Renal denervation: under pressure?
Rosa de Jager Cover Marthe Kalkhoven | Marthe Kalkhoven Illustraties Layout Renate Siebes | Proefschrift.nu Printed by Ridderprint, Ridderkerk ISBN 978-90-393-6758-2
© 2017 Rosa de Jager All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage or retrieved system, without permission in writing from the author. Renal denervation: under pressure?
Renale denervatie: onder druk?
(met een samenvatting in het Nederlands)
PROEFSCHRIFT
ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof. dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op dinsdag 27 juni 2017 des ochtends te 10.30 uur
door
Rosemarie Lara de Jager
geboren op 25 december 1983 te Nieuwegein Promotoren: Prof. dr. M.L. Bots Prof. dr. M.C. Verhaar
Copromotor: Dr. P.J. Blankestijn
St. Jude Medical and Chipsoft b.v. are gratefully acknowledged for their financial sup- port of this thesis.
The SYMPATHY trial was supported by unrestricted grants from The Netherlands Orga- nisation for Health Research and Development (ZonMw) [#837004006], Dutch Kidney foundation [Nierstichting Nederland #CPI12.02] and from Medtronic Inc. CONTENTS
Chapter 1 Introduction 7
Part 1 Renal denervation in resistant hypertension Chapter 2 The effect of renal denervation added to standard pharmacologic 19 treatment versus standard pharmacologic treatment alone in patients with resistant hypertension: rationale and design of the SYMPATHY trial Chapter 3 Impact of medication adherence on the effect of renal 43 denervation: the SYMPATHY trial Chapter 4 Prevalence of hypertensive disorders of pregnancy in resistant 77 hypertensive women and the effect of renal denervation
Part 2 The interpretation of the effect of renal denervation Chapter 5 Medication adherence in patients with apparent resistant 93 hypertension: findings from the SYMPATHY trial Chapter 6 Renal denervation in hypertensive patients not on blood pressure 111 lowering drugs Chapter 7 S100B as marker for nerve damage after renal denervation 133
Part 3 New indications for renal denervation Chapter 8 Chronic kidney pain in autosomal dominant polycystic kidney 149 disease: a case report of successful treatment by catheter-based renal denervation Chapter 9 Catheter-based renal denervation as therapy for chronic severe 159 kidney-related pain
Part 4 Future research and perspectives Chapter 10 Discussion 183 Chapter 11 English summary 200 Nederlandse samenvatting 206 Dankwoord 212 Curriculum Vitae 218 List of publications 220
CHAPTER
Introduction
Based on: de Jager RL, Blankestijn PJ. Pathophysiology I: the kidney and the sympathetic nervous system. EuroIntervention 2013;9 Suppl R:R42-R47. de Beus E*, de Jager RL*, Joles JA, Grassi G, Blankestijn PJ. Sympathetic activation secondary to chronic kidney disease: therapeutic target for renal denervation? J Hypertens 2014; 32: 1751-1761.
Vink EE, de Jager RL, Blankestijn PJ. Sympathetic hyperactivity in chronic kidney disease: pathophysiology and (new) treatment options. Curr Hypertens Rep 2013; 15: 95-101.
* equal contributors Chapter 1
Hypertension is defined as an office systolic blood pressure (SBP) > 140 mmHg and/ or > 90 mmHg diastolic blood pressure (DBP).1 Worldwide, 874 million adults suffer from an office SBP of 140 mmHg or higher, which is associated with an annual death rate of 106 per 100.000 patients.2 The percentage of patients achieving adequate blood pressure (BP) control to guideline target levels is only 35%, leaving uncontrolled patients at an increased cardiovascular risk.3 There is an unmet need to find new treatment options to control apparent resistant hypertension. For this matter, sympathetic overactivity has been suggested to be an important therapeutic target. Percutaneous renal denervation (RDN) could be a valuable treatment option to lower sympathetic activity and, subsequently, BP. This introduction will focus on the concomitant role of the sympathetic nervous system and the kidneys in the condition of apparent resistant hypertension. Further, pharmacological therapy and RDN are discussed as treatment options to attenuate sympathetic activity and lower BP. This introduction ends with open questions concerning the success of the RDN procedure.
Sympathetic nervous system
Sympathetic nerve activity is evolutionary of great importance for the direct response in a dangerous, so called, “fight or flight” situation. As part of the autonomic nervous system, the sympathetic nervous system (SNS) counteracts with the parasympathetic nervous system (PNS). Sympathetic outflow towards the body is called efferent nerve activity. The function of multiple organs is influenced by this efferent sympathetic nerve activity, including the heart, vasculature and the kidneys. There is no such thing as a “general” sympathetic outflow; sympathetic outflow to the various organs may greatly vary in that it is increased to one organ whereas it is low or absent towards another organ. The degree of efferent activity is modulated by afferent nerve signals. These are nerves coming from the various organs towards the central nervous system (Figure 1.1).
Sympathetic nervous system and the kidneys
The kidneys are both a recipient of efferent sympathetic signals as well as a generator of renal afferent sympathetic activity (Figure 1.1). Recently, some evidence also appeared for parasympathetic innervation of the kidney.4 The renal (sympathetic) nerves are located in the adventitia around the renal artery.4, 5 Experimental studies showed that stimulation of the renal efferent nerves resulted in a cascade of actions in the kidneys: first, as a result of renal vasoconstriction, renal blood flow and glomerular filtration
8 Introduction 1
Figure 1.1 Schematic representation of the kidney involvement in the pathogenesis of sympa- thetic overactivity. Minimal kidney damage, not necessarily affecting kidney function, results in area(s) of ischemia. This results in increased afferent nerve activity and increased activation of the renin-angiotensin system (RAS) and central nervous system (CNS). Increased central sympathetic outflow affects many organs also including the cardiovascular system. In addition, RAS activation may enhance sympathetic activity on the peripheral level
rate decreased; secondly, sodium re-absorption increases and angiotensin II (Ang II) is produced.6 Increased activity of the renin-angiotensin-system (RAS) enhanced the afferent sympathetic activity,7 suggesting reciprocal potentiation of the two systems. Kidney ischemia is seen as the effector. Even a minute lesion by injection of phenol into one kidney caused increased sympathetic activity and hypertension.8
Assessment of renal sympathetic nerve activity
Renal sympathetic nerve activity cannot be measured directly, at least not in humans. Two methods of quantifying the downstream effects of sympathetic activity have greatly increased our knowledge over the past 20 years. The first method is measurement of noradrenaline (NA), using a radiotracer technology, which has been used to quantify the regional sympathetic activity. This technology combines intravenous infusion of titrated NA with regional venous sampling. The second method is muscle sympathetic nerve activity (MSNA). This method assesses real nerve activity, and quantifies the centrally originated postganglionic efferent sympathetic nerve activity towards the resistance
9 Chapter 1
vasculature.9, 10 The microneurography records sympathetic activity as visual and acoustic identification of bursts (multi-fiber discharge).11 The down side of both assessments is that they are invasive, time consuming and it requires an investigator very experienced with the technique. Therefore, they are not suitable for routine use.
Sympathetic overactivity and the link with clinical disorders
Uncontrolled hypertension Uncontrolled hypertension can be partially due to secondary causes. We found that about 30% of the referred patients with uncontrolled hypertension had a treatable sec- ondary cause.12 However, the remaining patients are classified as patients with resistant hypertension, defined as uncontrolled hypertension despite the use of three or more BP lowering drugs. It was recognized that already in early hypertension renal NA spill over was significantly elevated as compared to controls, suggesting renal sympathetic overactivity.13, 14 Especially in patients with resistant hypertension, the SNS (assessed with MSNA) is over activated.15
Chronic kidney disease Sympathetic overactivity seems to be an early phenomenon in the clinical course of kidney failure. Even in the early stages of kidney failure MSNA levels are increased and this becomes more pronounced when eGFR is reduced.16 In patients with autosomal dominant polycystic kidney disease (ADPKD) MSNA was found to be already increased in hypertensive patients with normal kidney function.17 Of particular importance is the fact that in bilaterally nephrectomised patients sympathetic activity is comparable to controls and renin and Ang II are undetectable.18-20
Sympathetic overactivity as therapeutic target
Conventional therapy: BP lowering drugs There is abundant evidence that RAS inhibitors reduce MSNA in essential hypertension.21-23 The precise pathophysiologic mechanism how RAS inhibitors decrease MSNA is not clear. The central sympatholytic drug moxonidine reduces sympathetic activity in all stages of kidney failure.24, 25 In contrast, amlodipine, albeit an effective blood lowering agent, increases MSNA.26 Differences in sympathetic activation may exist between calcium-channel blockers.27 Older studies suggest that some beta-blockers may reduce
10 Introduction 1
MSNA whereas others did not.28, 29 Diuretics usually increase MSNA with the exception of spironolactone.30, 31
Experimental therapy: renal denervation RDN means literally: “disruption of the renal nerves”. RDN can be achieved in rodents by chemical sympathectomy with guanethidine, bilateral dorsal rhizotomy, or direct RDN by stripping the renal artery mechanically followed by application of phenol in alcohol directly on the renal artery. In brief, there is experimental evidence that RDN reduces blood pressure (BP) and has beneficial effects on proteinuria and glomerulosclerosis.5, 32-34
In humans, surgical sympathectomy at thoracolumbar level was already performed in the early fifties to reduce BP. Although this treatment induced a tremendous drop in BP and 5-year mortality rate, there were various serious side effects and pharmacological treatment became a better alternative.35 In 2009 the first successful case report was published, assessing the effect of percutaneous catheter-based RDN on lowering BP in a patient with uncontrolled hypertension.36 In this case-report MSNA dropped with more than 50%, which is far more than is achieved with pharmacological therapy. Later reports were less optimistic according to the effect of RDN on MSNA.37, 38 Almost one year after this case-report, the first randomized controlled trial (RCT) (51 RDN and 49 controls) showed a 33/11 mmHg more decline in office BP in the RDN group compared with the control group.39 A similar trend was seen for 24-hour ambulatory BP (24-h ABPM) and home BP (HBP), but these groups were much smaller and the difference was less pronounced.
Uncertainty concerning the success of renal denervation
The difficulty to measure sympathetic activity hampers the assessment of the success of RDN. MSNA is believed to be the most realistic method to quantify sympathetic activity, but is not eligible for daily practice.13 In the RDN field BP is embraced as an indirect marker of the success of the RDN procedure. Indeed, there is abundant evidence that the regulation of BP is associated with the sympathetic nervous system.15, 17, 40 However, already in the first RCT there was a wide variation in observed effect (standard deviation [SD] 23/11 mmHg) and 16% of the patients were classified as non-responder (< 10 mmHg decline in office SBP). Why is it that some patients did not respond to the therapy and others had an enormous drop in BP? Uncertainty rose about the question if some of the selected patients might have had another (secondary) cause of their hypertension.
11 Chapter 1
If so, sympathetic overactivity, probably, contributed little to their high BP. Moreover, why was the reduction seen after RDN not achieved with BP lowering drugs alone of which we know it also attenuates sympathetic nerve activity? The effort to collect data on patient characteristics (e.g. history of hypertensive disorders in pregnancy, adherence to prescribed medication), could be of relevance to determine what is needed to identify the best responders to RDN or interventional therapy in general. At procedural level there is an unmet need to be sure if the disruption of the renal nerves, accomplished with RDN, is enough to lower BP. Especially, as we do know not all nerves are effectively ablated.41 Biomarkers that are easy to assess, directly available after the procedure and have a high sensitivity for nerve damage, could be of interest in this matter. During the RDN procedure it is not possible to differentiate between sympathetic nerves and nerves of other origin (parasympathetic or sensory). This makes it also difficult to perform the procedure for a specific indication, such as hypertension. However, there also lays an opportunity to perform the procedure for other disorders in which the renal nerves might be involved. One example is kidney-related pain in chronic kidney diseases, like loin pain hematuria syndrome (LPHS) and ADPKD.
Outline of this thesis
The primary objective of this thesis is to study the effect of RDN on BP. In addition, this thesis will focus on the interpretation of the effect of RDN. Thirdly, we explore RDN for new indications.
Part I presents the effect of RDN on BP. Chapter 2 describes the rationale and design of the SYMPATHY trial. SYMPATHY is a multi-center randomized, open-label, controlled trial. Primary objective of this trial was to study the effect of RDN, added to usual care, on daytime systolic ABPM compared to usual care alone in patients with resistant hypertension. In Chapter 3 the main results of SYMPATHY are presented. Chapter 4 describes the effect of a RDN on BP in resistant hypertensive women with a history of hypertensive disorders of pregnancy (HDP).
Part II focuses on the interpretation of the effect of RDN. In Chapter 5 we explore the adherence to BP lowering drugs in patients with resistant hypertension, the determinants of non-adherence and the relation with BP. Chapter 6 presents the results of RDN on BP in patients not on BP lowering drugs. Chapter 7 is a pilot study to explore the role of S100B as biomarker for nerve damage and thus the direct effect of RDN.
12 Introduction 1
Part III suggests RDN as new therapeutic option for kidney-related pain. Chapter 8 reports a case in which RDN was performed for ADPKD-related pain. Chapter 9 presents a larger study of 11 patients with LPHS and ADPKD-related pain and the effect of RDN on pain relief and the use of analgesic medication.
Part IV will outline the main findings of the studies mentioned above. Chapter 10 will discuss the main findings and a summary of the studies is presented in Chapter 11.
13 Chapter 1
References
(1) Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens.2013;31(7): 1281-1357. (2) Forouzanfar MH, Liu P, Roth GA et al. Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015. JAMA.2017;317(2):165-182. (3) Pereira M, Lunet N, Azevedo A, Barros H. Differences in prevalence, awareness, treatment and control of hypertension between developing and developed countries. J Hypertens.2009;27(5):963-975. (4) van Amsterdam WA, Blankestijn PJ, Goldschmeding R, Bleys RL. The morphological substrate for Renal Denervation: Nerve distribution patterns and parasympathetic nerves. A post-mortem histological study. Ann Anat.2016;204:71-79. (5) Augustyniak RA, Picken MM, Leonard D, Zhou XJ, Zhang W, Victor RG. Sympathetic nerves and the progression of chronic kidney disease during 5/6 nephrectomy: studies in sympathectomized rats. Clin Exp Pharmacol Physiol.2010;37(1):12-18. (6) DiBona GF. Neural control of the kidney: past, present, and future. Hypertension.2003;41(3 Pt 2): 621-624. (7) Hendel MD, Collister JP. Renal denervation attenuates long-term hypertensive effects of Angiotensin ii in the rat. Clin Exp Pharmacol Physiol.2006;33(12):1225-1230. (8) Ye S, Gamburd M, Mozayeni P, Koss M, Campese VM. A limited renal injury may cause a permanent form of neurogenic hypertension. Am J Hypertens.1998;11(6 Pt 1):723-728. (9) Vallbo AB, Hagbarth KE, Torebjork HE, Wallin BG. Somatosensory, proprioceptive, and sympathetic activity in human peripheral nerves. Physiol Rev.1979;59(4):919-957. (10) Wallin BG, Sundlof G. A quantitative study of muscle nerve sympathetic activity in resting normotensive and hypertensive subjects. Hypertension.1979;1(2):67-77. (11) Grassi G, Esler M. How to assess sympathetic activity in humans. J Hypertens.1999;17(6):719-734. (12) Verloop WL, Vink EE, Voskuil M et al. Eligibility for percutaneous renal denervation: the importance of a systematic screening. J Hypertens.2013;31(8):1662-1668. (13) Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens.2010; 23(10):1052-1060. (14) Esler M, Jennings G, Lambert G. Noradrenaline release and the pathophysiology of primary human hypertension. Am J Hypertens.1989;2(3 Pt 2):140S-146S. (15) Grassi G, Seravalle G, Brambilla G et al. Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. Int J Cardiol.2014;177(3):1020-1025. (16) Grassi G, Quarti-Trevano F, Seravalle G et al. Early sympathetic activation in the initial clinical stages of chronic renal failure. Hypertension.2011;57(4):846-851. (17) Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J Am Soc Nephrol.2001;12(11): 2427-2433. (18) Converse RL, Jr., Jacobsen TN, Toto RD et al. Sympathetic overactivity in patients with chronic renal failure. N Engl J Med.1992;327(27):1912-1918. (19) Hausberg M, Kosch M, Harmelink P et al. Sympathetic nerve activity in end-stage renal disease. Circulation.2002;106(15):1974-1979. (20) Wenting GJ, Blankestijn PJ, Poldermans D et al. Blood pressure response of nephrectomized subjects and patients with essential hypertension to ramipril: indirect evidence that inhibition of tissue angiotensin converting enzyme is important. Am J Cardiol.1987;59(10):92D-97D. (21) Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Enalapril and losartan reduce sympathetic hyperactivity in patients with chronic renal failure. J Am Soc Nephrol.2003;14(2):425-430.
14 Introduction 1
(22) Neumann J, Ligtenberg G, Klein IH et al. Sympathetic hyperactivity in hypertensive chronic kidney disease patients is reduced during standard treatment. Hypertension.2007;49(3):506-510. (23) Siddiqi L, Oey PL, Blankestijn PJ. Aliskiren reduces sympathetic nerve activity and blood pressure in chronic kidney disease patients. Nephrol Dial Transplant.2011;26(9):2930-2934. (24) Hausberg M, Tokmak F, Pavenstadt H, Kramer BK, Rump LC. Effects of moxonidine on sympathetic nerve activity in patients with end-stage renal disease. J Hypertens.2010;28(9):1920-1927. (25) Neumann J, Ligtenberg G, Oey L, Koomans HA, Blankestijn PJ. Moxonidine normalizes sympathetic hyperactivity in patients with eprosartan-treated chronic renal failure. J Am Soc Nephrol.2004;15(11): 2902-2907. (26) Ligtenberg G, Blankestijn PJ, Oey PL et al. Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med.1999;340(17):1321-1328. (27) Grassi G, Seravalle G, Turri C, Bolla G, Mancia G. Short-versus long-term effects of different dihydropyridines on sympathetic and baroreflex function in hypertension. Hypertension.2003;41(3): 558-562. (28) Burns J, Mary DA, Mackintosh AF, Ball SG, Greenwood JP. Arterial pressure lowering effect of chronic atenolol therapy in hypertension and vasoconstrictor sympathetic drive. Hypertension.2004;44(4): 454-458. (29) Wallin BG, Sundlof G, Stromgren E, Aberg H. Sympathetic outflow to muscles during treatment of hypertension with metoprolol. Hypertension.1984;6(4):557-562. (30) Menon DV, Arbique D, Wang Z, ms-Huet B, Auchus RJ, Vongpatanasin W. Differential effects of chlorthalidone versus spironolactone on muscle sympathetic nerve activity in hypertensive patients. J Clin Endocrinol Metab.2009;94(4):1361-1366. (31) Raheja P, Price A, Wang Z et al. Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients. Hypertension.2012;60(2):319-325. (32) Gattone VH, Siqueira TM, Jr., Powell CR, Trambaugh CM, Lingeman JE, Shalhav AL. Contribution of renal innervation to hypertension in rat autosomal dominant polycystic kidney disease. Exp Biol Med (Maywood ).2008;233(8):952-957. (33) Hamar P, Kokeny G, Liptak P et al. The combination of ACE inhibition plus sympathetic denervation is superior to ACE inhibitor monotherapy in the rat renal ablation model. Nephron Exp Nephrol.2007;105(4):e124-e136. (34) Nagasu H, Satoh M, Kuwabara A et al. Renal denervation reduces glomerular injury by suppressing NAD(P)H oxidase activity in Dahl salt-sensitive rats. Nephrol Dial Transplant.2010;25(9):2889-2898. (35) Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension; results in 1,266 cases. J Am Med Assoc.1953;152(16):1501-1504. (36) Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med.2009;361(9):932-934. (37) Brandt MC, Mahfoud F, Reda S et al. Renal sympathetic denervation reduces left ventricular hypertrophy and improves cardiac function in patients with resistant hypertension. J Am Coll Cardiol.2012;59(10):901-909. (38) Brinkmann J, Heusser K, Schmidt BM et al. Catheter-based renal nerve ablation and centrally generated sympathetic activity in difficult-to-control hypertensive patients: prospective case series. Hypertension.2012;60(6):1485-1490. (39) Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet.2010;376(9756):1903-1909. (40) Esler M, Lambert G, Jennings G. Regional norepinephrine turnover in human hypertension. Clin Exp Hypertens A.1989;11 Suppl 1:75-89. (41) Vink EE, Goldschmeding R, Vink A, Weggemans C, Bleijs RL, Blankestijn PJ. Limited destruction of renal nerves after catheter-based renal denervation: results of a human case study. Nephrol Dial Transplant.2014;29(8):1608-1610.
15
Part 1 Renal denervation in resistant hypertension 1
CHAPTER The effect of renal ddenervationenervation added to standard pharmacologicogic treatment versus standard pharmacologic treatment alone in patients with resistant hypertension: rationale and design of the SYMPATHY trial
E.E. Vink, E. de Beus, R.L. de Jager, M. Voskuil, W. Spiering, E.J. Vonken, G.A. de Wit, K.C.B. Roes, M.L. Bots, P.J. Blankestijn
Am Heart J.2014;167:308-314 Chapter 2
Abstract
The first studies on renal denervation (RDN), suggest that this treatment is feasible, effective and safe in the short-term. Presently available data are promising, but important uncertainties exist, therefore SYMPATHY has been initiated. SYMPATHY is a multi-center, randomized, controlled trial in patients randomized to RDN in addition to usual care (intervention-group) or to continued usual care (control- group). Randomization will take place in a ratio of 2 to 1. At least 300 participants will be included to answer the primary objective. Sample size may be extended to a maximum of 570 to address key secondary objectives. The primary objective is to assess whether RDN added to usual care compared to usual care alone reduces blood pressure (BP) (ambulatory daytime systolic BP) in subjects with an average daytime systolic BP ≥ 135 mm Hg, despite use of ≥ 3 BP-lowering agents, six months after RDN. Key secondary objectives are evaluated at 6 months and at regular intervals during continued follow-up and include the effect of RDN on the use of BP-lowering agents, in different subgroups (across strata of eGFR and of baseline BP), on office BP, quality of life and cost-effectiveness.
20 Rationale and design SYMPATHY trial
Introduction Hypertension is a global public health concern. It is estimated that 30–40% of the adult 2 population in the developed world suffers from this condition. Despite availability of numerous safe and effective pharmacological therapies, only about one third of patients achieve an adequate controlled blood pressure (BP).1 A subgroup of these patients have resistant hypertension, defined by the American Heart Association as a BP that remains above treatment goals despite concurrent use of medication from three different antihypertensive classes at appropriate doses, one ideally being a diuretic.2
Increased activation of the sympathetic nervous system is identified as an important factor in development and progression of hypertension.3 In this context, a catheter- based approach has been developed to disrupt the renal sympathetic nerves, using radio-frequent energy. After a proof-of-principle study,4 the first randomized controlled trial (RCT); the Symplicity HTN-2 trial, showed in a relatively small number of patients (n=106, randomization ratio 1:1) that renal denervation (RDN) is efficacious.5 Office systolic blood pressure (SBP)/ diastolic blood pressure (DBP) values decreased with -32/-12mm Hg in patients treated with RDN, after six months of follow-up, while BP did not change in the control-group.5
Remaining questions
Presently available data are promising but important uncertainties exist. Firstly, in previous studies4, 5 and also in the ongoing Symplicity HTN-3 trial,6 inclusion and quantification of effect were based on office BP, without exclusion of white coat hypertension or confirmation of hypertension by more precise ambulatory blood pressure monitoring (ABPM). The second issue concerns safety: delivery of radio-frequent energy can potentially result in focal alterations of media and adventitia.7 In the HTN-1 and HTN-2 trials,4, 5 only one case of aggravation of a pre-existing renal artery stenosis was described, but case-reports of stenosis after RDN have recently been published.8, 9
Furthermore, patients with impaired renal function (eGFR < 45 mL/min/1.73m2) were excluded in previous studies. We hypothesize that RDN is especially beneficial for these patients, since impaired kidney function is a disease state characterized by sympathetic activation.10 A recent pilot study suggests that RDN has a favorable short-term safety profile and a beneficial effect on BP in patients with resistant hypertension and concomitant chronic kidney disease (stage 3–4 CKD).11 Likewise, efficacy and safety of
21 Chapter 2
RDN in patients with milder forms of hypertension (office SBP 140–160 mm Hg despite use ≥ 3 antihypertensive drugs) are not well known. A recent pilot study suggests that RDN is safe and efficacious for these patients.12
In Symplicity HTN-2, a broad range of effect was observed, evidenced by a standard deviation (SD) of 23/11 mm Hg. Moreover in 10% of patients, SBP did not decrease, being classified as non-responders.5 Evidence on factors determining the BP-lowering effect after RDN is limited.4
We observed that about 35% of the patients referred for treatment with RDN, has an additional renal artery (Verloop et al., unpublished data). According to exclusion criteria used in previous trials, these patients would have been excluded from treatment with RDN. We have decided not to primarily exclude these patients because of the high prevalence and lack of data.
RDN is a costly and invasive procedure. However, when the effects of RDN on BP are extrapolated to a reduction in cardiovascular events, with associated health gains and cost reductions, RDN can be a cost-effective treatment in the long run. RDN also has potential to reduce lifetime multiple drug use, with associated savings and implications for quality of life. Currently, only one modeling study on cost-effectiveness of RDN is published suggesting that RDN could be cost-effective in the long run.13 However, widespread implementation of RDN should be based on empirical data on effectiveness and cost-effectiveness, not only on modeling studies.
Study objectives
The SYMPATHY trial is registered in clinicaltrial.gov: NCT01850901. The primary objective is to assess whether RDN added to usual care compared to usual care alone reduces BP (average ambulatory day-time SBP determined using ABPM) after 6 months in subjects with an average mean day-time SBP ≥ 135 mm Hg determined using ABPM, despite use of ≥ three BP lowering-agents. The following key secondary objectives are evaluated at 6 months and at regular intervals during continued follow-up (12, 18 and 24 months):
1. To assess the effect of RDN on the use of BP-lowering agents (defined as defined daily dose (DDD) of all prescribed drugs).
22 Rationale and design SYMPATHY trial
2. To explore the effect of RDN in different subgroups: across strata of eGFR
2 2 (eGFR 20–60 mL/min/1.73m and eGFR > 60 mL/min/1.73m ) and of baseline 2 BP (office SBP 140–160 mm Hg and office SBP > 160 mm Hg). 3. To assess the effect of RDN on office BP.
Furthermore, information will be collected concerning:
– The effect of RDN on eGFR and incidence of peri-procedural complications (definition: Appendix 2A). – The long-term effect of RDN on fatal- and non-fatal cardiovascular events (definition: Appendix 2A). – The cost-effectiveness of RDN. – The impact of RDN on quality of life – The budget impact of introducing RDN in healthcare – The determinants and mechanisms of the BP-lowering effect.
Study design
SYMPATHY is a multi-center RCT in about 26 centers in the Netherlands (Appendix 2B). Randomization is in 2:1 ratio to addition of RDN to usual care or to continued usual care and in randomized blocks per stratum, with strata defined by hospital and eGFR using a web-based computerized approach. We have chosen for a 2:1 rate since in the Netherlands patients with resistant hypertension can be treated with RDN outside the context of a trial. Therefore, potential eligible participants might think that RDN is the solution for their longstanding hypertension and might favor treatment than opt for participation in a RCT. Therefore we believe that the 2:1 randomization is favorable for recruitment and does not affect internal validity of the trial.
Study population
The study population consists of adults with resistant hypertension (average ambulatory day-time SBP ≥ 135 mm Hg, despite use ≥ 3 BP lowering-agents). To determine eligibility for study participation, patients are screened. The ‘inclusion criterion’ for screening is an office SBP ≥ 140 mm Hg. The first aim of screening is to confirm diagnosis of hypertension by exclusion of white coat hypertension since several studies have indicated that a substantial proportion (up to one third) suspected of resistant hypertension based on
23 Chapter 2
office measurements, in fact has white coat hypertension when ABPM is applied.14, 15 This strategy complies with the European Society of Hypertension (ESH) position statement.16
During the screening period also secondary causes of hypertension are excluded according to current guidelines and non-invasive imaging of the renal arteries and kidneys is made. Furthermore, special attention is devoted to determine compliance. During the screening period, medication use and compliance are carefully verified using methods available in every day clinical practice: evaluation of the heart rate(beta-blocker use), determination of ACE in plasma (ACE-inhibitor use) and the ‘medication adherence scale’ from Morisky et al. 2008.17 After the screening period, all patients are discussed in a multidisciplinary meeting to decide whether a patient is eligible for inclusion. In- and exclusion criteria are shown in Table 2.1.
Table 2.1 In- and exclusion criteria
Inclusion criteria: 1. Individual has a mean day-time SBP ≥ 135 mm Hg, determined using ABPM, while the patient uses ≥ 3 antihypertensive agents for ≥ 3 months prior to inclusion. 2. Individual is ≥ 18 years of age.
Exclusion criteria: 1. Individual is unable or unwilling to sign informed consent. 2. Individual has a treatable secondary cause of hypertension 3. Individual has an eGFR < 20 mL/min/1.73m2 using the MDRD calculation. 4. Individual has renal artery anatomy that is ineligible for treatment. This is decided by the intervention radiologist and/or cardiologist. 5. Individual has any serious medical condition, which in the opinion of the investigator, may adversely affect the safety and/or effectiveness of the participant or the study. 6. Individual is pregnant, nursing or planning to be pregnant. 7. Individual has a known, unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions, or would be unlikely or unable to comply with study follow-up requirements. 8. Individual is currently enrolled in another investigational drug or device trial.
Study endpoints
The primary effectiveness endpoint is change in BP (average ambulatory day-time SBP) after 6 months of follow-up in the intervention-group compared to control-group. Key secondary endpoints are:
– Change in amount of antihypertensive medication defined as DDD of all prescribed drugs 6 months after intervention (intervention-group) or 6 months after baseline visit (control-group).
24 Rationale and design SYMPATHY trial
– The effect of RDN in different subgroups: across strata of eGFR and of baseline BP. 2 – Change in office BP 6 months after intervention (intervention-group) or 6 months after baseline visit (control-group).
Other study parameters concern:
– Safety during short- and long-term follow-up: – Change in eGFR 6 months after intervention (intervention-group) or 6 months after baseline visit (control-group) and during long-term follow- up (12, 18, 24 months after randomization). – Incidence of peri-procedural complications. – Incidence of Serious Adverse Events (SAEs; definition: Appendix 2C). – The cost-effectiveness of RDN. – The impact of RDN on quality of life. – The budget impact of introducing RDN in healthcare.
Study interventions
Usual care
Both intervention-group as well as the control-group are treated with usual care. In the intervention-group, RDN is added. Therapy is in line with national cardiovascular disease prevention guidelines based on for example NICE guidelines18 or European Society of Hypertension/ European Society of Cardiology19) for both groups.
Investigational treatment: renal denervation
RDN is performed by a certified interventional radiologist/ cardiologist in the angiography suite. Based on advice of the Health Care Insurance Board of the Netherlands (College Voor Zorgverzekeringen: CVZ, http://www.cvz.nl/en/home), the Minister of Health has decided to allow “conditional” reimbursement of RDN by the health care system starting Jan 1st, 2013 for a period of four years. The main condition of this “conditional” reimbursement was that the medical community would collect data on efficacy and safety of the procedure. The present study was aimed to comply with these conditions. At the time of writing (June 2013), reimbursement was only made available for the Medtronic Simplicity device, because at that time published data on safety and efficacy of this
25 Chapter 2
device were available. Therefore, this device will be used in current study. However, periodic re-evaluation of this position of the authorities is already scheduled. Since the RDN catheters fall under the reimbursement, these catheters are paid by the health insurance companies. In case other devices are allowed in context of the conditional reimbursement, the use of these devices is allowed in the current trial. One can speculate about consequences of using different devices. Only when a certain device is selectively used in a certain patient group with a high (or low) baseline probability at success of RDN, and when that certain device would indeed result in a greater (or lesser) magnitude of the BP-lowering effect, this may result to potential bias. Evidence to substantiate both notions is at present lacking. The SYMPATHY trial is to some extent protected against occurrence of such bias as randomization occurs in strata of centres. Furthermore, participating physicians are recommended to use only one device during certain time periods. The type of device will be registered and evaluated after the trial has ended.
Using local anesthetics, cannulation of the femoral artery is performed. A sheath is introduced and unfractionated heparin will be given. Renal angiograms are performed to confirm anatomic eligibility. Hereafter, the treatment catheter is introduced into each renal artery. Bilateral treatment of the renal arteries is performed using series of radio-frequent energy deliveries along each artery, aiming up to ≥ 4–6 treatment points per artery (approximately 8 Watts per treatment point). Intra procedural visceral pain is managed with intravenous analgesics and sedatives. A control angiography is performed after the procedure. Catheter tip impedance and temperature are constantly monitored during energy delivery.
Patients with an increased risk for contrast nephropathy will be treated with pre- and post-hydration according to guidelines.
Guidelines for adjustments in antihypertensive medication
Baseline antihypertensive medication is intended to be unchanged in both treatment- and control-group for at least 6 months, to evaluate the primary endpoint. However, in case changes in antihypertensive treatment are considered medically necessary (i.e., significant BP changes or adverse events directly related to BP or antihypertensive drugs), medications and/or doses may be adjusted according to predefined protocol (Appendix 2D). Changes in medication will be well documented.
26 Rationale and design SYMPATHY trial
Study procedures At the moment of the baseline visit, the informed consent is signed and the participant is 2 randomized. RDN is planned shortly after the baseline visit. Patients will visit the hospital at 1, 3, 6, 12, and 18 and 24 months after RDN (intervention-group) or after baseline visit (control-group). Appendix 2E shows an overview of study procedures.
Study measurements
Set of BP measurements
– Office BP is taken using an automatic device, in sitting position after 10 minutes of rest, twice at both arms using an appropriate cuff-size. The mean value of these measurements is used as ‘office BP’. – Orthostatic BP changes: BP is taken at the arm with highest BP after ≥ 5 minutes in supine position using an automatic device. Afterwards BP is taken after respectively 1 and 3 minutes in standing position. Complaints of orthostatic hypotension are noted. – Non Invasive semi-continuous BP measurement will be taken in sitting position, every 5 minutes using an automatic device during a 1-h resting period. – ABPM will be taken noninvasively, with readings taken every 30 minutes during day-time and every 60 minutes during night-time. A measurement is considered to be valid when ≥ 70% of the recordings has been successful. – Home BP measurements: After RDN (intervention-group) or after baseline procedures (control-group), patients receive a home BP-device (this is optional for centers, only when devices are available). They will measure their BP one week (twice in the morning and twice in the evening) per month according to the ESH guideline, during 12 months after randomization.
Laboratory measurements
– Blood sampling in a fasting state: Creatinine (μmol/L), potassium (mmol/L), glucose (mmol/L), cholesterol (mmol/L), triglycerides (mmol/L), HDL-cholesterol (mmol/L), LDL-cholesterol (mmol/L), HsCRP (mg/L) and insulin (mIU/L) will be determined. – Collecting urine for 24 hours: Sodium (mmol/24-hr), creatinine (mmol/24-hr), proteins (g/24-hr) and albumin (mg/24-hr) will be determined. In selected centers catecholamines are determined.
27 Chapter 2
Questionnaires
– Quality of life is monitored using two questionnaires: Short-Form 36 (SF-36)20 and EuroQol 5 Dimensions (EQ-5D).21 – Absence from work: Data on absence from work is retrieved using parts of the Short- Form Health and Labor Questionnaire.22 – Other questionnaires and diaries: A patient diary is used to collect data on health care resources use, such as length of hospital stay, duration of interventions, additional treatments for complications (if any), and number of general practitioner visits.
Sample size considerations
Based on results of the Simplicity HTN-2 trial (no change in BP in the reference group at 6 months),5 and observational results from Mahfoud et al.23 (mean difference of 10 mm Hg in day-time systolic ABPM among 346 patients, 6 months after RDN), we anticipate a mean difference in day-time systolic ABPM of 10 mm Hg in our study. The SD is difficult to estimate from published literature as these data are rarely presented. From a figure in the publication of Mahfoud et al.,23 the SD could be estimated as being around 15 mm Hg. Pilot data from our center (17 patients), show a SD around the mean difference in systolic ABMP of 22 mm Hg. Therefore, we assumed a SD around the mean difference of 20 mm Hg.
In order to detect a difference of 10 mm Hg (assuming an SD of 20 mm Hg and a simple t-test between groups), 195 participants have to be evaluated to have 90% power at a two sided alpha of 5% (randomization ratio 2:1, 130 in intervention-group and 65 in control-group). To conclude on the key secondary outcomes: i.e. change in medication (defined as defined daily dose) at 6 months, a larger sample size is considered necessary. Little experimental data on the anticipated effect of RDN is available. A sample size of 300 would be sufficient to detect a relative effect size of 0.35 with a power of 80% and a relative effect size of 0.4 with a power of 90%, both of which are considered a moderate effect. Therefore it is concluded that 300 patients in total is the target sample size to demonstrate both a clinically relevant effect on BP and a moderate effect on medication use.
Primary analysis will be based on a linear model including at least treatment arm and baseline SBP as covariates. If the correlation between baseline SBP and SBP at 6 months follow-up is 0.3 or higher, which is not unreasonable, statistical evaluation is approximately at least (0.3)2 more efficient than a simple t-test, so 9% less patients
28 Rationale and design SYMPATHY trial
would be required. On the other hand drop-out up to 6 months is anticipated, of the same order of magnitude. Taking drop out into account, total sample size is 300. In 2 addition, subgroup analyses are considered of substantial importance. Thus, sample size can be extended after analysis of the first 300 participants, to detect smaller differences between treatment groups. If the interaction effect is assumed to be about 50% of the main effect, 570 patients in total (in 2:1 ratio) are required to achieve 80% power at a significance level of 5% (Table 2.1), with the same assumed SD. This is the maximum sample size proposed. The DSMB will decide on actual sample size based on results of the first 300 patients. This decision is based on the estimated SD of the defined primary BP outcome (Appendix 2F), and considerations of clinical relevance.
Data analysis
Primary outcome
Primary efficacy analysis is based on the (modified) intention to treat population including all patients randomized with available BP-data ≥ one follow-up visit. The analysis model is an analysis of covariance, including at least baseline SBP as covariate and treatment group as factor. Inclusion of hospital as factor will be considered, if feasible considering number of hospitals and patients per hospital. Unless otherwise specified, a two-sided 0.05 level of significance is used.
Key secondary endpoints
To evaluate the effect of RDN in strata of eGFR, the same analysis is applied including eGFR strata as factors, and an interaction term of treatment by eGFR. In case of significant interaction at 5% level, treatment effects will be estimated per stratum and confidence intervals provided. Other subgroup analyses are performed in a similar fashion. The primary time point for comparison is at 6 months. The final subgroup analyses will be based on the complete sample, after potential increase in sample size. Primary analysis is performed when 6 months follow-up data of all patients are available. With extended follow-up up to 2 years, repeated measurements of SBP are available. These will be further analyzed using a mixed model for repeated measurements, including subject as random factor, baseline as covariate and time point, treatment group and interaction between time point and treatment group as fixed factors. An unstructured covariance matrix will be assumed.
29 Chapter 2
Other endpoints
Event rates of the composite cardiovascular endpoint will be compared between groups in an explorative fashion, according to the intention-to-treat principle, when 6 months follow-up data of all patients are available. After completing full follow-up of all patients, event rates will be compared again during prolonged follow-up. It is expected that during the longer period of follow-up, a non-negligible number of patients assigned to usual care may have switched to RDN. To avoid bias, event data are also analyzed in an ‘as treated’ analysis, in which longitudinal course of treatments is taken into account (marginal structural model).24-26
Incidences of key SAEs and adverse events (AEs), specifically cardiovascular events, will be presented per group.
