1 INTRODUCTION ORIGINAL PAPER

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1 Received: 5 December 2016 Revised: 27 January 2017 Accepted: 13 February 2017 DOI: /jch ORIGINAL PAPER Improvement in health- related quality of life after renal sympathetic denervation in real- world hypertensive patients: 12- month outcomes in the Global SYMPLICITY Registry Ingrid Kindermann MD 1 Sonja Maria Wedegärtner MSc 1 Felix Mahfoud MD 1,5 Joachim Weil MD 2 Nicole Brilakis MBA, MSc 3 Julia Ukena MSc 1 Sebastian Ewen MD 1 Dominik Linz MD, PhD 1 Martin Fahy MSc 3 Giuseppe Mancia MD 4 Michael Böhm MD 1 on behalf of the Global SYMPLICITY Registry Investigators 1 Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Universität des Saarlandes, Homburg, Germany 2 Medizinische Klinik II, Sana Kliniken Lübeck GmbH, Lübeck, Germany 3 Clinical Research, Medtronic, Santa Rosa, CA, USA 4 University of Milano-Bicocca, Milan, Italy 5 Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA Correspondence Ingrid Kindermann, MD, Klinik für Innere Medizin III (Kardiologie, Angiologie und Internistische Intensivmedizin), Universitätsklinikum des Saarlandes, Homburg/Saar, Germany. ingrid.kindermann@uks.eu Funding information Medtronic, Global SYMPLICITY Registry, NCT Renal denervation has been shown to reduce blood pressure in patients with uncontrolled hypertension, but less is known about its impact on quality of life. This analysis evaluated 12- month blood pressure and quality of life outcomes in 934 patients from the Global SYMPLICITY Registry who completed the EuroQoL five- dimensions threelevel questionnaire (EQ- 5D- 3L). At baseline, 32% of patients reported anxiety/depression and 48% reported pain/discomfort. At 12 months (n=496), office and 24- hour ambulatory systolic blood pressure were reduced by 13.9±26.6 and 7.7±19.3 mm Hg, respectively, and 8% (P<.001) more patients reported no problems in anxiety/depression. Furthermore, numerically more patients reported no problems in pain/discomfort (4%, P=.08). Perceived health- related quality of life (visual analog scale) improved from baseline to 12 months (68±18 vs 73±17, P<.001), and the improvement was largest among patients with severe anxiety/depression at baseline (50±24 vs 64±22, P=.005 [n=32]). In this analysis, renal denervation was associated with a significant improvement in health- related quality of life, particularly anxiety/ depression. 1 INTRODUCTION Hypertension is often associated with symptoms of anxiety 1 and depression. 2 High blood pressure (BP) may impair mental health and psychological functioning, 3 and anxiety may contribute to continuous increases in BP. 4 Hypertensive symptoms such as headache, dizziness, chest pain, and discomfort could be experienced as a threatening stimulus, thereby creating a vicious circle of anxiety with persistent hypertension. 5 Ingrid Kindermann and Sonja Wedegärtner contributed equally to the writing of this article. Portions of this work were presented at the 2015 Annual European Society of Cardiology Congress, August 29 September 2, 2015, London, United Kingdom. The renal sympathetic nerves contribute to the development and maintenance of hypertension through their effect in the kidney via sodium and water retention, increased renin release, and alterations in renal blood flow. 6 8 Among patients with hypertension and the metabolic syndrome, a disturbed muscle sympathetic nerve- firing pattern, as measured with microneurography, correlates with higher levels of anxiety and depression. 9 Anxiety and depression are independently associated with increased cardiovascular risk, 10,11 perhaps due to the elevated sympathoadrenal activity, in particular among patients with anxiety. 12 Catheter- based renal denervation (RDN) has been shown to decrease renal norepinephrine spillover, increase renal plasma flow, and reduce sympathetic nerve traffic to the skeletal muscle J Clin Hypertens. 2017;19: wileyonlinelibrary.com/journal/jch 2017 Wiley Periodicals, Inc. 833

