Aldosterone Antagonists and Renal Denervation
2014; Lippincott Williams & Wilkins; Volume: 65; Issue: 2 Linguagem: Inglês
10.1161/hypertensionaha.114.04119
ISSN1524-4563
AutoresFelix Mahfoud, Luís M. Ruilope, Michael Böhm, Roland E. Schmieder,
Tópico(s)Sodium Intake and Health
ResumoHomeHypertensionVol. 65, No. 2Aldosterone Antagonists and Renal Denervation Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAldosterone Antagonists and Renal DenervationFriends or Foes? Felix Mahfoud, Luis M. Ruilope, Michael Böhm and Roland E. Schmieder Felix MahfoudFelix Mahfoud From the Department of Internal Medicine III, Cardiology, Angiology, and Intensive Care Medicine, Saarland University, Homburg, Saarland, Germany (F.M., M.B.); Division of Hypertension and Nephrology, Hospital 12 de Octubre, Madrid, Spain (L.M.R.); and Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Munich, Germany (R.E.M.S.). , Luis M. RuilopeLuis M. Ruilope From the Department of Internal Medicine III, Cardiology, Angiology, and Intensive Care Medicine, Saarland University, Homburg, Saarland, Germany (F.M., M.B.); Division of Hypertension and Nephrology, Hospital 12 de Octubre, Madrid, Spain (L.M.R.); and Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Munich, Germany (R.E.M.S.). , Michael BöhmMichael Böhm From the Department of Internal Medicine III, Cardiology, Angiology, and Intensive Care Medicine, Saarland University, Homburg, Saarland, Germany (F.M., M.B.); Division of Hypertension and Nephrology, Hospital 12 de Octubre, Madrid, Spain (L.M.R.); and Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Munich, Germany (R.E.M.S.). and Roland E. SchmiederRoland E. Schmieder From the Department of Internal Medicine III, Cardiology, Angiology, and Intensive Care Medicine, Saarland University, Homburg, Saarland, Germany (F.M., M.B.); Division of Hypertension and Nephrology, Hospital 12 de Octubre, Madrid, Spain (L.M.R.); and Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Munich, Germany (R.E.M.S.). Originally published24 Nov 2014https://doi.org/10.1161/HYPERTENSIONAHA.114.04119Hypertension. 2015;65:280–282Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 See related article, pp 407–413Activation of the sympathetic nervous system plays an important role in the development and disease progression of hypertension and its comorbidities.1 Antihypertensive treatment approaches have focused on abrogation of activated neurohormonal systems associated with these conditions, including the renin–angiotensin–aldosterone system and the sympathetic nervous system. Despite the availability of effective antihypertensive drugs, certain patients remain uncontrolled to target blood pressure (BP) values.2 For these patients with uncontrolled hypertension, new device-based treatments have been developed, such as surgically implanted baroreceptor stimulators and catheter-based renal denervation.3 The available evidence suggests that renal denervation reduces renal sympathetic activity and office BP, as well as ambulatory BP in open-label registries and randomized, controlled trials in certain patients, but not in all patients.4 The BP-lowering effect of intensified drug treatment, with special focus on aldosterone antagonist treatment, compared with catheter-based renal denervation has not been investigated in detail.In this issue, the prospective, randomized, open-label multicenter PRAGUE-15 trial by Rosa et al5 investigated the efficacy and safety of catheter-based renal denervation (using Medtronic's Symplicity device) versus intensified pharmacological treatment, including spironolactone in patients with mild to moderate resistant hypertension (office systolic BP [SBP] at the baseline, >140 mm Hg; 24-hour BP at the baseline, >130 mm Hg). The adherence of patients was confirmed by plasma toxicological analyses at the beginning (but unfortunately not after 6 months), and secondary causes of hypertension were excluded systematically. The study provides interesting insights about the efficacy and safety of intensified drug treatment and catheter-based renal denervation in patients with resistant hypertension.Aldosterone Antagonists in Resistant Hypertension: Effective and Safe?The significant BP change (24-hour SBP, −8.1 mm Hg; P=0.001 and office SBP, −14.3 mm Hg; P 130/80 mm Hg, despite triple antihypertensive therapy and type 2 diabetes mellitus, the effect of adding 25 mg of spironolactone (n=57) or placebo (n=55) has been evaluated.8 Placebo-corrected BP changes were −8.9 mm Hg and −3.7 mm Hg for 24-hour SBP and diastolic BP (P<0.001), respectively. The reductions of BP in the above-mentioned trials, including