For economic evaluation, a cost-utility analysis (CUA) will be performed. In a CUA, efficiency is measured in terms of costs per Quality Adjusted Life Year (QALY). Incremental costs and incremental effects of the intervention- over the control arm of the trial are compared, using a time horizon of both 6 months and 2 years, following main analysis of effectiveness. Incremental cost effectiveness ratios (ICERs), i.e. difference in costs between treatments divided by differences in effect, are estimated. Probabilistic sensitivity analysis, using bootstrapping techniques, is used to estimate uncertainty in model outcomes. Results are presented in a cost-effectiveness plane and a cost- effectiveness acceptability curve (CEAC), the latter presenting the probability that implementing RDN is cost-effective compared to usual care, given different willingness to pay for a QALY thresholds. Costs and effects are discounted according to Dutch standards for discounting in health economic evaluation. To study cost-effectiveness in the long- run (10 and 20 years, lifetime) a Markov-type model will be developed, distinguishing the most-relevant health outcomes associated with hypertension. Secondary data from existing meta-analyses for associations between (decreased) hypertension and (decreased) mortality and morbidity from these diseases will be used. Also, annual cost and quality of life consequences associated with long-term sequelae of hypertension are used from secondary sources. All analyses are performed from societal perspective.
Direct health care costs are calculated by multiplying the volume of (healthcare) con- sumption as registered within the follow-up period by its cost. Standard reference cost pricing, as available from Dutch guidelines for costing research within economic evaluations is used. Both direct health care costs and direct and indirect non health care
30 Rationale and design SYMPATHY trial
costs are included, to measure costs from a societal perspective. The friction cost method is used to estimate indirect non-health care costs. The incremental RDN treatment costs 2 are calculated as the difference in total direct and indirect cost between both study arms.
The budget impact analysis (BIA) studies different scenarios of either or not introducing RDN in the treatment of resistant hypertension. The aim is to study costs of different scenarios for nationwide introduction of RDN in clinical care for hypertensive patients. The BIA is performed with a time-horizon of 10 years and split in results for all 10 years to demonstrate whether the return-on-investments improve over time. The BIA is performed from different perspectives: societal perspective, perspective from the health care budgetary framework and finally the perspective of health care insurance companies, including all reimbursed health care.
Ethical considerations
SYMPATHY is conducted according to the principles of the Declaration of Helsinki (59th amendment, Seoul 2008) and in accordance with the Medical Research Involving Human Subjects Act (WMO). SYMPATHY is approved by the Medical Research Ethics Committee of the University Medical Center Utrecht.
Data management
Handling of personal data complies with the Dutch Personal Data Protection Act. This study uses web-based Case Record Forms, developed by data management of the Julius Center.
Event adjudication committee
The definition of cardiovascular events is stated in Appendix 2A. From all reported events documentation are requested for the investigators. All events, including death, are formally evaluated by an independent event adjudication committee (blinded for the intervention allocation), consisting of physicians with different specializations. Events are coded as fatal and non-fatal.
31 Chapter 2
Data safety and monitoring board
An independent DSMB is installed to monitor the study according to present best practice as described in the DAMOCLES study.27 The DSMB consists of a biostatistician (chair), and two nephrologists. The study team ensures that the DSMB is provided with regular reports on study progress and intermediate safety reports (including adjudicated events), including primary outcomes in case relevant. The DSMB primarily monitors safety and scientific integrity and merit of the trial and advises on sample size extension. No interim stopping is foreseen for reasons of efficacy.
Sponsoring
SYMPATHY is an investigator-driven trial and received unrestricted grants from The Netherlands Organisation for Health Research and Development (ZonMw: http://www. zonmw.nl/en) and Medtronic. Publications are not restricted by ZonMw and Medtronic; they will only be informed of publications.
Summary
SYMPATHY will give insight in the effect of RDN on ABPM in patients with an office SBP ≥ 140 mm Hg despite the use of ≥ 3 antihypertensive drugs, the effect in subgroups (across strata of eGFR and of baseline BP), safety, cost-effectiveness, the budget impact of introducing RDN in healthcare and the impact on quality of life.
32 Rationale and design SYMPATHY trial
References (1) Pereira M, Lunet N, Azevedo A, Barros H. Differences in prevalence, awareness, treatment and control 2 of hypertension between developing and developed countries. J Hypertens.2009;27(5):963-975. (2) Calhoun DA, Jones D, Textor S et al. Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension.2008;51(6):1403-1419. (3) Schlaich MP, Sobotka PA, Krum H et al. Renal denervation as a therapeutic approach for hypertension: novel implications for an old concept. Hypertension.2009;54(6):1195-1201. (4) Krum H, Schlaich M, Whitbourn R et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet.2009;373(6971): 1275-1281. (5) Esler MD, Krum H, Sobotka PA et al. Renal sympathetic denervation in patients with treatment- resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet.2010; 376(9756):1903-1909. (6) Kandzari DE, Bhatt DL, Sobotka PA et al. Catheter-Based Renal Denervation for Resistant Hypertension: Rationale and Design of the SYMPLICITY HTN-3 Trial. Clin Cardiol.2012;35(9):528-535. (7) Rippy MK, Zarins D, Barman NC et al. Catheter-based renal sympathetic denervation: chronic preclinical evidence for renal artery safety. Clin Res Cardiol.2011;100(12):1095-1101. (8) Vonend O, Antoch G, Rump LC, Blondin D. Secondary rise in blood pressure after renal denervation. Lancet.2012;380(9843):778. (9) Kaltenbach B, Id D, Franke JC et al. Renal artery stenosis after renal sympathetic denervation. J Am Coll Cardiol.2012; 60: 2694-2695. (10) Vink EE, de Jager RL, Blankestijn PJ. Sympathetic hyperactivity in chronic kidney disease: pathophysiology and (new) treatment options. Curr Hypertens Rep.2013;15(2):95-101. (11) Hering D, Mahfoud F, Walton AS et al. Renal Denervation in Moderate to Severe CKD. J Am Soc Nephrol.2012;23(7):1250-1257. (12) Kaltenbach B, Franke J, Bertog SC et al. Renal sympathetic denervation as second-line therapy in mild resistant hypertension: A pilot study. Catheter Cardiovasc Interv.2012;81(2):335-339. (13) Geisler BP, Egan B, Cohen JT et al. Cost-effectiveness and clinical effectiveness of catheter-based renal denervation for resistant hypertension. J Am Coll Cardiol.2012;60(14):1271-1277. (14) Banegas JR, Messerli FH, Waeber B et al. Discrepancies between office and ambulatory blood pressure: clinical implications. Am J Med.2009;122(12):1136-1141. (15) Verloop WL, Vink EE, Voskuil M et al. Eligibility for percutaneous renal denervation: the importance of a systematic screening. J Hypertens.2013;31(8):1662-1668. (16) Schmieder RE, Redon J, Grassi G et al. ESH Position Paper: Renal denervation - an interventional therapy of resistant hypertension. J Hypertens.2012;30(5):837-841. (17) Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication adherence measure in an outpatient setting. J Clin Hypertens (Greenwich).2008;10(5):348-354. (18) NICE Clinical Guidelines 127. National Institute for Health and Clinical Excellence: Hypertension. London, UK; 2011 Aug. (19) Mancia G, De BG, Dominiczak A et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens.2007;25(12):1105-1187. (20) Ware JE, Snow KK, Kosinski M. SF-36 Health Survey-Manual and Interpretation Guide. Boston: The Health Institute, New England Medical Center; 2011. (21) EuroQol—a new facility for the measurement of health-related quality of life. Health Policy.2011; 16(3):199-208.
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(22) van Roijen L., Essink-Bot ML, Koopmanschap MA, Bonsel G, Rutten FF. Labor and health status in economic evaluation of health care. The Health and Labor Questionnaire. Int J Technol Assess Health Care.1996;12(3):405-415. (23) Mahfoud F, Ukena C, Schmieder RE et al. Ambulatory Blood Pressure Changes after Renal Sympathetic Denervation in Patients with Resistant Hypertension. Circulation.2013;128:132-140. (24) Hernan MA, Hernandez-Diaz S. Beyond the intention-to-treat in comparative effectiveness research. Clin Trials.2012;9(1):48-55. (25) Toh S, Hernan MA. Causal inference from longitudinal studies with baseline randomization. Int J Biostat.2008;4(1):Article. (26) Hernan MA, Hernandez-Diaz S, Robins JM. A structural approach to selection bias. Epidemiology. 2004;15(5):615-625. (27) A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet.2005;365(9460):711-722.
34 Rationale and design SYMPATHY trial
Appendix 2A: Defi nition of cardiovascular events and peri-proce- dural complications 2 Cardiovascular events are defined as death from cardiovascular causes and non-fatal cardiovascular events:
– Acute coronary syndrome: – Myocardial infarction (STEMI/NSTEMI), – Instable angina pectoris, – Congestive heart failure, – Coronary artery bypass graft, – Percutaneous transluminal coronary angioplasty and/or stenting, – Transient ischemic attack, – Cerebral vascular accident, – Therapeutic carotid procedure (endarterectomy and/or stenting), – Vascular intervention of peripheral arterial ischemia (revascularization, percutaneous transluminal angioplasty and/or stenting), – Kidney failure (requiring dialysis and not requiring dialysis)
Peri-procedural complications are defined as:
– Vascular complication: pseudo aneurysm, perforation or obstruction of the femoral artery, AV-fistula, – Haematoma, – Infection, – Anaphylaxis, – Mild allergic reaction, – Cardiac arrhythmias, – Kidney failure: an increase in creatinine of ≥ 50 micromol/L per day with a baseline value < 300 micromol/L, independent of urine production, – Bleeding: – Class I Hemorrhage: ≤ 15% loss of blood volume. No change in vital signs and fluid resuscitation is not necessary, – Class II Hemorrhage: 15–30% loss of total blood volume. Presence of tachy cardia, decreased blood pressure. Volume resuscitation is required,
35 Chapter 2
– Class III Hemorrhage: 30–40% loss of blood volume. Decreased blood pressure, increased heart rate. Fluid resuscitation and blood transfusion necessary, – Class IV Hemorrhage: loss of > 40% of blood volume. Aggressive resus- citation is required to prevent death, – Death, – Other.
36 Rationale and design SYMPATHY trial
Appendix 2B: SYMPATHY study organization
Participating centres: 2
– University Medical Centre Utrecht, Utrecht, The Netherlands (participating). – Maasstad Hospital, Rotterdam, The Netherlands (participating). – Leiden University Medical Centre, Leiden, The Netherlands (participating). – Medical Centre Alkmaar, Alkmaar, The Netherlands (participating). – Catharina Hospital, Eindhoven, The Netherlands (participating). – Canisius Wilhelmina Hospital Nijmegen, The Netherlands (participating). – Medical Centre Haaglanden, The Hague, The Netherlands (participating). – Isala Clinics, Zwolle, The Netherlands (participating). – Ziekenhuisgroep Twente, Almelo, The Netherlands (participating). – Martini Hospital, Groningen, The Netherlands (participating). – Albert Schweizer Hospital, Dordrecht, The Netherlands (participating). – Medical Centre Leeuwarden, Leeuwarden, The Netherlands (participating). – Anthonius Hospital, Nieuwegein, The Netherlands (participating). – Amphia, Breda, The Netherlands (participating). – Academic Medical Centre Amsterdam, Amsterdam, The Netherlands (participating). – University Hospital Maastricht, Maastricht, The Netherlands (participating). – Scheper Hospital, Emmen, The Netherlands (participating). – Rijnstate Hospital, Arnhem, The Netherlands (provisionally agreed). – Vrije Universiteit Medical Centre, Amsterdam, The Netherlands (provisionally agreed). – Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands (provisionally agreed). – Tweesteden Hospital, Tilburg, The Netherlands (provisionally agreed). – Jeroen Bosch Hospital, Den Bosch, The Netherlands (provisionally agreed). – IJsselland Hospital, Capelle aan de IJssel, The Netherlands (provisionally agreed). – HAGA Hospital, The Hague, The Netherlands (provisionally agreed). – ZorgSaam, Terneuzen, The Netherlands (provisionally agreed). – University medical Centre Groningen, Groningen, The Netherlands (provisionally agreed).
37 Chapter 2
Appendix 2C: defi nition of adverse events (AE) and serious ad- verse events (SAE)
Adverse events (AE) are defined as any undesirable medical experience occurring to a subject during a clinical trial that is spontaneously reported by the participant, whether or not considered related to the investigational treatment. All adverse events reported spontaneously by the subject or observed by the investigator or his staff will be recorded and entered in the electronic CRF.
A serious adverse event (SAE) is any untoward medical occurrence or effect that at any dose:
– results in death; – is life threatening (at the time of the event); – requires hospitalization or prolongation of existing inpatients’ hospitalization; – results in persistent or significant disability or incapacity; – is a congenital anomaly or birth defect; – is a new event of the trial likely to affect the safety of the subjects, such as an unexpected outcome of an adverse reaction, major safety finding from a newly completed animal study, etc.
38 Rationale and design SYMPATHY trial
Appendix 2D: Guidelines for antihypertensive medication adjust- ments 2 Adjustments in antihypertensive medication can be classified either as a ‘Low BP action’ or as a ‘High BP action’. The first action is defined as adjustment of medication for patients whose SBP is reduced to < 120 mm Hg (or < 110 mm Hg for diabetics) and have signs and symptoms of hypotension or reduced organ perfusion. These patients will have doses and/or classes of medications reduced. If at an office visit, SBP is < 120 mm Hg (or < 110 mm Hg for diabetics) without symptoms, a repeat visit for BP measurement is scheduled 7–14 days later. If SBP remains < 120 mm Hg (or < 110 mm Hg for diabetics), doses and/or classes of medications will be reduced. A high BP action is a clinical intervention which is required for patients whose SBP rises > 15 mm Hg above their baseline BP and have documented clinical adverse events possibly related to persistent or elevated hypertension. These patients may have either doses of medications increased or additional medications prescribed. If at an office visit, BP is > 15 mm Hg higher than baseline without symptoms, a repeat visit for BP measurement is to be scheduled 7–14 days later. If the SBP remains > 15 mm Hg above baseline, either doses of medications will be increased or additional medications will be prescribed.
39 Chapter 2 x months (visit 7&9) ± 14 days ± 14 days 12, 18, 24, xx (visit 7&9) (visit 7&9) x x ± 14 days ± 14 days 3 months 6 months ± 7 days ± 7 days xx x x ± 7 days ± 7 days b - x ± 3 days Renal Only in Denervation 1 week 1 month intervention group a x x x xxxxx V1 V2 V3: Telephone V4 V5 V6 V7–V9 Baseline randomization ≤ 2 weeks after Plasma tests 24-hr urine Intervention group Control-group SF-36 EQ-5D Intervention groupControl-group demographic information Record and medical history Documentation of adverse events use Documentation of healthcare Medication reviewPhysical examination x1-h non-invasive BP measurement x x x x x x x x x x x x x x x x x x x x x x x x x x x x ABPMLaboratory tests x Time window: Time Questionnaires Plasma Creatinine is only determinedSubject can go to a laboratory close home. Plasma Creatinine in the intervention group. Intervention group: 3 weeks before the RDN. 3 weeks before Intervention group: ABPM, Ambulatory Blood Pressure Monitoring. ABPM, Ambulatory Blood Pressure Appendix 2E: overview of study procedures a b
40 Rationale and design SYMPATHY trial
Appendix 2F: Guidance for total sample size
Interaction effect Standard deviation 2 (mm Hg) (assumption) Sample size (total) Power
2.5 8 570 94%
480 90%
390 83%
9 570 88%
480 82%
390 73%
10 570 80%
480 73%
390 64%
41
CHAPTER
Impact of medicationon adherence on the effect of renal denervation: the SYMPATHY trial
R.L. de Jager, E. de Beus, M.M.A. Beeftink, M.F. Sanders, E.J. Vonken, M. Voskuil, E.M. van Maarseveen, M.L. Bots, P.J. Blankestijn, on behalf of the SYMPATHY investigators
Hypertension.2017;69:678-684 Chapter 3
Abstract
Randomized trials of catheter-based renal denervation as therapy for resistant hypertension showed conflicting results in blood pressure lowering effect. Adherence to medication is modest in this patient group and may importantly drive these conflicting results.
SYMPATHY is a prospective open label multicenter trial in Dutch patients with resistant hypertension (NCT01850901). Primary outcome was change in daytime systolic ambulatory blood pressure at six months. Patients were randomly assigned to renal denervation on top of usual care. Adherence to blood pressure lowering drugs was assessed at baseline and follow-up, using blood samples drawn synchronously with blood pressure measurements. Patients and physicians were unaware of the adherence assessment.
Primary analyses showed a mean difference between renal denervation (n=95) and control (n=44) in changes in daytime systolic ambulatory blood pressure after six months of 2.0 (95% CI -6.1 to 10.2) mmHg in favor of control. In 80% of patients fewer medications were detected than prescribed and adherence changed during follow-up in 31%. In those with stable adherence during follow-up, mean difference between renal denervation and control for daytime systolic ambulatory blood pressure was -3.3 (-13.7 to 7.2) mmHg in favor of renal denervation.
Renal denervation as therapy for resistant hypertension was not superior to usual care. Objective assessment of medication use shows that medication adherence is extremely poor, when patients are unaware of monitoring. Changes over time in adherence are very common and affect treatment estimates considerably. Objective measurement of medication adherence during follow-up is strongly recommended in randomized trials.
44 Medication adherence and effect renal denervation
Introduction
The effects of percutaneous catheter-based renal denervation (RDN) as new therapy for resistant hypertension have been evaluated several times in the past years.1-8 First studies suggested large effects on blood pressure (BP). However, in the first sham- controlled randomized trial, no difference in treated versus controlled participants was found.2 Subgroup analyses of RDN studies have identified different factors of relevance 3 in determining the overall effect of the intervention on BP.9-11 Of particular interest is medication adherence. In order to quantify the effect of the addition of RDN to medical treatment, it is imperative that antihypertensive medical treatment remains unchanged. Recent small studies, using urine or blood samples to detect medication, suggested that adherence is particularly poor in presumed resistant hypertensive participants.12-14
The present randomized controlled trial (RCT) was designed to assess the efficacy of RDN in resistant hypertension participants, the primary endpoint being daytime systolic ambulatory blood pressure (ABPM) at six months after RDN. In addition, we explored the effect of adherence on the study outcomes.
Methods
Study design and population
The rationale and design of SYMPATHY have been described previously.15 Briefly, SYMPATHY is a multicenter RCT in 14 centers in the Netherlands. For this trial a system of “conditional reimbursement” was available for four years (2013–2016), indicating that the intervention was covered by the health care insurance, only when patients participated in SYMPATHY. The consequence was that SYMPATHY findings were used by National Health Care Institute (NHC) to advise the government at the end of 2016 whether RDN should be part of the standard reimbursement package of the Dutch health care insurances (https://english.zorginstituutnederland.nl/publications/reports/2012/04/06/ conditional-reimbursement-of-health-care). Since we had to deliver the report on the SYMPATHY findings to the NHC no later than August 1st 2016, participants had to be included before January 1st 2016.
In SYMPATHY adults were included with resistant hypertension, defined as an average daytime systolic ABPM measurement ≥ 135 mmHg, despite use ≥ three BP lowering- agents or with documented intolerance for ≥ two BP lowering-agents. Participating
45 Chapter 3
physicians were advised to exclude white coat hypertension, secondary causes of hypertension and anatomical abnormalities that would make RDN non-feasible, using a standardized protocol.16 Randomization was performed in a 2:1 ratio to receive either RDN on top of usual care or usual care alone using a web-based computerized approach, with stratification by hospital and eGFR (20–60 and > 60 ml/min/1.73m2).15
Ethics approval was obtained at the University Medical Center Utrecht (#12/540). All subjects gave informed consent. The trial was performed in accordance with the principles of the Declaration of Helsinki and Title 45, U.S. Code of Federal Regulations, Part 46, Protection of Human Subjects, Revised November 13, 2001, effective December 13, 2001.The trial is registered at clinicaltrials.gov, NCT01850901.
Outcome assessment
The primary outcome was change in daytime systolic ABPM six months after RDN or inclusion into the study (control group). Secondary outcomes were change in office systolic blood pressure (SBP), prescribed BP lowering drugs and change in kidney function. Other outcomes were peri-procedural complications. ABPM monitoring was performed noninvasively, with readings every 30 minutes during daytime and every 60 minutes during night time, and was considered valid when ≥ 70% of the recordings was successful. Office BP was taken using an automatic device, in sitting position after ten minutes of rest, twice at both arms using an appropriate cuff size. The mean was used as office BP. Both ABPM and office BP were measured with recommended devices according to the ESH/ESC guidelines.17 Blood was sampled on the same day as BP was assessed. At study visits the use of all medication was queried. BP lowering agents were classified according to the Anatomical Therapeutic Chemical classification (ATC) system of the World Health Organization Collaborating Centre for Drug Statistics. We calculated the defined daily dose (DDD) of BP lowering agents per participant per visit. The intention was to unchange baseline blood pressure lowering medication till the six months visit (primary endpoint). In case adjustments in medication were necessary, these were made according a predefined protocol.15
Important adjustments during the course of the trial
In January 2014 we added participants with documented intolerance to ≥ two BP lowering-agents. These participants represent a sizable group of difficult to treat hypertensive patients, for whom RDN could be beneficial as well. Second, from October
46 Medication adherence and effect renal denervation
2014, NHC allowed conditional reimbursement when participants were treated with the EnligHTNTM Ablation catheter (St Jude Medical, St Paul, MN, USA).15, 18 Choice of catheter was made by the interventionist.
During the course of the trial, it became increasingly clear that objective assessment of medication adherence is of utmost importance based on reports suggesting poor adherence in this class of participants.12-14 We decided to use stored samples for drug 3 level measurements. Of relevance, participants and attending physicians were unaware of the adherence assessments.
The original sample size estimation was set at 300 randomized participants. However, after Symplicity-HTN-3 inclusion slowed dramatically. DENERHTN provided data to assume that a study size of 100–150 participants could be sufficient.1 We estimated that such a number could be feasible by Jan 1st 2016. We expected a difference of 5 mmHg in SBP (with standard deviation of 10 mmHg) between the RDN and control group. Our power would be between 80 and 90% with a two-side alpha of 0.05. After consultation with the data safety monitoring board, we decided to continue the study. All described adjustments were approved by the Ethical Committee of University Medical Center Utrecht.
Adherence measurements
Liquid chromatography, combined with tandem mass spectrometry (LC-MS/MS) was used to screen BP lowering drugs. This technique has proved to be reliable, accurate and precise.19 The acquired mass spectra were compared with an in-house library (compound library and tandem mass spectrometry mass spectral library) built with automated screening software (TOD ID, Thermo Fisher Scientific) which contained the mass/charge of the precursor ion, retention time, product ions and the entire tandem mass spectrometry spectra of 40 compounds including metabolites covering over 95% of all BP lowering drugs registered in The Netherlands. Identification was achieved by comparing full tandem mass spectrometry spectra and/or mass/charge of precursor ion with confirmation by second selected reaction monitoring transitions. Using the developed method, the identification results from spiked serum samples within therapeutic concentration ranges indicated 95% sensitivity and 91% specificity.
Participants were categorized in adherent (81–100% match prescribed versus measured), poorly adherent (1–80% match prescribed versus measured) and completely non- adherent (0% match prescribed versus measured).20
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Intervention
Usual care was based on the guidelines of the European Society Hypertension / European Society of Cardiology.17 The RDN procedure was performed by an interventional radiologist or cardiologist
Data analyses
Primary efficacy analysis was based on the (modified) intention to treat population including all participants randomized with available BP data ≥ one follow-up visit. The primary analysis, i.e., mean of change in daytime systolic ABPM between treatment arms was based on t-test. All other analyses were performed using either t-tests (continuous variables (mean of change)) or chi-square test for dichotomous variables. Linear regression models were used to study whether treatment effects differed across predefined subgroups, using multiplicative interaction terms (treatment group * subgroup). Linear regression models with adjustments for life style changes and for changes in in prescribed and detected medication were run to study the effects of these factors on the observed change in the daytime ABPM and in office systolic pressure. A two-sided 0.05 level of significance is used. Statistical analyses were done using SPSS version 22 (IBM Corp., Armonk, NY, USA).
Meta-analysis
To place the SYMPATHY results in perspective of other RDN RCT results, we performed a systematic meta-analysis (supplementary material).
Results
From 23rd of May 2013 until 1st of January 2016 139 participants were randomized; 95 to RDN and 44 to usual care. After randomization, four participants declined RDN. One participant, randomized to the usual care group, received RDN within the first six months. Before the first six months visit, eight participants (five RDN) withdrew their participation for follow-up measurements (Figure 3.1). Baseline characteristics are shown in Table 3.1. Mean daytime systolic ABPM was 160 (SD 17) mmHg and daytime diastolic ABPM was 93 (15) mmHg. Mean office BP was 169 (25) / 96 (16) mmHg. In 60 participants the SymplicityTM catheter was used and in 31 the EnligHTNTM Ablation catheter. Mean number of ablations was 15 (7).
48 Medication adherence and effect renal denervation
Table 3.1 Baseline characteristics of the intention-to-treat population
Renal denervation group Control group Characteristics (n=95) (n=44)
Age (years) 62 (12) 60 (10) Malea 40 (42.1) 13 (29.5) Caucasiana 92 (96.8) 42 (95.5) History of cardiovascular diseasea 41 (43.2) 19 (43.2) 3 Current smokinga 22 (23.2) 10 (22.7) Diabetes mellitusa 26 (27.4) 14 (31.8) BMI (kg/m2) 28.6 (4.8) 29.4 (4.6) Plasma creatinine (μmol/l) 87 (36) 88 (27) eGFR estimated with CKD-epi (ml/min/1.73m2) 77 (19) 80 (21) LDL (mmol/l) 3.1 (1.1) 2.8 (1.0) Office SBP (mmHg) 170.3 (25.9) 164.7 (22.0) Office DBP (mmHg) 96.1 (17.7) 94.4 (12.5) 24-h systolic ABPM (mmHg) 157.3 (15.6) 155.8 (17.4) 24-h diastolic ABPM (mmHg) 90.1 (14.3) 91.4 (12.6) Daytime systolic ABPM (mmHg) 160.8 (16.0) 159.5 (18.2) Daytime diastolic ABPM (mmHg) 92.4 (15.0) 94.5 (13.5) Night time systolic ABPM (mmHg) 146.0 (16.7) 144.8 (16.7) Night time diastolic ABPM (mmHg) 81.7 (12.5) 82.7 (12.1) Number of BP lowering drugs 3.7 (1.5) 3.4 (1.5) Number BP lowering classes 3.5 (1.3) 3.2 (1.3) Daily Dose Used of BP lowering drugs 5.5 (4.0) 5.3 (3.4) Diureticsa,b 69 (72.6) 26 (59.1) Beta blockera 60 (63.2) 26 (59.1) ACE inhibitora* 25 (26.3) 15 (34.1) Angiotensin receptor blockera 57 (60) 26 (59.1) Renin inhibitora 3 (3.2) 0 (0) Calcium antagonista 60 (63.2) 27 (61.4) Spironolactonea 23 (24.2) 10 (22.7) Aldosterone antagonista 5 (5.3) 3 (6.8) Alpha blockera 30 (31.6) 11 (25.0) Centrally acting antihypertensive druga 9 (9.5) 3 (6.8) Othera 4 (4.2) 0 (0) Data are expressed as mean±SD unless stated otherwise. a Data are expressed as n (%). b Diuretics without spironolactone or other aldosterone antagonists. BMI, Body Mass Index; eGFR, estimated Glomerular Filtration Rate; LDL, Low Density Lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure; ABPM, ambulatory blood pressure measurement; BP, blood pressure; CKD-epi, chronic kidney disease epidemiology collaboration equation; ACE, Angiotensin Converting Enzyme.
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Effect of renal denervation on blood pressure
Six months data on daytime ABPM were available for 124 participants (Figure 3.1). Overall, BP levels declined significantly (Table 3.2). Mean differences between groups in changes in daytime systolic ABPM after six months was 2.0 mmHg (-6.1 to 10.2), in 24-h systolic ABPM 1.0 mmHg (-7.1 to 9.1) and in office SBP -8.2 mmHg (-17.1 to 0.7). The findings were the same when using a complete case analysis approach (Table S3.1) or sensitivity analysis for patients with true resistant hypertension, defined as the use ≥ three classes of blood pressure lowering drugs (data not shown). Our meta-analysis (including 984 subjects from seven studies) showed no significant benefit of RDN compared to usual care alone for daytime systolic ABPM (-1.60 [-4.32 to 1.11] mmHg) (supplementary material).
Adverse events
We observed 17 peri-procedural complications, including four vascular, eight bleeding and five other (mild) complications (Table S3.2). All participants recovered without sequelae. Kidney function declined by 1.5 (-3.1 to 0.1) ml/min/1.73m2 at six months, with no difference between groups. During six months follow-up 36 self-reported, un-
50 Medication adherence and effect renal denervation P-value
3 Mean difference between groups (95% CI) Mean difference Mean difference (95% CI) Mean difference Mean difference (95% CI) Baseline 6 months =95 N=83 N=44 N=41 160.8±16.0 155.2±23.992.4±15.0 -6.0 (-10.7 to -1.2)146.0±16.7 90.3±16.2 159.5±18.2 141.9±21.5 152.4±20.181.7±12.5 -3.5 (-6.4 to -0.7) -3.8 (-8.7 to 1.1) -7.9 (-14.7 to -1.3)157.3±15.6 80.2±13.3 94.5±13.5 2.0 (-6.1 to 10.2) 144.8±16.7 152.0±23.590.0±14.2 -2.6 (-5.6 to 0.4) 89.4±13.3 0.625 139.4±23.3 -5.6 (-10.2 to -0.9) 87.8±15.4 -7.9 (-15.0 to -0.8) 155.8±17.4 -4.7 (-8.3 to -1.1) 82.7±12.1N=95 4.1 (-4.4 to 12.6) 150.2±22.2 -3.5 (-6.3 to -0.8) 1.2 (-3.5 to 5.9) 80.6±13.9 -6.6 (-13.3 to -0.2)170.3±25.9 0.340 91.4±12.6 1.0 (-7.1 to 9.1) 162.7±26.7 -3.3 (-7.8 to 1.2) 0.615 96.1±17.7 N=94 -7.5 (-12.5 to -2.5) 87.2±12.8 0.805 0.7 (-4.5 to 5.9) 91.6±18.4 164.7±22.0 -3.9 (-7.7 to -0.1) 165.4±25.4 -4.4 (-7.4 to -1.4) 0.780 0.4 (-4.3 to 5.1) 0.7 (-6.9 to 8.3) 94.4±12.5 0.871 -8.2 (-17.1 to 0.7) 95.4±16.6 0.069 0.9 (-3.7 to 5.6) -5.3 (-10.7 to 0.1) 0.053 N=44 N=44 Renal denervation groupBaseline 6 months group Control Daytime systolic ABPM Daytime diastolic ABPM Night systolic ABPM Night diastolic ABPM 24-h systolic ABPM 24-h diastolic ABPM BP Office SBP Office DBP Office ABPM N Data are expressed as mean±SD unless stated otherwise. expressed Data are group. and control between the intervention group in effect for the mean difference P-value presented diastolic blood pressure. DBP, systolic blood pressure; SBP, blood pressure; BP, measurement; ABPM, ambulatory blood pressure Table 3.2 Table trial of all participants in the SYMPATHY levels at baseline, follow-up and the mean difference Blood pressure
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adjudicated serious adverse events were registered: 24 (26%) in the intervention group and 12 (27%) in the usual care group (Table S3.3).
Subgroup analyses
Predefined subgroup analysis showed no statistical significant interaction between kidney function or baseline BP and RDN effects on BP. None of several post hoc subgroup analyses (sex, body mass index, previous cardiovascular history, smoking, urinary sodium excretion, size of the hospital (large centers / small centers), baseline use of spironolactone, catheter type) reached statistical significance.
Medication adherence at baseline and follow-up
Prescribed medication did not differ significantly between treatment groups at six months and increased in both groups over time (Table 3.3 and Table S3.4). Information on adherence was available for 98 and 83 participants at baseline and at follow-up, respectively (78 pairs). At both study time points, adherence was poor: 80% were either poorly adherent or completely non-adherent. In 54 (29 in RDN group) participants adherence remained stable. The adherence category changed (e.g. from poorly adherent to completely non-adherent) in 31% of the participants (n=24). There was no significant difference in change in adherence between treatment arms (Table 3.3).
Medication adherence and blood pressure
Baseline and six month daytime systolic ABPM were the highest in participants completely non-adherent in an analysis restricted to the 78 participants with adherence measurements at baseline and at follow-up (Table S3.5). When medication adherence was the same at baseline and follow-up, daytime systolic ABPM was 3.3 (-13.7 to 7.2) mmHg lower in favor of the RDN group (Figure 3.2). The same trend was seen for 24-h systolic ABPM (-4.7 [-15.3 to 5.8]) mmHg) and office SBP (-14.0 [-25.7 to -2.4] mmHg) (P=0.422 for the interaction term). Baseline characteristics did not differ significantly between the intervention and control group in this selected population (Table S3.6). In particular, no difference was found in factors that potentially drive a larger RDN effect.
52 Medication adherence and effect renal denervation b Mean difference between groups od pressure lowering od pressure a 3 Mean change Control group Control a Mean change Renal denervation group 3.7±1.51.8±1.4 4.0±1.71.8 (1.3 to 2.2) 2.0±1.5 1.9 (1.5 to 2.4) 0.3±0.1 0.1±0.2 0.2±0.2 3.4±1.5 1.8 (1.3 to 2.4) 1.8 (1.3 to 2.3) 1.7±1.3 -0.1±0.2 3.9±1.2 2.0±1.0 0.2 (-0.4 to 0.8) 0.4±0.2 0.4±0.2 -0.1 (-0.4 to 0.1) -0.2 (-0.7 to 0.4) Determinants of BP lowering drugsNo. of BP lowering drugs prescribed Baseline (n=63)No. of BP lowering 6 months (n=51)drugs detected Mean difference between prescribed and measured P-value Baseline (n=35) 6 months (n=32) < 0.001 < 0.001 0.705 < 0.001 < 0.001 0.474 Mean difference between renal denervation and control group for changes six months after renal denervation. for changes six months after renal group denervation and control between renal Mean difference Mean change expressed as mean (±SE). Mean change expressed Table 3.3 Table (n=78) lowering drugs and change in adherence blood pressure versus measured Prescribed as mean ±SD, unless stated otherwise. expressed Data are a b drugs in blood. blood pressure. No., number; BP, P-value presented for the mean difference between number of prescribed blood pressure lowering drugs and number of measured blo lowering drugs and number of measured blood pressure between number of prescribed for the mean difference P-value presented
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Figure 3.2 Mean difference (±SE) between control group and renal denervation for change in systolic blood pressure after six months, presented for intention-to-treat population (n=139) and population with stable medication adherence (n=54). ABPM, ambulatory blood pressure measurement; SBP, systolic blood pressure; DBP, diastolic blood pressure.
Discussion
This is the second largest RCT studying the effect of RDN on BP in participants defined as treatment resistant hypertensives. Six months after RDN, no significant reduction in daytime or 24-h systolic ABPM was observed compared to usual care alone.
Effect of RDN on office SBP was of borderline significance. Results are in line with most of the other trials.1-3, 5, 6, 8 Our systematic review showed that the pooled effect of RDN on BP is most pronounced for office SBP (-5.4 mmHg, Figure S3.2). Yet, not statistically significant (P=0.27).
The possible reasons of the variability in the effects on BP between participants and between studies have been extensively discussed over recent years.9, 11, 21 Relevant factors could be related to the device, the procedure itself and participant characteristics. In this respect medication adherence is of particular relevance, because recent studies suggested poor adherence in this type of participants.12-14, 22-24 To our knowledge, we are the first trial on RDN to objectively assess medication adherence changes during
54 Medication adherence and effect renal denervation
the study. Strong features of our study are that blood samples were taken on the day of the ABPM and the fact that both participants and treating physicians were unaware of the assessments, resulting in an accurate representation of the every-day reality. Questionnaires used in trials on RDN are likely to overestimate adherence.1, 2, 4, 6 With a direct adherence assessment we confirm that BP medication adherence is very low at baseline as well as at follow-up. This finding is in line with the single direct adherence 3 measurements in the PRAGUE trial (at screening) and DENERHTN trial (at six months follow-up).7, 22 In addition, BP was higher in participants with poor adherence (Table S3.5). Therefore, our data support the notion that poor medication adherence contributes to the condition of apparent resistant hypertension.
A second important aspect is that in about one third of the participants adherence to BP lowering drugs either increased or decreased during follow-up. There was a trend towards more detected BP lowering pills at follow-up, more pronounced in the control group than in the RDN group. This may be due to more intensive follow-up during the trial and the absence of blinding for the intervention (no sham-procedure). The large percentage of change, with either decrease or increase in medication use, makes it virtually impossible to quantify the effect of the addition of RDN to medical treatment. This is especially the case when, as in our study, changes occur without the treating physicians knowing it. In those patients with the same number of medication at baseline and at follow-up, all BP measurements suggested a greater, albeit not statistically significant, decrease in the RDN arm. Figure 3.2 clearly suggests that the overall direction of the effect on BP considerably changed when taking medication adherence into account. In none of the previous RCTs in the RDN field, was adherence quantified in both arms at both baseline and follow-up. It could be that in the other trials adherence was better than in the present study, but it seems appropriate to conclude that poor adherence and changes in adherence were probably major factors of concern.
Our results may have considerable societal impact. These patients use healthcare facilities by (frequently) visiting physicians, by collecting medication from the pharmacy, without using it, meanwhile staying at increased cardiovascular risk. Although the relation between hypertension and increased cardiovascular risk is well established, some participants feel great resistance for prolonged pharmacological therapy. The reasons are likely complex, and include the fact that hypertension is usually free of symptoms and/or that participants experience side effects of medication. This triggers two lines of thinking. First, there is great need to more extensively focus on interventions that
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potentially improve medication adherence. Indeed, in DENERHTN, in which specific efforts were undertaken to improve medication use, full adherence was found in half of the study population,22 which is much better than the 20% found in the present study, but still far from perfect. Alternatively, society could accept that a certain percentage of hypertensive participants are not able or willing to use medical treatment for whatever (set of) reason(s). For such participants alternative approaches, including device related treatment strategies, could be considered as options worth exploration.
An important limitation of our trial is probably that participants were not blinded to the intervention (no sham-procedure). We tried to offset this by blinded assessment of the primary outcome, assessment of lifestyle changes that may affect BP for adjustment (salt intake, weight change), and objective measurements of (change in) medication adherence for use in the statistical analyses of the results. Secondly, although we had a mix of patients (resistant, intolerant), it is unlikely that this affects our findings, since our sensitivity analysis revealed no difference in effect when taken the resistant group separately. Another potential limitation might be the use of two different devices. This is only an issue when the two devices differ in their BP lowering effect, of which no evidence is available, yet. Further, not all patients were on diuretics, which is presently (more or less) accepted as mandatory to meet the definition “resistant hypertension”. At the time we designed our study that was not yet so clearly the case. Indeed, it is possible that the lack of diuretic use has influenced our results. Finally, the drug level measurements provided qualitative results: the drug is either detectable or not detectable. Therefore, we might have underestimated the number of changes, as dosage and class changes were not detected.
Perspectives
The present study shows in primary analysis that RDN is not superior to usual care in reducing BP in participants with resistant hypertension. Medication adherence seems to be very low when participants are unaware of monitoring. Our data suggests that poor adherence (partially) explains the condition of “resistant hypertension”. Secondly and importantly, our data suggest that the direction and the magnitude of the treatment effect considerably changes when medication adherence is taken into account. This factor could also have been of relevance in earlier RDN studies. It can only be overcome in future trials by studying un-medicated participants or by detailed monitoring of prescribed and actually used medication.