2 834 KINDERMANN et al. vasculature Clinical studies of RDN in patients with uncontrolled hypertension have demonstrated reductions in office and ambulatory BP Although one recent sham- controlled study showed a neutral result, 20 Azizi and colleagues 17 reported that RDN in combination with standardized stepped- care antihypertensive treatment decreases ambulatory BP more than the same standardized stepped- care antihypertensive treatment alone. However, limited information exists on the impact of RDN on quality of life, including anxiety and depression, as well as pain and discomfort, in a large population of real- world patients The Global SYMPLICITY Registry is the largest ongoing, prospective, open- label, multicenter, international registry conducted to evaluate the safety and effectiveness of RDN in real- world patients. The EuroQoL five- dimensions three- level questionnaire (EQ- 5D- 3L) is employed prospectively in the Global SYMPLICITY Registry. This tool allows patients to self- assess quality of life under five dimensions (mobility, self- care, usual activities, pain/discomfort, and anxiety/depression), as well as rate their health- related quality- of- life state on an analog visual scale. 2 METHODS 2.1 Global SYMPLICITY Registry The clinical design, as well as 6- month BP outcomes, of the Global SYMPLICITY Registry have recently been published. 16 In brief, the Global SYMPLICITY Registry is a prospective, open- label registry that is enrolling up to 3000 patients at 134 centers in Canada, Western Europe, Latin America, Eastern Europe, South Africa, Middle East, Asia, Australia, and New Zealand. The only inclusion criteria are age 18 years and older and eligibility for RDN using the Symplicity RDN system (Medtronic, Santa Rosa, CA, USA) as defined by local regulations. All BP assessors receive explicit instructions on the procedure to correctly measure office BP (3 BP measurements to be taken according to standard practice) and 24- hour ambulatory BP in compliance with published guidelines. 25 The EQ- 5D- 3L was self- administered by the patient (although the healthcare professional could be present) and recommended to be completed before the RDN procedure and at each follow- up visit. Only patients with matched information at baseline and 6 and 12 months on both the EQ- 5D- 3L and office systolic BP were included in the present analysis. 2.2 EQ- 5D- 3L instrument The EQ- 5D- 3L is a standardized instrument to measure health outcome and includes two sections. The first section asks patients to selfrate their health status on a visual analog scale of 0 ( worst imaginable ) to 100 ( best imaginable ; see Appendix S1). The second section comprises five questions requiring patients to rank each of five dimensions (mobility, self- care, usual activities, pain/discomfort, and anxiety/depression) on one of three levels (no problems, some problems, or severe problems; see Appendix S1). The EQ- 5D- 3L has previously been validated in studies of patients with hypertension and cardiovascular disease. 26,27 The EQ- 5D- 3L is a widely applied and validated survey to systematically assess patients health- related quality of life, and has shown test- retest reliability upon repeated measurements. 28, Statistical analysis Subanalyses were conducted in patients with resistant hypertension (defined as office systolic BP 140 mm Hg and 24- hour ambulatory systolic BP 130 mm Hg, despite 3 antihypertensive drugs), masked hypertension (office systolic BP <140 mm Hg but 24- hour ambulatory systolic BP 130 mm Hg or daytime systolic BP 135 mm Hg), based on sex and age, and also geographic location of enrollment (Europe, Asia excluding Australia and New Zealand, Australia and New Zealand, Canada, and other countries). Continuous measures were compared between groups using the Kruskal- Wallis test. Categorical measures (the five dimensions of the EQ- 5D) were compared between groups using the chi- square test. Changes between baseline and follow- up measurements with continuous variables (BP change and the visual analog scale) were analyzed using the Wilcoxon paired test. Continuous data are summarized as mean±standard deviation, and categorical data are summarized as percentages and counts. A P value <.05 was considered statistically significant. All analyses were performed using the SAS statistical package (version 9.3; SAS Institute Inc, Cary, NC, USA). 3 RESULTS 3.1 Patient population As of March 30, 2015, 934 patients had EQ- 5D- 3L reported on all five dimensions at baseline and at 6 and 12 months, along with corresponding office systolic BP measurements at all three time points. Visual analog scale measurements were not available for four of the 934 patients at all time points. Medications taken at baseline and at 12 months were collected in 923 patients. Ambulatory BP was available in 493 patients with both baseline and 12- month follow- up measurements. Baseline demographics are shown in Table 1. The mean age was 61±12 years, and 61% of the patients were men, with a high frequency of comorbidities, such as type 2 diabetes mellitus (39%), renal insufficiency (21%), and a history of heart failure (11%). At baseline, office systolic/diastolic BP was 163±24/89±16 mm Hg overall and 169±19/91±16 mm Hg in patients with resistant hypertension (53%). In addition, 24- hour ambulatory systolic/diastolic BP in all patients and those with resistant hypertension was 153±18/86±14 mm Hg and 156±17/88±14 mm Hg, respectively. 3.2 Antihypertensive medication prescription Antihypertensive medication prescription at baseline and 12 months is shown in Table 2. At baseline, patients were prescribed 4.6±1.3 antihypertensive medications. Most patients were prescribed a calcium channel blocker, an angiotensin II receptor blocker, a diuretic, and a β- blocker. The number of antihypertensive medications prescribed at 12 months was slightly lower (4.4±1.4, P<.001) due to a decrease