PRAGUE-15, were significantly lower compared with BP reductions documented in previous trials.The clinical use of aldosterone antagonists is often limited by adverse effects (overall 39% patients in the pharmacological group of PRAGUE-155 experienced adverse events), such as worsening of renal function, hyperkalemia, antiandrogen effects, and others, which obviously impact long-term treatment compliance. The risk of hyperkalemia, for instance, associated with the use of spironolactone can increase from 11% in treatment of resistant hypertension as in PRAGUE-155 to 39% in patients with chronic heart failure with impaired renal function (estimated glomerular filtration rate, 6 months) because hyperkalemia incidence will increase over time.Renal Denervation and Spironolactone: Addition to or Instead of?In PRAGUE-15,5 renal denervation and intensified drug treatment reduced office and ambulatory BP in patients with mild to moderate resistant hypertension to a similar extent. However, several aspects should be taken into consideration, while discussing the BP-lowering effect after renal denervation in PRAGUE-15, which was less pronounced compared with other studies.10 1, Baseline SBP has been identified as a predictor of response to treatment. The fact that baseline BP (office, 159 mm Hg; 24-hour, 149 mm Hg) was lower compared with previous published trials might, in part, account for the smaller BP-lowering effect after the procedure.11 2, PRAGUE-15 included patients with mild to moderate resistant hypertension (office BP at baseline, >140 mm Hg; 24-hour BP at baseline, >130 mm Hg). Preliminary data indicate that the effect in those patients is less pronounced compared with patients with severe resistant hypertension.12 3, The knowledge about the importance of the complex underlying human renal anatomy and physiology, and biophysics of radiofrequency lesion formation is evolving, and it has become clear that the impact of procedural performance was underestimated.13 This is especially important because there are no means of assessing effective destruction of renal sympathetic nerves intraprocedurally. Interestingly, post hoc analyses from the randomized, sham-controlled Symplicity HTN-3 study,14 which did not meet its primary efficacy endpoint, showed that the number of radiofrequency ablations and circumferential treatment correlated positively to BP response.15 In the present study, experienced and well-trained interventionists performed all renal denervation procedures using a monopolar radiofrequency device. However, in 7 patients (14%) undergoing renal denervation, the recommended number of complete radiofrequency ablations (≥4 per side) was not reached, of which 2 had only unilateral ablations. Interestingly, when comparing the small group of patients with <4 ablations per side to the group with ≥4 ablations per side, the BP and heart rate changes were numerically higher in the latter (office SBP, −4.7 versus −14.0 mm Hg; office diastolic BP, +0.9 mm Hg versus −9.2 mm Hg; 24-hour SBP, −5.0 versus −9.2 mm Hg; heart rate, +1.2 versus −4.4 beats per minute). The between-group differences were not statistically significant. The authors of PRAGUE-155 analyzed their data according to the intention-to-treat principle, an approach that is objectionable in face of a relatively small number of patients and the obvious pilot character of the study because of its premature stop. Per-protocol analyses with exclusion of patients receiving suboptimal treatment could have provided interesting insights. New renal denervation catheter developments and scientifically sound treatment recommendations might help to increase treatment success further. Although, the 6-month results of PRAGUE-155 confirmed the safety of renal denervation, currently available and next generation renal denervation devices have to show favorable safety profiles, especially long-term vascular safety because concerns have been raised that the procedure might induce renal artery stenosis.The role of aldosterone antagonist treatment in patients undergoing renal denervation is of special interest. A European multicenter study16 documented a significant reduction in the mean 24-hour BP by 11.9/7.1 mm Hg (both P<0.001) in the subgroup of patients (n=78), who were treated with spironolactone, which was comparable with the BP reduction in the entire cohort (n=346). Interestingly, post hoc analyses from the Symplicity HTN-3 trial15 identified prescription of an aldosterone antagonist at baseline as a positive predictor for increasing change in office SBP over time. One could argue that renal denervation contributes