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References
(1) 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(9981):1957-1965. (2) Bhatt DL, Kandzari DE, O’Neill WW et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med.2014;370(15):1393-1401. (3) Desch S, Okon T, Heinemann D et al. Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension.2015;65(6):1202-1208. 3 (4) Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet.2010;376(9756):1903-1909. (5) Fadl Elmula FE, Hoffmann P, Larstorp AC et al. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension.2014; 63(5):991-999. (6) Kario K, Ogawa H, Okumura K et al. SYMPLICITY HTN-Japan - First Randomized Controlled Trial of Catheter-Based Renal Denervation in Asian Patients -. Circ J.2015;79(6):1222-1229. (7) 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(2):407-413. (8) Mathiassen ON, Vase H, Bech JN et al. Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial. J Hypertens.2016;34(8):1639-1647. (9) Blankestijn PJ, Alings M, Voskuil M, Grobbee DE. The complexity after simplicity: how to proceed with renal denervation in hypertension? Eur J Prev Cardiol.2015;22(4):412-414. (10) Kandzari DE, Bhatt DL, Brar S et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J.2015;36(4):219-227. (11) Persu A, Jin Y, Fadl Elmula FE, Jacobs L, Renkin J, Kjeldsen S. Renal denervation after Symplicity HTN-3: an update. Curr Hypertens Rep.2014;16(8):460. (12) Jung O, Gechter JL, Wunder C et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens.2013;31(4):766-774. (13) Strauch B, Petrak O, Zelinka T et al. Precise assessment of noncompliance with the antihypertensive therapy in patients with resistant hypertension using toxicological serum analysis. J Hypertens.2013; 31(12):2455-2461. (14) Tomaszewski M, White C, Patel P et al. High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis. Heart.2014;100(11):855-861. (15) Vink EE, de Beus E, de Jager RL et al. The effect of renal denervation added to standard pharmacologic treatment versus standard pharmacologic treatment alone in patients with resistant hypertension: rationale and design of the SYMPATHY trial. Am Heart J.2014;167(3):308-314. (16) Verloop WL, Vink EE, Voskuil M et al. Eligibility for percutaneous renal denervation: the importance of a systematic screening. J Hypertens.2013;31(8):1662-1668. (17) Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens.2013; 31(7):1281-1357. (18) Papademetriou V, Tsioufis CP, Sinhal A et al. Catheter-based renal denervation for resistant hypertension: 12-month results of the EnligHTN I first-in-human study using a multielectrode ablation system. Hypertension.2014;64(3):565-572.
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(19) Olah TV, McLoughlin DA, Gilbert JD. The simultaneous determination of mixtures of drug candidates by liquid chromatography/atmospheric pressure chemical ionization mass spectrometry as an in vivo drug screening procedure. Rapid Commun Mass Spectrom.1997;11(1):17-23. (20) Osterberg L, Blaschke T. Adherence to medication. N Engl J Med.2005;353(5):487-497. (21) Schmieder RE. Renal denervation--a valid treatment option despite SYMPLICITY HTN-3. Nat Rev Cardiol.2014;11(11):638. (22) Azizi M, Pereira H, Hamdidouche I et al. Adherence to Antihypertensive Treatment and the Blood Pressure-Lowering Effects of Renal Denervation in the Renal Denervation for Hypertension (DENERHTN) Trial. Circulation.2016;134(12):847-857. (23) Ewen S, Meyer MR, Cremers B et al. Blood pressure reductions following catheter-based renal denervation are not related to improvements in adherence to antihypertensive drugs measured by urine/plasma toxicological analysis. Clin Res Cardiol.2015;104(12):1097-1105. (24) Schmieder RE, Ott C, Schmid A et al. Adherence to Antihypertensive Medication in Treatment- Resistant Hypertension Undergoing Renal Denervation. J Am Heart Assoc.2016;5(2).
58 Medication adherence and effect renal denervation Mean difference Mean difference (95% CI)
lood pressure. 3 6 months N=41 Baseline N=41 Mean difference Mean difference (95% CI) 6 months N=83 Renal denervation groupBaseline N=83 group Control Blood pressure ABPM Daytime systolic ABPM Daytime diastolic ABPMNight systolic ABPMNight diastolic ABPM 161.2±16.124-h systolic ABPM 93.9±14.624-h diastolic ABPM 155.2±23.9 -6.0 (-10.7 to -1.2) 90.3±16.2 BPOffice 145.2±16.5 82.5±12.1 SBPOffice -3.5 (-6.4 to -0.7) 141.5±21.3 DBPOffice 160.4±18.5 157.5±16.1 80.0±13.3 -3.8 (-8.7 to 1.1) 91.5±14.0 152.4±20.8 151.3±22.0 -2.6 (-5.6 to 0.4) 94.2±13.9 -8.0 (-14.6 to -1.3) 87.4±15.2 -6.2 (-10.7 to -1.7) 89.4±13.3 146.3±16.8 -4.1 (-6.8 to -1.4) 138.4±22.8 -4.7 (-8.3 to -1.1) 83.4±11.4 156.7±17.5 N=79 -7.9 (-15.0 to -0.8) 170.7±25.0 150.1±22.2 80.1±13.7 91.1±12.9 97.7±17.3 162.0±28.1 -6.6 (-13.3 to 0.2) -3.3 (-7.8 to 1.2) N=79 87.2±12.8 -8.7 (-14.0 to -3.2) 92.7±18.3 -3.9 (-7.7 to -0.1) -5.0 (-8.4 to -1.6) 165.5±22.3 165.4±25.4 94.0±12.7 -1.3 (-8.1 to 5.6) 93.1±14.3 -0.8 (-4.9 to 3.4) N=40 N=40 Supplementary material: Tables S3.1 Table trial in the SYMPATHY levels at baseline, follow-up and the mean difference Blood pressure data on both baseline and 6 months follow-up Only in participants with blood pressure Data analysed with paired samples T-test. Data analysed with paired as mean ±SD unless stated otherwise. expressed Data are diastolic b DBP, systolic blood pressure; SBP, blood pressure; 24-h, 24-hour; BP, measurements; ABPM, ambulatory blood pressure
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Table S3.2 Peri-procedural complications in renal denervation group
Complications No. of participants (%)
Vascular complications 4 (4.4) Aneurysm spurium 2 Arrhythmia 1 Other 1
Bleeding complications 8 (8.8) Hematoma 6 Other 2
Total no. of complications 12 (13.2)
Other complaints 5 (5.5) Back pain 3 Groin pain 1 Hypotension 1
Prolonged admission 4 (4.4) Data are expressed as number (percentage of denervated participants, n=91). No., number.
Definitions Vascular complications: pseudo aneurysm, perforation or obstruction of the femoral artery, arterio- venous-fistula, haematoma, infection, anaphylaxis, mild allergic reaction, cardiac arrhythmias, death. Kidney failure: decline of 30% of eGFR compared to baseline value.
60 Medication adherence and effect renal denervation
Table S3.3 Serious adverse events
Renal Control denervation group Serious adverse events group (n=91) (n=44)
Ablation retinae 1 Arrhythmia 4 1 Carcinoma 1 Cerebral Vascular Accident 2 3 Collapse 1 Collapse and weight loss 2 Decompensation cordis 1 Diarrhea 1 Dyspnea with fever 1 Elective coronary angiography 1 Elective Coronary Artery Bypass Grafting 1 Elective hospitalization to adjust antihypertensive medication 2 1 Elective surgery 4 4 Epileptic insult 2 Intoxication 1 Microcytic anemia 1 Pericarditis 1 Readmission due slow bleeding complication leg 1 Recanalization occluded stent 2 Trauma 1
Total number of serious adverse events 24 12 Serious adverse events were self-reported and not adjudicated.
Table S3.4 Mean change in prescribed medication between baseline and 6 months
Renal Determinants of prescribed denervation Control group Mean difference BP lowering drugs group (n=95) (n=44) (95% CI) P-value
No. of classes of BP 0.2±0.1 0.3±0.1 -0.1 (-0.3 to 0.1) 0.433 lowering drugs
Number of BP 0.3±0.1 0.4±0.2 -0.1 (-0.4 to 0.1) 0.331 lowering drugs
Daily defined use of BP -0.1±0.1 0.1±0.3 -0.1 (-0.6 to 0.4) 0.680 lowering drugs Data presented as mean change ±SE, unless stated otherwise. No., number; BP, blood pressure.
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Table S3.5 Daytime systolic ambulatory blood pressure at baseline and 6 months by adherence category
Daytime systolic ABPM Non-adherent Poorly-adherent Adherent
Baseline (n=18) (n=56) (n=24) 166.3 (16.9) 157.8 (15.5) 161.9 (19.8)
6 months (n=10) (n=60) (n=13) 173.2 (23.5) 148.6 (17.1) 147.6 (28.0) Data are expressed as mean ±SD, unless stated otherwise.
Table S3.6 Baseline characteristics of study population with a stable medication adherence
Renal denervation group Control group Characteristics (n=29) (n=25)
Age (years) 63 (10) 62 (10) Malea 14 (48.3) 8 (32.0) Caucasiana 28 (96.6) 23 (92.0) History of cardiovascular diseasea 15 (51.7) 11 (44.0) Current smokinga 6 (20.7) 6 (24.0) Diabetes mellitusa 7 (24.1) 8 (32.0) BMI (kg/m2) 28.6 (4.7) 29.5 (4.9) Plasma creatinine (μmol/l) 86 (22) 94 (26) eGFR estimated with CKD-epi (ml/min*1.73m2) 75 (18) 73 (19) LDL (mmol/l) 3.5 (1.2) 2.9 (1.1) Office SBP (mmHg) 163.1 (18.2) 160.3 (23.3) Office DBP (mmHg) 91.1 (12.6) 89.6 (11.5) 24-h systolic ABPM (mmHg) 155.3 (12.4) 154.0 (19.3) 24-h diastolic ABPM (mmHg) 89.4 (13.3) 89.0 (15.2) Daytime systolic ABPM (mmHg) 158.7 (12.5) 157.6 (19.8) Daytime diastolic ABPM (mmHg) 90.9 (13.7) 91.8 (15.9) Nighttime systolic ABPM (mmHg) 144.2 (16.4) 142.4 (16.6) Nighttime diastolic ABPM (mmHg) 81.9 (13.8) 79.9 (13.6) Data are expressed as mean±SD unless stated otherwise. a Data are expressed as n (%). BMI, Body Mass Index; eGFR, estimated Glomerular Filtration Rate; LDL, Low Density Lipoprotein; SBP, systolic blood pressure; DBP, diastolic blood pressure; 24-h, 24-hour; ABPM, ambulatory blood pressure measurements.
62 Medication adherence and effect renal denervation
SYMPATHY investigators and committees
• Albert Schweitzer Hospital Dordrecht (5 inclusions), O Elgersma, AJJ IJsselmuiden, PHM van der Valk, P Smak Gregoor, S Roodenburg. • Amphia Hospital, Breda (1), M Meuwissen, W Dewilde, I Hunze, J den Hollander. • Antonius Hospital, Nieuwegein (6), HH Vincent, B Rensing, WJ Bos, I. van Weverwijk. • Catharina Hospital, Eindhoven (8), PAL Tonino, BRG Brueren, CJAM Konings, H 3 Hendrix-van Gompel. • Isala Clinics, Zwolle (19), JE Heeg, J Lambert, JJ Smit, A Elvan, A Berends, B de Jager. • Hospital group Twente, Almelo (2), G Laverman, PAM de Vries, A van Balen, M Stoel. • Martini Hospital, Groningen (29), R Steggerda, L Niamut, W Bossen, J Biermann, I Knot. • Medical Center Alkmaar, Alkmaar (5), JOJ Peels, JB de Swart, G Kimman, W Bax, Y van der Meij, J Reekers. • Medical Center Haaglanden, The Hague (1), AJ Wardeh, JHM Groeneveld, C Dille. • Medical Center Leeuwarden, Leeuwarden (18), MH Hemmelder, R Folkeringa, M Sietzema, C Wassenaar. • Rijnstate Hospital, Arnhem (4), K Parlevliet, W Aengevaeren, M Tjon, M Hovens, A van den Berg, H Monajemi. • Scheper Hospital, Emmen (1), FGH van der Kleij, A Schramm, A Wiersum. • University Hospital Maastricht, Maastricht (2), B Kroon, M de Haan, M Das, H Jongen, E Herben, R Rennenberg. • University Medical Center Utrecht, Utrecht (34), PJ Blankestijn, ML Bots, MM Beeftink, E de Beus, B Dijker, GWJ Frederix, RL de Jager, E van Maarseveen, MF Sanders, W Spiering, IS Velikopolskaia, L Vendrig, WL Verloop, EE Vink, EPA Vonken, M Voskuil, GA de Wit.
All centers were located in The Netherlands.
Executive committee: PJ Blankestijn, ML Bots, E de Beus, RL de Jager, L Vendrig. Steering committee: PJ Blankestijn (chair), ML Bots (vice-chair), RL de Jager, L Vendrig, E de Beus, B Dijker, JE Heeg, J Vincent, CB Roes, J Deinum. Data Safety Monitoring Board: AJ Rabelink (chair), J Lenders, René Eijkemans. Monitoring: Julius Clinical.
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64 Medication adherence and effect renal denervation
Supplementary material: Meta-analysis
Methods
PubMed, Embase and Cochrane databases were searched. We chose “resistant hypertension” and “renal denervation” and their synonyms (Table S3.7) as search terms for titles and abstracts. Eligible for inclusion were reports of RCTs comparing 3 RDN with care as usual in resistant hypertension. SBP had to be measured by ABPM monitoring at baseline and at six months. We used the GRADE-approach (Grading of Recommendations, Assessment, Development and Evaluations) to critically assess study design, generalizability and quality of the study of the remaining RCTs and to give a final score for the available evidence in a summary of findings table
Table S3.7 Search strategy
Search items Pubmed Embase Cochrane
Domain ((((((((high BP*[Title/ hypertens*:ab,ti ((hypertens*:ti,ab OR Abstract]) OR elevated OR 'high BP':ab,ti “high BP”:ti,ab OR BP*[Title/Abstract]) OR OR 'elevated “elevated BP”:ti,ab OR hypertens*[Title/Abstract]) BP':ab,ti OR 'raised “raised BP”:ti,ab OR OR raised BP*[Title/ BP':ab,ti AND hypertension [MeSH]) Abstract]) OR hypertension (resistant:ab,ti OR AND (resistant:ti,ab [MeSH Terms])) AND uncontrolled:ab,ti OR uncontrolled:ti,ab (((resistant[Title/Abstract]) OR refractory:ab,ti) OR refractory:ti,ab)) OR uncontrolled[Title/ OR 'resistant Abstract]) OR hypertension'/exp refractory[Title/Abstract])))
AND
Determinant ((((((renal[Title/Abstract]) renal:ab,ti OR ((renal:ti,ab OR OR kidney[Title/ kidney:ab,ti OR kidney:ti,ab OR kidney Abstract]) OR kidney 'kidney'/exp AND [MeSH] OR “renal [MeSH Terms]) OR renal (denervation:ab,ti artery” [MeSH]) AND artery[MeSH Terms])) OR denervation:ti,ab OR AND (((((denervation[Title/ sympathectomy:ab,ti sympathectomy:ti,ab Abstract]) OR OR 'radio frequency OR sympathectomy[Title/ ablation':ab,ti) "radio frequency Abstract]) OR radio OR 'kidney ablation":ti,ab OR frequency ablation[Title/ denervation'/exp denervation [MeSH] Abstract]) OR OR sympathectomy sympathectomy[MeSH [MeSH])) Terms]) OR denervation[MeSH Terms]))
Outcome x x x
Results 852 hits 1888 hits 161 hits
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(http://clinicalevidence.bmj.com/x/set/static/ebm/learn/665072.html). We extracted the change in daytime systolic ABPM between baseline and six-month follow-up for both RDN and control groups. The pooled effect size and its confidence interval were estimated using Review Manager Version 5.3 (Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014). As we assumed that the true effect size differed among studies, we used a random-effects model.
Results
Our systematic review included seventeen relevant studies (Figure S3.1). One study was excluded, as treatment in the control group could not be considered care as usual. Eight other excluded studies did not provide data on six months. Finally, we included eight studies.1-8 Three studies were sham controlled, including the largest trial, HTN-3 (Tables S3.8, S3.9). In our meta-analysis, including the SYMPATHY results, pooled effect on daytime systolic ABPM and office BP showed no significant decline in favour of RDN (P=0.25 and P=0.27, respectively). The decline in systolic ABPM was significant in favor of the denervated population, with a mean difference of -2.8 (-5.4 to -0.1) mmHg (Table S3.10, Figure S3.2).
66 Medication adherence and effect renal denervation 139 (95/44) Drug treatment SYMPATHY 2016 Netherlands 58/71 62/60 97/96 Multiple 3.8/3.4 Daytime systolic Daytime ≥ 135/- Plasma drug concentrations at baseline and follow-up
3 Sham plus maintained drug treatment 99 (36/33) ReSET 2016 Denmark 25/27 Single Daytime ≥ 145/- Daytime systolic tion; CON, control. Drug treatment Symplicity-J 2015 60/560/0 54/57 97/97 4.9/4.9 4.1/4.2 24 hour ≥ 135/- Office Office systolic Diary - Japan (35/36) 41 (22/19) (35/36) 41 Sham plus maintained drug treatment Symplicity-F 2015 31/23 32/16 Single Multiple Daytime 135- 149/90-94 24 hour systolic Standard- ized drug treatment guided by home BP France Germany DENERHTN 2015 Daytime ≥ 135/≥ 85 Daytime systolic Diary Interview Intensified drug treat- ment plus spironolac- tone Republic PRAGUE 2015 56/59100/100 55/55 79/77 65/57 100/100 24 hour > 130/- 24 hour systolic Plasma drug con- centrations at baseline 20 (10/10) 106 (52/54) 106 (53/53) Drugs 71 adjusted to hemo- dynamic condition Oslo 2014 Single Multiple Multiple 5.1/5.0 5.4/5.4 3.0/3.0 4.4/4.3 Daytime > 135/- Office Office systolic intake 0/22 23/37 40/36 (364/171) Sham plus maintained drug treatment USA Norway Czech USA Norway HTN-3 2014 ≥ 160/- systolic 106 (52/54) 535 treatment Australia, New Zealand HTN-2 2010 - 24 hour 1-8 ) ≥ 45 ≥ 45 ≥ 45 - ≥ 40 ≥ 45 ≥ 45 > 30 ≥ 20 2 Treatment in control group group in control Treatment Drug %RDN/%CON Women 35/50 36/41 No. of participants randomised (No. RDN/CON) Location Europe, Center Multiple Multiple Characteristics Mean age (years)White ethnicity %RDN/%CON 98/96No. of BP lowering drugs 58/58 5.2/5.3 73/70 5.1/5.2 100/100 58/56 57/63 Primary BP endpoint systolic Office Office Drug adherence assessment Drug adherence Diary Diary Witnessed ABPM entry criteria (mmHg) eGFR criteria (ml/min/1.73m Table S3.8 Table Study characteristics BP, blood pressure; ABPM, ambulatory blood pressure measurement; eGFR, estimated glomerular filtration rate; RDN, renal denerva eGFR, estimated glomerular filtration rate; RDN, renal measurement; ABPM, ambulatory blood pressure blood pressure; BP,
67 Chapter 3 2016 SYMPATHY 2016 ReSET Table S3.9 continues on next page Table 2015 Symplicity-F 2015 Symplicity-J 2015 DENERHTN 2015 PRAGUE 2014 OSLO 2014 HTN-3 2010 HTN-2 Daytime systolic ABPM24-hour systolic ABPM SBPOffice 3 2 2 2 2 1 2 2 1 1 1 1 2 2 3 2 2 2 1 1 1 2 3 1 2 2 2 DesignSample size (a)Population of interest Intervention (b) (c)Control Outcome (d) + 106 RCT + 535 RCT + RCT 20 + + + + RCT 106 + + + + RCT 106 + + + + RCT 41 + + + + RCT 71 + + RCT + + 68 RCT + + + 139 + + + + + + + + + + Study GeneralGeneralizability Table S3.9 Table per study Quality assessment table for GRADE approach
68 Medication adherence and effect renal denervation 2016 SYMPATHY 2016 ReSET
sis. 3 2015 Symplicity-F 2015 Symplicity-J 2015 DENERHTN 2015 PRAGUE 2014 OSLO ++ + + + + + + 2014 HTN-3 a 2010 HTN-2 Outcome - + - - + - + + + Continued No selective inclusion of participants (e)Random sequence generation (f) +Concealment of allocation (g)Blinding Participant (h) + +/- ended as scheduled (i)Trial Loss to follow-up (j) + analysis (k)Intention-to-treat - + - (l)No selective outcome reporting No suspected conflict of interest + + + + + + + + - - - + + + + + - - - + + + + + - + + + - + + + + + - + - - + + + + + + + + + + + + + + + + - + + + + - + + + + + + Study Quality The sponsor designed the study in collaboration with the study investigators and was responsible for data collection and analy The sponsor designed the study in collaboration with investigators and was responsible (a) Participants with uncontrolled hypertension. (a) Participants with uncontrolled (b) Renal denervation. (c) Usual care. (d) 1: primary outcome; 2: secondary 3: not available. (e) +: no selective inclusion; -: inclusion. (f) +: random sequence generation; +/-: predetermined / small blocks; -: no generation reported. (g) +: concealed allocation; -: -no allocation or unclear method reported. -: open label. (h) +: sham-procedure; (i) +: ended as scheduled; -: trial preliminary. (j) + ≤ 20% loss to follow-up, non-selective; -: ≥ non-selective. analysis. analysis or per-protocol analysis; -: modified intention to treat (k) +: intention to treat -: selective outcome reporting. (l) +: non-selective outcome reporting; Table S3.9 Table a
69 Chapter 3 RCTs, Randomised RCTs, Comments on: (sham and open label studies), inconsistent results. Low score on: sham and open label studies, inconsistent of studies Low score results. on: sham and open label studies, inconsistent results, Low score concealment of allocation in some studies unclear. Quality of the evidence (GRADE) No. of participants (studies) -1.60 (-4.32 to 1.11) 984 (7)-2.76 (-5.43 to -0.10) 1110 (9) Moderate-5.44 (-15.09 to 4.22) Moderate generalizable to our population. on: RCTs, High score 1030 (7) number generalizable to our population, large on: RCTs, High score Moderate generalizable to our population. on: RCTs, High score Mean difference Mean difference (95% CI) mmHg resistant hypertension resistant renal denervation renal usual care usual care secondary / third line centers secondary / third Daytime systolic ABPM (follow-up 6 months) 24-hour systolic ABPM (follow-up 6 months) SBP Office (follow-up 6 months) Setting: Intervention: Comparison: Outcomes Renal sympathetic denervation as a new treatment for therapy resistant hypertension for therapy resistant Renal sympathetic denervation as a new treatment Study population: Controlled Trials; ABPM, ambulatory blood pressure measurement; SBP, systolic blood pressure. SBP, measurement; ABPM, ambulatory blood pressure Trials; Controlled GRADE, Grading of Recommendations, Assessment, Development and Evaluations, score based on BMJ Clinical Evidence; No., numbers; GRADE, Grading of Recommendations, Assessment, Development and Evaluations, score Table S3.10 Table Summary of findings table (meta-analysis)
70 Medication adherence and effect renal denervation
Pubmed Embase Cochrane 852 1888 161
2901 3
Excluding duplicates N=783
Screening title/abstract 2118 Inclusion criteria: domain, determinant, randomized controlled trial
Exclusion criteria (N=2097): -Not English or Dutch 21 -Not human
No full text available N=4
17
Screening full text Excluded (N=9): - Different follow-up (n=8) - No “care as usual” in control group (n=1).
Related citations/cross 8 reference check N=0
Search performed 11th July 2016
Figure S3.1 Systematic search of the literature.
71 Chapter 3 A. B.
72 Medication adherence and effect renal denervation
3 A), 24-hour systolic ambulatory 1-8 blood pressure (B) and office systolic blood pressure (C) 6 months after inclusion. systolic blood pressure (B) and office blood pressure C. S3.2 Figure ( for change in daytime systolic ambulatory blood pressure denervation vs. control plots of comparison renal Forest
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References
(1) 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;385:1957-1965. (2) Bhatt DL, Kandzari DE, O’Neill WW, D’Agostino R, Flack JM, Katzen BT, Leon MB, Liu M, Mauri L, Negoita M, Cohen SA, Oparil S, Rocha-Singh K, Townsend RR, Bakris GL. A controlled trial of renal denervation for resistant hypertension. N Engl J Med.2014;370:1393-1401. (3) Desch S, Okon T, Heinemann D, Kulle K, Rohnert K, Sonnabend M, Petzold M, Muller U, Schuler G, Eitel I, Thiele H, Lurz P. Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension.2015;65:1202-1208. (4) Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet.2010;376:1903-1909. (5) Fadl Elmula FE, Hoffmann P, Larstorp AC, Fossum E, Brekke M, Kjeldsen SE, Gjonnaess E, Hjornholm U, Kjaer VN, Rostrup M, Os I, Stenehjem A, Hoieggen A. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension.2014;63:991-999. (6) Kario K, Ogawa H, Okumura K, Okura T, Saito S, Ueno T, Haskin R, Negoita M, Shimada K. SYMPLICITY HTN-Japan - First Randomized Controlled Trial of Catheter-Based Renal Denervation in Asian Patients -. Circ J.2015;79:1222-1229. (7) 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;65:407-413. (8) Mathiassen ON, Vase H, Bech JN et al. Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial.J Hypertens.2016; 34:1639-1647.
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3
75
CHAPTER
Prevalence of hypertensivepertensive disorders of pregnancy in resistant hypertensive women and the effect of renal denervation
R.L. de Jager, M.M.A. Beeftink, M. Voskuil, P.J. Blankestijn, M.L. Bots, A.T. Lely
Submitted Chapter 4
Abstract
Objectives Women with a history of a hypertensive disorder of pregnancy (HDP) are at increased risk to develop hypertension later in life. Ten percent of preg- nancies are complicated by hypertension and sympathetic overactivity might contribute to this development. Our objective was to explore the prevalence of previous HDP in resistant hypertensive women. Secondly, we studied the effect of percutaneous renal denervation (RDN) on blood pressure (BP) in women with and without previous HDP.
Methods This cohort consisted of all Dutch female patients with apparent resistant hypertension referred to the University Medical Center Utrecht between 2011 and August 2014. A questionnaire was used to obtain information about pregnancy- related factors. BP measurements were collected from the National RDN Registry at baseline, six and 12 months.
Results Of the 121 women in the registry that were sent a questionnaire, 93 responded and 66 could be included. HDP was reported by 36 (64%) women, including 19 (34%) preeclampsia. Overall, office and 24-h systolic ambulatory BP (ABPM) decreased significantly after RDN (n=35), compared to baseline. At six months, office systolic BP decreased 15 (95% CI -44 to 13) mmHg more in the HDP group, compared to the non-HDP group. The mean difference in systolic 24-h ABPM was -6 (-25 to 13) mmHg at 12 months, in favor of the HDP group.
Conclusion The prevalence of a history of self-reported HDP in women with apparent resistant hypertension is remarkably high. Our data suggest that treatment of RDN is more effective in women with a history of HDP.
78 History of HDP and effect RDN
Introduction
Hypertensive disorders of pregnancy (HDP) occur in up to 10% of all pregnancies and are a major cause of maternal morbidity and mortality worldwide.1-3 HDP includes chronic hypertension, gestational hypertension and preeclampsia (PE): hypertension with end- organ damage with or without proteinuria.4 Despite normalization of hypertension and proteinuria after termination of pregnancy, a history of HDP entails long-term vascular consequences. Over the years, observational cohort studies have shown that women with a history of HDP have an almost four times higher risk to be diagnosed with hypertension, compared to women with normotensive pregnancies and an increased risk to develop premature cardiovascular diseases later in life.5, 6 4
The pathophysiology of HDP is multifactorial and consists of a placenta and maternal stage.7 The second stage is characterized by an inflammatory response with generalized endothelial dysfunction and increased vascular reactivity.8 Sympathetic overactivity has been suggested to contribute to the placental vasoconstriction in PE and other HDPs9-11 and is also an important factor in resistant hypertension.12 Furthermore, women with HDP had a higher angiotensin II sensitivity than women with normotensive pregnancies, which causes sympathetic overactivity and, subsequently, hypertension.13
Still, the etiology of sympathetic overactivity is multifactorial.14 Therefore, one specific treatment is difficult to establish. As the renal nerves are major contributors to the regulation of the sympathetic nerve activity,15 percutaneous renal denervation (RDN), disruption of the renal nerves, has been extensively used as therapeutic option for resistant hypertension.16-19 In the Netherlands, the Dutch RDN Registry was accomplished, containing valuable information about patients referred to the hospital with apparent resistant hypertension and RDN related information.20 We hypothesized that a history of HDP would be more present in women with resistant hypertension, due to the shared factor of sympathetic overactivity. Subsequently, we hypothesized that this group of women would have a greater decline in blood pressure (BP) after RDN, than women without previous HDP, given the more prominent contribution of sympathetic overactivity in the HDP women.
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Methods
Study design and population
This prospective cohort study consisted of patients with apparent resistant hypertension referred to the outpatient clinic of Hypertension Expertise at the University Medical Center Utrecht in the Netherlands. Patients were considered for RDN when office SBP was ≥ 160 mmHg or ambulatory systolic BP was ≥ 150 mmHg measured without the use of antihypertensive drugs and when secondary causes were excluded. Our screening program was described in detail elsewhere.21
All referred patients to our clinic were, anonymously, included in the Dutch RDN Registry of which details were published previously.20 Data collection concerning the Dutch RDN Registry was approved by the Medical Ethical Committee of the University Medical Center Utrecht. In short, this database contained information about BP, biochemical parameters, cardiovascular history, RDN procedure (if applicable) and medication. At August 2014 we identified all female patients who visited the clinic between 2011 and August 2014. Data used for our study was subtracted from the Registry database at baseline, six and 12 months after the screening visit or the RDN procedure. Except for 24-hour ambulatory BP (24-h ABPM), which was collected at baseline and 12 months. The Medical Ethical Committee of the University Medical Center Utrecht approved the current study and signed informed consent was obtained, according the Declaration of Helsinki.
Blood pressure assessment
Office BP and 24-h ABPM were assessed with recommended devices by the European Society of Hypertension and European Society of Cardiology.22 Office BP was calculated as the mean of three BP measurements and obtained in sitting position. Twenty-four hour ABPM was considered to be valid if more than 70% of the measurements could be taken into account. Percentage nocturnal dipping was calculated as [(mean daytime systolic BP - mean night time systolic BP) / daytime systolic BP] * 100%.23
Pregnancy related parameters
A questionnaire was used to obtain information about pregnancies, HDPs and treatment when HDP present. The following HDPs were explicitly asked: chronic hypertension, gestational hypertension and PE. Definitions of the different HDPs were obtained from
80 History of HDP and effect RDN
the International Society for the Study of Hypertension in Pregnancy (ISSHP).4 The answers of this questionnaire were entered in an electronic database and an independent data manager linked the data of the questionnaire to the data of the Registry.
Renal denervation
Our hypertension center is the expertise center in the Netherlands for RDN. The procedure was performed by an intervention-radiologist/cardiologist and is comparable with percutaneous transluminal angioplasty. A guidance catheter is inserted into the femoral artery and brought to the renal artery. Thereafter, a RDN catheter with electrode(s) is brought into the artery and set against the vessel wall. A small amount of (radiofrequency) 4 energy is given that ablates the renal nerves, located in the vessel wall. These burning points (ablations) were performed on as many places as possible (with 5 mm space). The RDN catheters used were the SymplicityTM catheter (Medtronic Inc., Santa Rosa, CA, USA) or EnligHTNTM Ablation catheter (St Jude Medical, St Paul, MN, USA) catheter. Both catheters are proven to be effective and safe.18, 24 Anesthetics and analgesic medication were given during the procedure at indication by the present anesthesiologist.
Statistical analysis
All normally distributed data were presented as mean (standard deviation) and not normally distributed data with median [interquartile]. Possible factors related to women with a history of HDP were identified with Spearman’s rank correlation analysis. Changes in BP after RDN were assessed with paired t- test. An independent t-test was used to assess the difference between the women with HDP and without a history of HDP (including women without pregnancies) in change in BP after RDN. The latter group was defined as the non-HDP group (reference group). Results were considered to be significant when a two-side level of ≤ 0.05 was reached. All analyses were performed using the IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY, USA).
Results
Baseline characteristics
Of the 121 female patients that were approached by mail, 93 (77%) returned an answer. Fourteen patients refused to participate in the study and 13 patients sent back an incomplete questionnaire or without informed consent. Therefore, 66 (55%) women
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could be included in the study. Mean age was 59 (SD 12) years and mean duration of hypertension was 22 (15) years. Overall, 24-h ABPM was 156 (21)/94 (13) and office BP was 194 (33) / 102 (16) mmHg. Baseline characteristics were not significantly different between the patients that refused to participate in the study or sent back an incomplete questionnaire and the included group of women (data not shown).
HDP related factors
One or more viable pregnancies (≥ 20 week duration) were reported by 56 (85%) women with a total of 119 pregnancies. On average two children were born per woman (with a maximum of 6). Hypertension during pregnancy was reported by 36 women (64%) in a total of 63 pregnancies (53%). Nineteen (34%) women had developed PE. The age of onset of hypertension was significantly lower in women with HDP (P < 0.001) than those without HDP, and subsequently these women had a longer duration of their hypertension (mean difference of 16 years [95% confidence interval 9 to 23]) (Table 4.1). Women with a history of HDP had a significant higher heart rate, measured with 24-h ABPM, with a mean difference of 9 beats per minute (3 to 15) compared to the non-HDP group. Further, the HDP-group had higher LDL levels compared to the non-HDP group with a mean difference of 0.4 mmol/l (0.1 to 1.6). Other life-style and biochemical factors were not found to be significantly different between both groups.
Effect of RDN on BP in women with a history of HDP
RDN was performed in 20 women with HDP (56%) and 15 without HDP (50%). In the remaining 31 women RDN could not be performed for several reasons: exclusion based on BP criteria (n=16), diagnosis of a secondary cause (n=2), refusal to be treated with RDN (n=2), ineligible renal anatomy for RDN (n=6), and other reasons (n=5). Baseline characteristics of the RDN group were comparable with the total study population of 66 women, except for heart rate, which was in this sub-population not significantly different between the HDP and non-HDP group (data not shown).
Overall, office BP and 24-h ABPM, but not heart rate, decreased significantly compared to baseline (Table 4.2). In the HDP group office BP changed with -46 (-66 to -27)/-14 (-21 to -8) mmHg compared to -31 (-54 to -8)/-13 (-24 to -2) mmHg in the non-HDP group at six months (Table 4.2, Figure 4.1). Mean difference in office SBP was -15 (-44 to 13) mmHg in favor of the HDP-group. Of 19 women (7 with HDP) 24-h ABPM was available at 12 months follow-up, which showed a mean difference in change of
82 History of HDP and effect RDN
systolic 24-h ABPM of -6 (-25 to 13) / -0.3 (-10 to 9) mmHg, in favor of the HDP group (Figure 4.1).
Table 4.1 Baseline characteristics for the total study population, assigned by the presence of a self-reported hypertensive disorder of pregnancy
HDP group Non-HDP Characteristics N=36 N=30 P-value
Age (years) 60 (11) 57 (12) 0.826 White race* 36 (100) 28 (93) 0.182 Cardiovascular history* 8 (22) 4 (13) 0.197 Current smoker* 3 (8) 3 (10) 0.825 4 Alcohol intake at least one unit a day* 5 (14) 1 (3) 0.330 Diabetes Mellitus type II* 4 (11) 2 (7) 0.107 Duration of hypertension (years) 29 (14) 14 (10) < 0.001 No. of blood pressure lowering drugs 3 (2) 3 (2) 0.888 Office blood pressure Systolic (mmHg) 197 (33) 189 (33) 0.670 Diastolic (mmHg) 102 (17) 103 (16) 0.676 Ambulatory blood pressure 24-hour systolic (mmHg) 158 (19) 153 (23) 0.489 24-hour diastolic (mmHg) 94 (11) 94 (14) 0.869 24-hour heart rate (bpm) 79 (11) 70 (8) 0.006 Percentage dipping 10 (8) 14 (8) 0.351 Body-Mass-Index (kg/m2) 29 (5) 26 (5) 0.154 eGFR-CKD epi (ml/min/1.73m2) 83 (19) 83 (18) 0.259 LDL (mmol/l) 3.9 (1.1) 3.0 (0.6) 0.013 HDL (mmol/l) 1.5 (0.5) 1.5 (0.4) 0.524 Renin (fmol/l/s) 468 (498) 805 (1012) 0.798 Urine albumin (mg/24h) 41 (38) 69 (82) 0.855 Urine noradrenalin (mmol/24h) 231 (109) 223 (80) 0.715 Pregnancy related factors Chronic hypertension* 18 (50) N/A N/A Gestational hypertension* 18 (50) N/A N/A Preeclampsia* 19 (53) N/A N/A Renal denervation performed* 20 (56) 15 (50) 0.969 Data are presented as mean (SD), unless stated otherwise. * Data presented as number (%). P-value represents difference between women with HDP and women without HDP. HDP, hypertensive disorder of pregnancy; No., number; eGFR CKD-epi, estimated Glomerular Filtration Rate based on the Chronic Kidney Disease Epidemiology Collaboration equation; LDL, Low-Density-Lipoprotein; HDL, High-Density-Lipoprotein.
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* PM, ambulatory blood ed hypertensive disorder ed hypertensive disorder (95% CI) Mean difference
* Mean difference (95% CI) 12 months N=35 N=35n=20 n=20n=15 N=19 n=15 n=7 n=12 Baseline 6 months Total study population Total SBP (mmHg)Office DBP (mmHg)Office 24-h systolic ABPM (mmHg)24-h diastolic ABPM (mmHg)24-h heart rate (bpm)HDP group SBP (mmHg)Office 156 (21) DBP (mmHg)Office 194 (33) 94 (13)24-h systolic ABPM (mmHg) 102 (16)24-h diastolic ABPM (mmHg) N.A.24-h heart rate (bpm) 168 (26) 76 (11) N.A. 95 (14)Non-HDP group SBP (mmHg)Office 158 (19) DBP (mmHg)Office -40 ( -54 to -26) 197 (33) 94 (11) N.A. N.A.24-h systolic ABPM (mmHg) 102 (17) -14 (-19 to -8) N.A.24-h diastolic ABPM (mmHg) N.A.24-h heart rate (bpm) 170 (22) 169 (29) 79 (11) N.A. 96 (14) N.A. 99 (16) 153 (23) -46 (-66 to -27) -38 (-65 to -11) 189 (33) 94 (14) N.A. N.A. 148 (21) 103 (16) -14 (-21 to -8) N.A. 90 (13) -10 (-22 to 1) N.A. 165 (32) 70 (8) 165 (31) N.A. -14 (-23 to -5) 94 (16) N.A. 72 (10) 94 (18) -9 (-14 to -5) -31 (-54 to -8) -57 (-99 to -15) N.A. 143 (18) N.A. -13 (-24 to -2) N.A. 86 (13) -1 (-4 to 2) -21 (-37 to -4) -18 (-40 to 4) 172 (29) 72 (12) N.A. 105 (13) -9 (-20 to 2) -19 (-57 to 20) 150 (24) 92 (13) 0 (-15 to 15) -3 (-9 to 3) -12 (-21 to -2) -9 (-14 to -4) 72 (8) -0 (-5 to 5) Data are presented as mean (SD), unless stated otherwise. presented Data are between follow-up and baseline. for the difference presented * Mean difference bpm: beats per minute; AB diastolic blood pressure; DBP, systolic blood pressure; SBP, of pregnancy; hypertensive disorder HDP, pressure measurement; N.A., not available. measurement; pressure Table 4.2 Table of a self-report at baseline and follow-up for the total study population assigned by presence Blood pressure of pregnancy
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4
Figure 4.1 Mean difference (SE) in blood pressure after renal denervation, compared to baseline. * P-value < 0.05 for difference between baseline and follow-up. ** P-value = 0.044 for difference in change in 12 M office DBP between the HDP group and non- HDP group. HDP, hypertensive disorder of pregnancy; 6 M, six months; 12 M, 12 months; SBP, systolic blood pressure; DBP, diastolic blood pressure; ABPM, ambulatory blood pressure measurement.
Discussion
The main finding of this study in referred apparent resistant hypertensive women was the high prevalence of 64% of women with a history of self-reported HDP. In addition, our data suggests a larger effect of RDN on BP in women with a history of HDP, which indicates the important contribution of sympathetic overactivity to resistant hypertension in the HDP population.
The prevalence of women with a history of self-reported HDP, found in this study, was much higher than the average prevalence of 10% found in previous studies.1, 2 The same holds for the prevalence of preeclamptic women (34% in the current study versus 2–5% in the general population).1, 3 Certainly, HDP is more common than in the general
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population. This observation may in part be due to recall bias, i.e., women referred to us for evaluation of high BP are more likely to recall abnormalities in BP during pregnancy. Yet, PE is a clinical disorder generally leading to specialist care, a happening that is not easy to forget by women. Moreover, this method of data collection is similar to other studies.25, 26 Secondly, our group found that self-reported HDP is a valid reflection of the diagnosis HDP, based on patient records. The high prevalence of self-reported HDP can also be due to sympathetic overactivity, as being a factor in developing HDP and, especially PE during pregnancy.10, 27 Some studies even indicated that sympathetic overactivity is a general phenomenon in pregnancy and demonstrated this already in the early phase of the pregnancy.11 There is also abundant clinical evidence that sympathetic overactivity is present in (resistant) hypertension.12, 28 Still, at our knowledge there are only two small studies in formerly preeclamptic women that assessed muscle sympathetic nerve activity (MSNA), which is the most direct measurement of sympathetic activity.25, 29 One study in 28 women with (controlled) hypertension and 40 years after developing HDP found evidence of increased MSNA, compared to women that were normotensive during pregnancy.25 The second, recently published, study found increased MSNA after an exercise stimulus, compared to women with a healthy pregnancy history, indicating impaired autonomic control.29 Indirect evidence of persistent increased sympathetic activity showed that formerly preeclamptic women still were more sensitive to fluctuations in the renin-angiotensin system, than formerly normotensive pregnant women.30, 31 The fact that the HDP-group had a significantly higher heart rate and a trend to less nocturnal dipping at baseline, might be regarded as support for a higher sympathetic activity in this specific group of patients.
There were several limitations of this study. First, our questionnaire was a self-designed, not validated questionnaire, despite that we used international guidelines for the definitions of HDP.4 There might have been selection bias of more response of women with a greater decline in BP after RDN. In this patient group HDP is very common. But this would mean that patients with less response after RDN were more likely to have had no history of HDP, leading to the high prevalence of HDP found in the current study. Therefore, confirmation of the high prevalence of HDP in resistant hypertensive women is needed. Third, our RDN data are based on a small number of patients and therefore we lack precision of the RDN treatment effect between women with and without HDP. We recommend for collaboration of centers with hypertension expertise to pool individual patient data (as this is a highly selected population), in order to achieve larger samples
86 History of HDP and effect RDN
sizes and thus more precision. Especially since there is, in any case, agreement about one thing: we need to identify upfront those that are likely to respond to RDN from those who do not. Previously, impaired kidney function and combined diastolic and systolic hypertension were related to a larger decline in BP after RDN.23, 32 Our data suggest that BP decreased more in women with self-reported HDP after RDN, than observed in resistant hypertensive women with healthy pregnancies (or without pregnancies). Moreover, self-reported HDP was highly present in the resistant hypertensive population. When confirmed in additional studies, screening of women with a history of HDP, would be helpful to identify the potential best responders to RDN. 4
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References
(1) Magee LA, Pels A, Helewa M, Rey E, von DP. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy. Pregnancy Hypertens.2014;4(2):105-145. (2) Moussa HN, Arian SE, Sibai BM. Management of hypertensive disorders in pregnancy. Womens Health (Lond).2014;10(4):385-404. (3) Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular trends in the rates of preeclampsia, eclampsia, and gestational hypertension, United States, 1987-2004. Am J Hypertens.2008;21(5):521-526. (4) Tranquilli AL, Brown MA, Zeeman GG, Dekker G, Sibai BM. The definition of severe and early- onset preeclampsia. Statements from the International Society for the Study of Hypertension in Pregnancy (ISSHP). Pregnancy Hypertens.2013;3(1):44-47. (5) Garovic VD, Bailey KR, Boerwinkle E et al. Hypertension in pregnancy as a risk factor for cardiovascular disease later in life. J Hypertens.2010;28(4):826-833. (6) Tooher J, Chiu CL, Yeung K et al. High blood pressure during pregnancy is associated with future cardiovascular disease: an observational cohort study. BMJ Open.2013;3(7). (7) Karumanchi SA, Granger JP. Preeclampsia and Pregnancy-Related Hypertensive Disorders. Hypertension.2016;67(2):238-242. (8) Steegers EA, von DP, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet.2010;376(9741):631-644. (9) Schobel HP, Fischer T, Heuszer K, Geiger H, Schmieder RE. Preeclampsia -- a state of sympathetic overactivity. N Engl J Med.1996;335(20):1480-1485. (10) Greenwood JP, Scott EM, Walker JJ, Stoker JB, Mary DA. The magnitude of sympathetic hyperactivity in pregnancy-induced hypertension and preeclampsia. Am J Hypertens.2003;16(3):194-199. (11) Jarvis SS, Shibata S, Bivens TB et al. Sympathetic activation during early pregnancy in humans. J Physiol.2012;590(15):3535-3543. (12) Grassi G, Seravalle G, Brambilla G et al. Marked sympathetic activation and baroreflex dysfunction in true resistant hypertension. Int J Cardiol.2014;177(3):1020-1025. (13) van der Graaf AM, Toering TJ, Faas MM, Lely AT. From preeclampsia to renal disease: a role of angiogenic factors and the renin-angiotensin aldosterone system? Nephrol Dial Transplant.2012;27 Suppl 3:iii51-iii57. (14) Fu Q. Microneurographic research in women. Front Physiol.2012;3:278. (15) de Jager RL, Blankestijn PJ. Pathophysiology I: the kidney and the sympathetic nervous system. EuroIntervention.2013;9 Suppl R:R42-R47. (16) 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(9981):1957-1965. (17) Bhatt DL, Kandzari DE, O’Neill WW et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med.2014;370(15):1393-1401. (18) Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet.2010;376(9756):1903-1909. (19) Mathiassen ON, Vase H, Bech JN et al. Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial. J Hypertens.2016;34(8):1639-1647. (20) Sanders MF, Blankestijn PJ, Voskuil M et al. Safety and long-term effects of renal denervation: Rationale and design of the Dutch registry. Neth J Med.2016;74(1):5-15. (21) Verloop WL, Vink EE, Voskuil M et al. Eligibility for percutaneous renal denervation: the importance of a systematic screening. J Hypertens.2013;31(8):1662-1668.
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(22) Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens.2013; 31(7):1281-1357. (23) Vink EE, Verloop WL, Bost RB et al. The blood pressure-lowering effect of renal denervation is inversely related to kidney function. J Hypertens.2014;32(10):2045-2053. (24) Papademetriou V, Tsioufis CP, Sinhal A et al. Catheter-based renal denervation for resistant hypertension: 12-month results of the EnligHTN I first-in-human study using a multielectrode ablation system. Hypertension.2014;64(3):565-572. (25) Collen AC, Manhem K, Sverrisdottir YB. Sympathetic nerve activity in women 40 years after a hypertensive pregnancy. J Hypertens.2012;30(6):1203-1210. (26) Kattah AG, Asad R, Scantlebury DC et al. Hypertension in pregnancy is a risk factor for microalbuminuria later in life. J Clin Hypertens (Greenwich).2013;15(9):617-623. (27) Fischer T, Schobel HP, Frank H, Andreae M, Schneider KT, Heusser K. Pregnancy-induced 4 sympathetic overactivity: a precursor of preeclampsia. Eur J Clin Invest.2004;34(6):443-448. (28) Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens.2010; 23(10):1052-1060. (29) Stickford AS, Okada Y, Best SA, Parker RS, Levine BD, Fu Q. Sympathetic neural and cardiovascular responses during static handgrip exercise in women with a history of hypertensive pregnancy. Clin Auton Res.2016;26(6):395-405. (30) Hladunewich MA, Kingdom J, Odutayo A et al. Postpartum assessment of the renin angiotensin system in women with previous severe, early-onset preeclampsia. J Clin Endocrinol Metab.2011; 96(11):3517-3524. (31) Spaan JJ, Ekhart T, Spaanderman ME, Peeters LL. Remote hemodynamics and renal function in formerly preeclamptic women. Obstet Gynecol.2009;113(4):853-859. (32) Mahfoud F, Bakris G, Bhatt DL et al. Reduced blood pressure-lowering effect of catheter-based renal denervation in patients with isolated systolic hypertension: data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry. Eur Heart J.2016.
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Part 2 The interpretation of the effect of renal denervation2
CHAPTER
Medication Adherenceerence in patients witwithh apparent resistant hypertension: fi ndings from the SYMPATHY trial
R.L. de Jager, E.M. van Maarseveen, M.L. Bots, P.J. Blankestijn, on behalf of the SYMPATHY investigators
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Abstract
Introduction Hypertension is only controlled in approximately 35% of the patients, which could be partially due to non-adherence. Our aim was to explore possible determinants of non-adherence in treatment resistant hypertension, assessed by a bioanalytical assay for antihypertensive agents in serum. Secondary aim was to study the effect of adherence on the change in BP.
Methods This project was a sub-study of SYMPATHY; an open-label randomized- controlled trial to assess the effect of renal denervation on BP six months after treatment compared to usual care in patients with resistant hypertension. Serum samples were screened for antihypertensive agents to assess adherence at baseline and six months after intervention, using liquid chromatography-tandem mass spectrometry. Office and 24-hour BP were measured at the same day blood was sampled. Patients and physicians were unaware of adherence measurements.
Results Ninety-eight baseline and 83 six-month samples were available for analysis. Sixty-eight percent (95% CI 59 to 78) of the patients was non-adherent (n=67). For every 1 pill more prescribed, 0.785 [0.529 to 0.891] prescribed pill less was detected in blood. A decrease of 1 pill in adherence between baseline and six months was associated with a significant rise in office systolic BP of 4 (0.2 to 8.9) mmHg.
Conclusion Objective measurement of BP lowering drugs in serum, to assess adherence, showed that non-adherence was common in patients with apparent resistant hypertension. The assessment results were related to (changes in) blood pressure. Our findings provide objective methodology to help the physician to understand and to improve the condition of apparent resistant hypertension.
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Introduction
Hypertension, defined as an office systolic blood pressure (SBP) > 140 mmHg and / or diastolic blood pressure (DBP) > 90 mmHg, is only controlled in approximately 35% of the patients.1, 2 Worldwide, 874 million adults suffer from an office SBP of 140 mmHg or higher, which is associated with an annual death rate of 106 per 100.000 patients.3 For the pharmacological control of hypertension adherence to blood pressure (BP) lowering drugs is essential. Poor adherence is associated with a higher residual cardiovascular risk (for the patient) and a high healthcare burden, due to greater effort to improve BP with additional diagnostic tests and interventions, such as renal denervation (RDN).4, 5 Previous cross-sectional studies published information on factors of non-adherence in patients with hypertension.6-10 However, almost all studies on adherence in hypertension are based on the self-assessment Morrisky questionnaire; a method shown to overestimate adherence and to be potentially biased. In contrast, the results of objective adherence measurements using drug screening in urine and blood are unbiased. In general, the 5 assessment based on screening in urine provides information on long term use, whilst detection in serum can be considered indicative of short-term drug intake.11 From a pharmacological perspective the latter is more related to BP measurements performed within the same time frame as sample collection.12
As unbiased information on adherence is of importance in the decision making process of the treating physician, an objective tool can be of great importance for example to refine or define treatment-resistant hypertension. Such a diagnostic tool can prevent new invasive treatment options and divert focus towards adherence training. In the present study we investigated drug adherence through bioanalytical screening for antihypertensive agents in serum and explored the relation between adherence and BP levels over time.
Methods
Study design and study population
The study was designed as a post-hoc analysis as part of the SYMPATHY-trial, in which adherence screening in serum was performed.4 The SYMPATHY-trial is an open-label randomized-controlled trial in which patients were randomized to RDN plus usual care versus usual care alone (clinicaltrials.gov number: NCT01850901).13 Patients were
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included in SYMPATHY from 14 different secondary and tertiary Dutch centres, from May 2013 till December 2015. Primary endpoint in the trial was BP lowering efficacy of RDN after six months. In order to be eligible to participate in this study, a subject had a mean day-time systolic BP ≥ 135 mmHg, as determined with the use of ambulatory BP measurement (ABPM), while having prescribed three or more antihypertensive agents for at least three months prior to inclusion or with documented intolerance to two or more of the four major classes antihypertensive drugs (ace-converting-enzyme/ angiotensin-receptor blocker, calcium channel blocker, beta blocker, diuretic) and no possibility to take three anti-hypertensive drugs. The most important exclusion criteria were a treatable secondary cause of hypertension, an eGFR < 20 ml/min/1.73m2 and an ineligible renal artery anatomy for treatment. The present post-hoc analysis on adherence originated from a new research question and permission was granted to use stored blood samples of SYMPATHY patients that gave a broad consent to use their blood for future research. The storage of blood samples was optional for participating centres (Appendix, Table S5.1). SYMPATHY and this sub-study were approved by the ethical committee of UMC Utrecht.
Adherence assessment
All prescribed medication, including BP lowering drugs, were listed at baseline and six months by their generic name, dosage and frequency. BP lowering drugs were identified according to the Anatomical Therapeutic Chemical (ATC) classification system of the World Health Organization Collaborating Centre for Drug Statistics (WHOCC). In addition, we registered the different classes of prescribed BP lowering drugs.
Blood was collected at baseline and six months on the same day 24-hour ambulatory and office BP measurements were performed and stored as serum at -80°C. Serum screening for BP lowering drugs using liquid chromatography, combined with tandem mass spectrometry (LC-MS/MS) was performed as a batch at the end of the study. Patients and physicians were unaware of the adherence assessment at the moment of blood sample collection.
Identification of BP lowering drugs was performed with LC-MS/MS combined with a spectra library search. First, phospholipid removal technology was employed for sample purification and enrichment. After purification, the samples were analysed using LC-MS/ MS under full-scan and data-dependent tandem mass spectrometry (MS/MS) mode.
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The acquired mass spectra were compared with an in-house library (compound library and MS/MS mass spectral library) built with automated screening software (Thermo Fisher Scientific) which contained the mass/charge of the precursor ion, retention time, product ions and the entire MS/MS spectra of 40 compounds including metabolites covering over 95% of all BP lowering drugs registered in The Netherlands. Identification was achieved by comparing full MS/MS spectra and/or mass/charge of precursor ion with confirmation by second selected reaction monitoring transitions. Furthermore, we randomly re-sampled a batch to test the reproducibility of the method. The analysts that performed LC-MS/MS and interpret the results were unaware of the patients’ BP or treatment arm.
Medication adherence was documented in three different categories: adherent (81–100% match prescribed versus measured), poorly adherent (1–80% match prescribed versus
14 measured) and completely non-adherent (0% match prescribed versus measured). 5 Change in adherence between baseline and follow-up was categorized as: decrease in adherence (baseline adherence higher than follow-up adherence), stable adherence (baseline adherence equal to follow-up adherence) and increase in adherence (baseline adherence lower than follow-up adherence).
Physical and biochemical parameters
A detailed description of the collection of physical and biochemical outcome measures has been previously published by our group.13 In short, office and 24-hour BP measurements were performed at baseline and six months using recommended devices from the ESH/ ESC guidelines and under standardized conditions.15 Office BP was an average of four BP measurements (two on each arm). 24-hour ambulatory BP measurements were considered valid when ≥ 70% of the recordings was successful. Information on cardiovascular history, smoking, alcohol, duration of hypertension and socio-economic status were collected at baseline. Biochemical parameters as lipid spectrum, and creatinine (and eGFR) were assessed at baseline and six months follow-up during routine patient care.
Statistical analysis
Due to the post-hoc nature of the study a formal sample size calculation was not done in advance. Data were expressed as mean (standard deviation), median (interquartiles), or as percentages (95% confidence interval), unless stated otherwise. Paired T-tests were used to compare means within individuals. To explore a relation between patient
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characteristics and the level of adherence we used a multivariable linear regression model with adherence as dependent variable and the following independent variables, based on literature or hypothesis: baseline office systolic BP, age, sex, duration of hypertension, education, number and type of class of BP lowering pills. A backward model was applied to minimize the chance on suppression of variables.16 To assess determinants of change in adherence, a similar multivariable linear regression analysis was applied. The treatment to which the patient was assigned in the original study (RDN or usual care) was added to this model. Univariable linear regression analysis was used to analyse the possible relationship between level of adherence and BP. A two-sided 0.05 level of significance was used. Statistical analyses were done using SPSS version 21 (IBM Corp., Armonk, NY, USA).
Results
Patient characteristics
Of the 139 patients included in SYMPATHY, 98 patients gave their consent to store blood specimens for future research purposes (Table 5.1). Mean age was 63 (standard deviation 11) years and 42% of the study population was male (n=41). The prevalence of cardiovascular morbidity was 48% (n=47). The average number of prescribed BP lowering pills was 3.6 (SD 1.4). RAS (renin-angiotensin system)-inhibitors and diuretics were most often prescribed (Table S5.1). Mean office BP was 167 (SD 25) / 92 (SD 16) mmHg and mean 24-hour BP was 157 (SD 17) / 90 (SD 15) mmHg. Baseline characteristics of those with adherence measurements did not significantly differ from the original sample of 139 patients in SYMPATHY (data not shown).4
Adherence to BP lowering medication
At baseline, 68% (95%CI 59 to 78) of the patients was non-adherent to their prescribed BP lowering drugs (n=67). Sixteen patients were completely non-adherent (16%), 51 poorly adherent (52%) and 31 adherent (32%) (Table 5.1). Overall, of the 3.6 number of drugs prescribed, 1.5 could be detected in the blood sample (P < 0.001) (Table S5.2). In seven patients more pills were detected than prescribed (Figure 5.1). Adherence at baseline declined significantly with the increase of number of prescribed drugs (Figure 5.1 and Table S5.3): for every 1 pill more prescribed, 0.785 prescribed pill was less detected in blood (B=0.785, P < 0.001). Other important determinants for non-adherence at baseline were: higher baseline office SBP (P < 0.001) and younger age (P=0.082) (Table S5.3).
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Table 5.1 Baseline characteristics of the studied population (n=98)
Non-adherent Poorly adherent Adherent N=16 N=52 N=30
Age (years) 57 (13) 65 (9) 63 (11) Sex male* 7 (44) 22 (43) 12 (39) Ethnicity Caucasian* 14 (88) 50 (98) 29 (94) Cardiovascular history* 7 (44) 24 (47) 16 (52) Diabetes Mellitus* 4 (25) 19 (37) 5 (16) Current smoking* 4 (25) 11 (22) 4 (13) Body-Mass-Index (kg/m2) 28.5 (5.2) 29.1 (5.0) 29.1 (4.7) No. of BP lowering drugs 3.9 (1.3) 4.0 (0.9) 2.6 (1.7) No. of classes of BP lowering drugs 3.4 (1.0) 3.7 (0.8) 2.7 (1.6) Office BP Systolic (mmHg) 184 (28) 162 (22) 165 (24) Diastolic (mmHg) 106 (22) 89 (14) 92 (13) Heart rate (bpm) 76 (11) 69 (12) 68 (12) 5 24-hour ABPM Systolic (mmHg) 162 (17) 155 (15) 158 (19) Diastolic (mmHg) 96 (17) 88 (15) 89 (13) Heart rate (bpm) 70 (12) 70 (11) 68 (12) Daytime ABPM Systolic (mmHg) 167 (17) 158 (15) 161 (19) Diastolic (mmHg) 100 (18) 90 (15) 91 (14) Heart rate (bpm) 72 (12) 72 (11) 70 (12) Night time ABPM Systolic (mmHg) 149 (21) 143 (15) 148 (18) Diastolic (mmHg) 85 (14) 79 (13) 82 (13) Heart rate (bpm) 65 (12) 65 (9) 62 (9) LDL (mmol/l) 2.8 (0.7) 3.1 (1.2) 3.2 (1.1) eGFR (ml/min/1.73m2) 91 (15) 74 (17) 74 (20) Renal denervation* 10 (63) 33 (65) 20 (65) Data are expressed as mean±SD, unless stated otherwise. * Data are expressed as number of patients (%). No., number; bpm, beats per minute; ABPM, ambulatory BP measurement; LDL, low-density lipoprotein; eGFR, estimated glomerular filtration rate.
Overall, the best adherence was found for RAS-inhibitors and beta-blockers (59% and 59% of the patients’ adherent, respectively) and the worst for calcium antagonists (27% of the patients adherent) (Figure 5.2). At six months a similar pattern was seen in the 83 patients of whom stored samples were available (data not shown).
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ϲ͕ϬϬ
Figure 5.1 Relation between the number of prescribed and the number of detected BP lowering pills in blood at baseline with line of identity (0=0, 1=1, etcetera). One dot represents one patient.
Using the described bioanalytical method for the identification of antihypertensive agents in serum a sensitivity of 95% and a specificity of 91% was reached. Reproducibility testing showed identical serum screening results in 49 of 52 samples (93%) of in total 147 analysed compounds.
Adherence and BP
Baseline office and ambulatory BP were the highest in the non-adherent group (Table 5.1). Low adherence to BP lowering medication was related to higher baseline BP (Table 5.2a). This relation was the strongest for office BP: for every prescribed yet undetected pill, office BP increased with 4/3 mmHg (P=0.018 and P=0.003, respectively). The same trend was seen for change in adherence after six months of follow-up. Office BP showed the largest rise after six months with an increase in BP of 4/2 mmHg (P=0.038 and P=0.044, respectively) for every prescribed yet undetected antihypertensive agent at six months, compared to baseline (Table 5.2b).
100 Medication adherence: findings from SYMPATHY
5
Figure 5.2 Number of patients that was prescribed to different classes of BP lowering drugs and the number of patients in which the prescribed class was detected. BP, blood pressure; RAS, renin-angiotensin system.
Table 5.2a Relation between baseline adherence and baseline blood pressure
B-coefficient 95% CI for B-coefficient P-value
Office systolic BP 3.563 0.637 to 6.490 0.018 Office diastolic BP 2.841 0.965 to 4.717 0.003 24-hour systolic ABPM 1.473 -0.551 to 3.497 0.152 24-hour diastolic ABPM 2.128 0.362 to 3.895 0.019
Table 5.2b Relation between change in adherence and change in blood pressure
B-coefficient 95% CI for B-coefficient P-value
Office systolic BP 4.081 0.230 to 8.932 0.038 Office diastolic BP 2.362 0.060 to 4.663 0.044 24-hour systolic ABPM 2.307 -0.803 to 5.417 0.144 24-hour diastolic ABPM 1.578 -0.263 to 3.420 0.092 Univariable analyses of the possible relation between baseline adherence and baseline BP (5.2a) and the relation between change in adherence and change in BP (5.2b). Example: when there is one prescribed BP lowering pill not detected at baseline, office systolic BP is 3.563 mmHg higher at baseline (5.2a). Or, when one prescribed pill is less detected at six months compared to baseline, office systolic BP increases with 4.081 mmHg at six months compared to baseline. BP, blood pressure; ABPM, ambulatory BP measurement.
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Change in adherence
Overall, the number of prescribed BP lowering drugs increased significantly with 0.3 pills (P < 0.001) at six months. The number of detected drugs increased also with 0.3 pills (P=0.058) (Table S5.2). Of the 27 changes in prescribed drug classes (e.g. diuretic was started or stopped) at six months, 19 (70%) were not detected in blood. Especially, prescribed changes in RAS-inhibitors and calcium antagonists were not found (Figure 5.3). In the 25 patients with a change in adherence over time, drug adherence increased in 13 (17%) patients and 12 (15%) patients were less adherent (Table S5.4).
Figure 5.3 The number of patients in which the prescription of BP lowering classes changed at six months compared to baseline (e.g. at baseline no diuretics, but at six months diuretics were prescribed) and the number of patients in which the change in prescription was detected in blood. BP, blood pressure; RAS, renin-angiotensin system.
Discussion
Objective assessment in serum of adherence to BP lowering drugs showed that adherence to BP lowering drugs was poor, with factors related to poor adherence being higher number of prescribed BP lowering pills, higher baseline BP and younger age. When adherence decreased overtime, office BP increased significantly. The present study
102 Medication adherence: findings from SYMPATHY
has three unique features: 1) patients and physicians were unaware of the adherence assessments, 2) BP lowering drugs were measured objectively in blood at different time-points, and 3) blood samples were taken synchronously with the BP measurements.
Medication adherence has been subject of debate for many years and different approaches have been used to screen drug adherence.17-20 The most widely used method is a questionnaire, of which the Morrisky is the best known and used in previous intervention studies with hypertensive patients.21-24 Questionnaires are relatively inexpensive and non-invasive. On the other hand, they are based on the patients’ self-report of adherence, often leading to overestimation. A small study of 47 patients with apparent treatment resistant hypertension concluded that, based on this questionnaire, 26% patients were non-adherent. However, based on serum screening using a bioanalytical assay, objectively assessed non-adherence was found to be 51%.25 Furthermore, in recent studies with resistant hypertensive patients the percentage 5 non-adherent patients (defined as taken < 80% of the prescribed medication detected in urine and blood) was on average 50%.18, 26, 27 Here, we report a higher prevalence of almost 70%. The discrepancy could be related to the use of urine samples for the assessment in most of the other studies, which could have led to detection long after drug administration. As half-lives of antihypertensive agents and the amount excreted by the kidneys (unchanged or as metabolite) largely vary, urine screening results are therefore more difficult to relate to short-term drug intake and concomitant BP.11 Of note, in one study reporting 50% non-adherence, patients were asked to give informed consent for adherence measurements beforehand, which could theoretically have led to an improvement in adherence.26
One of the perceived limitations may be that only part of the study population partici- pated, i.e., those in centre where storage of blood samples was possible. The none participation was mostly due to logistical reasons and expected to be random, and not selective. Indeed, this notion is confirmed by the fact that baseline characteristics did not differ between these two groups of centres. A second limitation may be that included patients were analysed as one group, despite that part of the group underwent RDN. This may have affected the six months results. However, we adjusted these multivariable analyses, by adding intervention as independent variable. Thirdly, the study population was part of a randomized trial, including a more invasive and frequent follow-up, which generally is associated with an increase in adherence.28 In this case underestimation
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of non-adherence as opposed to overestimation is expected. Finally, in seven patients more pills were detected than prescribed. We believe that this finding resembles daily practice (instead of a detection error), as “supranormal” adherence has been reported to be a common finding.29 In our study we considered these patients to be completely adherent.
Our results support that no or poor adherence is related to higher BP, which is also found in previous studies.18, 26, 27, 30 However, in contrast with earlier studies, in which no relationship was observed between change in adherence and change in BP during follow-up,26, 27 we found that office BP increased when adherence decreased during follow-up. As we and other studies found especially a low adherence to calcium channel blockers,8, 31 it is important to evaluate if there are alternatives for this class of BP lowering drug. Tablets with a combination of classes of BP lowering drugs are preferred, since it will increase the adherence. In conclusion, objective methodology, using a bioanalytical screening assay, to assess adherence to BP lowering drugs, provides a valuable tool to define true resistant hypertension and, when applicable, refine a treatment plan in consultation with the patient.
104 Medication adherence: findings from SYMPATHY
References
(1) Falaschetti E, Mindell J, Knott C, Poulter N. Hypertension management in England: a serial cross- sectional study from 1994 to 2011. Lancet.2014;383(9932):1912-1919. (2) Pereira M, Lunet N, Azevedo A, Barros H. Differences in prevalence, awareness, treatment and control of hypertension between developing and developed countries. J Hypertens.2009;27(5):963-975. (3) Forouzanfar MH, Liu P, Roth GA et al. Global Burden of Hypertension and Systolic Blood Pressure of at Least 110 to 115 mm Hg, 1990-2015. JAMA.2017;317(2):165-182. (4) de Jager RL, de Beus E., Beeftink MM et al. Impact of medication adherence on the effect of renal denervation. The SYMPATHY trial. Hypertension.2017;69(4):678-684. (5) Ettehad D, Emdin CA, Kiran A et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet.2016;387(10022):957-967. (6) Calderon-Larranaga A, Diaz E, Poblador-Plou B, Gimeno-Feliu LA, Abad-Diez JM, Prados-Torres A. Non-adherence to antihypertensive medication: The role of mental and physical comorbidity. Int J Cardiol.2016;207:310-316. (7) Farah R, Zeidan RK, Chahine MN et al. Predictors of Uncontrolled Blood Pressure in Treated Hypertensive Individuals: First Population-Based Study in Lebanon. J Clin Hypertens (Greenwich). 2016;18(9):871-877. (8) Krousel-Wood M, Joyce C, Holt E et al. Predictors of decline in medication adherence: results from the cohort study of medication adherence among older adults. Hypertension.2011;58(5):804-810. 5 (9) Meena J, Raghav P, Rustagi N. LBOS 03-06 Anti hypertensive treatment compliance and adverse effect profile among hypertension clinic attendees in jodhpur, India. J Hypertens.2016;34 Suppl 1:e552. (10) Napolitano F, Napolitano P, Angelillo IF. Medication adherence among patients with chronic conditions in Italy. Eur J Public Health.2016;26(1):48-52. (11) van Zwieten PA. Pharmacology of antihypertensive agents with multiple actions. Eur J Clin Pharmacol.1990;38 Suppl 2:S77-S81. (12) Moffat A, Osselton D, Widdop B, Watts J. Clarke’s Analysis of Drugs and Poisons. 4th ed. London: Pharmaceutical Press; 2011. (13) Vink EE, de Beus E, de Jager RL et al. The effect of renal denervation added to standard pharmacologic treatment versus standard pharmacologic treatment alone in patients with resistant hypertension: rationale and design of the SYMPATHY trial. Am Heart J.2014;167(3):308-314. (14) Osterberg L, Blaschke T. Adherence to medication. N Engl J Med.2005;353(5):487-497. (15) Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens.2013;31(7): 1281-1357. (16) Field A. Choosing a method. Discovering statistics using IBM SPSS Statistics.London: SAGE; 2013. 323. (17) Ayoade A, Oladipo I. Evaluation of the correlation between self-report and electronic monitoring of adherence to hypertension therapy. Blood Press.2012;21(3):161-166. (18) Jung O, Gechter JL, Wunder C et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens.2013;31(4):766-774. (19) Morisky DE, Ang A, Krousel-Wood M, Ward HJ. Predictive validity of a medication adherence measure in an outpatient setting. J Clin Hypertens (Greenwich).2008;10(5):348-354. (20) Zeller A, Schroeder K, Peters TJ. An adherence self-report questionnaire facilitated the differentiation between nonadherence and nonresponse to antihypertensive treatment. J Clin Epidemiol.2008;61(3):282-288.
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(21) 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(9981):1957-1965. (22) Bhatt DL, Kandzari DE, O’Neill WW et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med.2014;370(15):1393-1401. (23) Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet.2010;376(9756):1903-1909. (24) Kario K, Ogawa H, Okumura K et al. SYMPLICITY HTN-Japan - First Randomized Controlled Trial of Catheter-Based Renal Denervation in Asian Patients -. Circ J.2015;79(6):1222-1229. (25) Pandey A, Raza F, Velasco A et al. Comparison of Morisky Medication Adherence Scale with therapeutic drug monitoring in apparent treatment-resistant hypertension. J Am Soc Hypertens. 2015;9(6):420-426. (26) Ewen S, Meyer MR, Cremers B et al. Blood pressure reductions following catheter-based renal denervation are not related to improvements in adherence to antihypertensive drugs measured by urine/plasma toxicological analysis. Clin Res Cardiol.2015;104(12):1097-1105. (27) Schmieder RE, Ott C, Schmid A et al. Adherence to Antihypertensive Medication in Treatment- Resistant Hypertension Undergoing Renal Denervation. J Am Heart Assoc.2016;5(2). (28) Cramer JA, Scheyer RD, Mattson RH. Compliance declines between clinic visits. Arch Intern Med. 1990;150(7):1509-1510. (29) Rudd P, Byyny RL, Zachary V et al. Pill count measures of compliance in a drug trial: variability and suitability. Am J Hypertens.1988;1(3 Pt 1):309-312. (30) Tomaszewski M, White C, Patel P et al. High rates of non-adherence to antihypertensive treatment revealed by high-performance liquid chromatography-tandem mass spectrometry (HP LC-MS/MS) urine analysis. Heart.2014;100(11):855-861. (31) Reuter H, Markhof A, Scholz S et al. Long-term medication adherence in patients with ST-elevation myocardial infarction and primary percutaneous coronary intervention. Eur J Prev Cardiol.2015; 22(7):890-898.
106 Medication adherence: findings from SYMPATHY
Supplementary material
List of participating centres (bold if storage of blood samples)
– Albert Schweitzer Hospital Dordrecht, O Elgersma, AJJ IJsselmuiden, PHM van der Valk, P Smak Gregoor, S Roodenburg.
– Amphia Hospital, Breda, M Meuwissen, W Dewilde, I Hunze, J den Hollander.
– Antonius Hospital, Nieuwegein, HH Vincent, B Rensing, WJ Bos, I van Weverwijk.
– Catharina Hospital, Eindhoven, PAL Tonino, BRG Brueren, CJAM Konings, H Hendrix- van Gompel.
– Isala Clinics, Zwolle, JE Heeg, J Lambert, JJ Smit, A Elvan, A Berends, B de Jager.
– Hospital group Twente, Almelo, G Laverman, PAM de Vries, A van Balen, M Stoel.
– Martini Hospital, Groningen, R Steggerda, L Niamut, W Bossen, J Biermann, I Knot.
– Medical Center Alkmaar, Alkmaar, JOJ Peels, JB de Swart, G Kimman, W Bax, Y 5 van der Meij, J Reekers.
– Medical Center Haaglanden, The Hague, AJ Wardeh, JHM Groeneveld, C Dille.
– Medical Center Leeuwarden, Leeuwarden, MH Hemmelder, R Folkeringa, M Sietzema, C Wassenaar.
– Rijnstate Hospital, Arnhem, K Parlevliet, W Aengevaeren, M Tjon, M Hovens, A van den Berg, H Monajemi.
– Scheper Hospital, Emmen, FGH van der Kleij, A Schramm, A Wiersum.
– University Medical Center Maastricht, Maastricht, B Kroon, M de Haan, M Das, H Jongen, E Herben, R Rennenberg.
– University Medical Center Utrecht, Utrecht, PJ Blankestijn, ML Bots, MM Beeftink, E de Beus, B Dijker, GWJ Frederix, RL de Jager, E van Maarseveen, MF Sanders, W Spiering, IS Velikopolskaia, L Vendrig, WL Verloop, EE Vink, EPA Vonken, M Voskuil, GA de Wit.
All centres were located in The Netherlands.
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Supplemental Table S5.1 Prescribed classes of BP lowering medication (n=98)
Baseline 6 months
Diuretics* 69 (70.4) 74 (75.5) Beta-blocker 61 (62.2) 65 (66.3) RAS-inhibitor 85 (86.7) 89 (90.8) Calcium antagonist 63 (64.3) 67 (68.4) Aldosterone antagonist 29 (29.6) 28 (28.6) Alpha-blocker 30 (30.6) 31 (31.6) Centrally acting antihypertensive drug 3 (3.1) 6 (6.1) Other 3 (3.1) 3 (3.1) Number of patients using different classes of BP lowering drugs (%). RAS, renin-angiotensin system * Diuretics without aldosterone antagonists.
Supplemental Table S5.2 Prescribed and detected BP lowering drugs
Mean difference Baseline 6 months (95% CI) P-value
No. of BP lowering drugs 3.6±1.4 3.9±1.4 0.3 (0.1 to 0.4) < 0.001 prescribed No. of BP lowering drugs 2.0±1.5 2.2±1.4 0.3 (0.0 to 0.5) 0.058 detected Mean difference between 1.5 (1.2 to 1.9) 1.7 (1.3 to 2.0) 0.1 (-0.3 to 0.4) 0.743 prescribed and detected (95% CI) Data are expressed as mean±SD, unless stated otherwise. No., number.
Supplemental Table S5.3 Determinants of adherence at baseline
B-coefficient 95% CI for B-coefficient P-value
Number of BP lowering pills 0.785 0.529 to 0.891 < 0.001 Baseline office systolic BP (mmHg) 0.021 0.011 to 0.023 < 0.001 Age (years) -0.022 -0.046 to 0.003 0.082 Determinants related to the level of adherence at baseline, with the difference between prescribed and detected BP lowering pills as dependent variable. Example: when a patient had one prescribed BP lowering pill more at baseline, 0.785 BP lowering pill less was detected at baseline. BP, blood pressure.
108 Medication adherence: findings from SYMPATHY
Supplemental Table S5.4 Baseline characteristics of patients with stable or change in adherence during follow-up
Stable adherence Change in adherence (n=53) (n=25)
Age (years) 62 (9) 60 (13) Sex male* 20 (38) 10 (40) Ethnicity Caucasian* 52 (98) 21 (84) Cardiovascular history* 26 (49) 14 (56) Diabetes Mellitus* 14 (26) 7 (28) Current smoking* 12 (23) 5 (20) Body-Mass-Index (kg/m2) 29.1 (4.8) 28.7 (4.6) No. of BP lowering drugs 3.7 (1.3) 3.3 (1.6) No. of classes of BP lowering drugs 3.5 (1.0) 3.0 (1.4) Office BP at baseline Systolic (mmHg) 164 (20) 173 (31) Diastolic (mmHg) 92 (12) 97 (22) 5 Heart rate (bpm) 68 (12) 70 (12) 24-hour ABPM Systolic (mmHg) 155 (16) 161 (19) Diastolic (mmHg) 90 (14) 93 (17) Heart rate (bpm) 69 (12) 70 (12) Daytime ABPM Systolic (mmHg) 159 (17) 164 (20) Diastolic (mmHg) 92 (15) 96 (18) Heart rate (bpm) 72 (12) 73 (12) Night time ABPM Systolic (mmHg) 144 (17) 148 (20) Diastolic (mmHg) 82 (14) 83 (15) Heart rate (bpm) 64 (10) 64 (11) LDL (mmol/l) 3.2 (1.2) 3.0 (1.1) eGFR (ml/min/1.72m2) 73 (18) 84 (16) Renal denervation* 28 (53) 18 (72) Decrease in adherence* N.A. 12 (15) Increase in adherence* N.A. 13 (17) Data are expressed as mean±SD, unless stated otherwise. * Data are expressed as number of patients (%). No., number; bpm, beats per minute; ABPM, ambulatory blood pressure measurement; LDL, low- density lipoprotein; eGFR, estimated glomerular filtration rate; N.A., not applicable.
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CHAPTER
Renal denervation in hypertensive patients not on blood pressure lowering drugs
R.L. de Jager*, M.F. Sanders*, M.L. Bots, M.D. Lobo, S. Ewen, M.M. Beeftink, M. Bohm, J. Daemen, O. Dorr, D. Hering, F. Mahfoud, H. Nef, C. Ott, M. Saxena, R.E. Schmieder, M.P. Schlaich, W. Spiering, P.A. Tonino, W.L. Verloop, E.E. Vink, E.J. Vonken, M. Voskuil, S.G. Worthley, P.J. Blankestijn
*Both authors contributed equally to this article.
