solini A, Ruilope LM. How can resistant hypertension be identified and prevented? Nat Rev Cardiol  2013; 10: 293– 296. Google Scholar CrossRef Search ADS PubMed  8. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O’Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med  2014; 370: 1383– 1392. Google Scholar CrossRef Search ADS PubMed  9. Rossignol P, Claggett B, Liu J, Vardeny O, Pitt B, Zannad F, Solomon S. Spironolactone and resistant hypertension in heart failure with preserved ejection fraction. Am J Hypertens  2017; 31: 407– 414. Google Scholar CrossRef Search ADS   10. Duprez DA. Aldosterone and the vasculature: mechanisms mediating resistant hypertension. J Clin Hypertens (Greenwich)  2007; 9: 13– 18. Google Scholar CrossRef Search ADS PubMed  11. Calhoun DA. Hyperaldosteronism as a common cause of resistant hypertension. Annu Rev Med  2013; 64: 233– 247. Google Scholar CrossRef Search ADS PubMed  12. Sinnott SJ, Tomlinson LA, Root AA, Mathur R, Mansfield KE, Smeeth L, Douglas IJ. Comparative effectiveness of fourth-line anti-hypertensive agents in resistant hypertension: a systematic review and meta-analysis. Eur J Prev Cardiol  2017; 24: 228– 238. Google Scholar CrossRef Search ADS PubMed  13. Gupta A, Schiros CG, Gaddam KK, Aban I, Denney TS, Lloyd SG, Oparil S, Dell’Italia LJ, Calhoun DA, Gupta H. Effect of spironolactone on diastolic function in hypertensive left ventricular hypertrophy. J Hum Hypertens  2015; 29: 241– 246. Google Scholar CrossRef Search ADS PubMed  14. Funder JW. Spironolactone in cardiovascular disease: an expanding universe? F1000Res  2017; 6: 1738. Google Scholar CrossRef Search ADS PubMed  15. Flatt DM, Brown MC, Mizeracki AM, King BJ, Weber KT. Mineralocorticoid receptor antagonists in the management of heart failure and resistant hypertension: a review. JAMA Cardiol  2016; 1: 607– 612. Google Scholar CrossRef Search ADS PubMed  © American Journal of Hypertension, Ltd 2018. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Journal

American Journal of HypertensionOxford University Press

Published: Apr 1, 2018

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