Hypertension. Ambulatory Blood Pressure Changes After Renal Sympathetic Denervation in Patients With Resistant Hypertension

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1 Hypertension Ambulatory Blood Pressure Changes After Renal Sympathetic Denervation in Patients With Resistant Hypertension Felix Mahfoud, MD; Christian Ukena, MD; Roland E. Schmieder, MD; Bodo Cremers, MD; Lars C. Rump, MD; Oliver Vonend, MD; Joachim Weil, MD; Martin Schmidt, MD; Uta C. Hoppe, MD; Thomas Zeller, MD; Axel Bauer, MD; Christian Ott, MD; Erwin Blessing, MD; Paul A. Sobotka, MD; Henry Krum, MBBS, PhD; Markus Schlaich, MD; Murray Esler, MBBS, PhD, FRACP; Michael Böhm, MD Background Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. Less is known about the effect of RDN on 24-hour BP measured by ambulatory BP monitoring and correlates of response in individuals with true or pseudoresistant hypertension. Methods and Results A total of 346 uncontrolled hypertensive patients, separated according to daytime ambulatory BP monitoring into 33 with true resistant (office systolic BP [SBP] 172.2±22 mm Hg; 24-hour SBP 154±16.2 mm Hg) and 43 with pseudoresistant hypertension (office SBP 161.2±.3 mm Hg; 24-hour SBP 121.1±19.6 mm Hg), from 1 centers were studied. At 3, 6, and 12 months follow-up, office SBP was reduced by 21.5/23.7/27.3 mm Hg, office diastolic BP by 8.9/9.5/11.7 mm Hg, and pulse pressure by 13.4/14.2/14.9 mm Hg (n=245/236/9; P for all <.1), respectively. In patients with true treatment resistance there was a significant reduction with RDN in 24-hour SBP ( 1.1/ 1.2/ 11.7 mm Hg, P<.1), diastolic BP ( 4.8/ 4.9/ 7.4 mm Hg, P<.1), maximum SBP ( 11.7/ 1./ 6.1 mm Hg, P<.1) and minimum SBP ( 6./ 9.4/ 13.1 mm Hg, P<.1) at 3, 6, and 12 months, respectively. There was no effect on ambulatory BP monitoring in pseudoresistant patients, whereas office BP was reduced to a similar extent. RDN was equally effective in reducing BP in different subgroups of patients. Office SBP at baseline was the only independent correlate of BP response. Conclusions RDN reduced office BP and improved relevant aspects of ambulatory BP monitoring, commonly linked to high cardiovascular risk, in patients with true-treatment resistant hypertension, whereas it only affected office BP in pseudoresistant hypertension. Clinical Trial Registration URL: Unique identifiers: NCT and NCT (Circulation. 13;128:132-1.) Key words: ambulatory blood pressure monitoring hypertension resistant to conventional therapy sympathectomy Ambulatory blood pressure monitoring (ABPM) is important for the management of patients with hypertension, because it allows more sensitive and specific cardiovascular risk stratification compared with office blood pressure (BP) measurement. 1 3 International guidelines recommend ABPM in patients with resistant hypertension to exclude pseudoresistance and to more accurately assess BP control by treatment. 4 ABPM with 24-hour, day, and night average BP values correlate more closely to hypertensive or diabetic end-organ damage than office BP values. 5 7 Nighttime BP is more closely related to cardiovascular morbidity and mortality than daytime BP. 3,8 High nighttime BP and nondipping Continuing medical education (CME) credit is available for this article. Go to to take the quiz. Received September 7, 12; accepted May 17, 13. From the Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/ Saar, Germany (F.M., C.U., B.C., M.B.); Medizinische Klinik IV, Universitätsklinikum Erlangen, Germany (R.E.S., C.O.); Klinik für Nephrologie, Universitätsklinikum Düsseldorf, Germany (L.C.R., O.V.); Medizinische Klinik 2, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany (J.W.); Klinik für Kardiologie, Klinikum München-Bogenhausen, Germany (M.S.); Department für Innere Medizin II, Paracelsus Medical University Salzburg, Austria (U.C.H.); Klinik für Angiologie, Universitäts-Herzzentrum Bad Krozingen-Freiburg, Germany (T.Z.); Innere Medizin III, Universitätsklinikum Tübingen, Germany (A.B.); Medizinische Klinik III, Universitätsklinikum Heidelberg, Germany (E.B.); The