3 KINDERMANN et al. 835 TABLE 1 Baseline Demographics in All Patients in the prescription of most antihypertensive medication classes, including centrally acting sympatholytics (39% at baseline vs 35% at 12 months, P<.001 vs baseline) and β- blockers (76.6% at baseline vs 73.5% at 12 months, P=.004). 3.3 BP and heart rate N=934 Age, y 61.0±11.6 Men 61.2 (572) Body mass index, kg/m 2 31±5 Office SBP, mm Hg 162.7±23.7 Ambulatory SBP, mm Hg 152.9±17.8 Masked hypertension 13.7 (93) Heart rate, beats per min 69±13 History of cardiac disease 50.1 (463) History of vascular disease 22.8 (211) History of renal disease 30.0 (280) Renal insufficiency (egfr<60 ml/min/1.73 m 2 ) 20.5 (191) History of atrial fibrillation 12.2 (113) Obstructive sleep apnea 13.1 (111) Diabetes mellitus, type (361) Current smoker 9.2 (86) Abbreviations: egfr, estimated glomerular filtration rate; SBP, systolic blood pressure. Results are presented as mean±standard deviation or percentage (number). The 12- month changes in office and 24- hour ambulatory systolic BP were 13.9±26.6 (P<.001) and 7.7±19.3 mm Hg (P<.001), respectively, and larger in patients with resistant hypertension (Figure 1). Patients with severe anxiety/depression at baseline (n=32) also had significant reductions in both office and ambulatory BP at 12 months ( 21.0±29.5 mm Hg [P<.001] and 10.4±13.8 mm Hg [P=.003]). Heart rate in the overall population decreased by 1.4±12.1 beats per minute (P<.001) at 12 months compared with baseline and was similar among patients with resistant hypertension. 3.4 EQ- 5D- 3L outcomes Patients rated their perceived health state on the visual analog scale as 68±18 at baseline and 73±17 at 6 months (P<.001), which was sustained at 12 months and similar among patients with resistant hypertension (Figure 2). Notably, in patients with severe anxiety/depression at baseline, the perceived health state was 50±24 at baseline and improved to 64±22 at 12 months (P=.005; Figure 2). Table 3 shows the baseline and 6- and 12- month values in EQ- 5D- 3L outcomes on all five dimensions in all patients. At baseline, the classification some/severe problems was highest in the dimensions of pain/discomfort (48%) and anxiety/depression (32%). At both 6 and 12 months, 6% (n=60) were less likely to report some/severe problems in anxiety/depression (P<.001 for both). Similarly, the subgroup of patients with resistant hypertension reported 8% improvement in no problems in anxiety/depression (P<.001). Patients with no medication changes at baseline and 6 and 12 months (n=441) had a similar improvement in anxiety/depression at 12 months (8%, P<.001). Patients with masked hypertension, however, did not have an improvement in anxiety/depression. No significant association was observed between the improvement in anxiety/depression and change in office and ambulatory systolic BP. Numerically more patients with resistant hypertension reported improvements in the no problems classification with respect to pain/ discomfort (52% at baseline vs 56% at 12 months, P=.08). Severe pain/ discomfort significantly improved among the elderly ( 65 years; 5.4% vs 2.8%, P=.04) and in men (5.1% vs 3.0%, P=.03). No other EQ- 5D- 3L dimensions changed from baseline to 12 months. At baseline, men also reported a higher visual analog scale for higher health- related quality of life compared with women (70±19 vs 66±17, P<.001), but TABLE 2 Antihypertensive Medication Prescription at Baseline and 12 Months Antihypertensive medication classes, No. Angiotensin- converting enzyme inhibitor Baseline (n=923) 12 mo (n=923) P Value 4.6± ±1.4 < (323) 31.3 (289) <.001 Angiotensin receptor blocker 66.7 (616) 66.0 (610).399 Calcium channel blocker 81.0 (748) 78.4 (724).021 Diuretic 81.1 (749) 78.6 (726).034 Aldosterone antagonist 21.9 (202) 24.8 (229).009 α-adrenergic blocker 33.7 (311) 30.5 (282).009 Centrally acting sympatholytics 39.0 (360) 35.2 (325) <.001 β-blocker 76.6 (707) 73.5 (679).004 Direct renin inhibitor 6.2 (57) 4.4 (41).005 Vasodilator 14.1 (130) 13.5 (125).500 Abbreviation: No, number. Results are presented as mean±standard deviation or percentage (number).