Clin Res Cardiol.2016;105(9):755-762 Chapter 6
Abstract
Introduction Studies on the blood pressure lowering effect of renal denervation (RDN) in resistant hypertensive patients have produced conflicting results. Change in medication usage during the studies may be responsible for this inconsistency. To eliminate the effect of medication usage on blood pressure we focused on unmedicated hypertensive patients who underwent RDN.
Methods and results Our study reports on a cohort of patients who were not on blood pressure lowering drugs at baseline and during follow-up from eight tertiary centers. Data of patients were used when they were treated with RDN and had a baseline office systolic blood pressure (SBP) ≥ 140 mmHg and/or 24-hour ambulatory SBP ≥ 130 mmHg. Our primary outcome was defined as change in office and 24-hour SBP at 12 months after RDN, compared to baseline. Fifty-three patients were included. There were three different reasons for not using blood pressure lowering drugs: 1) documented intolerance or allergic reaction (57%); 2) temporary cessation of medication for study purposes (28%); and 3) reluc- tance to take antihypertensive drugs (15%). Mean change in 24-hour SBP was -5.7 mmHg (95% confidence interval [CI] -11.0 to -0.4; P=0.04). Mean change in office SBP was -13.1 mmHg (95% CI -20.4 to -5.7; P=0.001). No changes were observed in other variables, such as eGFR, body–mass-index and urinary sodium excretion.
Conclusion This explorative study in hypertensive patients, who are not on blood pressure lowering drugs, suggests that at least in some patients RDN lowers blood pressure.
112 RDN in unmedicated hypertensive patients
Introduction
Sympathetic overactivity and kidney injury are major contributors in sustaining high blood pressure (BP) levels.1 Percutaneous renal denervation (RDN) of the sympathetic nerves surrounding the renal arteries has been introduced as a therapy for (resistant) hypertension.2, 3 Several studies have shown a reduction in ambulatory systolic blood pressure (SBP) ranging from 5–10 mmHg at 6–12 months follow up after RDN.2, 4-6 In the Symplicity HTN-3 trial no difference in BP change between RDN-treated patients and the sham-treated control group was reported.7 This has greatly fueled the discussion on the role of RDN as an antihypertensive treatment approach. Technical and procedural insufficiency may have hampered the proof of an antihypertensive effect of RDN.8 In addition, it has been argued that the effects in earlier studies could be attributed to regression to the mean, improvement in life style factors and, in particular, to a change in medication use.9-11 In the Symplicity HTN-3 study, substantial differences in baseline anti-hypertensive medications and a striking 40% change in prescribed anti-hypertensives in both control and RDN-treated groups during the study has seriously limited evaluation of the true effect of RDN.7 Furthermore it is now well recognized that drug adherence in patients with hypertension is highly variable which further complicates assessment of anti- 6 hypertensive effects of drugs or device therapy.12-14 Recent RDN trials have attempted to overcome this problem by witnessed medication intake or by applying adherence questionnaires.6, 7, 15 In these randomized controlled trials the effect of RDN on 24-hour SBP ranged from no change to a reduction of 6 mmHg, with comparable medication adherence in RDN treated patients and the control group. Hypertensive patients on no medication seem to be an ideal population to quantify the effect of RDN on BP. Furthermore, patients with intolerance of anti-hypertensive medication pose a major challenge to clinicians and novel approaches are needed to improve their BP control given their high cardiovascular risk.16 This study reports on a collaborative initiative of eight centers active in device therapy of hypertension. We present the results of RDN in hypertensive patients who used no blood pressure lowering drugs for their BP before RDN and during follow-up.
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Methods
Design and study population
The study was designed to evaluate a cohort of patients that underwent RDN and who were either without blood pressure lowering drugs at baseline and follow-up, or, whose medication was withdrawn according to protocol. Our primary outcome was defined as change in office and 24-hour SBP at 12 months after RDN, compared to baseline. Eight international centers (seven in Europe and one in Australia) participated in this initiative and delivered patient records that met the following inclusion criteria: (Supplemental Table S6.1, which represents the participating centers) the patient was ≥ 18 years-old, treated with catheter-based RDN and had a baseline office SBP ≥ 140 mmHg and/or 24-hour SBP ≥ 130 mmHg. Patients were excluded if they were using medication for their hypertension or when no BP data were available at baseline or during follow-up visits. Local medical ethics committees approved the primary study in which the patient originally participated, in accordance with the Declaration of Helsinki.
Blood pressure assessments
Twenty-four hour BP and office BP measurements were collected at baseline and at 6 months and/or 12 months post RDN. Twenty-four hour BP was calculated as the mean of the readings at least every 30 minutes at daytime and every hour at night time. Office BP was calculated as the mean of three measurements obtained with a noninvasive automatic blood pressure measuring device with at least five minutes resting between each BP reading. All BP measurements were performed in accordance with the European guidelines and with recommended devices.17, 18 In the absence of a control group, we compared our results with the possible BP-lowering effect of simply taking part in a study. To assess this potential placebo effect, we selected studies from a recently published systematic review by Patel and co-workers (Supplemental Figure S6.1, which represents a forest plot of the selected studies).19
Other assessments
We collected physical (e.g. height, weight) and biochemical parameters (e.g. urinary sodium excretion) to explore life style and other potentially relevant factors at baseline and follow-up. We report on body mass index, kidney function and 24-hour urinary sodium excretion. Serum creatinine was determined as standard care at each study
114 RDN in unmedicated hypertensive patients
site (Jaffé or Enzymatic method).The estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) or Modification of Diet in Renal Diseases (MDRD) equation.20, 21 Measurements were standardized by converting the creatinine measurements with the Jaffé method to the Enzymatic method and the eGFR with MDRD to the CKD-EPI estimation.
RDN procedure
Study sites selected patients for RDN according to their own study protocol (Supplemental Table S6.1, which represents the participating centers). Percutaneous radiofrequency ablation was performed with SymplicityTM catheter (Medtronic Inc., Santa Rosa, California) or EnligHTNTM Ablation catheter (St Jude Medical, St Paul, MN, USA). Ultrasound RDN was performed with the use of PARADISETM technology (ReCor Medical, Ronkonkoma, NY, USA). The treating physician decided which renal arteries to treat, which device to use and how many ablations could be performed.
Statistical analysis
Results are presented as the mean difference between baseline and 12 months with 6 corresponding standard error and 95% CI interval, unless otherwise stated. When the 95% CI does not contain the zero value, the difference is considered statistically significant. Our primary outcome was change in BP 12 months after RDN. For missing data, we used the 6 months BP data carried forward. The rationale for this approach was to increase the number of individuals with an outcome variable. This was considered to be reasonable based on previous reports showing that over time the magnitude of the RDN effect does not seem to attenuate between 6 and 12 months, if anything an increase in RDN effect is expected.5, 22 To study the mean changes in BP we used paired analyses. To study change in BP and change in biological variables after RDN, we applied a linear regression model. Also, a linear regression model was applied to explore which baseline factors were related to the blood pressure change. Univariable models were the main approach due to the small sample size. To explore the data further, we applied a one-way ANOVA model to determine whether the reason for not using blood pressure lowering drugs resulted in different BP changes. In the present study we aimed to collect results of as many individuals who underwent RDN and were not using blood pressure lowering drugs as possible. Therefore, no sample size estimation was done upfront. All analyses were performed using the IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY, USA).
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Results
Baseline characteristics
Fifty-three records of patients, who complied with our inclusion criteria, were included. There were three different reasons for not using BP lowering drugs: 1) documented intolerance or allergic reaction (57%); 2) temporary cessation of medication for study purposes (followed by immediate resumption of drug treatment after study visits), using a highly standardized stepwise program (28%); and 3) reluctance to take antihypertensive drugs (15%).23, 24 Four patients for whom the reason was unknown were included in the first group. All patients underwent RDN between May 2011 and August 2014 in different study settings (Supplemental Table S6.1). Baseline characteristics are summarized in Table 6.1. Mean baseline 24-hour BP was 160±17/94±11 mmHg and mean office BP was 180±24/101±14 mmHg. Mean baseline eGFR estimated by CKD-EPI was 85±18 ml/ min/1.73m2. Three patients (6%) had moderately reduced kidney function (eGFR < 60 ml/min/1.73m2). Forty-two patients were treated with the Symplicity catheter, ten with the EnligHTN catheter and one was treated with ultrasound RDN. Baseline characteristics of the three groups of patients, according to the reason for not using blood pressure lowering drugs, are shown in Supplemental Table S6.2.
Change in blood pressure
Twenty-four hour BP and office BP data was available in 43 and 47 patients, respectively (6-months office and 24-hour BP data was carried forward for 7 and 14 patients, respectively). In the whole group, 24-hour SBP and diastolic BP (DBP) reduced after RDN as compared to baseline by -5.7 mmHg (95% confidence interval [CI], -11.0 to -0.4; P=0.04) and -4.0 mmHg (95% CI -6.6 to -1.4; P=0.003) respectively. Office SBP and DBP decreased significantly after RDN by -13.1 mmHg (95% CI -20.4 to -5.7; P=0.001) and -4.4 mmHg (95% CI -7.8 to -1.1; P=0.01), respectively (Table 6.2). There were no statistically significant differences in BP change between the three groups (P=0.45 and P=0.93 for 24-hour SBP and office SBP, respectively) (Supplemental Table S6.3). BP changes at 6 and 12 months are separately presented in Supplemental Table S6.4. Based on a systematic review, a selective pooling of previous studies was performed to assess the effect of participating in a trial on BP levels. Mean change in office SBP in the placebo controlled group was -4.0 mmHg (95% CI -7.5 to -0.4) and the change in 24-hour SBP -0.9 mmHg (95% CI -2.1 to 0.2) (Supplemental Figure S6.1, which represents a forest plot of the selected studies).
116 RDN in unmedicated hypertensive patients
Table 6.1 Baseline characteristics of the study population
All patients (n=53)
Age (yrs)a 62 (35–80)
Gender (male)b 24 (45.3)
Caucasianb 53 (100)
Body-mass index 28.4 (±4.9)
Comorbidity Dyslipidemiab 36% Diabetes Mellitus type 2b 11% Cardiovascular diseasesb 15% Cerebrovascular diseasesb 6%
Current smokingb 4 (8)
No. of antihypertensive drugsa 0 (0–0)
Reason for no medication use Intolerance, unknownb 30 (57) Study purposesb 15 (28) Never prescribedb 8 (15)
Office blood pressure Systolic (mmHg) 180 (±24) 6 Diastolic (mmHg) 101 (±14) Heart rate (bpm) 72 (±10)
Ambulatory blood pressure 24-hour systolic (mmHg) 160 (±17) 24-hour diastolic (mmHg) 94 (±11) 24-hour heart rate (bpm) 72 (±9)
eGFR, CKD epi (mL/min/1.73m2) 85 (±18)
Presence of accessory renal arteriesb 13 (25)
Not all renal arteries treatedb 7 (15)
Device used Symplicityb 42 (79) EnligHTNb 10 (19) PARADISEb 1 (2)
No. of ablationsa 13 (2–25) Data are expressed as mean ±SD, unless stated otherwise. Bpm, beats per minute; eGFR, estimated glomerular filtration rate; No., number. Body-mass index is the weight in kilograms divided by the square of the height in meters. a Data are mean (range). b Data are n (%).
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Table 6.2 Change in blood pressure and other relevant parameters after RDN
Mean change compared to baseline N (95% CI)
Ambulatory blood pressure 24-hour systolic (mmHg) 43 -5.7 (-11.0 to -0.4) 24-hour diastolic (mmHg) 43 -4.0 (-6.6 to -1.4) 24-hour heart rate (bpm) 35 -1.1 (-3.8 to 1.7) Day-time systolic (mmHg) 39 -8.2 (-13.4 to -3.0) Day-time diastolic (mmHg) 39 -4.9 (-7.9 to -2.5) Nighttime systolic (mmHg) 38 -6.3 (-14.1 to 1.4) Nighttime diastolic (mmHg) 38 -4.8 (-9.9 to 0.4)
Office blood pressure Systolic (mmHg) 47 -13.1 (-20.4 to -5.7) Diastolic (mmHg) 47 -4.4 (-7.8 to -1.1) Heart rate (bpm) 25 -2.6 (-6.7 to 1.5)
Body-mass index (kg/m2) 25 0.5 (-0.9 to 1.9)
eGFR, CKD epi (mL/min/1.73m2) 48 0.4 (-1.9 to 2.8)
Urinary sodium excretion (mmol/24h) 16 -23.3 (-89.3 to 42.7) N represents the number of patients with information on the variable of interest at baseline and at follow-up. Body-mass index is the weight in kilograms divided by the square of the height in meters. Bpm, beats per minute; eGFR, estimated glomerular filtration rate.
Anatomic and procedural determinants
Renal artery anatomy was established in 50 patients. Thirty-seven patients had a solitary artery on both sides, 13 patients had accessory renal arteries on one or both sides, of which three patients had more than one. Patients with solitary renal arteries were all treated in both renal arteries. Of the patients having accessory renal arteries, 7 patients could not be treated in all renal arteries. In Figure 6.1, the individual changes in BP are presented for the patients with solitary renal arteries. Mean change in 24-hour SBP is -5.4 mmHg (95% CI -10.7 to -0.11) and mean change in office SBP is -18.5 mmHg (95% CI -26.7 to -10.4). Individual changes of the patients with accessory renal arteries are shown in Supplemental Figure S6.2. Change in 24-hour SBP and office SBP did not differ between groups based on the device (Symplicity and EnligHTN) used for RDN (P=0.56; P=0.87, respectively). There was no relation between the number of ablations and the change in 24-hour SBP and office SBP (P=0.97; P=0.71, respectively). Data are not shown in this article.
118 RDN in unmedicated hypertensive patients &KDQJHLQRIILFH6%3 PP+J &KDQJHLQKRXU6%3 PP+J $ %
Figure 6.1 Individual changes in blood pressure after RDN, in patients with solitary renal arteries (A, n=35 and B, n=34). SBP, systolic blood pressure.
Explorative analyses into determinants of response to RDN
Univariable analysis showed no significant relation between baseline 24-hour SBP and change in 24-hour SBP after RDN (mean change in 24-hour SBP is -0.22 mmHg (95% CI 6 -0.53 to 0.083; P=0.15 ) for every mmHg increase in baseline 24-hour SBP).There was a significant relation between baseline office SBP and change in SBP after RDN (mean change in office SBP is -0.36 mmHg (95% CI -0.64 to -0.089; P=0.011) for every mmHg increase in baseline office SBP). We observed a relation between percentage dipping at baseline and change in SBP after RDN (mean change in 24-hour SBP is 0.76 mmHg (95% CI 0.18 to 1.35; P=0.01) and for office SBP 0.82 mmHg (95% CI 0.013 to 1.62; P=0.047) for every percentage increase in dipping (Supplemental Figure S6.3, which represents the relation between these variables). This demonstrates that patients with more nocturnal dipping have less reduction in blood pressure after RDN. Furthermore, nighttime BP was positively related to change in SBP after RDN (mean change in 24- hour SBP is -0.43 mmHg (95% CI -0.70 to -0.16; P=0.002) and for office SBP -0.35 mmHg (95% CI -0.74 to -0.054; P=0.088) for every percentage increase in nighttime BP). All univariable analyses are presented in Table 6.3. With regard to lifestyle and other biological factors, we observed no changes in BMI, eGFR and urinary sodium excretion after RDN (Table 6.2).
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Table 6.3 Univariable analyses of change in 24-hour systolic blood pressure
N B (95% CI)
Age 43 0.19 (-0.39 to 0.76)
Gender, female 43 1.58a (-9.23 to 12.38)
Body-mass index 40 0.52 (-0.53 to 1.58)
eGFR, CDK epi (mL/min/1.73m2) 40 -0.13 (-0.45 to 0.18)
Urine sodium mmol/24h 24 0.01 (-0.05 to 0.07)
Baseline 24-hour SBP (mmHg) 43 -0.22 (-0.53 to 0.08)
Baseline percentage dipping 38 0.76 (0.18 to 1.35)
Baseline nighttime SBP (mmHg) 38 -0.43 (-0.70 to -0.16)
No. of ablations 40 -0.03 (-1.75 to 1.69) Univariable analyses of the relation between baseline and/or procedural characteristics and the change in 24-hour systolic blood pressures after RDN in all patients. N represents the number of patients with information on both the change in 24-hour systolic blood pressure and the variable of interest. B, the regression coefficient, reflects the mean change in 24-hour systolic blood pressure by one unit increase in determinant. a B reflects the mean change in 24-hour systolic blood pressure if this characteristic is applied. Body-mass index is the weight in kilograms divided by the square of the height in meters. SBP, systolic blood pressure; No., number.
Discussion
To the best of our knowledge, this is the first report on the BP lowering effect of RDN in hypertensive patients who were not using blood pressure lowering drugs at baseline and during follow-up. Ambulatory and office BP were significantly reduced after RDN, in this patient group with considerable heterogeneity. So far, the effect of RDN has been investigated when added to medical therapy in patients with so called resistant hypertension. Resistant hypertension is defined as an office SBP ≥ 140 mmHg, despite the use of at least three BP lowering drugs.17 A major difficulty in such studies is that use of prescribed medication is highly variable and, importantly, may change over time. In the present study, this poorly controllable, but important effect modifier, has been eliminated by selecting patients not on antihypertensive drugs, allowing an estimation of the net effect of RDN. The magnitude of the RDN effect seen in our study is comparable to what has been documented in the DENERHTN study, in which the BP lowering efficacy of RDN plus standardized antihypertensive treatment was compared with standardized antihypertensive treatment alone in patients with resistant hypertension. In DENERHTN
120 RDN in unmedicated hypertensive patients
specific efforts were undertaken to maximize medication adherence.6 When looking at six months results, they noted a change in 24-hour BP of -5.9/-3.1 mmHg which is not very different from the -5.0/-2.0 mmHg we found in our study. In addition, we found a further decline to -7.0/-4.0 mmHg 12 months after RDN. As mentioned above. we observed considerable heterogeneity of BP response to RDN. This variability was also noted in previous studies.6, 22 Procedure and patient related factors could play a role. The majority of the renal denervation procedures were done with Medtronic’s Simplicity device. It is now increasingly clear that procedural factors such as completeness of circumferential coverage, depth and location of ablations may result in a variable and unpredictable degree of nerve destruction and as result a variable effect on BP.25, 26 In this small study sample, we found no relation between the number of ablations and BP effect and no difference in effect between the two devices. Explorative analyses were performed on patient related factors that may affect the degree of effect. As consistently reported earlier, we found that a higher baseline office SBP is associated with a larger BP reduction.22, 27 Interestingly, the BP lowering effect was larger in non-dipping patients. This finding is in line with the knowledge that reduced nocturnal dipping is a characteristic of an upregulated sympathetic nervous system.24 Furthermore, a comparable relation between nighttime BP and reduction in BP was seen. 6
For this study we collected records of patients previously treated with RDN, therefore a control group was lacking. This results in uncertainty whether the observed decline in BP after RDN may (partially) be due to other mechanisms, including life-style improvement, the effect of taking part in a trial and also the ‘regression to the mean’ phenomenon. Our data suggest no major changes in potentially relevant factors, such as BMI, eGFR and urinary sodium excretion. It is highly implausible that ‘regression to the mean’ can be responsible when observing sustained BP reductions 12 months post RDN. Furthermore, most patients already have a long history of hypertension. In order to overcome the limitation of having no control group, we assessed the BP lowering effect in the placebo arm of hypertension trials in patient populations not on antihypertensive drugs, based on a recently published systematic review (Supplemental Figure S6.1).19, 28-37 The comparison of this estimated placebo effect with the present analysis suggests that the 24-hour and office BP reduction after RDN (-5.7 and -13.0 mmHg systolic, respectively) is on average larger than could be expected from participating in a study per se (-0.9 and -4.0 mmHg change in SBP, respectively). Although, we believe this is the best available comparison, an important limitation is the heterogeneity of these
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studies and, on average, lower baseline BP compared with our study. Furthermore, the calculated study-/placebo effect was purely based on pharmacological interventions. The effect of a sham procedure might be different.
This study has some other limitations as well. Firstly, our study may consist of a highly selected population. However, when compared to earlier studies, our population did not differ in mean levels of predictors of response to RDN.6, 7, 15, 22, 38 Therefore, our results unlikely reflect a biased estimate. Secondly, we did not measure drug metabolites to check whether patients were really not using blood pressure medication during the measurement. However, it seems unlikely that patients are using drugs without prescription.
Conclusion
In conclusion, this explorative study suggests a beneficial effect of RDN on blood pressure in patients with hypertension, independent of medication change during the study. Furthermore, this supports the rationale to investigate the effects of RDN in a patient population not on blood pressure lowering drugs.39, 40
Acknowledgements
We would especially like to thank St. Jude Medical and Medtronic for providing part of the data and supporting the research at the applicable sites. Furthermore we would like to thank all contributors in the participating RDN centers.
122 RDN in unmedicated hypertensive patients
References
(1) DiBona GF, Esler M. Translational medicine: the antihypertensive effect of renal denervation. Am J Physiol Regul Integr Comp Physiol.2010;298(2):R245-R253. (2) Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet.2010;376(9756):1903-1909. (3) Schlaich MP, Sobotka PA, Krum H, Lambert E, Esler MD. Renal sympathetic-nerve ablation for uncontrolled hypertension. N Engl J Med.2009;361(9):932-934. (4) Krum H, Schlaich M, Whitbourn R et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet.2009;373(9671): 1275-1281. (5) Papademetriou V, Tsioufis CP, Sinhal A et al. Catheter-based renal denervation for resistant hypertension: 12-month results of the EnligHTN I first-in-human study using a multielectrode ablation system. Hypertension.2014;64(3):565-572. (6) 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(9981):1957-1965. (7) Bhatt DL, Kandzari DE, O’Neill WW et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med.2014;370(15):1393-1401. (8) Kandzari DE, Bhatt DL, Brar S et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J.2015;36(4):219-227. (9) Papademetriou V, Rashidi AA, Tsioufis C, Doumas M. Renal nerve ablation for resistant hypertension: how did we get here, present status, and future directions. Circulation.2014;129(13):1440-1451. (10) Persu A, Jin Y, Fadl Elmula FE, Jacobs L, Renkin J, Kjeldsen S. Renal denervation after Symplicity HTN-3: an update. Curr Hypertens Rep.2014;16(8):460. 6 (11) Schmieder RE. Renal denervation--a valid treatment option despite SYMPLICITY HTN-3. Nat Rev Cardiol.2014;11(11):638. (12) Burnier M, Schneider MP, Chiolero A, Stubi CL, Brunner HR. Electronic compliance monitoring in resistant hypertension: the basis for rational therapeutic decisions. J Hypertens.2001;19(2):335-341. (13) Jung O, Gechter JL, Wunder C et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens.2013;31(4):766-774. (14) Strauch B, Petrak O, Zelinka T et al. Precise assessment of noncompliance with the antihypertensive therapy in patients with resistant hypertension using toxicological serum analysis. J Hypertens.2013; 31(12):2455-2461. (15) Fadl Elmula FE, Hoffmann P, Larstorp AC et al. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension.2014; 63(5):991-999. (16) Antoniou S, Saxena M, Hamedi N et al. Management of Hypertensive Patients With Multiple Drug Intolerances: A Single-Center Experience of a Novel Treatment Algorithm. J Clin Hypertens (Greenwich).2016;18(2):129-138. (17) Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens.2013;31(7): 1281-1357. (18) O’Brien E, Pickering T, Asmar R et al. Working Group on Blood Pressure Monitoring of the European Society of Hypertension International Protocol for validation of blood pressure measuring devices in adults. Blood Press Monit.2002;7(1):3-17.
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(19) Patel HC, Hayward C, Ozdemir BA et al. Magnitude of blood pressure reduction in the placebo arms of modern hypertension trials: implications for trials of renal denervation. Hypertension.2015; 65(2):401-406. (20) Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med.1999;130(6):461-470. (21) Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Ann Intern Med.2009;150(9):604-612. (22) Esler MD, Krum H, Schlaich M, Schmieder RE, Bohm M, Sobotka PA. Renal sympathetic denervation for treatment of drug-resistant hypertension: one-year results from the Symplicity HTN-2 randomized, controlled trial. Circulation.2012;126(25):2976-2982. (23) Verloop WL, Vink EE, Voskuil M et al. Eligibility for percutaneous renal denervation: the importance of a systematic screening. J Hypertens.2013;31(8):1662-1668. (24) Vink EE, Verloop WL, Bost RB et al. The blood pressure-lowering effect of renal denervation is inversely related to kidney function. J Hypertens.2014;32(10):2045-2053. (25) Tzafriri AR, Mahfoud F, Keating JH et al. Innervation patterns may limit response to endovascular renal denervation. J Am Coll Cardiol.2014;64(11):1079-1087. (26) Tzafriri AR, Keating JH, Markham PM et al. Arterial microanatomy determines the success of energy-based renal denervation in controlling hypertension. Sci Transl Med.2015;7(285):285ra65. (27) Kandzari DE, Bhatt DL, Sobotka PA et al. Catheter-based renal denervation for resistant hyperten- sion: rationale and design of the SYMPLICITY HTN-3 Trial. Clin Cardiol.2012;35(9):528-535. (28) Chan TY, Woo KS, Nicholls MG. The application of nebivolol in essential hypertension: a double- blind, randomized, placebo-controlled study. Int J Cardiol.1992;35(3):387-395. (29) Chrysant SG, Weber MA, Wang AC, Hinman DJ. Evaluation of antihypertensive therapy with the combination of olmesartan medoxomil and hydrochlorothiazide. Am J Hypertens.2004;17(3):252-259. (30) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-437_Inspra_Medr_P3.pdf (Date accessed: 1 July 2015). (31) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2011/200796Orig1s000MedR.pdf (Date accessed: 1 July 2015). (32) http://www.accessdata.fda.gov/drugsatfda_docs/nda/2002/21-286_Benicar_medr_P2.pdf (Date accessed: 1 July 2015). (33) Saruta T, Kageyama S, Ogihara T et al. Efficacy and safety of the selective aldosterone blocker eplerenone in Japanese patients with hypertension: a randomized, double-blind, placebo- controlled, dose-ranging study. J Clin Hypertens (Greenwich).2004;6(4):175-183. (34) Saunders E, Smith WB, DeSalvo KB, Sullivan WA. The efficacy and tolerability of nebivolol in hypertensive African American patients. J Clin Hypertens (Greenwich).2007;9(11):866-875. (35) Weinberger MH, Roniker B, Krause SL, Weiss RJ. Eplerenone, a selective aldosterone blocker, in mild-to-moderate hypertension. Am J Hypertens.2002;15(8):709-716. (36) White WB, Weber MA, Sica D et al. Effects of the angiotensin receptor blocker azilsartan medoxomil versus olmesartan and valsartan on ambulatory and clinic blood pressure in patients with stages 1 and 2 hypertension. Hypertension.2011;57(3):413-420. (37) White WB, Carr AA, Krause S, Jordan R, Roniker B, Oigman W. Assessment of the novel selective aldosterone blocker eplerenone using ambulatory and clinical blood pressure in patients with systemic hypertension. Am J Cardiol.2003;92(1):38-42. (38) 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(2):407-413.
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(39) Mahfoud F, Bohm M, Azizi M et al. Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design. Eur Heart J.2015;36(33):2219- 2227. (40) Weber MA, Kirtane A, Mauri L, Townsend RR, Kandzari DE, Leon MB. Renal Denervation for the Treatment of Hypertension: Making a New Start, Getting It Right. J Clin Hypertens (Greenwich). 2015;17(10):743-750. (41) Laird NM, Ware JH. Random-effects models for longitudinal data. Biometrics. 1982;38:963-974.
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Supplemental information
Supplemental Table S6.1 Overview of participating centers
Participating centers Primary outcome N Pubmed ID
University Medical Center Utrecht, Netherlands Registry blood pressure 22 25326543 DREAMS insulin sensitivity and 8 25646297 blood pressure
Barts Health Trust and the William Harvey blood pressure 6 NA Research Institute London, UK
Universitätsklinikum Erlangen, Germany albuminuria 3 24681017
Universitätsklinikum Gießen, Germany blood pressure 3 NA
Bakers IDI Heart and Diabetes Institute, blood pressure 3 NA Melbourne, Australia
Universitätsklinikum des Saarlandes, Germany blood pressure 2 NA
Erasmus Medical Center Rotterdam, blood pressure 1 NA Netherlands
Catharina Ziekenhuis Eindhoven, Netherlands blood pressure 1 NA
Global SYMPLICITY Registry blood pressure 4 25691618 RDN, renal denervation; N, number of patients without blood pressure lowering drugs; ID, iden- tification number; NA, not applicable.
126 RDN in unmedicated hypertensive patients
Supplemental Table S6.2 Baseline characteristics by reason for not taking blood pressure lowering drugs
Intolerance Study purposes Never prescribed (n=30) (n=15) (n=8)
Age (yrs) 61 (±12) 59 (±9) 58 (±10)
Gender, femaleb 20 (67) 5 (33) 4 (50)
Body-mass index (kg/m2) 27.6 (±4.7) 28.9 (±5.5) 30.2 (±4.5)
Comorbidity Dyslipidemia 27% 64% 29% Diabetes Mellitus type 2 3% 27% 13% Cardiovascular diseases 15% 27% 0% Cerebrovascular diseases 11% 0% 0%
Current smoking 9% 7% 14%
No. of antihypertensive drugsa 0 (0–0) 0 (0–0) 0 (0–0)
Office blood pressure Systolic (mmHg) 181 (±25) 185 (±24) 167 (±22) Diastolic (mmHg) 100 (±13) 105 (±14) 101 (±14) Heart rate (bpm) 72 (±11) 72 (±8) UN
Ambulatory blood pressure 24-hour systolic (mmHg) 159 (±14) 170 (±17) 145 (±18) 6 24-hour diastolic (mmHg) 94 (±10) 98 (±13) 88 (±13) 24-hour heart rate (bpm) 72 (±8) 72 (±10) 73 (±9)
eGFR, CDK epi (mL/min/1.73m2) 85 (±16) 81 (±20) 90 (±17)
Presence of accessory renal arteriesb 7 (23) 3 (20) 3 (38)
Not all renal arteries treatedb 3 (11) 3 (20) 1 (13)
Device used Symplicityb 21 (70) 13 (87) 8 (100) EnligHTNb 8 (27) 2 (13) 0 (0) PARADISEb 1 (3) 0 (0) 0 (0)
No. of ablationsa 13 (6–25) 12 (10–16) 13 (2–17) Data are expressed as mean ±SD, unless stated otherwise. Bpm, beats per minute; eGFR, estimated glomerular filtration rate; No., number; UN, unknown. Body-mass index is the weight in kilograms divided by the square of the height in meters. a Data are mean (range). b Data are n (%).
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Supplemental Table S6.3 Blood pressure changes in strata of the reason for not taking blood pressure lowering drugs during the blood pressure measurements
Intolerance Study purpose Never prescribed
Ambulatory blood pressure N=22 N=15 N=6 24-hour systolic (mmHg) -3.7 (-12.4 to 5.0) -10.2 (-18.1 to -2.3) -1.8 (-17.4 to 13.8) 24-hour diastolic (mmHg) -2.3 (-5.9 to 1.3) -6.7 (-11.7 to -1.8) -3.3 (-11.1 to 4.5) 24-hour heart rate (bpm) -1.8 (-6.4 to 2.9) -0.15 (-2.8 to 2.5) 0.0 (-25.4 to 25.4) Daytime systolic (mmHg) -7.1 (-16.0 to 1.8) -10.3 (-18.9 to -1.8) -6.5 (-20.0 to 7.0) Daytime diastolic (mmHg) -3.2 (-6.6 to 0.19) -6.1 (-11.5 to -0.6) -6.8 (-13.6 to -0.1)
Office blood pressure N=29 N=10 N=8 Systolic (mmHg) -14.1 (-24.0 to -4.2) -12.1 (-34.6 to 10.4) -10.5 (-19.9 to -1.1) Diastolic (mmHg) -3.1 (-7.7 to 1.5) -7.1 (-16.4 to 2.2) -5.9 (-11.4 to -0.4) Heart rate (bpm) -3.2 (-7.7 to 1.2) 2.0 (-19.5 to 23.5) UN Data are expressed as mean change compared to baseline (95% CI). When all groups are compared, P=0.45 and P=0.93 for 24-hour systolic blood pressure and office systolic blood pressure, respectively. N represents the number of patients with information on the variable of interest at baseline and at follow-up. Bpm, beats per minute; UN, unknown.
128 RDN in unmedicated hypertensive patients * N Baseline 12 months P-value
6 * N Baseline 6 months P-value 24-hour systolic (mmHg)24-hour diastolic (mmHg) 1924-hour heart rate (bpm) 19 159 (±15)Daytime systolic (mmHg) 17 92 (±9) 154 (±22)Daytime diastolic (mmHg) 15 73 (±9) 15 90 (±10) 164 (±17) 0.314Systolic (mmHg) 95 (±9) 158 (±23) 71 (±10) 0.032Diastolic (mmHg) 24-hour systolic (mmHg) 92 (±11)Heart rate (bpm) 0.218 0.283 36 24-hour diastolic (mmHg) 0.032 160 (±18) 36 Daytime systolic (mmHg) 36 24-hour heart rate (bpm) 36 177 (±25) 153 (±19) 93 (±12) 35 30 22 Daytime diastolic (mmHg) 98 (±13) 164 (±28) 165 (±18) 0.016 35 73 (±11) 89 (±12) 72 (±9) 94 (±14) 156 (±19) 0.004 97 (±12) 70 (±10) 0.004 71 (±9) 0.036 0.001 92 (±12) Systolic (mmHg) 0.786 0.774 Diastolic (mmHg) 0.001 Heart rate (bpm) 33 177 (±23) 33 100 (±12) 166 (±28) 21 94 (±14) 74 (±11) 0.013 69 (±12) 0.008 0.163 Ambulatory blood pressure blood pressureOffice Ambulatory blood pressure blood pressure Office Data are expressed as mean ±SD. Bpm, beats per minute. expressed Data are baseline to 6 or 12 months follow-up. from in mean blood pressure * P-value for the difference Supplemental Table S6.4 Supplemental Table with baseline blood pressure at 6 and 12 months compared Blood pressure
129 Chapter 6
A
B
Supplemental Figure S6.1 Forest plot of studies examining the effect of being in a trial and receiving a placebo on the change in systolic blood pressure (SBP) over time (A: office SBP; B: 24-hour SBP). We selected from Patel et al. those that met the following criteria: no use of blood pressure lowering drugs in the control group and a follow-up ≥ 12 weeks. Results were obtained using a random effect model, weighted by using the inverse of standard error.41 The mean differences of 4.0 mmHg and 0.9 mmHg reflect a reduction in SBP. &KDQJHLQRIILFH6%3 PP+J &KDQJHLQKRXU6%3 PP+J $ %
Supplemental Figure S6.2 Individual changes in BP after RDN, in patients with accessory renal arteries (A, n=8 and B, n=13). SBP, systolic blood pressure.
130 RDN in unmedicated hypertensive patients
$
6
%
Supplemental Figure S6.3 The relation between percentage dipping at baseline and change in SBP after RDN. For every percentage increase in dipping at baseline, the mean change in 24-hour SBP is 0.76 mmHg (A) and for office SBP 0.82 mmHg after RDN (B). This means that patients with more nocturnal dipping have less reduction in BP after RDN. SBP, systolic blood pressure.
131
CHAPTER
S100B as marker fdfor nerve damage after renal denervation
R.L. de Jager, M.M. Beeftink, M.F. Sanders, E.J. Vonken, M.L. Bots, P.J. Blankestijn, on behalf of the UMCU RDN study group
Submitted Chapter 7
Abstract
Background Renal denervation (RDN) has been used to reduce blood pressure (BP) in resistant hypertensive patients with variable effect. Therefore, we explored S100B, a neurotrophic protein increased in nerve damage, as direct marker for the success of RDN.
Methods In this pilot study we included ten resistant hypertensive patients who underwent RDN. S100B levels were measured in arterial and venous samples at different time-points (pre- and post-RDN). Office BP and 24-hour BP were assessed at baseline and six months post-RDN.
Results S100B levels increased at all time-points between baseline and 24-hours post-RDN. The maximum level was reached six hours post-RDN with a median increase of 10% [-11 to 119]. We observed a trend for a relation between increase of S100B levels and decline in BP.
Conclusion S100B increases after RDN, which suggests nerve damage. However, further research to assess the relation between S100B level and change in BP is needed.
134 S100B as marker for nerve damage after RDN
Introduction
In multiple studies percutaneous renal denervation (RDN) has been applied as a new therapy for resistant hypertension.1 The procedure is meant to destroy the renal nerves which are located around the renal artery. A common finding of the studies is that there is a great variability in the blood pressure (BP) reduction after RDN.2-5 There is increasing awareness that a highly variable completeness of the denervation is obtained with the most commonly used device.6 So, there is a need for a biomarker that represents nerve tissue damage that shows detectable changes shortly after the induction of the damage and that is easily measurable. S100B is of particular interest, because it is one of the most specific biomarkers of nerve tissue damage.7 S100B is increased after traumatic brain injury and relates to neuropsychological outcome.7-10 However, it seems likely that nerve tissue damage after RDN is only limited and could be insufficient to cause an increase in S100B in blood.
The aim of the present pilot study was to explore the direct effects of RDN on the levels of S100B in hypertensive patients. We hypothesized that a RDN procedure results in a detectable increase in S100B. Secondly, we explored whether any rise in S100B relates to the effect on BP.
Methods
Study design and population 7 This study was set up as a pilot study with an observational design. The primary objective was to assess whether S100B increased after RDN as a reflection of nerve damage. Further, we wanted to explore a possible relation between the maximum concentration S100B after the procedure and BP change after RDN., The population of this pilot study consists of adults with an average ambulatory daytime BP ≥ 135 mmHg, despite the use of three or more BP-lowering drugs or with documented intolerance for more than two of the four major classes of BP lowering drugs (ACE/ARB, calcium channel blocker, beta blocker, diuretic) and no possibility to take three anti-hypertensive drugs.11 Patients were not included when the patient had renal anatomy ineligible for RDN or the presence of comorbidities that, potentially, influence S100B levels (neurodegenerative disease, melanoma, other nerve injuries).12
135 Chapter 7 Figure 7.1 Figure denervation (RDN). and post renal Timeline of S100B samples pre
136 S100B as marker for nerve damage after RDN
S100B assessment
Whole blood samples of 500 μl each were collected at protocolled time points as presented in Figure 7.1. Before RDN (baseline) a venous (T1) and arterial (T2) sample of the first treated renal artery were taken. The timing of the follow-up samples was based on the experience from studies investigating S100B in traumatic brain injury.8, 10, 13 Samples were stored at -80°C, until all samples were collected. Then, all samples were analysed in one batch using an electrochemiluminescence immunoassay (Modular E170 Roche, Basel, Switzerland).14
Blood pressure assessment
Office BP was performed at baseline and six months after RDN. The measurement was an average of two measurements in the morning on both arms and done with an automatic device recommended by the European Society for Hypertension.15 24-hour ambulatory BP was assessed at baseline and six months after RDN and measured, non- invasively, with a recommended automatic device.
RDN procedure
RDN was performed by a certified intervention radiologist or cardiologist. At the time of initiating this study, the National Health Care Institute in the Netherlands permitted us to use only the Simplicity catheter (Medtronic Inc., Santa Rosa, CA, USA) or EnligHTNTM Ablation catheter (St Jude Medical, St Paul, MN, USA) for RDN, based on the knowledge 7 about effectiveness and safety.1 The choice of the device, as well as the location and amount of ablations, was left to the discrepancy of the interventionist.