an additive BP-lowering effect to the pre-existing neurohormonal blockade in patients treated with aldosterone antagonists. In light of concerns about the long-term safety of spironolactone, and the fact that not all patients respond to such treatment, controversy exists whether the use of aldosterone antagonists is a prerequisite eligibility criterion to undergo renal denervation. Indeed, both the European Society of Cardiology3 and the European Hypertension Society consensus documents17 do not generally recommend that only patients in whom treatment with mineralocorticoid receptor antagonists has failed should be considered for renal denervation. Preliminary data from a Spanish group, although, suggests that renal denervation can effectively lower office and 24-hour BP in patients not responding to spironolactone therapy.18What Next?In this issue, the findings presented by Rosa et al5 prompt several questions that need to be answered in the near future.If renal denervation is as effective as intensified drug treatment in lowering blood pressure, should we give patients the choice?Should renal denervation be offered to patients who refuse initiation of spironolactone, who are at risk to develop, or who have experienced serious side effects?Is renal denervation a valid therapy option for patients not responding to spironolactone treatment?It will require additional rigorously performed, randomized, controlled clinical studies to determine the role of renal denervation in hypertension treatment finally, with or without spironolactone.Sources of FundingF. Mahfoud was supported by Deutsche Hochdruckliga und Deutsche Gesellschaft für Kardiologie. F. Mahfoud and M. Böhm have received research grants, speaker honorarium, and consultancy fees from Medtronic/Ardian, St. Jude, Boston Scientific, and Cordis. L. Ruilope received consultancy and advisory fees from Medtronic and St. Jude. R.E. Schmieder has received research grants, speaker honorarium, and consultancy fees from Medtronic/Ardian, Recor, and Kona.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Felix Mahfoud, Klinik für Innere Medizin III Kardiologie, Angiologie und Internistische Intensivmedizin Universitätsklinikum des Saarlandes, Homburg, Saarland, Germany. E-mail [email protected]References1. Esler M. 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Rosa J, Widimský P, Waldauf P, Zelinka T, Petrák O, Táborský M, Branny M, Toušek P, Čurila K, Lambert L, Bednář F, Holaj R, Štrauch B, Václavík J, Kociánová E, Nykl I, Jiravský O, Rappová G, Indra T, Krátká Z and Widimský J (2017) Renal denervation in comparison with intensified pharmacotherapy in true resistant hypertension, Journal of Hypertension, 10.1097/HJH.0000000000001257, 35:5, (1093-1099), Online publication date: 1-May-2017. Sharp A, Davies J, Lobo M, Bent C, Mark P, Burchell A, Thackray S, Martin U, McKane W, Gerber R, Wilkinson J, Antonios T, Doulton T, Patterson T, Clifford P, Lindsay A, Houston G, Freedman J, Das N, Belli A, Faris M, Cleveland T, Nightingale A, Hameed A, Mahadevan K, Finegold J, Mather A, Levy T, D'Souza R, Riley P, Moss J, Di Mario C, Redwood S, Baumbach A, Caulfield M and Dasgupta I (2016) Renal artery sympathetic denervation: observations from the UK experience, Clinical Research in Cardiology, 10.1007/s00392-015-0959-4, 105:6, (544-552), Online publication date: 1-Jun-2016. Schwerg M, Eilers B, Wienecke A, Baumann G, Laule M, Knebel F, Stangl K and Stangl V (2016) Galectin-3 and prediction of therapeutic response to renal sympathetic denervation, Clinical and Experimental Hypertension, 10.3109/10641963.2016.1148157, 38:4, (399-403), Online publication date: 18-May-2016. Rosa J, Widimský P, Waldauf P, Lambert L, Zelinka T, Táborský M, Branny M, Toušek P, Petrák O, Čurila K, Bednář F, Holaj R, Štrauch B, Václavík J, Nykl I, Krátká Z, Kociánová E, Jiravský O, Rappová G, Indra T and Widimský J (2015) Role of Adding Spironolactone and Renal Denervation in True Resistant Hypertension, Hypertension, 67:2, (397-403), Online publication date: 1-Feb-2016.Oparil S and Schmieder R (2015) New Approaches in the Treatment of Hypertension, Circulation Research, 116:6, (1074-1095), Online publication date: 13-Mar-2015. Mahfoud F and Serruys P (2015) Renal denervation reloaded: where to go from here?, EuroIntervention, 10.4244/EIJV10I10A187, 10:11, (1135-1137), Online publication date: 1-Feb-2015. February 2015Vol 65, Issue 2 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.114.04119PMID: 25421977 Originally publishedNovember 24, 2014 PDF download Advertisement SubjectsHypertension
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