4 836 KINDERMANN et al. were less likely to report no problems in anxiety/depression at baseline; however, Europeans and Asians were more likely to report improvements in their perceived health state. 4 DISCUSSION FIGURE 1 Twelve- month change in systolic blood pressure (SBP). (A) Office SBP and (B) 24- hour ambulatory SBP. Resistant hypertension is defined as office SBP 140 mm Hg and 24- hour SBP 130 mm Hg, despite use of three or more antihypertensive drugs. Masked hypertension is defined as office SBP <140 mm Hg but 24- hour ambulatory SBP 130 mm Hg or daytime SBP 135 mm Hg both experienced a significant and similar improvement at 12 months (4.4±18.1% for men and 6.0±18.9% for women, P<.001 for both vs baseline). Additionally, some/severe anxiety/depression was reported by 27.1% of men and 40.9% of women at baseline, and improved at 12 months by -4.6% in men (P=.019) and by -9.4% in women (P<.001). Geographic differences in quality of life were also observed (Figure 3). Europeans rated their perceived health state lowest and The present investigation is the largest cohort to date reporting the effect of RDN therapy on quality of life. Twelve- months post- RDN therapy, a significant improvement in the overall perceived health state as well as anxiety/depression was observed in addition to a significant reduction in office and 24- hour ambulatory BP. Additionally, improvements in pain/discomfort were observed among the elderly, men, and patients with resistant hypertension. These results indicate that RDN therapy is associated with improvements in specific indices of quality of life in patients with uncontrolled hypertension. Whether this improvement is related to concomitant BP reduction, reduced sympathetic tone, or the Hawthorne effect remains uncertain. A subanalysis indicated that the observed changes in quality of life were not correlated to changes in BP. However, patients reporting severe problems in anxiety/depression at baseline had the largest reduction at 12 months in office ( 21.0±29.5 mm Hg, P<.001) and 24- hour ambulatory ( 10.4±13.8 mm Hg, P=.003) systolic BP, and the largest improvement in the visual analog scale (14 points, P=.005). Previous smaller clinical studies have examined the impact of RDN on quality of life. Lenski and colleagues 24 reported improvements in patients with resistant hypertension after RDN in office systolic BP, quality of life based on the Short Form- 12 health survey, anxiety and depression scores based on the Hospital Anxiety and Depression Scale, and the intensity of headache. 24 Systolic BP was correlated with anxiety and depression, and there was a trend toward a correlation in heart rate and anxiety, and intensity of headache and diastolic BP. 24 In a separate investigation, Lambert and colleagues 22 reported a decrease in office systolic BP in patients with resistant hypertension, as well as trait anxiety, depression, and the Short Form- 36 mental component summary score after RDN. Lambert and associates also found, similar to our analysis, differences in post- RDN quality- of- life FIGURE 2 EuroQoL five-dimensions three-level questionnaire (EQ- 5D- 3L) overall health state reported on the visual analog scale at baseline and at 6 and 12 months. Results are presented as mean±standard error

5 KINDERMANN et al. 837 TABLE 3 EQ- 5D- 3L Reported Degree of Severity at Baseline and at 6 and 12 Months in All Patients Baseline (n=934) 6 mo (n=934) P Value 12 mo (n=934) P Value Mobility No problems 72.8 (680) 74.3 (694) 70.8 (661) Some problems 27.2 (254) 25.6 (239) 29.0 (271) Severe problems 0.0 (0) 0.1 (1) 0.2 (2) Self- care No problems 92.9 (868) 92.8 (867) 92.9 (868) Some problems 6.2 (58) 6.4 (60) 6.4 (60) Severe problems 0.9 (8) 0.7 (7) 0.6 (6) Usual activity No problems 70.9 (662) 73.4 (686) 72.1 (673) Some problems 26.2 (245) 24.3 (227) 25.9 (242) Severe problems 2.9 (27) 2.2 (21) 2.0 (19) Pain/discomfort No problems 52.0 (486) 54.9 (513) 54.2 (506) Some problems 42.3 (395) 39.8 (372) 41.8 (390) Severe problems 5.7 (53) 5.2 (49) 4.1 (38) Anxiety/depression <.001 <.001 No problems 67.6 (631) 74.7 (698) 74.0 (691) Some problems 29.0 (271) 23.3 (218) 23.8 (222) Severe problems 3.4 (32) 1.9 (18) 2.2 (21) Abbreviation: EQ- 5D- 3L, EuroQoL five- dimensions three- level questionnaire. Values are presented as percentage (number). FIGURE 3 Perceived health state stratified by geographic location at baseline and 12 months. Five- way P value at baseline <.001; 5- way P value on the 12- month change=.177. * Asia excludes Australia and New Zealand. ** Other countries includes South Africa, Middle East, and Latin America measures based on sex. Thus, our results extend and confirm those from previous reports in the largest global cohort of real- world RDNtreated patients with quality- of- life assessment. A survey conducted in Sweden of individuals using general population health survey data found that the dimension anxiety/ depression had the greatest impact on a patient s perceived health state as measured by the EQ- 5D- 3L visual analog scale. 30 Thus, the presently observed improvement in the overall perceived health state may be related to the improvement in anxiety/depression. Given that patients who experience anxiety and depression have increased activation of the sympathetic nervous system, 31 a reduction in sympathetic activity following RDN may explain the improvement in anxiety/ depression, and hence overall quality of life after RDN. One important question in the context of quality- of- life measurement is the clinical meaningfulness of observed changes. The minimally important difference reflects such meaningfulness and is defined as the smallest change in quality of life as a result of a treatment that is considered important to a patient. To the best of our knowledge for the EQ- 5D visual analog scale score, no minimally important difference is defined in hypertensive patients. However, empirical work

6 838 KINDERMANN et al. on the minimally important difference for the EQ- 5D- 3L score on the visual analog scale has been done for several other diseases, such as stroke, Crohn s disease, lower back pain, and cancer, and the minimally important difference has ranged from 4.2 to The reported change in hypertensive patients lies within this range and thus can be carefully assumed as clinically meaningful. Since quality of life can vary among countries and by socioeconomic status, we performed a subanalysis of scores by geographic region. The results showed significant geographic differences in perceived health state at baseline but similar improvements after RDN for most regions except for the combined region of South Africa, Middle East, and Latin America. Further randomized studies are needed to determine whether the observed quality- of- life improvements are different between treated and untreated control patients. The recently commenced SPYRAL HTN Global Clinical Trial program will enroll approximately 220 patients in two separate trials randomized 1:1 to RDN vs sham control in the first phase of the program, with patients on and off antihypertensive medication therapy (NCT and NCT ). 38 Blinding will be maintained and EQ- 5D- 3L will also be recorded at baseline and up to 1 year. This will be the first trial to date to compare quality of life between blinded patients out to 1 year and should add further insight into the relationship between RDN therapy and improved quality of life. 4.1 Limitations The present results should be interpreted within the constraints of some potential limitations. The present single- group analysis does not include a control group. Thus, the impact of time or repeated measurements may have influenced the outcome, and there is no way to rule out a placebo/hawthorne effect caused by participation and care during a registry or study. 39 However, significant improvements were only observed in selected parameters and not across the board. The EQ- 5D- 3L test is not a highly specific instrument, and there is no way to separate out the type of anxiety (stress, tension, worry) or separate anxiety and depression. However, the test is simple and cognitively undemanding. Furthermore, a common phenomenon observed in measuring changes in a health profile questionnaire, including the EQ- 5D, is a ceiling effect. The ceiling is represented by the no problems option, creating an upper limit on quality of life. Thus, the distribution of data is non- Gaussian, and hence the possible benefit could be larger than that observed here. Lastly, approximately 15% of patients in the Global SYMPLICITY Registry met the definition for masked hypertension ; the decision for RDN treatment was based on ambulatory BP readings in these patients, and many likely had a history of high office BP or other comorbidities associated with poor outcomes. 