Statistical analysis
Data was presented as mean (SE) when normally distributed or as median [interquartile] if not normally distributed. Absolute changes in S100B levels were analyzed, using the Wilcoxon signed-rank test. Paired t-tests were used to compare changes in BP. To assess a possible relation between change in BP and the percentage change in S100B concentration after RDN, Spearman’s rank correlation analysis was used. A two-sided level of ≤ 0.05 was considered to be significant. All analyses were performed using the IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY, USA).
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Results
Ten patients were enrolled in this pilot study between July 2014 and July 2015. RDN was performed in the same period. Mean age was 63 (43–77) years. Patients had, on average, a normal kidney function (eGFR 76±21 ml/min/1.73m2) and seven patients were male (Table 7.1). Median baseline S100B concentration was 0.050 [0.038–0.063] and 0.045
Table 7.1 Baseline characteristics
Study population (n=10)
Age (years)£ 63 (43–77) Male¥ 7 Caucasian¥ 10 Body-Mass-Index 27.8 (±1.0) Comorbidity¥ Dyslipidemia 0 Diabetes Mellitus type 2 0 (Cardio)vascular diseases 4 Current smoking¥ 3 No. of antihypertensive drugs 3 (±1) Office blood pressure Systolic (mmHg) 185 (±5) Diastolic (mmHg) 100 (±3) Heart rate (bpm) 67 (±5) 24-hour ambulatory blood pressure Systolic (mmHg) 151 (±5) Diastolic (mmHg) 83 (±3) Heart rate (bpm) 62 (±1) S100B concentration (venous) μg/l* 0.050 [0.038–0.063] S100B concentration (arterial) μg/l* 0.045 [0.040–0.063] eGFR, CKD epi (mL/min/1.73m2) 76 (±7) Presence of accessory renal arteries 4 Accessory artery treated 1 Diameter treated renal arteries (mm) 5 (±0.3) Device used Symplicity 7 EnligHTN 3 No. of ablations 15 (±1) All values are expressed as mean (±SE), unless stated otherwise. * Value represents median [interquartile]. ¥ Value represents number of patients. £ Value represents mean (range). eGFR, estimated glomerular filtration rate; bpm, beats per minute. No., number.
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[0.040–0.063] μg/l for the venous and arterial sample, respectively (P=0.55, representing the difference between venous and arterial sampling). Average BP was 185±15/100±9 mmHg for office BP and 151±16/83±10 mmHg for mean 24-hour ambulatory BP.
S100B concentration
Median S100B level increased at all time-points after RDN. Figure 7.2 demonstrates the individual percentages of change in S100B level at different time-points compared with baseline S100B level. The maximum S100B concentration was reached six hours after RDN (0.065 [0.053 to 0.070] μg/l), which was a median increase of 10 [-11 to 119] %, compared to baseline. At six months follow-up, S100B level returned to 0.040 [0.030 to 0.060] μg/l] (median difference compared to baseline: 0.000 [-0.020 to 0.008] μg/l).
Change in blood pressure after renal denervation
The individual changes in BP are depicted in Figure 7.3. Mean change in office BP at six months, compared to baseline, was -8±9/0±5 mmHg (P=0.38 and P=0.94, respectively).
7
Figure 7.2 Individual data of percentage of change in S100B level measured at different time- points, compared to baseline. RDN, renal denervation.
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Twenty-four hour ambulatory BP changed with 4±6/4±3 mmHg at six months (P=0.50 and 0.18, respectively). There was a trend for 24-hour ambulatory BP observed, showing a slightly larger decrease in BP after RDN, when percentage of change in S100B level increased (correlation coefficient= -0.277, P=0.51).
A
B
Figure 7.3 Individual data of change in blood pressure at six months after renal denervation compared to baseline. A: office systolic blood pressure. B: 24-hour systolic blood pressure. SBP, systolic blood pressure; RDN, renal denervation.
140 S100B as marker for nerve damage after RDN
Discussion
The present pilot study shows that S100B increased (at least in some patients) in the first 24 hours after RDN. Levels on average returned to baseline after one week and six months. The data supports the hypothesis that a detectable change in this biomarker of nerve tissue damage occurs within 24 hours after RDN.
Our baseline S100B levels were similar to the 0.05 μg/l found in healthy individuals in earlier studies.16, 17 Baseline levels of venous and arterial samples were comparable. The pattern of change suggests that levels of S100B rise within hours after the procedure, reaching a maximum somewhere between six and 24 hours. The degree of rise is much lower than what is seen in patients with traumatic brain damage, whose maximum levels varied between 0.4 and 3.14 μg/L.8, 9, 18 It seems logical to assume that in those studies nerve tissue damage was much more extensive, than the damage caused by RDN.
To the best of our knowledge, there are only two earlier papers exploring the concept of measuring a neuro biomarker after RDN. A Chinese study in dogs reported a rise in S100B after RDN with a maximum after three days and levels gradually returning to baseline within two to four weeks (paper in Chinese).19 Recently, Dörr et al. published a letter on brain-derived neurotrophic factor (BDNF). This is a key mediator of neuronal and synaptic plasticity and regulates neurotransmitter production in the sympathetic nervous system.20 They measured BDNF in 100 hypertensive patients before RDN and two hours and six months after RDN. A decrease in BDNF shortly after the procedure was 7 observed, which correlated with the effect on blood pressure at six months. Both BDNF and S100B are considered to be markers in traumatic brain injury. One study suggests that S100B is a stronger predictor of neurological outcome than BDNF, which could mean that it closer reflects the level of tissue damage.21 Results of the present and these two earlier studies are compatible with the idea that RDN results in detectable changes in two different types of neuro biomarkers. Obviously, the key question is whether these changes really reflect nerve tissue damage. Unfortunately, in the experimental study (a Chinese paper), the change was not related to histological quantification of the degree of nerve damage.19 Such a validation study relating changes in levels of these markers to degree of nerve damage, which should be considered the gold standard in this respect, is necessary and can for obvious reasons only be done in experimental settings. Further, it needs to be established what should be considered as an adequate rise in S100B. In other words, what level of increase could indicate (near) total renal nerve denervation?
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A limitation of this concept is that the information on the degree of nerve damage is only available after the patient already has left the angioroom. Ideally, this information should be available during the procedure, so that it can be used by the interventionist to deliver an adequate treatment. Such a method could be the intra-procedural catheter based nerve stimulation.22, 23 However, this procedure is time consuming and troublesome.
Still, we think that these neuro biomarkers are of potential clinical relevance. The ultimate goal of RDN is to reduce blood pressure. However, blood pressure is determined by many other factors other than renal nerves as well. It is very likely that not all hypertensive patients will respond to RDN, despite of the fact that the intervention is properly done. So for instance, a rise in S100B without an effect on blood pressure would indicate that the patient is unresponsive to RDN and not that the procedure was improperly done. This distinction is of significant clinical relevance.
We found a small trend between rise in S100B and effect on blood pressure. But, our sample size is too small to draw any firm conclusions.
In conclusion, our pilot-study suggests that a detectable rise in S100B, a biomarker known to indicate nerve tissue damage, occurs in the first 24 hours after RDN. It would be of value to further explore both experimentally and clinically the potential role of this concept.
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References
(1) de Jager RL, de Beus E., Beeftink MM et al. Impact of medication adherence on the effect of renal denervation. The SYMPATHY trial. Hypertension. 2017;69(4):678-684. (2) 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(9981):1957-1965. (3) Bhatt DL, Kandzari DE, O’Neill WW et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370(15):1393-1401. (4) Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010;376(9756):1903-1909. (5) Papademetriou V, Tsioufis CP, Sinhal A et al. Catheter-based renal denervation for resistant hypertension: 12-month results of the EnligHTN I first-in-human study using a multielectrode ablation system. Hypertension. 2014;64(3):565-572. (6) Kandzari DE, Bhatt DL, Brar S et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J. 2015;36(4):219-227. (7) de K, Jr., Leffers P, Menheere PP, Meerhoff S, Twijnstra A. S-100B and neuron-specific enolase in serum of mild traumatic brain injury patients. A comparison with health controls. Acta Neurol Scand. 2001;103(3):175-179. (8) Ingebrigtsen T, Romner B. Biochemical serum markers for brain damage: a short review with emphasis on clinical utility in mild head injury. Restor Neurol Neurosci. 2003;21(3-4):171-176. (9) Naeimi ZS, Weinhofer A, Sarahrudi K, Heinz T, Vecsei V. Predictive value of S-100B protein and neuron specific-enolase as markers of traumatic brain damage in clinical use. Brain Inj. 2006;20(5):463-468. (10) Korfias S, Papadimitriou A, Stranjalis G et al. Serum biochemical markers of brain injury. Mini Rev Med Chem. 2009;9(2):227-234. (11) Sanders MF, Blankestijn PJ, Voskuil M et al. Safety and long-term effects of renal denervation: Rationale and design of the Dutch registry. Neth J Med. 2016;74(1):5-15. (12) Donato R, Cannon BR, Sorci G et al. Functions of S100 proteins. Curr Mol Med. 2013;13(1):24-57. (13) Michetti F, Gazzolo D. S100B protein in biological fluids: a tool for perinatal medicine. Clin Chem. 7 2002;48(12):2097-2104. (14) Alber B, Hein R, Garbe C, Caroli U, Luppa PB. Multicenter evaluation of the analytical and clinical performance of the Elecsys S100 immunoassay in patients with malignant melanoma. Clin Chem Lab Med. 2005;43(5):557-563. (15) Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31(7):1281-1357. (16) Nygaard O, Langbakk B, Romner B. Age- and sex-related changes of S-100 protein concentrations in cerebrospinal fluid and serum in patients with no previous history of neurological disorder. Clin Chem. 1997;43(3):541-543. (17) Wiesmann M, Missler U, Gottmann D, Gehring S. Plasma S-100b protein concentration in healthy adults is age- and sex-independent. Clin Chem. 1998;44(5):1056-1058. (18) Rodriguez-Rodriguez A, Egea-Guerrero JJ, Leon-Justel A et al. Role of S100B protein in urine and serum as an early predictor of mortality after severe traumatic brain injury in adults. Clin Chim Acta. 2012;414:228-233. (19) Jiang F, Wang X, Zhu F et al. [Changes of blood pressure and S-100B, neuron specific enolase protein in hypertensive dogs after renal sympathetic denervation]. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2014;39(3):245-251.
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(20) Dorr O, Liebetrau C, Mollmann H et al. Brain-derived neurotrophic factor as a marker for immediate assessment of the success of renal sympathetic denervation. J Am Coll Cardiol. 2015;65(11):1151- 1153. (21) Di Battista AP, Buonora JE, Rhind SG et al. Blood Biomarkers in Moderate-To-Severe Traumatic Brain Injury: Potential Utility of a Multi-Marker Approach in Characterizing Outcome. Front Neurol. 2015;6:110. (22) de Jong MR, Adiyaman A, Gal P et al. Renal Nerve Stimulation-Induced Blood Pressure Changes Predict Ambulatory Blood Pressure Response After Renal Denervation. Hypertension. 2016;68(3):707-714. (23) Persu A, Scavee C, Staessen JA, Blankestijn PJ. Electric nerve stimulation to monitor the efficacy of renal denervation. Hypertension. 2013;61(2):288-289.
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Part 3 New indications for renal denervation 3
CHAPTER
Chronic kidney painin in autosomal dominant polycystic kidney diseasedisease: a case report of successful treatment by catheter-based renal denervation
N.F. Casteleijn, R.L. de Jager, M.P. Neeleman, P.J. Blankestijn, R.T. Gansevoort
Am J Kidney Dis.2014 Jun;63(6):1019-1021 Chapter 8
Abstract
Chronic pain is a common concern in patients with autosomal dominant polycystic kidney disease (ADPKD). We report what to our knowledge is the first catheter- based renal denervation procedure in a patient with ADPKD resulting in successful management of chronic pain. The patient was a 43-year-old woman whose chronic pain could not be controlled by pain medication or splanchnic nerve blockade. Transluminal radiofrequency renal denervation was performed as an experimental therapeutic option with an excellent result, indicating that this procedure should be considered for chronic pain management in ADPKD.
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Introduction
Up to 60% of all patients with autosomal dominant polycystic kidney disease (ADPKD) experience some pain, which in some individuals can be debilitating enough to lead to decreased psychosocial functioning and limitation in daily activities.1 Chronic pain in ADPKD may be multifactorial, and can be caused by cystic enlargement of the kidneys resulting in distension of the renal capsule; by pressure on adjacent tissues; or may be unrelated to ADPKD. Bajwa et al. introduced a stepwise approach for effective pain management in ADPKD, beginning with non-pharmacological therapies, such as ice pads and psychological behavioral modification, stepping up to non-opioid analgesics, opioids, transcutaneous electrical nerve stimulation, and finally surgical procedures.2 Several surgical procedures, such as cyst aspiration and cyst fenestration, have been tried with success to relieve ADPKD-related pain. However, pain relief is often only temporary, and aspiration and fenestration are associated with a high risk for infection.2 Renal denervation also has been proposed for patients with intractable ADPKD-related pain and was performed by laparoscopic and thoracoscopic procedures with satisfactory results.3, 4 Recently a catheter-based percutaneous transluminal method has been introduced to ablate efferent and afferent renal sympathetic nerve fibres. This procedure now is applied mainly in patients with therapy-resistant hypertension.
We report a case of a patient with ADPKD and chronic pain who underwent catheter- based renal denervation for pain treatment, with an excellent result.
Case report
A 43-year-old woman with ADPKD was referred to our tertiary-care hospital with a history of pain that was difficult to treat since 2008. The diagnosis of APDKD was made based 8 upon the revised Ravine criteria.5
At presentation in May 2013, the patient reported progressive abdominal pain, in particular on the left side in the epigastric region with a visual analogue scale score ranking 6–8 of 10. The pain was constant and described as stabbing and nagging, with radiation toward the left upper abdomen. On the right side, she also experienced pain, but this was less intense. Because of the pain, she could not sleep on her left side and woke up at least 5 times every night, leading to progressive fatigue. Inspiration increased her pain sensation, suggesting a visceral origin. Defecation and micturition did not influence pain, whereas exercise worsened it. Her symptoms were debilitating,
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influencing her social life and leading to an inability to work full-time. For blood pressure control, the patient used losartan, 100 mg, once daily; amlodipine, 10 mg, once daily; and hydrochlorothiazide, 25 mg, once daily, on which her mean daytime blood pressure was 139/95 mm Hg during a 24-hour ambulatory blood pressure measurement.
Previous attempts at pain control using non-pharmacologic therapies or acetaminophen had not been effective. Buprenorphine patches (regulated dose release, 10 μg/h) were tried, but the pain remained and the patient experienced side effects of drowsiness and progressing fatigue that precluded dose increases. Two years earlier, a successful temporary blockade of the left splanchnic nerve had been performed for pain control. Therefore a long-term neurolytic nerve block with phenol was given on both sides with some success. Unfortunately, after 2 months the pain returned with the same intensity as before. A second long-term neurolytic nerve block was attempted with only temporary limited pain relief. In the patient’s eyes, the best option was now to remove her left kidney, although this procedure might shorten her time to end-stage renal disease.
Spiral computed tomography was performed and showed the presence of multiple bilateral renal and hepatic cysts, leading to enlargement of kidneys and liver (Figure 8.1). The patient’s right kidney volume was 1142 mL; left kidney volume, 1472 mL; and liver volume, 2004 mL. These images did not show cyst bleeding, cyst infections, kidney stones or extra-renal abnormalities that might cause pain. This scan also showed no signs that her kidneys compressed adjacent tissue, indicating that this theoretical cause of intractable pain also was less likely. Given her serious situation, we decided to try catheter-based renal denervation of the afferent sensory nerves using the Symplicity Catheter System, a 6F-compatible single-use radio frequency (RF) probe. Before introducing the RF probe, a renal angiogram was performed and showed no contra- indications for the procedure. Subsequently, the system was introduced into the renal artery and the catheter electrode was positioned in contact with the vessel wall at the most distal location possible. The catheter was connected to an automated RF generator, and 5 applications of RF energy in a spiral pattern along the renal artery from distal to proximal and with 5-mm interspaces were performed (Figure 8.2).
Immediately after the procedure, the pain was different and more intense, which was thought to be the result of using too low a dose of fentanyl during the procedure. The patient was discharged without complications on the day after the procedure. In the following days, her pain completely disappeared on the left side and she needed only
152 Case report: RDN for ADPKD-related pain
Figure 8.1 Spiral computed tomography scan.
half the dosages of her pain medication. Because of this satisfactory result, the patient requested to denervate the right kidney as well. Four months later, a right-sided renal denervation was performed. The procedure was uncomplicated and she was pain free 8 immediately. Moreover, her blood pressure had decreased to 117/79 mm Hg. Therefore, we reduced her antihypertensive medication before discharge the next day.
Four months later, the patient was still pain free, reported a visual analogue scale score of 0 of 10, did not use pain relief medication and had resumed her normal working and social life. Office blood pressure had decreased from a pre-intervention level of 145/96 mm Hg to 120/75 mm Hg, even though her antihypertensive medication had been reduced from 3 to 2 agents. Her eGFR had not changed (76 mL/min/1.73m2 pre- intervention vs. 78 mL/min/1.73m2 post-intervention).
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Distal aorta Left renal artery
Tip of the catheter: ablation point
Outline left kidney
Figure 8.2 Angiography of the renal denervation procedure. The solid line represents the Symplicity Catheter System (a 6F-compatible, single-use radio frequency probe) that was introduced into the renal artery. The catheter electrode is positioned at the most distal location possible in the renal artery.
Discussion
Chronic abdominal pain in ADPKD can be directly or indirectly related to the cystic enlarged kidneys.2 The renal nerves, which carry both sympathetic efferent and sensory afferent nerve fibers, are distributed circumferentially in the adventitia around the renal
154 Case report: RDN for ADPKD-related pain
artery. Two previous case reports have described the possibility of renal denervation for direct ADPKD-related pain by thoracoscopic or laparoscopic procedures.3, 4 However, these invasive techniques are difficult to perform and require surgical experience, which is difficult to gain because there is only a limited number of patients with intractable ADPKD-related pain. We performed transluminal RF renal denervation as an alternative procedure to surgery with an excellent result.
Recent studies demonstrated the beneficial effect of renal denervation for treating resistant hypertension, heart failure and insulin resistance.6, 7 Catheter-based renal ablation may be effective for pain-related syndromes as well. This procedure has been shown to be successful in a single patient with the loin pain haematuria syndrome.7 One case report suggested that catheter-based renal denervation also might have a beneficial effect on pain in cystic disease.8 However, in this case, the procedure was performed for therapy-resistant hypertension and the patient only had several one-sided renal cysts, rather than ADPKD.8
The present evidence suggests that this procedure is safe up to 3 years after intervention.9 Another reason aside from pain management to apply renal denervation in patients with ADPKD is to treat hypertension. Hypertension in patients with ADPKD is associated with higher sympathetic activity.10-12 This indicates that patients with ADPKD could benefit from renal denervation for hypertension treatment. Our patient’s blood pressure control improved after the procedure. Contra-indications for this procedure are a history of renal artery stenting, renal artery stenosis > 50%, the presence of multiple arteries, or the renal artery having an average diameter ≤ 4 mm or being < 20 mm long. Because contrast is used during the procedure, local prevailing guidelines to prevent contrast nephropathy should be followed. 8 In conclusion, this case report suggests that percutaneous catheter-based renal denervation may be a simple and effective procedure for pain relief in selected patients with ADPKD in whom chronic pain is likely to be related directly to the increase in size of the kidneys and for whom oral analgesics did not result in effective pain treatment. Further research will have to be performed to indicate the place that renal denervation could have in the stepwise approach for effective pain management in ADPKD.
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References
(1) Gabow PA. Autosomal dominant polycystic kidney disease--more than a renal disease. Am J Kidney Dis.1990;16(5):403-413. (2) Bajwa ZH, Gupta S, Warfield CA, Steinman TI. Pain management in polycystic kidney disease. Kidney Int.2001;60(5):1631-1644. (3) Valente JF, Dreyer DR, Breda MA, Bennett WM. Laparoscopic renal denervation for intractable ADPKD-related pain. Nephrol Dial Transplant.2001;16(1):160. (4) Chapuis O, Sockeel P, Pallas G, Pons F, Jancovici R. Thoracoscopic renal denervation for intractable autosomal dominant polycystic kidney disease-related pain. Am J Kidney Dis.2004;43(1):161-163. (5) Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of ultra- sonographic diagnostic criteria for autosomal dominant polycystic kidney disease. Lancet.1994; 343(8901):824-827. (6) Mahfoud F, Ukena C, Schmieder RE, et al. Ambulatory blood pressure changes after renal sym- pathetic denervation in patients with resistant hypertension. Circulation.2013; 128(2):132-140. (7) Gambaro G, Fulignati P, Spinelli A, Rovella V, Di Daniele N. Percutaneous renal sympathetic nerve ablation for loin pain haematuria syndrome. Nephrol Dial Transplant.2013;28(9):2393-2395. (8) Shetty SV, Roberts TJ, Schlaich MP. Percutaneous transluminal renal denervation: a potential treatment option for polycystic kidney disease-related pain? Int J Cardiol.2013;162(3):e58-9. (9) Ormiston JA, Watson T, van Pelt N, et al. Renal denervation for resistant hypertension using an irrigated radiofrequency balloon: 12-month results from the Renal Hypertension Ablation System (RHAS) trial. EuroIntervention.2013;9(1):70-74. (10) Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J Am Soc Nephrol.2001;12(11): 2427-2433. (11) Cerasola G, Vecchi M, Mule G, et al. Sympathetic activity and blood pressure pattern in autosomal dominant polycystic kidney disease hypertensives. Am J Nephrol.1998;18(5):391-398. (12) Wang D, Strandgaard S. The pathogenesis of hypertension in autosomal dominant polycystic kidney disease. J Hypertens.1997;15(9):925-933.
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Catheter-based renal denervation as therapy for chronic severe kidney-related pain
R.L. de Jager, N.F. Casteleijn, E. de Beus, M.L. Bots, E.J. Vonken, R.T. Gansevoort, P.J. Blankestijn
Nephrol Dial Transplant. 2017: in press. Chapter 9
Abstract
Background Loin pain hematuria syndrome (LPHS) and autosomal dominant polycystic kidney disease (ADPKD) are the most important non-urological conditions to cause chronic severe kidney-related pain. Multidisciplinary programs and surgical methods have shown inconsistent results with respect to pain reduction. Percutaneous catheter-based renal denervation (RDN) could be a less invasive treatment option for these patients.
Methods Our aim was to explore the change in perceived pain and use of analgesic medication from baseline to three, six and 12 months after RDN. Patients with LPHS or ADPKD, who experienced kidney-related pain ≥ 3 months with a visual analog scale (VAS)-score of ≥ 50/100, could be included. Percutaneous RDN was performed with a single electrode radio-frequency ablation catheter.
Results In eleven patients (six with LPHS and five with ADPKD) RDN was performed. Perceived pain declined in the whole group with 23 mm (p=0.012 for the total group). In patients with LPHS and ADPKD, the median daily defined dosage of analgesic medication, decreased from 1.6 [interquartile range 0.7–2.3] and 1.4 [0.0–7.4] at baseline to 0.3 ([0.0–1.9], P=0.138) and 0.0 ([0.0–0.8], P=0.285) at 12 months, respectively. Mean eGFR decreased in the whole group with 5.4 ml/min/1.73m2 at six months compared to baseline (P=0.163).
Conclusions These results suggest that percutaneous catheter-based RDN reduces pain complaints and use of analgesic medication in patients with LPHS or ADPKD. The present results can serve as the rationale for a larger, preferably randomized (sham) controlled study.
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Introduction
Loin pain hematuria syndrome (LPHS) and autosomal dominant polycystic kidney disease (ADPKD) are the most important non-urological conditions to cause kidney- related pain. LPHS is a rare disease and a diagnosis per exclusionem. Patients often experience intense, sometimes invalidating unilateral or bilateral flank pain longer than six months and hematuria (with or without dysmorphic erythrocytes). This disease can be associated with glomerulonephritis, usually IgA nephropathy.1 Pain in LPHS is thought to be caused by tubular obstruction due to erythrocytes and/or microcrystals, which leads to capsular distension and, eventually, visceral pain.2, 3 LPHS is usually not associated with deterioration in kidney function, infection or hypertension.3, 4
ADPKD is a leading cause of end-stage renal disease in Europe.5 Patients with ADPKD can experience invalidating pain, which may be caused by distension of the renal capsule by expansion of renal cysts, which causes visceral pain.6 Chronic pain in LPHS and ADPKD is sometimes difficult to treat. Often analgesic medication is necessary to control the pain, in many cases also including opioids.7 Surgical procedures, such as nephrectomy, renal auto-transplantation or laparoscopic renal denervation (RDN) have proven to be effective in pain relief.3, 8 However, these procedures are invasive and nephrectomy of a still functioning kidney will bring the patient at greater risk for end-stage kidney disease, especially in ADPKD.
Catheter-based RDN was introduced as a possible treatment of apparent resistant hypertension.9 It aims to disrupt the renal sympathetic nerves by using variable methodologies within the renal arteries including radiofrequency, intravascular ultrasound and local application of neurotoxic agents, such as ethanol.10-14 Conceptually, catheter- based RDN may be an attractive option for treating kidney-related pain as the majority of pain-conducting nerve fibers are located circumferentially around the renal artery and the hilum.4, 15 At present, there are some case reports that suggest a beneficial effect of catheter-based RDN in LPHS.16-19 In addition, we published a case report on the effects of catheter-based RDN in a patient with ADPKD on both sides with a tremendous drop 9 in perceived pain.16
Our aim was to study the effect of catheter-based RDN on perceived pain and the use of analgesic medication in patients with LPHS or ADPKD with kidney-related pain in a larger group of patients to guide further research. Secondly, we summarized available evidence in the literature.
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Subjects and methods
This pilot study was designed as a prospective cohort. Patients were referred to our department by colleagues of our own hospital and from other centers across the Netherlands between May 2013 and April 2015. Patients had either kidney-related pain due to LPHS or to ADPKD. All LPHS patients had a history of urological and nephrological analysis to rule out other treatable causes of their complaints, as well as consultation of a pain specialist and/or psychologist. Patients with ADPKD were thoroughly screened for other causes of pain, as they participated in a study that investigated the effect of sequential nerve blocks on pain relief in ADPKD patients with refractory chronic pain. As first step a diagnostic, temporary celiac plexus block with local anesthetics was performed.20 In case there was no pain relief after this nerve block, we assumed that the pain stimuli relayed via the aortico-renal plexus and RDN could be an option. All patients were discussed in a multidisciplinary setting.21 They were considered eligible for RDN when they were ≥ 18 years old, had invalidating kidney-related pain (≥ 3 months pain duration, ≥ 50/100 on Visual Analogue Scale (VAS) and insufficient response to previous analgesic therapies) and when a computer tomography angiogram or magnetic resonance angiogram showed a diameter > 4 mm and a length of > 20 mm of the renal artery at the side of the pain. All patients gave their permission to be part of this study, in accordance with the declaration of Helsinki.
Pain assessment
Perceived pain was assessed with a validated Dutch questionnaire (MPQ-DV), which is based on the McGill pain questionnaire (MPQ).22, 23 In this questionnaire patients were asked to fill out their maximal visual analogue scale (VAS)-score. The VAS-score is the maximum pain a patient has experienced in the last two weeks on a scale from 0 (no pain at all) to 100 mm (maximum of pain possible). Patients were asked to fill out the questionnaire at baseline (pre-RDN), three, six and 12 months post-RDN.
Analgesic use assessment
Medication was screened for analgesic medication, according to the Anatomical Therapeutic Chemical (ATC) classification system of the World Health Organization Collaborating Centre for Drug Statistics (http://www.whocc.no/atc_ddd_index/) at baseline, three, six and 12 months. We registered the number of different classes of analgesics and we calculated the total daily defined use (DDD) of analgesic medication per patient per visit.
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Kidney function and blood pressure assessment
At baseline and six months, the estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.24 Office blood pressure measurements were collected at baseline and at six months and calculated as the average of three measurements on each arm. All blood pressure measurements were done with methods and devices in accordance with the latest recommendations of the European Hypertension Consensus.25
Renal denervation
The UMC Utrecht is a European Society of Hypertension center of excellence and participated in a number of RDN trials for hypertension. Detailed information on the procedure is published elsewhere.26, 27 The procedure was performed by an experienced interventionist using the radiofrequency ablation SymplicityTM catheter (Medtronic Inc., Santa Rosa, California), only in the renal arteries located on the side where the patient experienced pain. The interventionist decided on the number of ablations and if all (accessory) arteries could be treated on that particular side. When the patient experienced pain on both sides, the side with the highest VAS-score would be treated first and three months later the other side, if no procedural complications had occurred the first time. Adverse events were collected at follow-up.
Statistical analysis
Normally distributed variables are expressed as mean ± SD, whereas non-normally distributed variables are reported as median [Interquartile range]. Changes in VAS score, analgesics used and DDD between baseline and follow-up were analyzed with the Wilcoxon signed-rank test. Changes were analyzed for the whole group, as well as stratified for ADPKD and LPHS. Paired T-test analysis was used to analyze changes in blood pressure and eGFR between baseline and six months. A two-tailed p-value < 0.05 was considered to indicate statistical significance. All statistical analyses were performed using IBM SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY, USA). 9
Pooling data of other published case-reports
PubMed and Embase were searched for case reports assessing RDN and the effect on pain relief in patients with LPHS and ADPKD. The following broad search terms were used to cover all the aspects, as we hypothesized that there would only be small series and case-
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reports available: kidney pain, renal denervation, autosomal dominant polycystic kidney disease, ADPKD, loin pain hematuria syndrome, LPHS. Eligible for inclusion were reports of kidney-related pain and percutaneous catheter-based RDN. We extracted, if possible, data on change in perceived pain and in analgesic medication between baseline and six and 12 months follow-up.
Results
Baseline characteristics
Eleven patients with kidney-related pain were included: six patients with LPHS and five patients with ADPKD (Table 9.1). Mean age was 40±9 years and nine of the 11 patients were female. All patients with ADPKD and one LPHS patient used antihypertensive medication. Kidney function was impaired in the ADPKD group as compared to the LPHS group (eGFR 51±31 vs. 117±15 ml/min/1.73m2). Median duration of chronic pain was longer in the ADPKD group with 4.0 [2.4–19.5] years, as compared with 1.5 [0.5–6.5] years in the LPHS group. Fifty-five percent of all patients experienced pain at the right side. The LPHS group noted the highest pain experience, with a median VAS-score of 84 [77–94] mm compared to a VAS-score of 76 [64–86] mm in the ADPKD group. In addition, patients in the LPHS group used, on average, one class of analgesic medication more than patients in the ADPKD group (3.0 versus 2.0 pills). Fifty-five percent of the patients (n=6) used daily some type of opioid as treatment for their pain.
Change in perceived pain after renal denervation
RDN was performed on both sides in two patients and unilaterally in nine. Mean number of ablations per kidney was 7(±1). There were no serious adverse events reported after the procedure. Figure S9.1 represents the individual data of the VAS-score, per patient group (LPHS and ADPKD). Perceived pain declined in the overall population from 82 [70–92] mm to 68 [55–79] mm (P=0.036) and 59 [0–71] mm (P=0.012) at three and 12 months after RDN, respectively. The decrease was consistent in both groups (Table 9.2).
Change in use of analgesic medication after renal denervation
In the whole group the median number of classes of analgesic medication decreased significantly from 2.0 [2.0–3.0] at baseline to 1.5 [0.8–2.3] at three months (P=0.033) and decreased slightly further at 12 months to 1.0 [0.0–2.0] (P=0.011) (Table 9.2). Figure S9.2
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Table 9.1 Baseline characteristics
Autosomal- Loin pain Dominant Total group hematuria Polycystic Kidney (n=11) syndrome (n=6) Disease (n=5)
Age (years) 40 (9) 37 (10) 45 (7) Malea 2 (18) 1 (17) 1 (20) Caucasiana 11 (100) 6 (100) 5 (100) Hypertensiona 5 (45) 1 (17) 5 (100) Dyslipidemiaa 0 (0) 0 (0) 0 (0) Diabetes Mellitus type 2a 2 (18) 1 (17) 1 (20) (Cardio)vascular diseasesa 1 (9) 1 (17) 0 (0) Pain duration (years) 2.5 [0.75–6.0] 1.5 [0.5–6.5] 4.0 [2.4–19.5] Visual Analog Scale score (mm) 82 [70–92] 84 [77–94] 76 [64–86] Pain side Right 6 (55) 4 (67) 2 (40) Left 3 (27) 2 (33) 1 (20) Both 2 (18) 0 (0) 2 (40) Classes pain medication 2.0 [2.0–3.0] 2.5 [2.0–3.0] 2.0 [0.5–3.5] Use of opioidsa 6 (55) 4 (67) 2 (40) DDD pain medication 1.4 [0.4–2.1] 1.6 [0.7–2.3] 1.4 [0.0–7.4] Body-mass index (kg/m2) 27.2 (4.7) 25.8 (2.5) 28.9 (6.4) Office blood pressure Systolic mmHg 130 (21) 118 (16) 144 (17) Diastolic mmHg 80 (13) 72 (8) 91 (9) Heart rate bpm 77 (11) 78 (12) 74 (9) Classes antihypertensive medication 1.0 [0.0–3.0] 0.0 [0.0–1.0] 3.0 [1.0–3.5] eGFR, CKD epi ml/min/1.73m2 90 (37) 115 (14) 60 (33) eGFR < 60 ml/min/1.73m2 2 (18) 0 (0) 2 (40) Continuous values are expressed as mean (±SD) or as median [interquartile] when applicable. a Value represents number of patients (%). No., Number; eGFR, estimated glomerular filtration rate; bpm, beats per minute; DDD, daily defined dose.
9 represents the individual data of the DDD of analgesic medication. Overall, a reduction in DDD was seen from 1.4 [0.4–2.1] at baseline to 0.6 [0.3–1.4] and 0.0 [0.0–1.6] at three and 12 months (P=0.018 and 0.068, respectively). In the LPHS group the DDD was reduced from 1.6 [0.7–2.3] at baseline to 0.6 [0.5–1.4] and 0.3 [0.0–1.9] at three and 12 months (P=0.042 and P=0.138, respectively). This was similar for the ADPKD
165 Chapter 9 s follow-up. variable of interest at baseline variable of interest Baseline 3 months (n=11) P-value 6 months (n=11) P-value 12 months (n=11) P-value Baseline 3 months (n=6) P-value 6 months (n=6) P-value 12 months (n=6) P-value Baseline 3 months (n=5) P-value 6 months (n=5) P-value 12 months (n=5) P-value Visual Analog Scale score (mm)Visual Analog Scale score No. of classes pain medicationDaily defined use of pain medication 82 [70–92] 2.0 [2.0–3.0] 1.4 [0.4–2.1] 68 [55–79] 1.5 [0.8–2.3] 0.6 [0.3–1.4] 0.033 0.018 0.036 2.0 [0.0–2.0] 0.4 [0.0–0.9] 61 [34–66] (mm)Visual Analog Scale score 0.084No. of classes pain medication 0.214Daily defined use of pain medication 0.028 1.0 [0.0–2.0] 0.0 [0.0–1.6] 84 [77–94] 2.5 [2.0–3.0] 1.6 [0.7–2.3] 59 [0–71] 73 [34–88] 1.5 [1.0–2.0] 0.011 0.6 [0.5–1.4] 0.068 0.012 0.034 0.042 0.144 2.0 [2.0–2.3] 0.4 [0.4–1.8] 64 [47–70] (mm)Visual Analog Scale score No. of classes pain medication 0.157 0.345 0.180Daily defined use of pain medication 1.5 [0.0–2.0] 0.3 [0.0–1.9] 76 [64–86] 2.0 [0.5–3.5] 69 [15–94] 1.4 [0.0–7.4] 64 [55–73] 1.5 [0.0–3.8] 0.7 [0.0–10.4] 0.039 0.138 0.109 0.180 0.414 0.068 0.0 [0.0–1.2] 0.0 [0.0–2.5] 52 [11–65] 0.465 0.197 0.068 0.0 [0.0–0.8] 0.5 [0.0–2.0] 45 [0–62] 0.285 0.109 0.043 and at follow-up. MM, millimeters; No., number; P-value represents the mean difference from baseline to three, six and 12 month baseline to three, from the mean difference and at follow-up. MM, millimeters; No., number; P-value represents Data are expressed as median [interquartile] compared to baseline. N represents the number of patients with information on the to baseline. N represents compared as median [interquartile] expressed Data are Table 9.2a Table pain and use of medication in the whole group Change in perceived 9.2b Table pain and use of medication in Loin Pain Hematuria Syndrome Change in perceived 9.2c Table pain and use of medication in Autosomal-Dominant Polycystic Kidney Disease Change in perceived
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group, where at three months and 12 months the DDD decreased to, respectively, 0.7 ([0.0–10.4), P=0.180) and 0.0 ([0.0–0.8], P=0.285).
Kidney function and blood pressure
Figure S9.3 shows the available data on eGFR in each individual patient (n=11). Overall, eGFR decreased (87±41 versus 82±41 ml/min/1.73m2) (Table S9.1). The change seems to be mainly caused by one LPHS patient (Figure S9.3). In the ADPKD group office systolic blood pressure declined at six months with a mean of 5±6 mmHg compared to baseline, accompanied with a median reduction in the use of blood pressure lowering drugs of 1.5 pills. The mean blood pressure increased in the LPHS group (109±13/70±9 versus 116±6/71±5 mmHg). Still, the only patient with hypertensive medication in this group could stop with this medication, due to better regulation of his blood pressure (Table S9.1).
Pooled data of other published case-reports
One-hundred-thirty-six studies were found to be eligible to our research question (49 in PubMed). We subtracted 32 duplicates. After screening of title and abstract, we found one case series with four patients and one case-report exploring the effect of RDN on kidney-related pain in LPHS (Table S9.2 and S9.3). Data about use of analgesic medication could be extracted.17, 18 However, in the case series, the VAS was based on a quality of life assessment scale (EQ-5D) and for our research question not eligible to assess perceived pain.18 The other case-report was of Gambaro et al., in which no baseline VAS was published.17 We found two case-reports about RDN in ADPKD, of which one was from our center (Table S9.2 and S9.3).16, 19 The second report was published by Shetty et al., and which VAS and number of classes of analgesic medication could be extracted.19 Follow-up data on kidney function were lacking in all case-reports. The pooled effect of RDN on decline in number of classes of analgesic medication at six months in patients with LPHS and ADPKD was more pronounced with a median decline of -1.0 [-2.0–0.0] pills (p=0.010) and -2.0 [-2.5–-0.5] pills (p=0.066) (Table S9.4). 9
Discussion
This pilot study reports on the largest dataset of results of percutaneous catheter-based RDN for the treatment of kidney-related pain in patients with LPHS and ADPKD. The results suggest that a reduction of pain occurred despite of the fact that also the use
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of analgesic medication decreased. Our data also suggests that this effect is sustained, at least for 12 months.
There are only a few case reports that describe RDN may result in pain relief and reduction in the use of analgesics in patients with kidney-related pain.16-19 Our results are in line with those reports. However, comparison of the various reports is difficult because of the lack of standardization in pain assessment. A difference in VAS of ≥ 11 mm is considered to be of clinically significant importance,28 which was the case in both the LPHS and ADPKD group. The reduction in analgesic drug use is also of interest and of particular relevance in ADPKD. Acetaminophen (paracetamol) is often insufficient, non-steroidal anti-inflammatory agents are contra-indicated in patients with CKD and opioids are associated with relevant side effects.7 Indeed, six of the 11 patients were on opioids. Some patients reported difficulties in reducing and stopping opioids because of physical and mental dependency, and needed professional guidance and support for that. We believe that the sustained effect (up to 12 months), the reduction in medication use and the reported difficulties in stopping opioids, do give support to the idea that the effect of RDN on pain is real. Obviously, we cannot rule out a placebo-effect since a sham-control arm was missing.
LPHS often is a difficult to treat medical condition. The precise pathogenesis is uncertain. Psychological evaluation is also recommended. Taba et al. recently reviewed possible therapies for kidney-related pain in patients with LPHS. Minimal invasive therapies like bivacaine infusion and a celiac plexus block gave inconclusive results on efficacy and safety. More invasive methods as surgical RDN and kidney auto-transplantation were reported to have higher success rates, but can be associated with relevant complications. Further, recurrence of pain after surgical RDN can be up to 75% after 12 months,3 which is in contrast to our study. Moreover, percutaneous RDN would be much easier and safe to repeat for recurrence of pain.
For ADPKD, several approaches have been studied to reduce perceived pain. Tolvaptan, a vasopressin V2 receptor antagonist, which reduces cysts growth, may be helpful to reduce acute pain events.29 More invasive procedures include percutaneous nerve blocks, transcatheter arterial embolization (TAE) and finally nephrectomy.8 Percutaneous catheter-based RDN may therefore be an alternative in both disease conditions, as it is less invasive with low complication rate. However, it is important to emphasize that our ADPKD population was highly selected and only found eligible, when a celiac plexus block did not reduce the pain.30
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Presently, RDN is mainly applied in patients with so called resistant hypertension. There is no specific pathophysiologic argument for that.31 Earlier, we hypothesized that patients with kidney injury were more likely to have increased activity of the renal nerves and therefore could benefit of RDN.32-34 Indeed, all ADPKD patients were on antihypertensive drugs and showed a decrease in blood pressure and in number of antihypertensive drugs after RDN. Despite the fact that most of these patients were only treated unilateral. However, the observed decline in blood pressure may also be explained, partially, due to a better pain control. There was a small overall reduction in renal function six months after RDN, assessed as eGFR. This seems to be mainly explained by one LPHS patient. Unfortunately no repeat measurements are available in this patient. In our study, patients with reduced renal function at baseline were pre- and post-hydrated according to our hospital protocol for preventing contrast nephropathy. Possible other explanations for the decline in renal function can be: lower perfusion of the kidney due to a decline in blood pressure, normal variation overtime or progression of the underlying kidney disease. Obviously, in future studies eGFR should to be closely monitored.
Some limitations of the study need to be discussed. First, this study should be considered as a pilot study. It lacks a control group and has a small sample size. Secondly, the effect on pain showed a great variability, i.e. in some patients there was little or no effect, while in others a substantial effect was found. All procedures were done with the Medtronic Symplicity device. It is now clear that, with this device, a highly variable degree of denervation is obtained.35, 36 Also the location in the renal artery of application and the number of ablation points seem to be of critical importance.36, 37 So, it is possible that the variability in the observed effect is partially explained by a variable degree of completeness of denervation. Further, our data seem to suggest that the effect on pain increases over time. Thirdly, there could have occurred regression to the mean, but patients had experienced pain with a median duration of 1.5 years, which was at least three months stable. In addition, serious adverse events related to the RDN procedure were not reported.
In conclusion, the present data suggest that catheter-based RDN can have a beneficial 9 effect on kidney-related pain and the use of analgesic medication in patients with LPHS and ADPKD. This needs further exploration, because alternative strategies in these disease conditions are insufficient, associated with side effects and / or (much) more invasive. A next study on this subject should be a randomized, preferably sham-controlled clinical study in order to determine whether catheter-based RDN is a meaningful addition to the treatment options in these often difficult to treat patients.
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References
(1) Dube GK, Hamilton SE, Ratner LE, Nasr SH, Radhakrishnan J. Loin pain hematuria syndrome. Kidney Int.2006;70(12):2152-2155. (2) Spetie DN, Nadasdy T, Nadasdy G et al. Proposed pathogenesis of idiopathic loin pain-hematuria syndrome. Am J Kidney Dis.2006;47(3):419-427. (3) Taba T, V, Alam T, Sollinger H. Loin pain hematuria syndrome. Am J Kidney Dis. 2014;64(3):460- 472. (4) de Beus E., Blankestijn PJ, Fox JG, Zoccali C. Catheter-based renal denervation as a novel treatment for loin pain haematuria syndrome. Nephrol Dial Transplant.2013;28(9):2197-2199. (5) Willey CJ, Blais JD, Hall AK, Krasa HB, Makin AJ, Czerwiec FS. Prevalence of autosomal dominant polycystic kidney disease in the European Union. Nephrol Dial Transplant.2016. (6) Bajwa ZH, Gupta S, Warfield CA, Steinman TI. Pain management in polycystic kidney disease. Kidney Int.2001;60(5):1631-1644. (7) Davison SN, Koncicki H, Brennan F. Pain in chronic kidney disease: a scoping review. Semin Dial.2014;27(2):188-204. (8) Tellman MW, Bahler CD, Shumate AM, Bacallao RL, Sundaram CP. Management of pain in autosomal dominant polycystic kidney disease and anatomy of renal innervation. J Urol.2015;193(5):1470- 1478. (9) Krum H, Schlaich M, Whitbourn R et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet.2009;373(9671): 1275-1281. (10) 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(9981):1957-1965. (11) Bertog S, Fischell TA, Vega F et al. Randomized, Blinded and Controlled Comparative Study of Chemical and Radiofrequency-Based Renal Denervation in a Porcine Model. EuroIntervention.2017; 12(15):e1898-e1906. (12) Neuzil P, Ormiston J, Brinton TJ et al. Externally Delivered Focused Ultrasound for Renal Denervation. JACC Cardiovasc Interv.2016;9(12):1292-1299. (13) Papademetriou V, Tsioufis CP, Sinhal A et al. Catheter-based renal denervation for resistant hypertension: 12-month results of the EnligHTN I first-in-human study using a multielectrode ablation system. Hypertension.2014;64(3):565-572. (14) Prochnau D, Heymel S, Otto S, Figulla HR, Surber R. Renal denervation with cryoenergy as second-line option is effective in the treatment of resistant hypertension in non-responders to radiofrequency ablation. EuroIntervention.2014;10(5):640-645. (15) Sakakura K, Ladich E, Cheng Q et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol.2014;64(7):635-643. (16) Casteleijn NF, de Jager RL, Neeleman MP, Blankestijn PJ, Gansevoort RT. Chronic kidney pain in autosomal dominant polycystic kidney disease: a case report of successful treatment by catheter- based renal denervation. Am J Kidney Dis.2014;63(6):1019-1021. (17) Gambaro G, Fulignati P, Spinelli A, Rovella V, Di DN. Percutaneous renal sympathetic nerve ablation for loin pain haematuria syndrome. Nephrol Dial Transplant.2013;28(9):2393-2395. (18) Prasad B, Giebel S, Garcia F, Goyal K, St Onge JR. Renal Denervation in Patients With Loin Pain Hematuria Syndrome. Am J Kidney Dis.2017;69(1):156-159. (19) Shetty SV, Roberts TJ, Schlaich MP. Percutaneous transluminal renal denervation: a potential treatment option for polycystic kidney disease-related pain? Int J Cardiol.2013;162(3):e58-e59.
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(20) Casteleijn NF, Visser FW, Drenth JP et al. A stepwise approach for effective management of chronic pain in autosomal-dominant polycystic kidney disease. Nephrol Dial Transplant.2014;29 Suppl 4:iv142-iv153. (21) Verloop WL, Vink EE, Voskuil M et al. Eligibility for percutaneous renal denervation: the importance of a systematic screening. J Hypertens.2013;31(8):1662-1668. (22) Melzack R. The McGill Pain Questionnaire: major properties and scoring methods. Pain.1975;1(3): 277-299. (23) Vanderiet K, Adriaensen H, Carton H, Vertommen H. The McGill Pain Questionnaire constructed for the Dutch language (MPQ-DV). Preliminary data concerning reliability and validity. Pain.1987;30(3): 395-408. (24) Levey AS, Stevens LA, Schmid CH et al. A new equation to estimate glomerular filtration rate. Ann Intern Med.2009;150(9):604-612. (25) Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens.2013;31(7): 1281-1357. (26) de Jager RL, de Beus E, Beeftink MM et al. Impact of medication adherence on the effect of renal denervation. The SYMPATHY trial. Hypertension.2017;69(4):678-684. (27) Verloop WL, Spiering W, Vink EE et al. Denervation of the renal arteries in metabolic syndrome: the DREAMS-study. Hypertension.2015;65(4):751-757. (28) Kelly AM. Does the clinically significant difference in visual analog scale pain scores vary with gender, age, or cause of pain? Acad Emerg Med.1998;5(11):1086-1090. (29) Casteleijn NF, Blais JD, Chapman AB et al. Tolvaptan and Kidney Pain in Patients With Autosomal Dominant Polycystic Kidney Disease: Secondary Analysis From a Randomized Controlled Trial. Am J Kidney Dis.2017;69(2):210-219. (30) Casteleijn NF, Gastel MDA, Blankestijn PJ et al. Novel treatment protocol for ameliorating refractory, chronic pain in patients with autosomal dominant polycystic kidney disease. Kidney Int.2017;(16):30709-8. (31) de Beus E, de Jager RL, Joles JA, Grassi G, Blankestijn PJ. Sympathetic activation secondary to chronic kidney disease: therapeutic target for renal denervation? J Hypertens.2014;32(9):1751-1761. (32) Blankestijn PJ, Ritz E. Renal denervation: potential impact on hypertension in kidney disease? Nephrol Dial Transplant.2011;26(9):2732-2734. (33) Blankestijn PJ, Joles JA. Hypertension: Renal denervation in chronic kidney disease. Nat Rev Nephrol.2012;8(8):439-440. (34) Klein IH, Ligtenberg G, Oey PL, Koomans HA, Blankestijn PJ. Sympathetic activity is increased in polycystic kidney disease and is associated with hypertension. J Am Soc Nephrol.2001;12(11): 2427-2433. (35) Vink EE, Goldschmeding R, Vink A, Weggemans C, Bleijs RL, Blankestijn PJ. Limited destruction of renal nerves after catheter-based renal denervation: results of a human case study. Nephrol Dial Transplant.2014;29(8):1608-1610. (36) Kandzari DE, Bhatt DL, Brar S et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J.2015;36(4):219-227. 9 (37) Pekarskiy SE, Baev AE, Mordovin VF et al. Denervation of the distal renal arterial branches vs. conventional main renal artery treatment: a randomized controlled trial for treatment of resistant hypertension. J Hypertens.2017;35(2):369-375.
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Supplemental information
Supplemental Table S9.1 Change in kidney function and blood pressure 6 months after renal denervation
Baseline 6 months P-value
Total group eGFR, CKD epi ml/min/1.73m2 (n=11) 87 (41) 82 (41) 0.163 Office blood pressure mmHg (n=7) 125(18) /81 (13) 125(11)/81 (13) 0.972 / 0.847 No. of classes of antihypertensive 1.0 [0.0–3.0] 0.0 [0.0–1.3] 0.066 medication (n=7)
Loin pain hematuria syndrome eGFR, CKD epi ml/min/1.73m2 (n=6) 117 (15) 110 (22) 0.400 Office blood pressure mmHg (n=3) 109(13)/70(9) 116(6)/71(5) 0.385 / 0.911 No. of classes of antihypertensive 0.0 [0.0–1.0] 0.0 [0.0–0.0] 0.157 medication (n=3)
Autosomal-Dominant Polycystic Kidney Disease eGFR, CKD epi ml/min/1.73m2 (n=5) 51 (31) 46 (29) 0.073 Office blood pressure mmHg (n=4) 137(10)/89(8) 132(7)/89(5) 0.180 / 0.895 No. of classes of antihypertensive 3.0 [1.0–3.5] 1.5 [0.3–2.8] 0.180 medication (n=4) Data are expressed as mean (±SD) or median [interquartile], if applicable. N represents the number of patients with information on the variable of interest at baseline and at follow-up. P-value represents the difference in mean blood pressure from baseline to six months follow-up. eGFR, estimated glomerular filtration rate; No., number.
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Supplemental Table S9.2 Study characteristics of the included studies
Current study Prasad et al. Gambaro et al. Shetty et al.
Journal N/A Am J Kidney Nephrol Dial Int J Cariol Dis Transplant Publication year N/A 2016 2013 2013 PMID N/A 27528372 23658250 22721643 Country Netherlands Canada Italy Australia Study design Cohort Cohort Single case Single case Study population ADPKD (n=5) / LPHS (n=4) LPHS (n=1) ADPKD LPHS (n=6) (n=1) Follow-up 6 months 6 months 6 months 12 months Pain assessment tool McGill pain EQ-5D VASa Unknown Comparative questionnaire Pain Scale Type device used Symplicity Vessex Symplicity Symplicity PMID, PubMed Identification number; N/A, not applicable; ADPKD, autosomal-dominant polycystic kidney disease; LPHS, loin pain hematuria syndrome. a Not suitable for pain assessment, as it is designed for quality of life assessment.
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Supplemental Table S9.3 Baseline characteristics of all included studies in meta-analysis
Loin pain Autosomal- hematuria Dominant Total group syndrome Polycystic Kidney (n=17) (n=11) Disease (n=6)
Age (years) 41 (11) 37 (12) 49 (8) Sexe malea 2 (12) 1 (9) 1 (17) Caucasiana 17 (100) 11 (100) 6 (100) Hypertensiona 7 (41) 1 (14) 6 (100) Pain duration (years) 4.0 [1.1–6.0] 1.5 [0.5–6.5] 4.0 [2.4–19.5] Visual Analog Score (mm) 80 [70–92] 84 [77–94] 76 [64–86] Pain side Right 11 (65) 8 (27) 3 (50) Left 4 (23) 3 (73) 1 (17) Both 2 (12) 0 (0) 2 (33) No. of classes pain medication 2.0 [2.0–3.0] 2.5 [2.0–3.0] 2.0 [0.5–3.5] Daily defined use of pain 1.1 [0.2–1.6] 1.1 [0.7–1.8] 1.4 [0.0–7.4] medication Office blood pressure (mmHg) 133 (23) / 83 (15) 118 (16) / 72 (8) 148 (19) / 94 (10) 24-hour ABPM (mmHg) 140 (18) / 88(6) N/A 140 (18) / 88 (6) No. of classes antihypertensive 1.0 [0.0–3.0] 0.0 [0.0–1.0] 3.0 [1.0–3.5] medication eGFR, CKD epi ml/min/1.73m2 89 (31) 102 (21) 66 (34) Device used Symplicity 13 (77) 7 (64) 6 (100) Vessex 4 (23) 4 (36) 0 (0) Continuous values are expressed as mean (±SD) or as median [interquartile] when applicable. a Value represents number of patients (%). No., Number; ABPM, ambulatory blood pressure measurement; eGFR, estimated glomerular filtration rate; bpm, beats per minute.
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Supplemental Table S9.4a Results of the pooled data: change in perceived pain and use of pain medication in patients with kidney related pain (total group)
Baseline 6 months (n=16) P-value
Visual Analog Scale score (mm) 80 [70–92] 59 [0–66] 0.028 No. of classes of pain medication 2.0 [2.0–3.0] 1.0 [0.0–2.0] 0.002 Daily defined use of pain medication 1.1 [0.2–1.6] 0.0 [0.0–0.4] 0.034
Supplemental Table S9.4b Results of the pooled data: change in perceived pain and use of pain medication in Loin Pain Hematuria Syndrome
Baseline 6 months (n=11) P-value
Visual Analog Scale score (mm)a 84 [77–94] 64 [47–70] 0.180 No. of classes of pain medication 2.5 [2.0–3.0] 1.0 [1.0–2.0] 0.010 Daily defined use of pain medication 1.1 [0.7–1.8] 0.3 [0.0–0.4] 0.086
Supplemental Table S9.4c Results of the pooled data: change in perceived pain and use of pain medication in Autosomal-Dominant Polycystic Kidney Disease
Baseline 6 months (n=5) P-value
Visual Analog Scale score (mm) 76 [64–86] 45 [0–63] 0.068 No. of classes of pain medication 2.0 [0.5–3.5] 0.0 [0.0–1.5] 0.066 Daily defined use of pain medicationa 1.4 [0.0–7.4] 0.0 [0.0–1.2] 0.465 Data are expressed as median [interquartile] compared to baseline. N represents the number of patients with information on the variable of interest at baseline and at follow-up. a Data could only be obtained of the original study. MM, millimeters; No., number; P-value represents the mean difference from baseline to six months follow-up.
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A
B
Supplemental Figure S9.1 Individual data for baseline and follow-up. Presented for the score on visual analogue scale and assigned by loin pain hematuria syndrome (A) or autosomal dominant polycystic kidney disease (B).
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A
B 9 Supplemental Figure S9.2 Individual data for baseline and follow-up. Presented for the daily defined use and assigned by loin pain hematuria syndrome (A) or autosomal dominant polycystic kidney disease (B).
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Supplemental Figure S9.3 Individual data for baseline and six months. Presented for estimated glomerular filtration rate (eGFR). – Loin Pain Hematuria Syndrome – Autosomal Dominant Polycystic Kidney Disease
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Part 4 Future research and perspectives 4
CHAPTER
Discussion Chapter 10
The primary objective of this thesis was to study the effect of renal denervation (RDN) on blood pressure (BP). Further, we determined factors related to the effect of RDN. Finally, we explored RDN as therapeutic option for severe kidney-related pain.
Key fi ndings
1. RDN was not superior to usual care to lower BP in apparent resistant hypertensive patients.
2. Poor adherence was common in patients with apparent resistant hypertension.
3. Medication changes considerably affected the magnitude and direction of the RDN effect on BP.
4. Higher number of prescribed pills and higher office BP were significantly related to lower adherence.
5. In patients without BP lowering drugs RDN significantly lowered BP.
6. Resistant hypertensive women with previous hypertensive disorders of pregnancy (HDP) are likely to have a larger decline in BP after RDN than women without previous HDP.
7. S100B might serve as direct biomarker to predict the success of nerve damage after the RDN procedure.
8. RDN could be a new therapeutic option for patients with severe kidney-related pain, as RDN relieved kidney-related pain and decreased the use of analgesic medication.
Course of renal denervation studies between 2010-2016
The main finding of this thesis is that, in a randomized-controlled setting, RDN is not superior to usual care to lower BP (Chapter 3). During the conduct of the SYMPATHY- trial (2013-2016) seven randomized controlled trials (RCTs) were published of which all assessed the effect of RDN on BP.1-7 All of these trials, including SYMPATHY, were initiated after the very encouraging results of the HTN-2 trial, published in 2010. HTN-2 observed a decrease in office BP of 33/11 mmHg more in the RDN group, compared to the usual care group.8 The second trial was published in April 2014, which was the HTN-3 trial.2 This randomized-sham-controlled trial was conducted in the United States and had as primary endpoint office systolic BP (SBP) after six months. HTN-3 showed no beneficial effect of RDN on top of usual care. What had happened in the four years
184 Discussion
between the positive HTN-2 and the neutral HTN-3 trial and why were other trials not published in between? Especially since the number of patients in these trials was much lower than in the HTN-3 trial (±600 patients). First, already after HTN-2, it became clear that there were responders and non-responders, according to the wide variability in effect observed after the RDN procedure (standard deviation 23/11 mmHg). This fueled the need to determine factors that could identify the potential best responders to RDN on forehand. To explore these factors larger study populations were needed than necessary for the primary question: does RDN lower BP on top of usual care? Factors of interest could be divided into patient, procedural and design related determinants.
Patient related factors: responder versus non-responder
In general, patients can be divided into two groups, namely: the responder versus the non- responder to RDN. To this matter SYMPATHY was designed to determine if patients with impaired kidney function had more benefit of the procedure (Chapter 2). A logical step, as we showed in Chapter 1 that there was abundant experimental evidence to conclude that RDN lowered BP and alternated progression of kidney failure and proteinuria. Furthermore, there was some clinical evidence from uncontrolled observational studies that RDN was especially promising in patients with chronic kidney disease.9-11 However, as was stated in Chapter 3, our predefined subgroup analysis on kidney function, turned out to be insufficient, due to small sample size. The low number of included patients was partially due to reluctance of healthcare providers to refer patients for RDN after the published results of the HTN-3 trial, but was also related to our screening program (i.e., zorgpad Hypertensie). Previously, our research group published the results of this screening program, which showed that about one third of the referred patients with apparent resistant hypertension had either no hypertension (e.g. white coat hypertension) or other causes of their high BP, like primary hyperaldosteronism.12 With this in mind, the fact that in the HTN-3 trial patients only were screened on pheochromocytoma, could have led to inclusion of a considerable number of patients in whom no response on RDN was expected. Since there was a high probability that secondary causes were still present in the selected population, sympathetic overactivity might be only a minor contributor to the hypertension seen in the HTN-3 population. Moreover, a post-hoc analysis of the HTN-3 data showed that an Afro-American race (26% of the HTN-3 population) negatively influenced the BP lowering effect of RDN, but only in combination with some other 10 patient characteristics.13 Another suggested non-responding group was the patient group
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with isolated systolic hypertension (ISH, office SBP ≥ 140 and DBP ≤ 90 mmHg), since in those patients elevated BP is due to increased arterial stiffness rather than sympathetic overactivity.14 Indeed, combined data of the HTN-3 trial and global Symplicity registry showed a less pronounced BP lowering effect of RDN, compared to patients with combined systolic and diastolic hypertension (mean difference of -3.0 mmHg, [95% CI -5.4 to -0.6]).14 Notable is the fact that in SYMPATHY 30% of the study population (n=42) had ISH and a sub-group analysis showed no relation between the presence of ISH and the observed RDN effect. Alternatively, we can also select patient that have probably a greater response to RDN. For instance, resistant hypertensive women with a previous hypertensive disorder of pregnancy (HDP) showed a larger effect of RDN on BP, than women without a history of HDP (Chapter 4). Or perhaps, patients with a low salt intake, in whom the elevated pressure may be more due to increased sympathetic activity (de Beus E et al., submitted). Finally, all RCTs (except ReSET), implicated the importance of adequate medication intake, as this would hopefully minimize the influence of medication use on the observed change in BP after RDN. The trials applied different methods to assess the adequate use of BP lowering drugs. These methods were: 1) diaries (HTN-2, HTN-3, Symplicity-J and DENERHTN), 2) witnessed intake (OSLO), 3) analysis of blood samples at screening (PRAGUE), 4) interviews (Symplicity-F).
Patient related factors: adequate use of blood pressure lowering drugs
What is adequate use of BP lowering drugs? The logical answer is the prescription of BP lowering medication according the most recent guidelines of the European Society for Hypertension and Cardiology.15 However, there is a lack of consistency between the RCTs in the RDN field of what usual care is and thus the definition of the reference group. Six (including SYMPATHY) of the nine published RCTs continued with the drug treatment, as was prescribed at baseline. However, the other three RCT’s had different regimes, which makes it difficult to compare the “true” RDN effect. Two of the RCTs were also preliminary stopped after the publication of the results of HTN-3: 1) the PRAGUE-trial intensified drug treatment and added spironolactone and 2) the OSLO-trial performed witnessed intake to assure the patient was true resistant hypertensive.4, 7 Both showed no beneficial added effect of RDN on BP, but sample sizes were not sufficient to answer their primary endpoint properly. The third trial, with enough power for his primary endpoint (change in daytime systolic ABPM after six months), was the DENERHTN- trial in France. This trial had a standardized stepped-care antihypertensive treatment
186 Discussion
protocol, meaning that patients in both treatment arms were taken off their own drug treatment and set on amlodipine, ramipril and indapamide. Data of the DENERHTN showed a significant greater decline in daytime systolic ABPM after RDN, compared to controls (mean difference of -5.9 mmHg [95% CI -11.3 to -0.5]).1
Patient related factors: medication adherence
This thesis added an important point of view to the answer what usual care is, by having adherence to prescribed medication objectively measured. We showed that usual care differed between and within patients over time (Chapter 5). Moreover, these changes in medication use modified the direction and magnitude of the effect of RDN on BP (Chapter 3). When patients were stable in their medication use, there was indeed a larger BP lowering effect in the RDN group, compared to reference group (Chapter 3). The prevalence of 20% adherent patients is probably comparable with most of the other RCTs in the field. The fact that DENERHTN showed a significant beneficial effect of RDN on BP could be related to the higher level of adherence in their population (±50%), due to intensive follow-up. However, they could not provide information on changes in adherence during the conduct of the trial.16 The question remains how we have to interpret the results of RDN in previous trials of which neither of them had an objective measurement of medication adherence at baseline. One hypothesis could be that there was an underestimation of the effect of RDN; due to changes in adherence during the conduct of the trial in both treatment arms in opposite directions (e.g. a decrease in adherence in the intervention group and increase in adherence in the reference group). The contribution of (change in) medication adherence to the neutral effect in previous trials, is supported by the calculated change in systolic 24-h ABPM of -5.8 mmHg in the pooled control group of our meta-analysis (Chapter 3, Supplementary data). This change was much larger than the expected placebo effect of -0.9 mmHg (Chapter 6). Change in adherence might partially explain the extent to which BP dropped in previous trials. We observed in SYMPATHY a significant improvement in adherence in the control group, which was slightly larger than in the RDN group, but the difference was not significant, yet. Furthermore, in patients without BP lowering drugs (and thereby excluding changes in medication use as effect modifier), RDN indeed significantly lowered BP (Chapter 6).
To summarize, anamnesis (history of HDP, prescribed medication), physical examination (24-h ABPM, office BP) and objective assessment of medication adherence are of upmost 10 importance to identify the potential best responder to RDN.
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Procedural related factors
Since the promising results of HTN-2 several medical companies published data of new methods to perform RDN, varying from radio-frequency ablation with multiple electrodes,17 chemical ablation with alcohol,18 cryoenergy ablation19 and, externally delivered ultra-sound.20 The eagerness to develop new RDN methods is understandable, as doubt was raised whether the first device used (Symplicity, single-electrode catheter) was capable enough of really denervating the renal nerves around the renal arteries.21 However, a direct method to quantify nerve damage in humans was and is not available yet and therefore determination of the direct effect of RDN remains difficult. It would be much more informative to have had more experimental/histological studies on the procedural effectiveness, than to invest in new techniques without this knowledge. There is some evidence indicating the importance of procedural aspects. First, there is a positive relation between higher number of ablations and extent of decline in BP.22 Second, it is important to perform the ablation in a four-quadrant pattern.22 One small study in porcine models defined that ablation in the distal segment or the branches of the renal artery was associated with a larger reduction of the axonal density, than RDN only performed in the main renal artery. Furthermore, this was a better predictor of success of RDN than a higher number of ablations.23 The former study was recently supported by a double-blinded RCT in which they randomized patients to conventional RDN (only in the main artery) or to distal RDN (RDN applied in the distal branches and main artery beyond the main bifurcation). They found a significant larger reduction in systolic 24-h ABPM in the distal group, compared to the conventional group (mean difference of -13.2 [95% CI -24.9 to -1.5] mmHg).24 However, a (sham)-control group was lacking, which could have provided a more accurate net effect of the RDN procedure, by excluding a possible placebo effect. Further, a direct marker of nerve damage after the procedure could have empowered the results. S100B has the potential to be useful as such a marker to quantify the amount of nerve damage and thereby the success of the RDN procedure. Our pilot-study explored the (change in) S100B level shortly after the RDN procedure and found that S100B increased after RDN and there was a slight trend for a positive relation between an increase in S100B concentration and decline in BP after RDN (Chapter 7). Recently a nerve stimulator has been developed to immediately check if BP still rose after an ablation by stimulation of the ablated nerves. This enables the interventionist to directly repeat the ablation when BP still increased.25 A promising development, but the duration of the procedure becomes very long. Results have to
188 Discussion
be approved by a randomized-controlled trial, which is not expected yet. Therefore, at present we should assess a high number of ablations on a more distal location of the renal artery to perform a successful procedure. Further research is needed to explore possible biomarkers of nerve damage that are immediately available after the procedure and that are related to decline in BP.
Design related factors
There is no doubt that the RDN field has held his horses till the HTN-3 results were published. HTN-3, the first randomized sham-controlled trial, had been considered as the golden standard to assess the effect of RDN on BP. Especially in the United States, where the FDA (Food Drug Administration) made it mandatory to perform only sham-controlled studies in this field.26 The European guidelines partially supported the FDA, but they did not recommend a sham procedure in patients with mild to moderate hypertension, as the possible harm of the procedure may not out way the benefits.27 The existence of a possible placebo effect in device-related studies is definitely present, but its extent is unknown, but likely considerable. In pharmacological studies in hypertensive patients, the placebo effect (of only participating in a study) varied from -0.9 to -4.0 mmHg for systolic 24-h ABPM and office SBP, respectively (Chapter 6). Our study in drug naive patients showed a change in systolic ABPM of -5.7 (95% CI -11.0 to -0.4) mmHg after RDN (Chapter 6); still more than the predefined possible placebo effect, but the placebo effect could be larger in intervention studies. Therefore, a sham-controlled study would be a good alternative to rule out this placebo effect. Three sham-controlled studies are published till now and none of them showed RDN as superior therapy for BP control.2, 3, 6 However, in all three trials the BP reduction in the control groups was much larger than the expected placebo effect. Patient factors are not likely to have influenced the results, due to the randomized sham-controlled design. Procedural related factors are more probable to have confounded the observed change in BP.
Recommendations for daily practice and future research
Screening the best patient; the best adherence; the best outcome measurement
A well conducted study starts before the baseline visit; in other words: before inclusion. Screening of patients is of upmost importance. The physician must ascertain that the 10 patient is correctly diagnosed with resistant hypertension. Twenty-four hour ABPM should
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be the first step to exclude white coat hypertension. Next, secondary causes have to be excluded, preferably in the absence of antihypertensive treatment. For example aldosterone antagonists can interfere with the diagnostics tests for hyperaldosteronism, which is one of the major secondary causes found in this population.12 Recently, our study group showed that discontinuation of antihypertensive medication for study purposes did not increase the risk of acute cardiovascular events, compared to a matched reference group with medication (Beeftink MMA et al., submitted). In the presently ongoing SPYRAL HTN Global Clinical Trial Program, in which the effect of RDN on BP is studied in resistant hypertensive patients, the use of spironolactone is an exclusion criterium. The investigators stated that spironolactone is not first- or second line therapy and that spironolactone is often used to attenuate aldosterone excess. It is questionable to use this kind of exclusion, as this patient group has often good reasons why they do not use first choice therapy (e.g. side effects). Moreover, since we know that spironolactone attenuate sympathetic activity,28 this exclusion could lead to selection of the “non-responder”. In particular since other BP lowering drugs than spironolactone were preferred in the selected patient group, thereby suggesting that sympathetic overactivity contributed little to their hypertension. In that case, the effect of RDN could be underestimated, due to selection of the “wrong” patient. The next step would be an objective assessment if the prescribed drugs are taken as was advised by the treating physician. Similar to the “toothbrush phenomenon”, the patient takes his medication better when he has a doctor appointment, which could lead to an overestimation of the adherence.29 However, most of the patients with resistant hypertension referred to a third line hospital are eager to participate in a therapeutic device trial (to quit their medication) and the willingness to meet defined BP criteria of a trial can lead to intentional non-ingestion of BP lowering drugs. Therefore it is mandatory to implement adherence assessment in the screening phase of a trial. But, the consequence of the finding of non-adherence could lead to two opposite directions: 1) the physician starts with shared-decision making to optimize the use of BP lowering drugs (e.g. prescription of combination tablets) and BP is reevaluated or, 2) we accept the non-adherence, as it is probably every-day reality and the patient is included in the study. The latter makes more sense, as the patient is still at increased risk to develop cardiovascular diseases (CVD). However, for research purposes, objective assessment of (change in) adherence should be obtained ór the patient has to be set off his medication for the best interpretation of the treatment effect.
190 Discussion
Finally, this author would like to revive the importance of office SBP as effect estimator after RDN. We could hypothesize that office SBP is a better indirect marker of sympathetic activation than systolic 24-h ABPM. Due to stress at the moment of the office BP assessment and thereby activation of the SNS. A decline in office SBP would therefore be a good indirect marker of a successful RDN procedure. Our meta-analysis showed that almost all RCTs had a larger decline in office SBP in favor of RDN (Chapter 3, supplementary data). In the SYMPATHY study population, there was a significant correlation between delta office SBP and delta systolic 24-h ABPM for the whole study population with a Spearman’s rho of 0.442 (P < 0.001). The hypothesis that office SBP might be an important indirect marker for a successful RDN procedure, is supported by the finding that patients with a successful RDN procedure (defined as > 10 mmHg decline in office SBP) had the strongest decline in 24-hour systolic ABPM (R2=0.146). This relation was not observed for controls with > 10 mmHg decline, in which 24-hour systolic ABPM remained constant (R2=0.001). Further, cardiovascular risk analyses can be well determined with automated office BP measurements, as was accomplished within the SPRINT-trial.30 In addition, office BP measurements are cheaper and easier to perform in low income countries. However, 24-h ABPM remains relevant for dipping pattern or nighttime BP, all previously related to response after RDN.11
To conclude: identification of patient characteristics related to the best response after RDN consists of a thorough anamnesis (history of HDP, number of prescribed medication, side effects), a physical examination with 24-h ABPM and office BP (ISH) and objective measurement of medication adherence. Most of these factors are also important to define the condition of resistant hypertension. During the conduct of an (intervention) trial an objective tool to quantify medication adherence is mandatory. Office SBP might be a valuable surrogate marker for the successfulness of the RDN procedure.
Open questions
The results of RDN are mainly focused on BP reduction. Still, the effort to control BP has the intention to reduce the incidence of CVD. To answer the question if RDN also reduces the risk of CVD long term follow-up with large number of patients are needed. The total number of patients enrolled in published RCTs till now was ±1100, which is probably a poor reflection of daytime reality. It has been estimated that, in Europe, approximately 20,000 RDN procedures were performed for the indication of resistant hypertension.4 10 We can question if the publication bias of preferably successful reports has enabled us to
191 Chapter 10
overestimate the effect of RDN. There are also national resistant hypertension registries published.30-36 Unfortunately, these registries are not mandatory in most countries and contained only individual data of approximately 1000 patients.31-37 Obviously, pooling this individual patient data could potentially give precise answers to determinants of response to RDN, safety of the procedure and potentially reduced incidence of CVD. The latter is especially important, since a lower risk on CVD is more comprehensible for the patient, instead of the importance to control BP (of which often the patient has no complaints). In the Netherlands, the Renal denervation Registry will provide us with long term information.36 First results, concerning safety, showed no significant change in kidney function after RDN (median follow-up 9 months) and in only three patients (3.1%) renal vascular changes were observed after RDN (Sanders MF et al., submitted).
Another interesting objective is the assessment of the effect of RDN on quality of life. Our experience is that the patient has a better quality of life after RDN. Only one observational study with a follow-up ≥ 12 months has been published till now, showing a promising improvement in quality of life, which was related to decline in BP.38 SYMPATHY obtained three health questionnaires at different time-points (up till 24 months). It would be of great value to assess change in patients’ perceived quality of life after the procedure, as we could rule out a possible placebo effect with our control group.
Renal denervation: can we control the resistance in the community?
With all this in mind, the results of the SPYRAL HTN Global Clinical Trial Program (first results expected late 2017) are thought to have a great impact on the implementation of RDN in the treatment for hypertension.39 In this program a standardized on-med and an off-med randomized sham-controlled trial is performed to study the effect of RDN on BP. In both trials almost all new patient information (exclusion of the patient with ISH, objective assessment of adherence at baseline and follow-up) ánd procedural information (location of ablations, latest catheter) are taken into account. In this way, they will be able to include the best responder to RDN. Unfortunately, no potential biomarkers are assessed to monitor the successfulness of the procedure. There are different scenarios possible how the medical community will react on the results. First, if RDN shows a (clinically) significant larger decline in BP in both trials compared to the sham-controlled group, the “believers” will be motivated to invest in RDN as treatment for hypertension. If RDN is only superior in the off-med group, then BP lowering drugs
192 Discussion
are probably an important confounder of the observed RDN effect in the on-med trial. Second, if RDN fails to be superior in both the on-med and off-med trial, this will probably mean the end of percutaneous RDN. Theoretically, the most difficult scenario to interpret would be if RDN is only superior in the on-med trial and not in the off-med trial. One hypothesis could be that some of the BP lowering classes (e.g. thiazides) will activate the sympathetic nervous system and, in that case, a larger effect of RDN can be expected in the on-med trial. However, reservations of the community will remain in any case, as long as we do not know for certain that RDN indeed disrupts the nerves. Moreover, evidence of a reduction in CVD endpoints is not available, yet. In conclusion, to answer the question if RDN might encounter a place in our healthcare system, there has to be progress. This author thinks there is but international collaboration of RDN experts to combine patient data ánd a lot of patience are essential to control the resistance.
10
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References
(1) 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(9981):1957-1965. (2) Bhatt DL, Kandzari DE, O’Neill WW et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med.2014;370(15):1393-1401. (3) Desch S, Okon T, Heinemann D et al. Randomized sham-controlled trial of renal sympathetic denervation in mild resistant hypertension. Hypertension.2015;65(6):1202-1208. (4) Fadl Elmula FE, Hoffmann P, Larstorp AC et al. Adjusted drug treatment is superior to renal sympathetic denervation in patients with true treatment-resistant hypertension. Hypertension. 2014;63(5):991-999. (5) Kario K, Ogawa H, Okumura K et al. SYMPLICITY HTN-Japan - First Randomized Controlled Trial of Catheter-Based Renal Denervation in Asian Patients -. Circ J.2015;79(6):1222-1229. (6) Mathiassen ON, Vase H, Bech JN et al. Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial. J Hypertens.2016;34(8):1639-1647. (7) 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(2):407-413. (8) Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet.2010;376(9756):1903-1909. (9) Hausberg M, Kosch M, Harmelink P et al. Sympathetic nerve activity in end-stage renal disease. Circulation.2002;106(15):1974-1979. (10) Hering D, Mahfoud F, Walton AS et al. Renal denervation in moderate to severe CKD. J Am Soc Nephrol.2012;23(7):1250-1257. (11) Vink EE, Verloop WL, Bost RB et al. The blood pressure-lowering effect of renal denervation is inversely related to kidney function. J Hypertens.2014;32(10):2045-2053. (12) Verloop WL, Vink EE, Voskuil M et al. Eligibility for percutaneous renal denervation: the importance of a systematic screening. J Hypertens.2013;31(8):1662-1668. (13) Flack JM, Bhatt DL, Kandzari DE et al. An analysis of the blood pressure and safety outcomes to renal denervation in African Americans and Non-African Americans in the SYMPLICITY HTN-3 trial. J Am Soc Hypertens.2015;9(10):769-779. (14) Mahfoud F, Bakris G, Bhatt DL et al. Reduced blood pressure-lowering effect of catheter-based renal denervation in patients with isolated systolic hypertension: data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry. Eur Heart J.2016. (15) Mancia G, Fagard R, Narkiewicz K et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens.2013; 31(7):1281-1357. (16) Azizi M, Pereira H, Hamdidouche I et al. Adherence to Antihypertensive Treatment and the Blood Pressure-Lowering Effects of Renal Denervation in the Renal Denervation for Hypertension (DENERHTN) Trial. Circulation.2016;134(12):847-857. (17) Papademetriou V, Tsioufis CP, Sinhal A et al. Catheter-based renal denervation for resistant hypertension: 12-month results of the EnligHTN I first-in-human study using a multielectrode ablation system. Hypertension.2014;64(3):565-572. (18) Bertog S, Fischell TA, Vega F et al. Randomized, Blinded and Controlled Comparative Study of Chemical and Radiofrequency-Based Renal Denervation in a Porcine Model. EuroIntervention.2016.
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(19) Prochnau D, Heymel S, Otto S, Figulla HR, Surber R. Renal denervation with cryoenergy as second-line option is effective in the treatment of resistant hypertension in non-responders to radiofrequency ablation. EuroIntervention.2014;10(5):640-645. (20) Neuzil P, Ormiston J, Brinton TJ et al. Externally Delivered Focused Ultrasound for Renal Denervation. JACC Cardiovasc Interv.2016;9(12):1292-1299. (21) Vink EE, Goldschmeding R, Vink A, Weggemans C, Bleijs RL, Blankestijn PJ. Limited destruction of renal nerves after catheter-based renal denervation: results of a human case study. Nephrol Dial Transplant.2014;29(8):1608-1610. (22) Kandzari DE, Bhatt DL, Brar S et al. Predictors of blood pressure response in the SYMPLICITY HTN-3 trial. Eur Heart J.2015;36(4):219-227. (23) Mahfoud F, Tunev S, Ewen S et al. Impact of Lesion Placement on Efficacy and Safety of Catheter- Based Radiofrequency Renal Denervation. J Am Coll Cardiol.2015;66(16):1766-1775. (24) Pekarskiy SE, Baev AE, Mordovin VF et al. Denervation of the distal renal arterial branches vs. conventional main renal artery treatment: a randomized controlled trial for treatment of resistant hypertension. J Hypertens.2017;35(2):369-375. (25) de Jong MR, Adiyaman A, Gal P et al. Renal Nerve Stimulation-Induced Blood Pressure Changes Predict Ambulatory Blood Pressure Response After Renal Denervation. Hypertension. 2016;68(3): 707-714. (26) White WB, Galis ZS, Henegar J et al. Renal denervation therapy for hypertension: pathways for moving development forward. J Am Soc Hypertens.2015;9(5):341-350. (27) Mahfoud F, Bohm M, Azizi M et al. Proceedings from the European clinical consensus conference for renal denervation: considerations on future clinical trial design. Eur Heart J.2015;36(33):2219- 2227. (28) Raheja P, Price A, Wang Z et al. Spironolactone prevents chlorthalidone-induced sympathetic activation and insulin resistance in hypertensive patients. Hypertension.2012;60(2):319-325. (29) Cramer JA, Scheyer RD, Mattson RH. Compliance declines between clinic visits. Arch Intern Med. 1990;150(7):1509-1510. (30) Myers MG, Kaczorowski J, Dolovich L, Tu K, Paterson JM. Cardiovascular Risk in Hypertension in Relation to Achieved Blood Pressure Using Automated Office Blood Pressure Measurement. Hypertension.2016;68(4):866-872. (31) Kim BK, Bohm M, Mahfoud F et al. Renal denervation for treatment of uncontrolled hypertension in an Asian population: results from the Global SYMPLICITY Registry in South Korea (GSR Korea). J Hum Hypertens.2016;30(5):315-321. (32) de Sousa AM, de Araujo GP, Branco P et al. Impact of Renal Sympathetic Denervation on Left Ventricular Structure and Function at 1-Year Follow-Up. PLoS One.2016;11(3):e0149855. (33) Zweiker D, Lambert T, Steinwender C et al. Effects of Renal Denervation Documented in the Austrian National Multicentre Renal Denervation Registry. PLoS One.2016;11(8):e0161250. (34) Tsioufis C, Ziakas A, Dimitriadis K et al. Blood pressure response to catheter-based renal sympathetic denervation in severe resistant hypertension: data from the Greek Renal Denervation Registry. Clin Res Cardiol.2016. (35) Kadziela J, Prejbisz A, Kostka-Jeziorny K et al. Effects of renal sympathetic denervation on blood pressure and glycaemic control in patients with true resistant hypertension: results of Polish Renal Denervation Registry (RDN-POL Registry). Kardiol Pol.2016;74(9):961-968. (36) Sanders MF, Blankestijn PJ, Voskuil M et al. Safety and long-term effects of renal denervation: Rationale and design of the Dutch registry. Neth J Med.2016;74(1):5-15. (37) Mahfoud F, Brilakis N, Bohm M et al. TCT-761 Long-term (3-year) safety and effectiveness from the Global SYMPLICITY Registry of renal denervation in a real world patient population with uncontrolled hypertension. J Am Coll Cardiol.2016;68(18S):B308. 10
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(38) 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(11):2350-2358. (39) 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(1):82-91.
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CHAPTER English summarymmary Nederlandsese samenvattinsamenvattingg Dankwoordd Curriculum Vitae List of publications English summary The main focus of this thesis is the effect of percutaneous renal denervation (RDN) on blood pressure (BP). In line with our primary objective, was our secondary objective to study factors that potentially could influence the effect of RDN on BP. Furthermore, as the sympathetic renal nerves cannot be identified on forehand, RDN may not only be beneficial in lowering BP, but also for other diseases related to the kidneys.
The primary aim of this thesis is to determine the BP lowering effect of percutaneous RDN. Secondary aim was to explore which factors influence the effect of RDN on BP. Third aim was to determine the potential of RDN on pain relief in patients with kidney-related pain.
In Chapter 1, the introduction, we described that 871 million people worldwide suffers from hypertension. Only 35% of the treated patient achieves guideline targets. In the introduction the role of sympathetic overactivity in the development of hypertension and kidney disease is reviewed. It was explained why the assessment of sympathetic nerve activity is invasive and not useful in daily practice. Furthermore, conventional, medical therapy is discussed as therapy to attenuate sympathetic overactivity, of which only renin-angiotensin system inhibitors, moxonidine and spironolactone are proven to be effective. Thereafter, RDN is described as new therapeutic option in the treatment of sympathetic overactivity and, thereby, resistant hypertension. Finally, we discussed possible factors that make it difficult to interpret the “true” effect of RDN on BP: patient related factors (history of hypertension disorders of pregnancy (HDP), medication adherence), procedural related factors (missing of a direct marker of destruction of the renal nerves) and design related factors (lack of a sham procedure).
Part I
Chapter 2 described the rationale and design of the SYMPATHY-trial. SYMPATHY is a multi-center randomized, open-label, controlled trial. Primary objective of this trial was to study the effect of RDN, added to usual care, on daytime systolic ambulatory BP (ABPM) compared to usual care alone in patients with resistant hypertension. Primary endpoint was at six months. Patients were randomized with a 2: 1 ratio to RDN on top of usual care or usual care alone. Secondary outcomes were: the effect of RDN on office systolic BP (SBP) and kidney function and the prevalence of peri-procedural complications.
In Chapter 3 the main findings of SYMPATHY were presented. Important adjustments during the conduct of the study were: 1) inclusion of patient with documented intolerance
201 11 English summary
for ≥ two BP lowering drugs and not able to use ≥ three BP lowering drugs; 2) allowance of the use of the EnligHTN catheter (st. Jude Medical) next to the Symplicity catheter (Medtronic Inc.); 3) adjustment of our sample size to 100–150 patients (instead of 300 patients) to answer our primary endpoint. Furthermore, two new secondary objectives were added: 1) to study the adherence to BP lowering drugs at baseline and 2) to study the change in adherence during the conduct of the study and the effect this change had on the observed change in BP after RDN. Medication adherence was objectively assessed with stored blood, sampled at baseline and follow-up, without knowledge of patients and physicians. One hundred thirty-nine patients were randomized (95 RDN). Our primary analysis showed no beneficial effect of RDN on daytime systolic ABPM, compared to usual care alone after six months (mean difference of 2 [-6.1 to 10.2] mmHg in favor of control group). Pre-defined subgroup analyses, based on kidney function and baseline office SBP, revealed no significant interaction with the effect of RDN on BP. Our data suggested that RDN was a safe procedure. Medication adherence was poor in both the RDN and control group and adherence changed in 31% of the patients. These changes modified the magnitude and direction of the change in BP observed after RDN. Therefore, objective measurement of medication adherence during follow- up is strongly recommended in randomized trials.
Chapter 4 described the prevalence of women with resistant hypertension and a self- reported hypertensive disorder of pregnancy (HDP). Secondary aim was to determine if this selected patient group had a greater decline of SBP after RDN, compared to resistant hypertensive women without pregnancies or normotensive pregnancies. Sixty-six women of a prospective cohort with referred resistant hypertensive patients were included. In women with resistant hypertension a history of HDP was more prevalent than in the normal (hypertensive) population, which also accounted for pre-eclampsia. Heart rate and low-density lipoprotein were significantly higher in the HDP group compared with non-HDP group. RDN decreased BP in all patient groups, but tended to lower BP at a larger extent in the HDP group than in the non-HDP group.
Part II
We presented a sub-study of SYMPATHY in Chapter 5. Aims were: 1) to determine different factors related to poor adherence; 2) to study the relation between level of adherence with blood pressure and the change overtime. Stored blood samples were
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available at baseline (98 patients) and six months (83 patients) and we had both follow- up moments for 78 patients. At baseline, 68% (n=67) of the patients were (partially) non-adherent. The higher the number of prescribed BP lowering pills or the higher office SBP was, the lower the adherence was. Office blood pressure increased when adherence declined overtime. This study showed poor adherence in patients with resistant hypertension, which was related to a higher BP. An objective tool to assess adherence could help the physician to define resistant hypertension and improve blood pressure.
Chapter 6 described the effect of RDN on blood pressure, when patients are not on BP lowering drugs at baseline and follow-up. In this international cohort of eight tertiary centers patients were included when they were treated with RDN and had a baseline office SBP ≥ 140 mmHg and/or 24-h systolic ABPM ≥ 130 mmHg. Our primary outcome was defined as change in office SBP and 24-hour systolic ABPM at 12 months after RDN, compared to baseline. We included 53 patients with intolerance (57%), temporary cessation of medication for study purposes (28%) and reluctance to use BP lowering drugs (15%). Both 24-h systolic ABPM and office SBP declined significantly 12 months after RDN (-5.7 mmHg [-11.0 to -0.4] mmHg and -13.1 [-20.4 to -5.7] mmHg, respectively). These results suggested that RDN is beneficial in at least some patients.
In Chapter 7 we determined S100B as direct marker for success of the RDN procedure. Primary aim was to assess whether S100B increased after RDN as a reflection of nerve damage. Second, we explored a possible relation between the maximum S100B level and the change in BP after RDN. This study was conducted as a pilot-study and included ten patients who underwent RDN. Blood was venous and/or arterial sampled at different time-points pre- and post RDN. S100B level increased at all time-points after RDN, compared to baseline and reached his maximum concentration six hours post-RDN. As marker for success in terms of a BP lowering effect, our results were not convincing. Further research in larger studies is needed to investigate the dynamics of S100B concentrations following RDN and to determine whether elevated S100B is related to BP reduction after RDN.
Part III
Chapter 8 introduced RDN as new therapeutic option to treat pain related to autosomal dominant polycystic kidney disease (ADPKD). A case report was presented of a 43-year old woman whose chronic kidney-related pain could not be controlled by analgesic
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medication or splanchnic nerve blockade. Percutaneous RDN was performed at both sides on separate moments. Two months later she was pain free, reported a VAS-score of zero out of ten, did not use any pain relief medication and had resumed her normal working and social life. Office BP had decreased from 145/96 to 120/75 mmHg pre- versus post-intervention, respectively, although her antihypertensive medication had been reduced from 3 to 2 agents. Her kidney function remained stable.
Chapter 9 reported on the first 11 patients with chronic kidney-related pain in which RDN was performed for pain relief. The primary outcome in this pilot study was defined as change in perceived pain and use of analgesic medication 12 months after catheter- based RDN. Six patients with loin pain hematuria syndrome (LPHS) and five with ADPKD were included. Perceived pain was assessed with the VAS-score. Perceived pain declined in the whole group significantly with 22 mm (P=0.018) after 12 months. In addition, in both LPHS and ADPKD the use of analgesic medication continued to decline at 12 months. Our results suggested that RDN could be beneficial to reduce kidney-related pain in LPHS and ADPKD.
Part IV
In Chapter 10 the results of this thesis are put into perspective and recommendations are presented for daily practice and future research.
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Dit proefschrift heeft als belangrijkste doel om het effect van renale denervatie (RDN) op bloeddruk te onderzoeken. Daarnaast wilden we ook factoren identificeren die ons per individu helpen te voorspellen wat het uiteindelijke effect van RDN is op bloeddruk. Als derde doel hebben we RDN als nieuwe therapie voor pijn afkomstig van de nieren onderzocht, omdat we denken dat met RDN ook sensorische (pijn)zenuwen worden uitgeschakeld.
Het primaire doel van dit proefschrift is om het bloeddrukverlagende effect van RDN te onderzoeken. Secundair doel was om uit te vinden welke factoren het effect van RDN op de bloeddruk beïnvloeden. Het derde doel was de potentie van RDN te onderzoeken voor het verminderen van niergerelateerde pijn.
In Hoofdstuk 1, de introductie, wordt beschreven dat wereldwijd 871 miljoen mensen voldoen aan de definitie van hypertensie. Slechts 35% van de mensen die hiervoor behandeld wordt, bereikt de gewenste streefwaarde. In de introductie wordt de relatie tussen sympathische overactiviteit en hypertensie en nierinsufficiëntie beschreven. Verder wordt uitgelegd waarom het meten van sympathische zenuwactiviteit erg invasief is en niet bruikbaar in de dagelijkse praktijk. Conventionele, medicamenteuze therapie, zoals renine-angiotensine systeeminhibitors, moxonidine en spironolacton hebben bewezen sympathische zenuwactiviteit te verlagen. RDN zou voor (medicamenteuze) therapieresistente hypertensie een nieuwe behandeling kunnen zijn. Tot slot worden factoren besproken die mogelijk het bloeddrukverlagende effect van RDN kunnen beïnvloeden: patiëntgerelateerde factoren (voorgeschiedenis van hypertensieve aandoeningen tijdens de zwangerschap (HDP), therapietrouw), procedurele gerelateerde factoren (ontbreken van een directe marker van zenuwschade) en studieopzetgerelateerde factoren (ontbreken van een nep (sham) procedure).
Deel I
Hoofdstuk 2 beschrijft de achtergrond en studieopzet van de SYMPATHY studie. SYMPATHY is een multicenter, gerandomiseerde, niet geblindeerde, gecontroleerde studie. Het primaire doel was om te onderzoeken wat het effect was van RDN, toegevoegd aan de gebruikelijke medicamenteuze therapie, op de systolische bloeddruk overdag gemeten met een 24-uurs meter, vergeleken met alleen de gebruikelijke medicamen- teuze therapie in patiënten met resistente hypertensie. Het primaire eindpunt lag op zes maanden. Patiënten werden in een 2:1 ratio gerandomiseerd voor RDN plus gebruikelijke
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medicamenteuze therapie of alleen gebruikelijke medicamenteuze therapie. Secundaire uitkomstmaten waren het effect van RDN op systolische spreekkamerbloeddruk en nierfunctie en het vóórkomen van peri-procedurele complicaties.
In Hoofdstuk 3 worden de belangrijkste bevindingen van de SYMPATHY studie bespro- ken. Gedurende de studie is er een aantal aanpassingen gedaan aan de studieopzet: 1) uitbreiding van de inclusie met patiënten met intolerantie voor ≥ twee bloeddrukver- lagende middelen en die geen mogelijkheid hebben om ≥ drie bloeddrukverlagende middelen in te nemen; 2) het gebruik van de EnligHTN katheter van St. Jude Medical, naast de Symplicity katheter van Medtronic Inc.; 3) aanpassing van de groepsgrootte naar 100–150 deelnemers (in plaats van 300) voor de beantwoording van ons primaire eindpunt.
Daarnaast hebben we twee secundaire onderzoeksdoelen toegevoegd: 1) om de therapietrouw ten aanzien van bloeddrukverlagende middelen te onderzoeken; 2) om de verandering in therapietrouw te onderzoeken gedurende de studie en het effect daarvan op de verandering in bloeddruk na RDN. Therapietrouw werd objectief gemeten met opgeslagen serum, afgenomen op baseline en verschillende follow-up-momenten, zonder medeweten van deelnemers aan de studie en hun behandelaars.
Honderdnegenendertig deelnemers werden gerandomiseerd, waarvan 95 naar RDN. Onze primaire analyse liet geen toegevoegde waarde van RDN zien. Er werd geen significante relatie gevonden tussen het bloeddrukverlagende effect van RDN en nierfunctie of hoogte van de systolische bloeddruk. Onze resultaten laten zien dat RDN een veilige procedure is.
Therapieontrouw kwam vaak voor in zowel de RDN-groep als de controlegroep. Ook veranderde de mate van therapietrouw gedurende de studie. Deze veranderingen beïnvloedden de grootte en richting van het geobserveerde bloeddrukverlagende effect van RDN. Het is daarom aan te raden om in toekomstige studies een objectieve methode te gebruiken om de therapietrouw te meten.
Hoofdstuk 4 beschrijft de prevalentie van een voorgeschiedenis van hypertensieve aandoeningen gedurende de zwangerschap (HDP) in een groep vrouwen met resistente hypertensie. Daarnaast onderzochten we of er een verschil in bloeddrukverlaging is na RDN tussen vrouwen met een voorgeschiedenis van HDP en zonder voorgeschiedenis van HDP. Er werden 66 vrouwen met resistente hypertensie geïncludeerd in ons
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prospectieve cohort. Deze vrouwen rapporteerden veel vaker een voorgeschiedenis van HDP dan de bekende prevalenties in de normale (hypertensieve) bevolking. Vrouwen met een verleden van HDP hadden een significant hogere hartslag en hoger LDL. RDN verlaagde de bloeddruk bij alle vrouwen, maar in een grotere mate bij de vrouwen die een voorgeschiedenis met HDP hadden gerapporteerd.
Deel II
In Hoofdstuk 5 wordt een substudie van de SYMPATHY studie gepresenteerd. De onderzoeksdoelen van deze substudie waren: 1) uitvinden welke factoren de mate van therapietrouw beïnvloeden; 2) de relatie tussen therapietrouw en bloeddruk beschrijven. Er was opgeslagen bloed beschikbaar op baseline van 98 patiënten en op zes maanden van 83 patiënten. Van 78 patiënten was opgeslagen materiaal van beide momenten beschikbaar. Op baseline waren 67 patiënten (68%) gedeeltelijk of helemaal niet therapietrouw. Hoe meer bloeddrukverlagende middelen ze kregen voorgeschreven, des te minder van deze middelen er werd terug gevonden in het bloed. Als de therapietrouw lager werd, gedurende de studie, dan steeg de spreekkamerbloeddruk significant. Een objectieve methode om therapietrouw te meten zou de behandelaar kunnen helpen om de diagnoseresistente hypertensie nauwkeuriger vast te stellen, evenals de hypertensie beter te behandelen.
Hoofdstuk 6 laat het effect zien van RDN op bloeddruk, wanneer bloeddrukverlagende medicatie dit effect niet kan beïnvloeden. Deze internationale studie vanuit acht centra, includeerde patiënten behandeld met RDN, die op baseline een spreekkamer systolische bloeddruk ≥ 140 mmHg hadden of een 24-uur systolische bloeddruk ≥ 130 mmHg. Bovendien mochten de patiënten op baseline én follow-up geen bloeddrukverlagende middelen hebben gebruikt. Drieënvijftig patiënten konden worden geïncludeerd. Twaalf maanden na RDN waren de systolische spreekkamer- en 24-uurs bloeddruk significant gedaald. Daaruit kunnen we concluderen dat RDN een bloeddrukverlagend effect heeft, in ieder geval bij sommige patiënten.
In Hoofdstuk 7 onderzochten we of S100B, een marker voor zenuwschade, een rol kan spelen als directe marker van een succesvolle RDN-procedure. Primair doel was te bestu- deren of S100B stijgt na RDN, als teken van (nieuwe) zenuwschade. Daarnaast wilden we kijken of de concentratie S100B na RDN gerelateerd was aan de bloeddrukverandering. Deze pilotstudie werd uitgevoerd bij tien patiënten, die allemaal RDN hebben gehad.
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Bloed werd op verschillende tijdsmomenten, voorafgaand en na RDN én arterieel en veneus, afgenomen. S100B steeg op alle tijdsmomenten na de behandeling met de maximale concentratie zes uur na de procedure. We konden geen duidelijke relatie aantonen tussen de verandering in S100B-concentratie en bloeddrukverandering. Grotere studies zijn nodig om de dynamiek van S100B vast te stellen en of een stijging in S100B is gerelateerd aan de bloeddrukdaling na RDN.
Deel III
Hoofdstuk 8 introduceert RDN als nieuwe behandelmethode voor pijn gerelateerd aan de nieren. In dit hoofdstuk beschrijven we een 42-jarige vrouw, bekend met autosomaal dominant polycysteus nierziekte (ADPKD), die ondraaglijke pijn aan de nieren had, ondanks medicatie en splanchicusblokkade. Ze werd aan beide kanten behandeld met percutane RDN. Twee maanden later had ze geen pijn meer, gebruikte ze geen pijnmedicatie meer en kon ze haar normale, dagelijkse leven weer oppakken. Daarnaast was haar spreekkamerbloeddruk gedaald van 145/96 naar 120/75 mmHg. Haar nierfunctie bleef stabiel.
Hoofdstuk 9 rapporteert over de eerste 11 patiënten met chronische pijn gerelateerd aan de nieren, die behandeld zijn met RDN. Primaire uitkomst was verandering in ervaren pijn (aangegeven op een visueel analoge schaal [VAS]) en verandering in het gebruik van pijnmedicatie 12 maanden na RDN. Zes patiënten met LPHS (flankpijn hematuriesyndroom) en 5 met ADPKD werden geïncludeerd. De pijnklachten werden significant minder in de gehele groep. Ook daalde het gebruik van pijnmedicatie in beide groepen. Onze resultaten suggereren dat RDN een nieuwe behandelmethode zou kunnen zijn om pijn gerelateerd aan de nieren te verminderen in patiënten met LPHS en ADPKD.
Deel IV
In Hoofdstuk 10 worden de resultaten van dit proefschrift besproken en in perspectief geplaatst. Verder worden er verschillende aanbevelingen gedaan voor de dagelijkse praktijk en voor toekomstig onderzoek.
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211 11 Dankwoord Dankwoord
Dankjulliewel! Dit boek, waar ik ongelooflijk trots op ben, had niet tot stand kunnen komen zonder jullie medewerking.
Allereerst wil ik alle deelnemers aan de beschreven studies ontzettend bedanken voor hun bereidheid, soms meerdere malen, naar Utrecht af te reizen voor onderzoek. De persoonlijke interesse die vaak werd getoond (zeker wanneer we elkaar twee jaar lang frequent zagen), was hartverwarmend. Het gaat u allen goed!
Geachte Prof. Bots, beste Michiel, als promotor was je mijn rots in de branding gedurende het gehele promotietraject. Met je pragmatische kijk, directheid en laagdrempeligheid heb je dit proefschrift naar een hoger niveau getild. Ook de interesse buiten werk om, heb ik als zeer prettig ervaren.
Geachte Prof. Verhaar, beste Marianne, bij onze allereerste ontmoeting (lang geleden) liet je meteen merken dat er naast het functioneren op de werkvloer, ook oog moest zijn voor de privésituatie. Dat is een uiterst prettige manier van starten in een nieuwe omgeving. Ook wil ik je bedanken voor je bereidheid mee te kijken bij de afronding van mijn proefschrift.
Geachte Dr. Blankestijn, beste Peter, na het uitkomen van de HTN-3 studie had je als copromotor te stellen met twee promovendi waarbij eigenlijk het hele proefschrift qua inhoud moest worden aangepast. Dank voor je vindingrijkheid, de rust en dat ik altijd voor raad en daad bij je binnen kon lopen.
Prof. Roel Goldschmeding, Prof. Rick Grobbee, Prof. Frank Visseren, Prof. Guy Rutten, Prof. Niels Riksen: hartelijk dank voor uw bereidheid plaats te nemen in de beoorde- lingscommissie van mijn proefschrift.
Beste Dr. Joles, Dr. Spiering, Dr. Voskuil en Dr. Vonken; beste Jaap, Wilko, Michiel en Evert-Jan: bedankt voor de leerzame besprekingen en bijdragen aan de verschillende manuscripten in dit proefschrift.
Graag wil ik de deelnemende ziekenhuizen aan de SYMPATHY-trial hartelijk danken voor hun medewerking en vertrouwen in een goede afloop.
Beste onderzoekers van het Nefrologielab. Dank voor het meedenken met mijn onder- zoek tijdens de researchbesprekingen en de gezellige labstapdagjes!
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De stafleden, AIOS, verpleegkundigen en secretaresses van de afdeling Nefrologie & Hypertensie van het UMC Utrecht: dank voor jullie interesse in mijn onderzoek en de praktische hulp. We zullen elkaar de komende jaren zeker nog tegenkomen!
Het opleidingsteam van de Interne geneeskunde in het UMC Utrecht. Dank dat ik de kans heb gehad om voor dit promotietraject mijn opleiding te onderbreken. De van- zelfsprekendheid waarmee jullie meedenken om de opleiding zoveel mogelijk bij de persoonlijke wens van de AIOS aan te laten sluiten, is bijzonder.
Ook dank voor mijn oude opleidingsteam van het Meander Medisch Centrum in Amersfoort. Ik heb daar een hele fijne basis gehad, van waaruit mijn opleidingstraject zich verder heeft ontwikkeld. Speciale dank aan Chris Hagen, Renate Bosma, Peter Luik, Carlo Gaillard en Rob Fijnheer voor hun enthousiasme voor de Nefrologie en de kans om mijn eerste stappen in het onderzoek te zetten.
Dr. Verhaar, beste Harald, dank voor de kans die ik krijg om de opleiding tot internist Ouderengeneeskunde te volgen in het UMC Utrecht. Ik heb er ontzettend veel zin in om van mijn traject, maar zeker ook van de opleiding zelf, een succes te maken!
Dr. van Schelven en Dr. Oey, beste Leonard en Liam, bedankt voor jullie inzet voor de MSNA studie. Ik heb heel veel bewondering voor jullie deskundigheid en geduld, die nodig zijn voor deze metingen.
Beste Bram Dijker en Julia Velikopolskaia, wat zullen jullie bij datamanagement af en toe met de handen in het haar hebben gezeten over weer een verandering in Research Online. Gelukkig was er altijd tijd voor een praatje en ik wil jullie danken voor de prettige samenwerking.
Beste Niek Casteleijn en Prof. Ron Gansevoort uit het UMC Groningen: door onze samenwerking is een aantal mooie studies gepubliceerd. Dank voor alle suggesties en het kritisch meekijken.
Dr. Lely, beste Titia, bedankt dat je jouw enorme kennis over de pathofysiologie van hypertensie gedurende de zwangerschap met mij wilde delen. Ik heb er heel veel van geleerd en we hebben hierover een prachtig artikel kunnen schrijven.
Dr. van Maarseveen, beste Erik, wat kwam het eind 2013 ontzettend goed uit dat wij elkaar troffen! Met jouw enthousiasme en kennis is het gelukt om een zeer fraaie methode
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te ontwikkelen voor het meten van antihypertensiva in bloed. Heel veel succes met het verder uitrollen van deze methode en we komen elkaar vast nog tegen in de toekomst!
Beste Eva en Willemien, de “pioniers” op het gebied van onderzoek naar renale de- nervatie. Bedankt voor de wegen die jullie voor de “volgende generatie”, waaronder ik val, hebben gebaand.
Beste Esther, knap hoe jij de afgelopen jaren, naast je werk als Nefroloog, kans zag om te promoveren. Succes in Rotterdam en we komen elkaar vast nog tegen!
Beste Nicolette, wat heb je je promotietraject snel afgerond, chapeau! Heel veel succes met het uitstippelen van je toekomst!
Beste Martine, “gedeelde smart is halve smart” en zo voelde het toch wel een beetje. Ons promotietraject was niet de gemakkelijkste, maar daarom mogen we des te trotser zijn op het eindresultaat! Succes bij de cardiologie; dat je een doorzetter bent, daar kan niemand aan twijfelen.
Beste Alies, Anka, Anne en Judith van de dagbehandeling Nefrologie. Mede doordat de communicatie zo soepel verliep, zijn de metingen voor de verschillende studies zo goed gelukt. Dank voor de sociale praatjes, de lieve kaartjes en de praktische hulp.
Beste Maaike van Gelder: wat heb jij een ontzettend gaaf promotietraject. Ik kan nu al uitkijken naar je resultaten. Heel veel succes de komende jaren!
Beste Thijs: ik zal nooit meer je bananensokken vergeten. Fijn dat we nog even samen hebben gezeten in het “kippenhok”. Knap hoe snel je het onderzoek hebt opgepakt. Heel veel succes de komende tijd!
Beste Maaike van Wijk: dank voor je attente kaartjes en je gezelligheid. Ik ben nog wel steeds benieuwd hoe jullie wonen.
Lieve Lizeth, de officiële functie was projectmanager van SYMPATHY, maar het was veel meer dan dat! Wat hebben we veel gespuid, gebeld en stad en land afgereisd om weer een ziekenhuis te bezoeken. Ik vond het ontzettend fijn samen met jou dit project te mogen doen. Kom je snel weer, samen met de meiden, verstoppertje spelen met Milou?
Dan het “kippenhok”, zoals ons kamertje ook wel werd genoemd. Wat hebben we daar veel lief en leed met elkaar gedeeld. Hoewel het officieel een flexplek is (wat ik overigens
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ook begrijp), ben ik blij dat wij (ik, Margreet, Laura en Ismay) zo honkvast waren de afge- lopen jaren. Laura, ik heb bewondering voor je doorzettingsvermogen met betrekking tot je celletjes, zeker als er weer iets anders uit lijkt te komen dan je verwacht. Je was een bijzonder prettig luisterend oor. Ik wens je, na deze roerige tijd, heel veel geluk en liefde toe!
Ismay, wij hebben veel overeenkomsten wat betreft opleiding en interesses daarin. Het was erg fijn om daarover te spuien. Bedankt voor je openheid en interesse. Ik kijk ernaar uit om in de toekomst samen te werken!
Lieve vrienden, wat heb ik toch een geluk dat ik jullie tot mijn vriendengroep mag rekenen!
Lieve Joost, Nienke, Leonie, Roel, Brenda, Hugo, Brecht, Sophie, Wouter, Cyntha en Jeff: of het nu Lowlands is of een vrijmibo, het is altijd een feest! Ik voel me echt verrijkt dat ik jullie via Viktor heb leren kennen. Jullie oprechte interesse, medeleven en gezelligheid is goud waard!
Lieve meiden uit Wageningen, Liesbeth, Noera, Renske, Irene en Evelien. Al 20 jaar delen we lief en leed. Ondanks dat we elkaar minder frequent zien, blijft het onverminderd vertrouwd. Ik kijk uit naar onze “lustrum” trip naar Berlijn!
Lieve studievrienden, Vera, Marleen, Bastiaan, Lotte, Sanne en Marjolein. Het is niet voor niets dat het “beschrijvende specialisme” de boventoon voert in onze groep. Bedankt voor de gezelligheid afgelopen jaren. We houden de Nieuwjaarsborrel erin!
Lieve Daniëlle, als huisgenoten en later overburen hebben we heel wat avonden samen in Maastricht door gebracht. Ik hoop dat jij, Jasper en Jasmijn jullie thuis vinden in Maastricht of Roermond.
Lieve Lotte, Sanne en Marjolein. Wat ben ik blij dat we zo dicht bij elkaar zijn komen te wonen! De ongeveer halfjaarlijkse dagjes relaxen met z’n viertjes zijn heerlijk om even goed te ontspannen. Snel weer een dagje plannen?
Lieve paranimfen, Margreet en Marjolein. Margreet, voor mij was meteen duidelijk dat jij de Registry zou aanpakken en er het maximale uit zou halen. Je bijt je in iets vast en laat niet snel los. Een goede aanvulling bij mijn, meer pragmatische, instelling. Qua life events lijken we dan weer meer op elkaar: heel veel geluk met het afronden van je boekje, de opleiding, jullie nieuwe huis en natuurlijk met het moeder zijn.
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Marjolein, het mag gezegd, je bent de motor achter veel borrels, dagjes weg en het regelen van gezamenlijke cadeaus. Dank daarvoor! Je bent één van de meest attente personen die ik ken en hoewel ik helemaal niet van bellen houd, lukt het jou toch een telefoongesprek lang te laten duren. Ik heb bewondering voor je doorzettingsvermogen met je promotie en wens je alle geluk met Ruud en Max.
Lieve schoonfamilie, Jan Pieter, Saskia en Paul. De afgelopen jaren hebben we het nodige meegemaakt en ik koester de hechte band, die we daardoor hebben gekregen. Ik kan nu al uitkijken om Tim en Tygo samen te zien voetballen (met Milou als scheidsrechter natuurlijk). Ook dank aan Tonnie en Dré voor de lieve kaartjes en kadootjes voor de kinderen en jullie interesse in mijn loopbaan. Lieve Ellen, dank voor je prachtige zoon.
Lieve broers, Peter en Almar. Ik kan onmogelijk meer broertjes zeggen, ik ben toch echt de kleinste. Peter, ik heb veel bewondering voor de weg die je hebt afgelegd en wat je nu hebt bereikt. De komende jaren kan ik hopelijk, op de fiets naar huis, nog vaak even langskomen voor een praatje. Ik wens je veel geluk en een mooie toekomst toe. Almar, ongelooflijk wat jij allemaal voor elkaar krijgt, maar wat je zeker ook verdient. Het is bijzonder om te zien dat zes jaar leeftijdsverschil toch echt geen rol meer speelt. Ik wens je alle geluk en liefde toe, samen met Puck.
Lieve mama en papa. Mama, de zorgende kant heb ik niet van een vreemde. Je denkt aan elke bijzondere gelegenheid en bent een meester in het vinden van leuk speelgoed voor de kinderen. Ik hoop dat we in de toekomst nog veel dagjes weg kunnen samen! Papa, ik heb ontzettend veel bewondering voor wat jij allemaal hebt bereikt in het leven. Geen kans heb je onbenut gelaten om verder te komen. Nu mag je genieten van je pensioen. Gaan we snel een stuk Pieterpad wandelen?
Lieve Milou en Tygo, door jullie geboorte heb ik mezelf beter leren kennen. Jullie laten mij geluk zien in de kleinste dingen en trots voelen van ongekende omvang! Liefde is iets bijzonders, zeker als je voelt dat het zo natuurlijk en ongeremd wordt gegeven.
Lieve Viktor, mijn eerste herinnering aan jou, is je lach. Terwijl ik dit schrijf, moet ik ook lachen, want je maakt me ongelooflijk gelukkig. Ik kan niet wachten om weer nieuwe ideeën toe te voegen aan ons, zoals jij zegt, 11-jarenplan. Vik, ik houd van je!
217 11 Curriculum Vitae Curriculum Vitae
Rosemarie (Rosa) Lara de Jager was born on the 25th of December 1983 in Nieuwegein, the Netherlands. She graduated from secondary school at “het Pantarijn” in Wageningen in 2002. Thereafter, she started her study Medicine at the University of Maastricht of which she obtained her medical degree in 2008. Next, she worked as ANIOS Internal Medicine at the Meander Medisch Centrum in Amersfoort under supervision of Prof. C.A.J.M Gaillard and Dr. R. Fijnheer. During this period her enthusiasm for Internal Medicine resulted in a residency in Internal Medicine from January 2010 until present. From May 2012 Rosa continued her residency at the University Medical Center Utrecht under supervision of Prof. M.M.E. Schneider. January 2013 Rosa interrupted her residency for her PhD research project at the department of Nephrology and Hypertension at the University Medical Center Utrecht under supervision of Prof. M.C. Verhaar, Prof. M.L. Bots and Dr. P.J. Blankestijn. In addition Rosa followed the post-graduate Master of Science in Clinical Epidemiology at the University Utrecht. May 2017 Rosa will continue her residency at the University Medical Center Utrecht under supervision of Prof. K.A. Kaasjager. In September 2017 she will start with her differentiation to become Internist in Geriatric Medicine, under supervision of Dr. H.J.J. Verhaar. Rosa is married with Viktor with whom she has a daughter (Milou) and son (Tygo).
219 11 Publication list Publication list
(1) de Jager RL, Casteleijn NF, de Beus E, Bots ML, Vonken EJ, Gansevoort RT, Blankestijn PJ. Catheter-based renal denervation as therapy for kidney-related pain. Nephrol Dial Transplant.2017; In press.
(2) de Jager RL, de Beus E, Beeftink MMA, Sanders MF, Vonken EJ, Voskuil M, van Maarseveen EM, Bots ML, Blankestijn PJ. Impact of medication adherence on the effect of renal denervation. The SYMPATHY trial. Hypertension.2017; 69(4):678-684.
(3) Casteleijn NF, van Gastel MD, Blankestijn PJ, Drenth JP, de Jager RL, Stellema R, Wolff AP, Groen GJ, Gansevoort RT. Novel treatment protocol for ameliorating refractory, chronic pain in patients with autosomal dominant polycystic kidney disease. Kidney Int.2017; 91(4):972-981.
(4) Beeftink MM, Spiering W, Bots ML, Verloop WL, de Jager RL, Sanders MF, Vonken EJ, Blankestijn PJ, Voskuil M. Renal Denervation in a Real Life Setting: A Gradual Decrease in Home Blood Pressure. PLoS One.2016;11(9):e0162251.
(5) de Jager RL*, Sanders MF*, Bots ML, Lobo,MD, Ewen S, Beeftink MM, Bohm M, Daemen J, Dorr O, Hering D, Mahfoud F, Nef H, Ott C, Saxena M, Schmieder RE, Schlaich MP, Spiering W, Tonino PA, Verloop WL, Vink EE, Vonken EJ, Voskuil M, Worthley SG, Blankestijn PJ. Renal denervation in hypertensive patients not on blood
pressure lowering drugs. Clin Res Cardiol.2016;105(9):755-762. *Equal contributors
(6) de Jager RL, Rutten FH, Bots ML, Spiering W, Blankestijn PJ. [Treatment-resistant hypertension]. Huisarts Wet. 2016;59(1):24-6.
(7) Casteleijn NF, de Jager RL, Neeleman MP, Blankestijn PJ, Gansevoort RT. Chronic kidney pain in autosomal dominant polycystic kidney disease: a case report of successful treatment by catheter-based renal denervation. Am J Kidney Dis.2014; 63(6):1019-1021.
(8) de Beus E*, de Jager RL*, Joles JA, Grassi G, Blankestijn PJ. Sympathetic activation secondary to chronic kidney disease: therapeutic target for renal denervation? J
Hypertens. 2014;32(9):1751-1761.*Equal contributors
(9) Vink EE, de Beus E, de Jager RL, Voskuil M, Spiering W, Vonken EJ, de Wit GA, Roes KC, Bots ML, Blankestijn PJ.The effect of renal denervation added to standard pharmacologic treatment versus standard pharmacologic treatment alone in patients with resistant hypertension: rationale and design of the SYMPATHY trial. Am Heart J.2014;167(3):308-314.
221 11 Publication list
(10) de Jager RL, Blankestijn PJ. Pathophysiology I: the kidney and the sympathetic nervous system. EuroIntervention.2013;9 Suppl R:R42-R47.
(11) de Jager RL, Vink EE, Verloop WL, de Beus E, Bots ML, Blankestijn PJ. Renale denervatie bij therapieresistente hypertensie De ‘Sympathy’-studie en de ‘Dutch renal denervation registry’-studie. Ned Tijdschr Geneeskd. 2013;157:A6530.
(12) Vink EE, de Jager RL, Blankestijn PJ. Sympathetic hyperactivity in chronic kidney disease: pathophysiology and (new) treatment options. Curr Hypertens Rep.2013; 15(2):95-101.
(13) van Bladel ER*, de Jager RL*, Walter D, Cornelissen L, Gaillard CA, Boven LA, Roest M, Fijnheer R. Platelets of patients with chronic kidney disease demonstrate
deficient platelet reactivity in vitro. BMC Nephrol.2012;13:127. *Equal contributors
(14) de Jager RL, Groot OA. [A woman in acute respiratory distress]. Ned Tijdschr Geneeskd.2012;156(50):A4318.
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