Ohio State University, Columbus, OH (P.A.S.); Ardian, Inc, Palo Alto, CA (P.A.S.); Centre of Cardiovascular Research and Education in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia (H.K.); and Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia (M.S., M.E.). Drs Mahfoud and Ukena contributed equally. Correspondence to Felix Mahfoud, MD, Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Kirrberger Str, Geb, Homburg/Saar, Germany. Felix.Mahfoud@uks.eu 13 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 Mahfoud et al ABPM After RDN and Correlates of Response 133 patterns have been associated with increased sympathetic activity in hypertensives. 9 Clinical Perspective on p 1 Catheter-based renal denervation (RDN) offers a new approach to interrupt renal sympathetic innervation and has been shown to reduce renal and total body norepinephrine spillover RDN significantly reduced office systolic and diastolic BP in patients with resistant hypertension, 13,14 reduced left ventricular mass, and improved diastolic function 15 and glucose metabolism 16 without negatively affecting renal function 17 or causing chronotropic incompetence during exercise. 18 However, only limited information about the impact of RDN on daytime, nighttime, and average BP from the Symplicity HTN-2 trial is available. 13 Furthermore, information about the effectiveness of RDN according to patients baseline characteristics and predictors of response are lacking. This study aimed to investigate the effects of RDN on out-of-office BP by 24-hour ABPM and assessed the potential correlates of response to treatment in the largest cohort of patients with true resistant and pseudoresistant hypertension analyzed so far. Methods Local ethic committees approved the study. All patients gave written informed consent and were treated between March 9 and December 11 with subsequent follow-up to 12 months. Eligible patients were aged 18 years and had an office systolic blood pressure (SBP) 16 mm Hg ( 15 mm Hg for type 2 diabetic patients), despite being treated with 3 antihypertensive drugs (including 1 diuretic) at maximum or maximum tolerated doses, with no changes in medication for a minimum of 2 weeks before enrolment. Optimization of antihypertensive therapy was considered in all patients before RDN. A total of 346 patients from 9 centers in Germany and 1 center in Australia were enrolled following protocols of ongoing therapeutic renal denervation trials. Seventy-one patients were included in the Symplicity HTN-1 or HTN-2 trial. In all other patients the measurements were performed as an extension to the Symplicity protocol (NCT and NCT888433), using the same inclusion and exclusion criteria. Patients were excluded if they had an estimated glomerular filtration rate of <45 ml/min per 1.73 m 2 or a known secondary cause of hypertension other than sleep apnea or chronic kidney disease. All patients underwent a complete history and physical examination, assessment of vital signs, and review of medication. Patients were interviewed whether they had taken their complete medication at defined doses. Treating physicians and patients were instructed not to change medications except when medically required. Office SBP, diastolic BP (DBP), and pulse pressure (PP) as well as ABPM readings were obtained at entry and 3, 6, and 12 months after treatment. Office BP readings were taken in a seated position with an automatic oscillometric Omron HEM-75 monitor (Omron Healthcare, Vernon Hills, IL) after 5 minutes of rest according to the Standard Joint National Committee VII Guidelines. 19 At baseline, BP was measured at each arm, and the arm with the higher BP was used for all subsequent readings. Averages of the triplicate measures were calculated and used for analysis. ABPM was performed using an oscillometric Spacelabs 97 monitor (Spacelabs Healthcare, Issaqua, WA) with readings taken every 15 minutes in daytime and every 3 minutes at nighttime. ABP readings were averaged for 24 hours, day (7 am to 1 pm), and night (1 pm to 7 am). Patients were assessed while adhering to their usual diurnal activity and nocturnal sleep routine. Pseudo-resistance was prospectively defined as mean ambulatory 24-hour SBP <13 mm Hg (n=43), despite elevated office SBP readings. Patients were graded according to their baselinedipping pattern into 4 groups: extreme dippers (nighttime BP fall >%, n=42), dippers (nighttime BP fall >1% and <%, n=92), nondippers (nighttime BP fall <1% and >%, n=125), and reversedippers (nighttime BP > daytime BP, n=). Data on baseline dipping pattern were missing in 47 patients as a result of missing nighttime average values. The BP was considered at target when daytime and nighttime values were <135/85 and <1/7 mm Hg, respectively. The RDN procedure was performed as previously described. 13 Statistical Analysis Data are presented as mean±standard deviation (SD) unless otherwise specified. Comparisons between groups were performed using the Pearson χ 2 test for categorical variables and the Wilcoxon rank sum test or a paired t test for continuous variables where appropriate. Linear mixed-effects models were used to assess changes within groups over follow-up time. A 2-tailed probability value of <.5 was regarded as statistically significant. Multivariable unconditional logistic regression analysis was performed for risk analyses with response (reduction of office SBP 1 mm Hg and reduction of SBP on ABPM 5 mm Hg at 6 months) as outcome variable. All statistical analyses were performed with SPSS statistical software (version 15., SPSS Inc, Chicago, IL). Results Patient characteristics of the entire patient population (true resistant and pseudoresistant) are depicted in Table 1. Patients mean age was 62.7±1.8 years, 64% were male, with a mean body mass index of 3.4±5.6 kg/m 2. Type 2 diabetes mellitus was diagnosed in 135 patients (39%). Diagnosis was confirmed as recommended by the American Diabetes Association. 21 Coronary artery disease was prevalent in 83 patients (24%). Patients were treated with 5.2±1.6 antihypertensive drugs on average (Table 1). True resistant hypertensive patients were less often treated with β-blockers compared with pseudoresistant (75% versus 93%; P=.8). Despite antihypertensive drug treatment, baseline SBP, DBP, and PP were 17.8±22.1 mm Hg, 91.3±15.2 mm Hg, and 79.3±18.7 mm Hg, respectively, with a heart rate of 7.2±13.6 beats per minute (bpm). Office and 24-hour mean SBP at baseline was 172.2±22 and 154±16.2 mm Hg in true resistant hypertension and 161.2±.3 and 121.1±19.6 mm Hg in pseudoresistant hypertension, respectively. Except for the use of β-blockers, SBP, and APBM values, the baseline characteristics between true treatment-resistant and pseudoresistant patients were well matched regarding their baseline characteristics (Tables 1 and 2). Office-based BP at 3, 6, and 12 months were significantly reduced in the overall cohort: SBP by 21.5/23.7/27.3 mm Hg, DBP by 8.9/9.5/11.7 mm Hg, and PP by 13.4/14.2/14.9 mm Hg (n=245/236/9; P for all <.1), respectively. At 3-, 6-, and 12-month follow-up, 24-hour SBP decreased by 8.4/8.7/9.9 mm Hg and DBP by 4.2/4.3/6.6 mm Hg (n=245/236/9; p for all <.1), respectively. Changes in office SBP and DBP were significantly more pronounced than changes in 24-hour SBP and DBP (P<.1 for SBP and DBP at each time point). Although office BP reductions were comparable between treatment-resistant and pseudoresistant hypertensive patients (Figure 1), only in patients with true treatment resistance were 24-hour mean SBP and DBP significantly reduced 3, 6, and 12 months after treatment (SBP: 1.1/ 1.2/ 11.7 mm Hg, P<.1 versus +2.7/+1.2/ 4.4 mm Hg, P=.362/.465/.386; DBP: 4.8/ 4.9/ 7.4 mm Hg, P<.1 versus +.3/.3/.2, P=.757/.991/.96). In those patients changes of office SBP correlated poorly with changes of 24-hour mean SBP, even if this limited correlation achieved statistical significance (3 months: r=.198, P<.1). Even in

3 134 Circulation July 9, 13 Table 1. Patient Characteristics All Patients n=346 the subgroup of patients treated with an aldosterone antagonist (n=78), specifically recommended in patients with resistant hypertension, RDN significantly lowered office SBP/DBP/ PP ( 29./ 11.4/ 15.2 mm Hg, P for all <.1) and 24-hour SBP/DBP ( 11.9/ 7.1 mm Hg, P for both <.1) 6 month after RDN. At 3, 6, and 12 months, maximum and minimum 24-hour SBP ( 11.7/ 1./ 6.1 mm Hg and 6./ 9.4/ 13.1 mm Hg, P<.1 compared with baseline) as well as minimum 24-hour DBP ( 3.8/ 3.9/ 7.6 mm Hg, P<.1 compared with baseline; n=175/153/48) declined. In patients with true resistance daytime and nighttime ABPM were similarly reduced (Figure 2). In the overall cohort the percentage of nondippers and reverse dippers was not altered after RDN (baseline: 43.2%/14.7%; 3 months: 43.3%/.1%, P=.1; 6 months: 45.4%/12.6%, P=.15; 12 months: 37.9%/17.2%, P=.233). Patients with a SBP reduction of 1 mm Hg in office-based measurements and 5 mm Hg in ABPM average were subsequently defined as responders to RDN. Although, these thresholds were not provided by guidelines they represent clinical relevant BP reductions and were used in the Symplicity trials. Figure 3 depicts rates of responders according to office and 24-hour BP at 3, 6, and 12 months follow-up. Odds ratios (OR) for response at 6 months according to sex, age >75 years, per 1 kg/m 2 increase in body mass index, diabetes mellitus, glomerular filtration rate >6 ml/min/1.73 m 2, number of antihypertensive more than median, treatment with aldosterone antagonists, True Resistant n=33 Pseudoresistant n=43 P Value* Demographics Age, y 62.7± ± ± Male sex 223 (64%) 194 (64%) 29 (67%).661 Body mass index, kg/m 2 3.4± ± ± Risk factors and target organ damage Type II diabetes mellitus 135 (39%) 124 (41%) 11 (26%).54 CAD 83 (24%) 7 (23%) 13 (3%).35 Cystatin C GFR (ml/min) 79.8± ± ± Office blood pressure and heart rate measurements SBP, mm Hg 17.8± ± ±.3.13 DBP, mm Hg 91.3± ± ± PP, mm Hg 79.3± ± ± Heart rate, bpm 7.2±13.6 7± ± Antihypertensive treatment No. of antihypertensive drugs 5.2± ± ± ACE-I/ARB 34 (88%) 264 (87%) (93%).268 β-blockers 267 (77%) 227 (75%) (93%).8 Calcium channel blockers 261 (75%) 224 (74%) 37 (86%).84 Diuretics 318 (92%) 239 (79%) 38 (88%).145 Aldosterone antagonists 88 (25%) 78 (26%) 1 (23%).726 Central sympatholytics 19 (55%) 167 (55%) 23 (53%).841 Direct vasodilators 1 (29%) 88 (29%) 12 (28%).876 ACE-I indicates angiotensin-converting enzyme inhibitors; ARB, angiotensin receptor blockers; CAD, coronary artery disease; DBP, diastolic blood pressure; GFR, glomerular filtration rate; PP, pulse pressure; and SBP, systolic blood pressure. *P values for comparison between true resistant and pseudoresistant. treatment with central sympatholytics, office SBP greater than median, office DBP greater than median, office PP greater than median, ABPM average greater than median, and dipping pattern are shown in Table 3, indicating that RDN was equally effective in terms of BP lowering in all of the analyzed subgroups. After adjusting for covariates as age, sex, body mass index, diabetes mellitus, and glomerular filtration rate, office SBP at baseline was identified as a correlate of response at 6 months follow-up (as continuous variable [per 1 mm Hg]: OR 1.26, 95% confidence interval [CI] , P=.17; office SBP >17 mm Hg: OR 2.32, 95%-CI , P=.29). Patients and physicians were instructed not to change antihypertensive medication during the study period. However, antihypertensive drug regimen was reduced during follow-up in 118 patients (34%), as a result of confirmed BP levels below respective target BP or the development of symptoms of hypotension and confirmed low BP. Antihypertensive treatment was increased in 23 patients (7%) who remained above target BP. When excluding those 23 patients, BP effects remained unchanged: reduction of office SBP by 21.9/23.8/26.9 mm Hg and 24-hour SBP by 8.6/8.6/9.7 mm Hg at 3, 6, and 12 months, respectively (P<.1 for all). No differences existed concerning medication reductions (P=.524) or increases (P=.399) between trueresistant and pseudoresistant patients. Figure 4 illustrates the distribution of office and daytime BP levels at baseline preprocedure and at 3, 6, and 12 months postprocedure.

4 Mahfoud et al ABPM After RDN and Correlates of Response 135 Table 2. ABPM Parameters All Patients True Resistant Pseudoresistant P Value* Baseline n=346 n=33 n=43 Mean SBP 149.9± ± ±19.6 <.1 Mean DBP 84.9± ± ±8.6 <.1 Daytime SBP 153.9± ± ±8.7 <.1 Daytime DBP 87.8± ± ±8.7 <.1 Nighttime SBP 141.3± ± ±11.4 <.1 Nighttime DBP 77.6± ± ±7 <.1 Non-/reverse-dipping (n=299) 165 (55%) 15 (58%) 15 (38%).72 Maximum SBP 191.3± ± ±.3 <.1 Maximum DBP 113.6± ± ±14.4 <.1 Minimum SBP 111.3± 115± ±11.8 <.1 Minimum DBP 57.6± ± ±8.7 <.1 3 mo n=245 n=213 n=32 Mean SBP 141.9± ± ±13.5 <.1 Mean DBP 8± ± ±1.2 <.1 Daytime SBP 141.8± ± ±13.6 <.1 Daytime DBP 85.6± ± ±13.4 <.1 Nighttime SBP 132± ± ±15.1 <.1 Nighttime DBP 73.5± ± ±1.1 <.1 6 mo n=236 n=6 n=3 Mean SBP 141.9± ± ±1.3 <.1 Mean DBP 8.6± ± ±9.1 <.1 Daytime SBP 144.6± ± ±11.7 <.1 Daytime DBP 82.4± ± ±11 <.1 Nighttime SBP 133.5± ± ±15.8 <.1 Nighttime DBP 73± ± ±9.9 <.1 12 mo n=9 n=8 n=1 Mean SBP 1.8± ± ±15.2 <.1 Mean DBP 79.4±1.5 8± ±7.6 <.1 Daytime SBP 143.7± ± ±16.1 <.1 Daytime DBP 82± ± ±9 <.1 Nighttime SBP 13.2± ± ±15.3 <.1 Nighttime DBP 71.1±1.5 72± ±5.8 <.1 DBP indicates diastolic blood pressure; and SBP, systolic blood pressure. *P values for comparison of true resistant and pseudoresistant. Discussion Renal denervation offers a novel and well-tolerated approach to selectively interrupt sympathetic fibers and effectively reduce systolic and diastolic office BP. 11,12 Recently, concerns have been raised that RDN might not reduce ABP equally effectively. 22 The results of the present multi-center study in >3 patients now confirm that RDN significantly reduces office and 24-hour average, daytime, and nighttime BP in patients with true resistant hypertension and increases the rate of patients controlled to target BP values, both according to office BP and ABPM. Of note, office BP also declined in pseudoresistant patients. Blood pressure varies throughout the circadian period with a prolonged decrease during nocturnal sleep. 1 Daytime BP is more variable than nighttime BP in terms of different physical and mental activity, and nighttime BP is closely related to sympathetic outflow to the heart and the muscle vasculature. 23 Sympathetic activation has been shown to be a major contributor in the development and progression of hypertension and represents a potential mechanism for the day night BP difference. 24 Recently, a close inverse relationship between the degree of sympathetic activation and the magnitude of the nighttime drop in SBP and DBP has been reported. 9 The day night BP differences correlated inversely with sympathetic nerve activity (r=.76, P<.1) with the highest sympathetic activity observed in patients with reverse dipping. 9 The Dublin Outcome Study included 5292 hypertensive patients and demonstrated that nocturnal BP was an independent predictor of cardiovascular mortality. 25 A 1-mm Hg increase in mean nighttime SBP corresponded to a 21% increase in cardiovascular mortality. The Anglo-Scandinavian Cardiac Outcome Trial (ASCOT) ABPM substudy has demonstrated that nighttime SBP is superior compared with office SBP in predicting stroke. 26 Herein,

5 136 Circulation July 9, 13 Office BP changes All patients (n=346) True resistant hypertension (n=33) Pseudo-resistant hypertension (n=43) DBP p=.15* BP changes (mm Hg) - - p<.1 p<.1 p<.1 p<.1 p<.1 p<.1 p<.1 p<.1 p<.1-6 p<.1 p<.1 p<.1-8 (n=245) p<.1 (n=236) p<.1 (n=9) (n=213) p<.1 (n=6) p<.1 (n=8) (n=32) p<.1 (n=3) p<.1 (n=1) S BP D BP 24h-BP changes All patients (n=346) True resistant hypertension (n=33) Pseudo-resistant hypertension (n=43) SBP p=.218* DBP p=.977* BP changes (mm Hg) p<.1 p<.1 (n=245) p<.1 p<.1 (n=236) p<.1 p<.1 (n=9) p<.1 p<.1 (n=213) p<.1 SBP p<.1 (n=6) Figure 1. Office and 24-hour blood pressure (BP) changes 3, 6. and 12 months after renal denervation. DBP indicates diastolic blood pressure; and SBP, systolic blood pressure. Whiskers indicate 5 and 95 percentile. Probability values are for comparison with baseline values. *Probability values are comparison of within group changes over time using linear mixed-effects models. p<.1 (n=8) DBP p<.1 p=.362 p=.757 (n=32) p=.465 p=.991 (n=3) p=.386 p=.96 (n=1) RDN significantly reduced both nighttime SBP by 11.9 mm Hg, 1.9 mm Hg, and 12.6 mm Hg (P<.1) and daytime SBP by 13.6 mm Hg, 1.7 mm Hg, and 11.6 mm Hg (P<.1) at 3, 6, and 12 months, respectively. However, no clear improvement in dipping status was found after RDN, which might be related (1) to the poor reproducibility of the classification of patients into dippers and nondippers over time 27,28 and (2) to the fact that ABPM was performed as usually done in clinical practice with fixed time intervals for day and nighttime periods, which might affect the calculation of nocturnal dipping. The office BP reductions were more pronounced than the reduction in ABPM, a plausible finding which has been consistently demonstrated in antihypertensive drug treatment trial. 29 In a meta-analysis including 44 studies with >58 patients, the averaged weighted reductions in 24-hour SBP or DBP were 36.5% and 36.8% less than the reduction in the office based values. 29 The differences between office BP and 24-hour BP reductions found herein might be partially influenced by other factors, including a possible regression to the mean of office BP readings over repeated visits, a phenomenon which by definition

6 Mahfoud et al ABPM After RDN and Correlates of Response 137 Table 3. Correlate of Response Univariable Analysis Multivariable Analysis* Variable Wald OR 95% CI P Value Wald OR 95% CI P Value All patients Male sex Age >75 yr Per 1 kg/m 2 increase in BMI Diabetes mellitus GFR >6 ml/min/1.73m >5 antihypertensive drugs (m) Use of an aldosterone antagonist Use of a central sympatholytic Office SBP >17 mm Hg (m) Office DBP >91 mm Hg (m) Office PP >79 mm Hg (m) ABP >151 mm Hg (m) Non-/reverse-dipping True resistant hypertension Male sex Age >75 yr Per 1 kg/m 2 increase in BMI Diabetes mellitus GFR >6 ml/min/1.73m >5 antihypertensive drugs (m) Use of an aldosterone antagonist Use of a central sympatholytic Office SBP >17 mm Hg (m) Office DBP >91 mm Hg (m) Office PP >79 mm Hg (m) ABP >151 mm Hg (m) Non-/reverse-dipping Odds ratios for response (office SBP 1 mm Hg) at 6 mo in all patients and in patients with true resistant hypertension. ABP indicates ambulatory blood pressure 24-h average; BMI, body mass index; CI, confidence interval; DBP, diastolic blood pressure; GFR, glomerular filtration rate; m, variable was dichotomized according to the median; OR, odds ratio; PP, pulse pressure; and SBP, systolic blood pressure. *Variables entered in the multivariate analysis were age, sex, BMI, GFR, diabetes mellitus, and variables with P<.1 in the univariable analysis. cannot affect mean ABP. Furthermore, it can be hypothesized that the disparity might be partially mediated by a suppression of the white-coat effect, frequently encountered in resistant hypertension and associated with increased sympathetic activity. 3 However, the differences between the entire population and the group of patients with true resistant hypertension were comparable, indicating that this cannot only be attributed to the inclusion of patients with pseudoresistant hypertension whose ABPM values after RDN remain unchanged. The ASPIRANT (Addition of Spironolactone in Patients With Resistant Arterial Hypertension) trial 31 demonstrated in patients treated with a mean of 4.5 antihypertensive drugs a reduction of daytime BP by 5.4 mm Hg (P=.24), nighttime by 8.6 mm Hg (P=.11), and 24-h SBP by 9.8 mm Hg (P=.4) without significantly influencing DBP by addition of 25 mg spironolactone once daily. However, the different effects of spironolactone on BP in the ASPIRANT trial and RDN herein has to be interpreted in view of the different baseline BP values (office BP: 154/92 versus 171/91 mm Hg, 24-hour ABP: 141/8 versus 15/85 mm Hg, day-time ABP: 142/82 versus 154/88, and night-time ABP: 136/77 versus 141/78 mm Hg). Despite the fact that the patients analyzed herein were intensively treated (mean 5.2±1.6 antihypertensive drugs), RDN was more effective in lowering 24-hour BP on top of concomitant antihypertensive medication, even in the subgroup of patients (n=78) who were already treated with spironolactone (mean 24-hour BP changes 6 months after RDN: 11.9/ 7.1 mm Hg, P for both <.1). Maximum daytime SBP has been shown to predict risk of stroke and coronary events, particularly after adjustment for mean daytime SBP. 32 At 3, 6, and 12 months follow-up, RDN significantly reduced maximum SBP. Both the office and 24-hour BP reductions and the improvement in control rates after RDN found herein, may have relevant implications for cardiovascular morbidity and mortality in patients at risk.

7 138 Circulation July 9, 13 Daytime change Nighttime change BP changes (mm Hg) - - p<.1 p<.1 p<.1 p<.1 p<.1 p<.1 p<.1 p<.1 p<.1 Figure 2. Daytime and nighttime blood pressure (BP) changes in patients with true treatmentresistant hypertension at 3, 6, and 12 months follow-up. DBP indicates diastolic blood pressure; and SBP, systolic blood pressure. Whiskers indicate 5 and 95 percentile. Probability values are for comparison with baseline values. *Probability values are comparison of within group changes over time using linear mixed-effects models. -6 p<.1 p<.1 p<.1-8 (n=183) (n=161) (n=54) (n=183) (n=161) (n=54) SBP DBP Although it was not mandatory to exclude pseudoresistant hypertension according to the Symplicity protocol, 13,14 the percentage was rather small ( 12%). Not surprisingly, in patients with pseudoresistant hypertension office BP was significantly reduced, whereas ABPM was not influenced after RDN. Our findings are in line with recent recommendations of several national 33 and international societies (including the European Society of Cardiology 34 and the European Society of Hypertension 35 ), aimed at avoiding to treat patients with RDN if only office BP but not ABP is elevated. However, it has been shown that pseudoresistant hypertension is a risk indicator of sustained hypertension and is associated with an increased risk for cardiovascular end points, including cardiovascular death, stroke, and hypertensive organ damage. 36,37 Therefore, further investigations are deserved to assess the effects of office BP reductions by RDN on cardiovascular morbidity, mortality, Proportion (%) (n=213) 65 (n=6) 76.7 Reduction of office SBP 1 mm Hg Reduction of ABP 5 mm Hg 7 (n=8) Figure 3. Rates of responders in patients with true treatmentresistant hypertension, defined as a systolic blood pressure (SBP) reduction of 1 mm Hg in office-based measurements or 5 mm Hg in ambulatory blood pressure monitoring (ABPM) average at 3 months, 6 months, and 12 months follow-up. and the development of sustained hypertension in patients with elevated clinic and normal 24-hour BP. Response to RDN has been defined as a reduction in office SBP 1 mm Hg 6 months after treatment. To avoid invasive treatment by RDN in patients with low probability of BP lowering afterward, identification of correlates of response are essential. In different subgroups, according to patients baseline characteristics, RDN was similarly effective in terms of blood pressure reductions. Office SBP at baseline was the only correlate of response identified herein (per 1 mm Hg OR 1.26, 95% CI , P=.17). Of note, current medication with spironolactone or central sympathetic agents were no correlates. Our study might have some limitations. Despite the advantages of ABPM, it is not generally used in prospective trials investigating cardiovascular protection by antihypertensive treatments. Actually there is not a single prospective study relating BP changes by ABPM to future cardiovascular outcome, which might be a result of difficulties of the procedure (time consumption, repeated device checking, data heterogeneity, costs, etc.). 29 It can be speculated that such a profound reduction of BP after RDN might have increased patient s exercise capacity and daily physical workload and thereby also increased ABP, especially during daytime, which might explain the similar BP reductions during daytime and nighttime. Although preliminary data suggest that RDN reduces BP variability, 38 assessment of BP variability was not part of the study protocol. As the study was mainly focused on the BP changes after 3 or 6 months, the number of patients completing 12-month follow-up is lower compared with the other time points. Therefore, the group of patients with 12-month follow-up should be regarded as a subgroup, illustrating that the effects of RDN on BP are sustained over a longer time period. Changes in antihypertensive drug treatment might also have influenced ABP measurements. During the study period antihypertensive treatment was reduced in 34% (118 patients), as a result of symptomatic hypotension

8 Mahfoud et al ABPM After RDN and Correlates of Response 139 Proportion (%) Proportion (%) Office BP h-BP Baseline SBP >16 mm Hg SBP 1-16 mm Hg SBP <1 mm Hg Baseline with SBP <1 mm Hg, and increased in 7% (23 patients, all nonresponders). Even after censoring for postprocedural medication changes, no significant differences were found, making a relevant influence of treatment intensification unlikely. Conclusions Renal denervation reduces office, 24-hour, daytime, nighttime, maximum, and minimum BP in patients with true treatmentresistant hypertension on top of background antihypertensive medication. In the largest cohort of patients analyzed so far, RDN was equally effective in terms of BP reduction in different subgroups. Additional trials with longer-term follow-up are needed to investigate the impact of these alterations on cardiovascular outcome in patients with resistant hypertension. Sources of Funding The Symplicity HTN1 and HTN2 were sponsored by Medtronic/ Ardian Inc. Disclosures Drs Mahfoud, Ukena, and Böhm are supported by the Ministry of Science and Economy of the Saarland. Dr Mahfoud is supported by the Deutsche Hochdruckliga and Deutsche Gesellschaft für Kardiologie. Drs Mahfoud, Ukena, and Böhm are supported by the SBP >15 mm Hg SBP mm Hg SBP <13 mm Hg Figure 4. Distribution of office and 24-hour blood pressure (BP) levels at baseline preprocedure and at 3, 6, and 12 months postprocedure in patients with true resistant hypertension Deutsche Forschungsgemeinschaft (KFO 196). Dr Schlaich is supported by a National Health and Medical Research Council Senior Research Fellowship. Dr Sobotka was an employee of Medtronic Ardian Inc. All authors received scientific support and speaker honorarium from Medtronic Ardian Inc. References 1. Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N Engl J Med. 6;354: Ohkubo T, Imai Y, Tsuji I, Nagai K, Watanabe N, Minami N, Itoh O, Bando T, Sakuma M, Fukao A, Satoh H, Hisamichi S, Abe K. 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[Expert consensus statement on interventional renal sympathetic denervation for hypertension treatment]. Dtsch Med Wochenschr. 11;136: Mahfoud F, Lüscher TF, Andersson B, Baumgartner I, Cifkova R, Dimario C, Doevendans P, Fagard R, Fajadet J, Komajda M, Lefevre T, Lotan C, Sievert H, Volpe M, Widimsky P, Wijns W, Williams B, Windecker S, Witkowski A, Zeller T, Böhm M. Expert consensus document from the European Society of Cardiology on catheter-based renal denervation. Eur Heart J. 13 in press. DOI1.193/eurheartj/eht Schmieder RE, Redon J, Grassi G, Kjeldsen SE, Mancia G, Narkiewicz K, Parati G, Ruilope L, van de Borne P, Tsioufis C. ESH position paper: renal denervation - an interventional therapy of resistant hypertension. J Hypertens. 12;3: Verdecchia P, Reboldi GP, Angeli F, Schillaci G, Schwartz JE, Pickering TG, Imai Y, Ohkubo T, Kario K. Short- and long-term incidence of stroke in white-coat hypertension. Hypertension. 5;45: Mancia G, Bombelli M, Facchetti R, Madotto F, Quarti-Trevano F, Polo Friz H, Grassi G, Sega R. Long-term risk of sustained hypertension in white-coat or masked hypertension. Hypertension. 9;54: Zuern CS, Rizas KD, Eick C, Stoleriu C, Bunk L, Barthel P, Balletshofer B, Gawaz M, Bauer A. Effects of Renal Sympathetic Denervation on 24-hour Blood Pressure Variability. Front Physiol. 12;3:134. Clinical Perspective Ambulatory blood pressure monitoring (ABPM) is important to identify hypertensive patients at risk. Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. However, less is known about the effect of RDN on 24-hour BP and predictors of response in individuals with true or pseudoresistant hypertension. A total of 346 uncontrolled hypertensive patients (office systolic BP 16 mm Hg, 15 mm Hg for type 2 diabetes mellitus), separated according to daytime ABPM into 33 with true resistant and 43 with pseudoresistant hypertension, from 1 multinational centers were studied. Office systolic, diastolic and pulse pressure (SBP/DBP/PP) and ABPM (including daytime, nighttime, maximum, minimum BP) were measured at entry, and at 3, 6, and 12 months after RDN. After RDN office SBP, DBP, and PP were significantly reduced in the overall cohort. In patients with true treatment resistance there was a significant reduction after RDN in 24-hour mean SBP, DBP, maximum SBP, and minimum SBP, whereas there was no effect on ABPM in pseudoresistant patients. RDN was equally effective in reducing BP in different subgroups of patients (age, estimated glomerular filtration rate, dipping pattern, diabetic status, etc). Office SBP at baseline was the only independent predictor of BP response. Our data from the largest cohort of patients treated by RDN and followed with ABPM up to 12 months demonstrate that, in patients with true resistant hypertension, the procedure improves relevant aspects of ABPM commonly linked to high cardiovascular risk, whereas it only affected office BP in pseudoresistant hypertension. Go to to take the CME quiz for this article.