5 CONCLUSIONS The Global SYMPLICITY Registry is the largest study to measure quality of life in 934 patients treated with RDN. At 12 months, patients reported a significant improvement in health- related quality of life as well as less anxiety/depression after RDN, suggesting that RDN may provide benefits beyond BP reduction. STATEMENT OF FINANCIAL DISCLOSURE The Global SYMPLICITY Registry and this study are funded by Medtronic. F.M. received speaker honoraria from Medtronic and St Jude Medical, and is supported by Deutsche Hochdruckliga and Deutsche Gesellschaft für Kardiologie. J.W. is a consultant for Medtronic. N.B. and M.F. are employees of Medtronic. G.M. is a consultant for Medtronic. D.L. is supported by the Deutsche Gesellschaft für Kardiologie, Deutsche Herzstiftung, and the Else- Kröner- Fresenius Foundation. M.B. received research support and speaker fees from Medtronic and St Jude Medical and is supported by the Deutsche Forschungsgemeinschaft. All other authors have nothing to disclose. REFERENCES 1. Bajko Z, Szekeres CC, Kovacs KR, et al. Anxiety, depression and autonomic nervous system dysfunction in hypertension. J Neurol Sci. 2012;317: Meng L, Chen D, Yang Y, Zheng Y, Hui R. Depression increases the risk of hypertension incidence: a meta- analysis of prospective cohort studies. J Hypertens. 2012;30: Battersby C, Hartley K, Fletcher AF, et al. Quality of life in treated hypertension: a case- control community based study. J Hum Hypertens. 1995;9: White WB, Baker LH. Episodic hypertension secondary to panic disorder. Arch Intern Med. 1986;146: Ladwig KH, Lederbogen F, Albus C, et al. Position paper on the importance of psychosocial factors in cardiology: update Ger Med Sci. 2014;12:Doc Esler M, Jennings G, Lambert G, Meredith I, Horne M, Eisenhofer G. Overflow of catecholamine neurotransmitters to the circulation: source, fate, and functions. Physiol Rev. 1990;70: Sobotka PA, Mahfoud F, Schlaich MP, Hoppe UC, Böhm M, Krum H. Sympatho- renal axis in chronic disease. Clin Res Cardiol. 2011;100: Giannattasio C, Del Bo A, Cattaneo BM, et al. Reflex vasopressin and renin modulation by cardiac receptors in humans. Hypertension. 1993;21: Lambert E, Dawood T, Straznicky N, et al. Association between the sympathetic firing pattern and anxiety level in patients with the metabolic syndrome and elevated blood pressure. J Hypertens. 2010;28: Nakamura S, Kato K, Yoshida A, et al. Prognostic value of depression, anxiety, and anger in hospitalized cardiovascular disease patients for predicting adverse cardiac outcomes. Am J Cardiol. 2013;111: Roest AM, Martens EJ, de Jonge P, Denollet J. Anxiety and risk of incident coronary heart disease: a meta- analysis. J Am Coll Cardiol. 2010;56: Paine NJ, Watkins LL, Blumenthal JA, Kuhn CM, Sherwood A. Association of depressive and anxiety symptoms with 24- hour urinary catecholamines in individuals with untreated high blood pressure. Psychosom Med. 2015;77: DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integ Comp Physiol. 2010;298:R245 R Mancia G, Grassi G. The autonomic nervous system and hypertension. Circ Res. 2014;114:

7 KINDERMANN et al Grassi G, Seravalle G, Brambilla G, et al. Blood pressure responses to renal denervation precede and are independent of the sympathetic and baroreflex effects. Hypertension. 2015;65: Böhm M, Mahfoud F, Ukena C, et al. First report of the Global SYMPLICITY Registry on the effect of renal artery denervation in patients with uncontrolled hypertension. Hypertension. 2015;65: Azizi M, Sapoval M, Gosse P, et al. Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open- label, randomised controlled trial. Lancet. 2015;385: Rosa J, Widimsky P, Tousek P, et al. Randomized comparison of renal denervation versus intensified pharmacotherapy including spironolactone in true- resistant hypertension: six- month results from the Prague-15 study. Hypertension. 2015;65: Esler MD, Böhm M, Sievert H, et al. Catheter- based renal denervation for treatment of patients with treatment- resistant hypertension: 36 month results from the SYMPLICITY HTN- 2 randomized clinical trial. Eur Heart J. 2014;35: Bhatt DL, Kandzari DE, O Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370: Dörr O, Liebetrau C, Mollmann H, et al. Influence of renal sympathetic denervation on quality of life. J Interv Cardiol. 2013;26: Lambert GW, Hering D, Marusic P, et al. Health- related quality of life and blood pressure 12 months after renal denervation. J Hypertens. 2015;33: Lambert T, Blessberger H, Gammer V, et al. Effects of renal denervation on ambulatory blood pressure measurements in patients with resistant arterial hypertension. Clin Cardiol. 2014;37: Lenski D, Kindermann I, Lenski M, et al. Anxiety, depression, quality of life and stress in patients with resistant hypertension before and after catheter- based renal sympathetic denervation. EuroIntervention. 2013;9: O Brien E, Parati G, Stergiou G, et al. European Society of Hypertension position paper on ambulatory blood pressure monitoring. J Hypertens. 2013;31: Dyer MT, Goldsmith KA, Sharples LS, Buxton MJ. A review of health utilities using the EQ- 5D in studies of cardiovascular disease. Health Qual Life Outcomes. 2010;8: Theodorou M, Kaitelidou D, Galanis P, et al. Quality of life measurement in patients with hypertension in Cyprus. Hellenic J Cardiol. 2011;52: Lundy JJ, Coons SJ. Test- retest reliability of an interactive voice response version of the EQ- 5D in a sample of cancer survivors. Patient. 2012;5: Yang Y, Brazier J, Longworth L. EQ- 5D in skin conditions: an assessment of validity and responsiveness. Eur J Health Econ. 2015;16: Kjellgren KI, Ahlner J, Dahlof B, Gill H, Hedner T, Saljo R. Perceived symptoms amongst hypertensive patients in routine clinical practice a population- based study. J Intern Med. 1998;244: Carney RM, Freedland KE, Veith RC. Depression, the autonomic nervous system, and coronary heart disease. Psychosom Med. 2005;67(Suppl 1):S29 S Chen P, Lin KC, Liing RJ, Wu CY, Chen CL, Chang KC. Validity, responsiveness, and minimal clinically important difference of EQ- 5D- 5L in stroke patients undergoing rehabilitation. Qual Life Res. 2016;25: Coteur G, Feagan B, Keininger DL, Kosinski M. Evaluation of the meaningfulness of health- related quality of life improvements as assessed by the SF- 36 and the EQ- 5D VAS in patients with active Crohn s disease. Aliment Pharmacol Ther. 2009;29: Nolan CM, Longworth L, Lord J, et al. The EQ- 5D- 5L health status questionnaire in COPD: validity, responsiveness and minimum important difference. Thorax. 2016;71: Pickard AS, Neary MP, Cella D. Estimation of minimally important differences in EQ- 5D utility and VAS scores in cancer. Health Qual Life Outcomes. 2007;5: Remenschneider AK, D Amico L, Gray ST, Holbrook EH, Gliklich RE, Metson R. The EQ- 5D: a new tool for studying clinical outcomes in chronic rhinosinusitis. Laryngoscope. 2015;125: Soer R, Reneman MF, Speijer BL, Coppes MH, Vroomen PC. Clinimetric properties of the EuroQol- 5D in patients with chronic low back pain. Spine J. 2012;12: Kandzari DE, Kario K, Mahfoud F, et al. The SPYRAL HTN global clinical trial program: rationale and design for studies of renal denervation in the absence (SPYRAL HTN OFF- MED) and presence (SPYRAL HTN ON- MED) of antihypertensive medications. Am Heart J. 2016;171: Finniss DG, Kaptchuk TJ, Miller F, Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet. 2010;375: SUPPORTING INFORMATION Additional Supporting Information may be found online in the supporting information tab for this article. How to cite this article: Kindermann I, Wedegärtner SM, Mahfoud F, et al. Improvement in health- related quality of life after renal sympathetic denervation in real- world hypertensive patients: 12- month outcomes in the Global SYMPLICITY Registry. J Clin Hypertens. 2017;19: