Renal Denervation After Symplicity HTN-3 – Back to Basics. Review of the Evidence

Login or register to view PDF.
Abstract

Renal sympathetic denervation (RDN) has been proposed as a new treatment modality in patients with apparent treatment resistant hypertension, a condition defined as office blood pressure elevation despite prescription of at least three antihypertensive drugs including a diuretic. However, the impressive fall in blood pressure reported after RDN in Symplicity HTN-2, the first randomised study, and multiple observational studies has not been confirmed in the US sham-controlled trial Symplicity HTN-3 and four subsequent prospective randomised studies, all published or presented in 2014. The blood pressure reduction documented in earlier studies may be largely due to non-specific effects such as improvement of drug adherence in initially poorly adherent patients (Hawthorne effect), placebo effect and regression to the mean. The overall blood pressure lowering effect of RDN seems rather limited and the characteristics of true responders remain largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with apparent drug-resistant hypertension, drug monitoring and subsequent improvement of drug adherence may prove more effective and cost-beneficial to achieve blood pressure control. In the meantime, research should aim at identifying characteristics of those few patients adherent to drug treatment and with true resistant hypertension who may respond to RDN.

Disclosure
Sverre Kjeldsen has received lecture and consultancy honoraria from AZ, Bayer, Medtronic, MSD, Novartis, Serodus, and Takeda, unrestricted grants from AZ, Hemo Sapiens and Pronova and royalty payments from Gyldendal (publisher). Fadl Elmula M Fadl Elmula has received speaker honorarium from Medtronic and Hemo Sapiens. Alexandre Persu, Ingrid Os, Yu Jin and Jan A Staessen declare that they have no conflict of interest.
Correspondence
Prof Alexandre Persu, MD PhD, Division of Cardiology, Cliniques Universitaires Saint-Luc (UCL), 10 Avenue Hippocrate, 1200, Brussels, Belgium. E: alexandre.persu@uclouvain.be
Received date
06 October 2014
Accepted date
09 November 2014
DOI
https://doi.org/10.15420/ecr.2014.9.2.110

Renal sympathetic denervation (RDN) has been introduced as a novel approach to treat patients with so-called resistant hypertension.1–3 The first randomised clinical trial showed an impressive 32/12 mmHg fall in blood pressure after six months in the intervention group (n=52) compared to the control group (n=54). However, with the recent publication of the Symplicity HTN-3 study in the US4 the world has become in doubt whether RDN lowers blood pressure. An editor of distinguished journal5 published his reflections and stated that the Symplicity HTN-3 results came as a shock to the world; a single but large and properly designed prospective randomised clinical trial could on its own neutralise hundreds of mostly observational studies, case reports and other enthusiastic publications emphasising the amazing effect of RDN, not only in patients with resistant hypertension, but also in a host of other diseases and conditions.

The initial enthusiasm followed by the setback of RDN can probably be summarised by a handful of explanations: 1) The role of the sympathetic system in the pathophysiology of hypertension is substantiated by a wealth of experimental and clinical arguments.6–12 On this background, enthusiasm surged when an intervention in this system seemed to drastically lower blood pressure; 2) Market-driven industry took control and exerted unprecedented influence on the medical community; 3) Subsequently, pitfalls in apparent treatmentresistant hypertensive patients, which are simple but well-known for decades, were suddenly forgotten including well described phenomena such as the placebo effect, regression to the mean, poor drug adherence13–15 and the Hawthorne effect.

The history of the rise and decline of RDN deserves a more in-depth analysis. The first and for long the only prospective randomised clinical trial in this field, the Symplicity HTN-2 study2, was monitored by Ardian (Medtronic) who collected and processed the data.2 Usually, when such a task is given to industry, all measures are taken to secure confidence and trials are prospective, randomised and double-blinded.16–19 However, in this case, everything was open, making the trial particularly vulnerable to patients, physicians and sponsor-related biases.19 As indicated by Shun-Shin et al. in a recent editorial,20 “measurement of a noisy variable by unblinded optimistic staff is a known recipe for calamitous exaggeration”. This is illustrated in Figure 1. It is unfortunate that selection of patients enrolled in Symplicity HTN-2 and evaluation of efficacy were based on office rather than ambulatory blood pressure (ABPM), which is state-ofthe art,21 particularly in resistant hypertension.22 ABPM reduces observer bias and measurement error, minimises the white-coat effect and has greater reproducibility, and therefore provides a better estimate of a patient’s usual blood pressure and cardiovascular prognosis.23,24 Notwithstanding the well-known, major contribution of poor drug adherence to apparently resistant hypertension13–15,25–27, drug adherence was not monitored, either at baseline or during follow-up. This made the study vulnerable to the Hawthorne effect, i.e. patients changing behaviour – in this case starting taking their drugs as prescribed – in response to the intervention and massive attention devoted to them. The lack of blood pressure decrease in the control group also raised concerns. One would indeed suspect that patients in the control group had not taken their medications properly, in order to keep their blood pressure at a higher level that made them eligible for cross-over to RDN group.28,29 Finally, placebo effect and regression to the mean must also be taken into account. Noteworthy, the placebo effect is small by using ambulatory blood pressures21,30; however ambulatory blood pressures remain as sensitive to the Hawthorne effect as office blood pressure.

Figure 1: Blood Pressure Reduction According to Study Design

Download original
Open in new tab

Despite the major limitations and potential biases of Symplicity HTN-2, a small open study with suboptimal design including only 106 patients followed up for six months, RDN was adopted in hundreds of centres worldwide. Medtronic Inc® (Minneapolis, Minnesota) paid $800 million to purchase Ardian® (Mountain View, California), the company that had developed the technology5, and more than ten companies developed their own RDN systems, five of which obtained the CE mark. The procedure was quickly reimbursed in Germany, and later on in Switzerland, Sweden and the Netherlands. While RDN remained an investigational procedure in the US, at least 8,00031, possibly 15,000 to 20,000 procedures were performed in Europe and in the rest of the world in less than four years, most of them using the Ardian-Medtronic® catheter. It may be hypothesised that the massive incomes generated by selling the Symplicity catheter to enthusiastic Europeans contributed to the expenses of the Symplicity HTN-3 study4, required by the Food and Drug Administration (FDA) before approval of RDN in the US.

In Symplicity HTN-34, blinding of patients through the use of a sham procedure and wider use of ambulatory blood pressure measurement balanced and limited the differential impact of the Hawthorne, white coat, placebo and regression to the mean effects in both treatment arms. This disclosed to the world the true size of blood pressure decrease attributable to RDN, at least in patients meeting the Symplicity criteria; it was less than 3 mmHg systolic based on ambulatory blood pressure monitoring (Table 1). Sham-procedure is however not feasible in clinical practice but was required by FDA in the Symplicity HTN-3 Study to overcome all the pitfalls in hypertension research mentioned above in order to investigate whether RDN has a true blood pressure lowering effect and the procedure may be characterised as “evidence based medicine”. Taken together with another four prospective and randomised clinical trials published or presented in 2014, discussed below, RDN as of today obviously does not fulfill these criteria and should not be used outside research protocols.

Figure 2: Overview of the ENCOReD Network

Download original
Open in new tab

For all aforementioned reasons, and in view of the complexity and multifactorial character of hypertension, the failure of RDN to normalise or substantially reduce blood pressure in all patients with apparently resistant hypertension was a reasonable working hypothesis for us, even before the Medtronic announcement that Symplicity HTN-3 had failed to meet its primary endpoint (http://www.tctmd.com/show. aspx?id=123265 ). We32–34 and others19,28 had predicted that the true effect of RDN might have been overestimated and may considerably shrink in properly designed studies.19,29 In particular, in preliminary analysis of the European Network COordinating research on Renal Denervation (ENCOReD) network,35 we were struck by the imbalance between the 17.6 mmHg decreases in office blood pressure, vs only 5.9 mmHg for 24-h ambulatory blood pressure.

The ENCOReD site in Oslo, with longstanding traditions for randomised research in hypertension36, applied a simple and practical way to deal with pitfalls in the recruitment of patients with resistant hypertension. After extensively ruling out secondary hypertension, and improving drug treatment in the run-in phase, patients had to qualify for the RDN protocols by having elevated daytime ambulatory blood pressures after witnessed oral intake of their prescribed blood pressure medication.33 This was a convenient way to identify the true treatment-resistant hypertensive patients and to exclude patients with white coat hypertension or those non-adherent patients whose blood pressure normalised after witnessed drug intake. Meanwhile a centre in Germany37 published a small but well documented series of patients whose blood pressure remained unchanged after RDN. We were thus not surprised when the Oslo activity found no change in either office or ambulatory blood pressures following RDN, first in an open series of six patients33 and later followed by a randomised study, the Oslo-RDN trial.38 Patients who were randomly assigned to further improvement of drug treatment guided by noninvasive haemodynamic monitoring had normalised blood pressures. In contrast, patients exposed to RDN experienced only a small and probably partly placebo-induced fall in office and ambulatory blood pressures (see Table 1). The decreases averaged 20 mmHg more for office and 9 mmHg more for ambulatory systolic blood pressure in the haemodynamically guided drug treatment group compared to the RDN group.

In the absence of solid evidence of efficacy, how can we explain the uncontrolled deployment of RDN in Europe and worldwide (with the notable exception of the US where RDN remained an investigational procedure)? Of course, publications of the Symplicity studies and of multiple observational studies, and enthusiastic reports, editorials and reviews1–3,39,40 had a substantial impact, and the lack of strict rules for introduction of device-based therapies in Europe facilitated the large-scale implementation of the technique. However, this phenomenon would have remained limited without the huge promotion by device-producing industry. Medical journals were swamped by reviews and meta-analyses showing the powerful blood pressure lowering effects as recorded in observational studies and in the single available randomised study, Symplicity HTN-2. Comments pointing out the defects and inconsistencies in such meta-analysis encountered great delay in getting published.41 Many never questioned whether RDN should be implemented, but when it should start in an institution. By all means, the purpose was to disseminate the enthusiasm for RDN from the technically-oriented invasive radiologists and cardiologists who usually had little interest or experience in the treatment of hypertension to the “hypertension establishment.” The European Society of Hypertension issued specific guidelines,42,43 but maintained reservations that more data was needed, and eventually it had to be proven that RDN would lower morbidity and mortality before being generally accepted in the treatment of true or apparent treatment- resistant hypertension.

Unfortunately, the most enthusiastic proponents of RDN do not seem to have fully accepted the lessons of Symplicity HTN-3. In the aftermath of Symplicity HTN-3, a campaign has been set up to criticise the study because of including inexperienced investigators, who did not appropriately document the delivery of ablation energy in the renal arteries, and enrolling too many African American patients who improved their drug adherence in the course of the trial.31,44 Symplicity HTN-3 may have had its weaknesses, however, no subgroup analysis was statistically significant4 and all the hypotheses explaining the failure of Symplicity HTN-3 by showing a difference in blood pressure were post hoc and speculations. Besides, also this study was overseen by procedure experts (proctors) from the sponsoring company, namely Medtronic. Furthermore, the Symplicity HTN-3 results are diluted by non-scientific comparisons with the Medtronic® registry45 which is hampered by all the weaknesses touched upon in this commentary, and even more as it is a pure industry-ran activity. Finally, while RDN will not become available in the US, and ongoing research in Asia was stopped, Medtronic and other companies continued making their catheters available for clinical use in Europe and did not restrain from heavily promoting the technique, for example at the Euro PCR conference in Paris in May 2014 (www.medscape.com/author/shelley-wood).

One-year results of Symplicity HTN-34 were presented at the European Society of Cardiology (ESC) meeting in Barcelona in end of August 2014. Following the six-month evaluation all subjects and clinicians were unblinded and antihypertensive medications changes were allowed. Of the 171 original sham control group subjects, 101 who still fulfilled all of the baseline inclusion and exclusion criteria, and agreed to receive the procedure, crossed over to RDN. The remaining 70 sham control subjects did not cross over and were not treated with RDN. At one year post-procedure, both office and 24 hour mean ambulatory systolic blood pressure continued to demonstrate a decrease in the original RDN group. Similarly, the crossover group showed blood pressure reductions six months following RDN (Δ systolic blood pressure: 17.7 mm Hg, P<0.001). The non-crossover group also had large reductions in office pressure one year post randomisation (Δ systolic blood pressure: 21.4 mm Hg, P<0.001) (http://congress365. escardio.org/). In the summary session of the ESC meeting the keynote speaker (Bryan Williams, London, U.K.) on September 3 pointed out the uncertain future of RDN based on the recent randomised studies performed in Oslo38 and in the US.4

The key message of Symplicity HTN-34 is simple and we should be wise enough to accept it: the true overall benefit of RDN on systolic blood pressure is modest, <3 mmHg, without evidence of a favourable impact on morbidity-mortality so far. The results of three other recent rigorously designed randomised controlled trials, Oslo RDN38 (see Table 1), DENER-HTN46, and PRAGUE-1547 including a smaller number of well-trained operators are in line with those of Symplicity HTN-34, and confirm that the failure of RDN to achieve superiority over medical treatment in the latter cannot be merely explained by inclusion of a high proportion of African Americans or insufficient degree of renal nerve ablation. Along the same lines, a fourth randomised shamcontrolled study performed in mild resistant hypertension (daytime systolic blood pressure between 135 and 149 mmHg and/or diastolic blood pressure between 90 and 94 mmHg on ≥ 3 drugs classes including a diuretic), Symplicity Flex48, failed to show an advantage of RDN compared to drug treatment alone.

Does the failure of Symplicity HTN-3 mean the end of RDN? Not necessarily. Indeed, as already mentioned, RDN is based on a solid rationale substantiated by over fifty years of meticulous research of the sympathetic nervous system and its involvement in the pathophysiology of hypertension.6–12 Furthermore, it has been shown in cohorts recruited from the third (The effect of progressive sympathectomy on blood pressure, Walter Bradford Cannon 1931, http://www.ncbi.nlm.nih.gov/ pubmed/2204236) until the fifth decade of the last century49,50 that abdominal sympathectomy associated to splanchnicectomy is effective in the treatment of severe hypertension. Finally, many centres report major responses to RDN in a minority of patients.33,35,38 Accordingly, research should go on to find out the minority of patients who are true responders to RDN, and identify predictors of effective RDN. The ENCOReD network (see Figure 2) is set up to include hundreds of patients in randomised protocols, observational studies and registries independent of industry. Some early results35,51 from this joint effort have already been published and suggest that it may be worthwhile searching for potential predictors of response to RDN.

Figure 1: Blood Pressure Reduction According to Study Design

Download original
Open in new tab

As of now, the modest overall benefits and high cost of RDN should be balanced with its potential risks. In particular, more than 20 cases of de novo renal artery stenosis have been reported after RDN,52 most of them after the announcement that Symplicity HTN-3 failed to meet its primary endpoint. RDN deserves further investigation but is not ready for clinical deployment and its use should be restricted to research protocols. Accordingly, in Germany, the insurances companies which were the first in Europe to reimburse the procedure have terminated their coverage, and even well-known proponents of the technique acknowledge that RDN “should be returned back to the academic arena”53 before further clinical deployment.

In a substantial proportion of patients, resistant hypertension may reflect resistance to taking medications rather than true treatment resistance.54 In this perspective, therapeutic drug monitoring may prove an effective strategy, not only for detecting poor drug adherence but also for improving blood pressure control. Indeed, when non-adherent patients are confronted with their low or undetectable drug levels and provided additional counselling to overcome barriers of adherence, blood pressure control improves considerably without intensification of therapy.55 Along the same lines, a recent analysis based on German data and life statistics showed that therapeutic drug monitoring is a cost-effective health care intervention in patients diagnosed with apparent drug-resistant hypertension, and this finding is valid for a wide range of patients, irrespective of age and sex.56 Even in truly resistant hypertensive patients with demonstrated drug adherence, blood pressure control may be achieved in a substantial proportion of patients by skilful drug treatment adjustment.33,38 While RDN deserves more in depth research, in the present state of knowledge, initiatives aiming at diagnosing and improving poor drug adherence56,57 and optimisation of drug treatment51 may prove much more cost-effective, both at the individual and public health level.

References
  1. 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;373:1275–81.
    Crossref | PubMed
  2. 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;376:1903–9.
    Crossref | PubMed
  3. Krum H, Schlaich MP, Böhm M, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: final 3-year report of the Symplicity HTN-1 study. Lancet 2014;383:622–9.
    Crossref | PubMed
  4. Bhatt DL, Kandzari DE, O’Neill WW, et al. SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med. 2014;370:1393-1401.
    Crossref | PubMed
  5. Demaria AN. Reflections on renal denervation. J Am Coll Cardiol 2014;63:1452–3.
    Crossref | PubMed
  6. Von Euler US, Hellner S, Purkhold A. Excretion of noradrenaline in urine in hypertension. Scand J Clin Lab Invest 1954;6:54–9.
    Crossref | PubMed
  7. Julius S, Esler M. Autonomic nervous cardiovascular regulation in borderline hypertension. Am J Cardiol 1975;36:685–96.
    Crossref | PubMed
  8. Esler M, Zweifler A, Randall O, et al. Agreement among three different indices of sympathetic nervous system activity in essential hypertension. Mayo Clin Proc. 1977;52:379–82.
    PubMed
  9. Esler M, Jackman G, Leonard P, et al. Determination of noradrenaline uptake, spillover to plasma and plasma concentration in patients with essential hypertension. Clin Sci (Lond) 1980;59 Suppl 6:311s–3s.
    PubMed
  10. Kjeldsen SE, Flaaten B, Eide I, et al. Increased peripheral release of noradrenaline and uptake of adrenaline in essential hypertension? Clin Sci (Lond) 1981;61(Suppl 7):215s–7s.
    PubMed
  11. Kjeldsen SE, Zweifler AJ, Petrin J, et al. Sympathetic nervous system involvement in essential hypertension: increased platelet noradrenaline coincides with decreased betaadrenoreceptor responsiveness. Blood Press 1994;3:164–71.
    Crossref | PubMed
  12. Manolis AJ, Poulimenos LE, Kallistratos MS, et al. Sympathetic overactivity in hypertension and cardiovascular disease. Curr Vasc Pharmacol 2014;12:4–15.
    Crossref | PubMed
  13. Gifford RW. An algorithm for the management of resistant hypertension. Hypertension 1988;11:I-171–5.
    Crossref | PubMed
  14. Klein LE. Compliance and blood pressure control. Hypertension 1988;11:I-161–4.
    Crossref | PubMed
  15. Ceral J, Habrdova V, Vorisek V, et al. Difficult-to-control arterial hypertension or uncooperative patients? The assessment of serum antihypertensive drug levels to differentiate nonresponsiveness from non-adherence to recommended therapy. Hypertens Res 2011;34:87–90.
    Crossref | PubMed
  16. Staessen JA, Fagard R, Thijs L, et al. Randomised doubleblind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet 1997;350:757–64.
    Crossref | PubMed
  17. Dahlöf B, Devereux RB, Kjeldsen SE, et al. for the LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:995–1003.
    Crossref | PubMed
  18. Julius S, Kjeldsen SE, Weber M, et al. Cardiac events, stroke and mortality in high-risk hypertensives treated with valsartan or amlodipine: Main outcomes of The VALUE Trial. Lancet 2004;363:2022–31.
    Crossref | PubMed
  19. Howard JP, Nowbar AN, Francis DP. Size of blood pressure reduction from renal denervation: insights from meta-analysis of antihypertensive drug trials of 4,121 patients with focus on trial design: the CONVERGE report. Heart 2013;99:1579–87.
    Crossref | PubMed
  20. Shun-Shin MJ, Howard JP, Francis DP. Removing the hype from hypertension. Symplicity HTN-3 illustrates the importance of randomisation and blinding for exciting new treatments. BMJ 2014;348:g1937.
    Crossref | PubMed
  21. O’Brien E, Parati G, Stergiou G, et al. European society of hypertension position paper on ambulatory blood pressure monitoring. J Hypertens 2013;31:1731–68.
    Crossref | PubMed
  22. Persu A, O’Brien E, Verdecchia P. Use of ambulatory blood pressure measurement in the definition of resistant hypertension: a review of the evidence. Hypertens Res 2014;37:967-972.
    Crossref | PubMed
  23. Kikuya M, Hansen TW, Thijs L, Björklund-Bodegård K, Kuznetsova T, Ohkubo T, Richart T, et al., IDACO investigators. Diagnostic thresholds for ambulatory blood pressure monitoring based on 10-year cardiovascular risk. Blood Press Monit 2007;12:393–5.
    Crossref | PubMed
  24. Salles GF, Cardoso CR, Muxfeldt ES. Prognostic influence of office and ambulatory blood pressures in resistant hypertension. Arch Intern Med 2008;168:2340–6.
    Crossref | PubMed
  25. Jung O, Gechter JL, Wunder C et al. Resistant hypertension? Assessment of adherence by toxicological urine analysis. J Hypertens 2013;31:766–74.
    Crossref | PubMed
  26. Rosa J, Zelinka T, Petrák O, et al. Importance of thorough investigation of resistant hypertension before renal denervation: should compliance to treatment be evaluated systematically? J Hum Hypertens 2014 Feb 6. [Epub ahead of print]
    Crossref | PubMed
  27. 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;100:855–61.
    Crossref | PubMed
  28. Azizi M, Steichen O, Frank M, et al. Catheter-based radiofrequency renal-nerve ablation in patients with resistant hypertension. Eur J Vasc Endovasc Surg 2012;43:293–9.
    Crossref | PubMed
  29. Persu A, Renkin J, Thijs L, Staessen JA. Renal denervation: ultima ratio or standard in treatment-resistant hypertension. Hypertension 2012;60:596–606.
    Crossref | PubMed
  30. Staessen JA, Thijs L, Bieniaszewski L, et al. Ambulatory monitoring uncorrected for placebo overestimates long-term antihypertensive action. Systolic Hypertension in Europe (SYST-EUR) Trial Investigators. Hypertension 1996;27:414–20.
    Crossref | PubMed
  31. Lüscher TF, Mahfoud F. Renal nerve ablation after SYMPLICITY HTN-3: confused at the higher level? Eur Heart J 2014;35:1706–11.
    Crossref | PubMed
  32. Persu A, Azizi M, Burnier M, Staessen JA. Residual effect of renal denervation in patients with truly resistant hypertension. Hypertension 2013;62:450–2.
    Crossref | PubMed
  33. Fadl-Elmula FEM, Hoffmann P, Fossum E, et al. Renal sympathetic denervation in patients with treatmentresistant hypertension after witnessed intake of medication before qualifying ambulatory blood pressure. Hypertension 2013;62:526–32.
    Crossref | PubMed
  34. Persu A, Renkin J, Asayama K, et al. Renal denervation in treatment-resistant hypertension: the need for restraint and more and better evidence. Expert Rev Cardiovasc Ther 2013;11:739–49.
    Crossref | PubMed
  35. Persu A, Jin Y, Azizi M, et al. on behalf of the European Network Coordinating research on REnal denervation (ENCOReD). Blood pressure changes after renal denervation at 10 European expert centers. J Hum Hypertens 2014;28:150–6.
    Crossref
  36. Helgeland A. Treatment of mild hypertension: a five year controlled drug trial. The Oslo study. Am J Medicine 1980:69:725–32.
    Crossref | PubMed
  37. 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;60:1485–90.
    Crossref | PubMed
  38. Fadl Elmula FE, Hoffman P, Larstorp AC, et al. Adjusted drug treatment is superior to sympathetic renal denervation in patients with true treatment resistant hypertension. Hypertension 2014;63:691–9.
    Crossref | PubMed
  39. Mahfoud F, Ukena C, Schmieder RE, et al. Ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension. Circulation 2013;128:132–40.
    Crossref | PubMed
  40. Ott C, Mahfoud F, Schmid A, et al. Renal denervation in moderate treatment-resistant hypertension. J Am Coll Cardiol 2013;62:1880–6.
    Crossref | PubMed
  41. Jin Y, Persu A, Staessen JA. Letter by Jin et al. regarding article, “ambulatory blood pressure changes after renal sympathetic denervation in patients with resistant hypertension”. Circulation 2014;129:e499.
    Crossref | PubMed
  42. Schmieder RE, Redon J, Grassi G, et al. ESH Position Paper: Renal Denervation - an Interventional Therapy of Resistant Hypertension. J Hypertens 2012;30:837–41.
    Crossref | PubMed
  43. Schmieder RE, Redon J, Grassi G, et al. Updated ESH position paper on interventional therapy of resistant hypertension. Euro Intervention 2013;9:R58–66.
    Crossref | PubMed
  44. Schmieder RE. How should data from SYMPLICITY HTN 3 be interpreted? Nat Rev Cardiol. Advance online publication 20 May 2014;doi:10.1038/nrcardio.2014.70.
    Crossref | PubMed
  45. Pathak A, Ewen S, Fajadet J, et al. From SYMPLICITY HTN-3 to the Renal Denervation Global Registry: where do we stand and where should we go? Euro Intervention 2014;10:21–3.
    Crossref | PubMed
  46. Azizi M, Monge M, Pereira H, Sapoval M on behalf of DENER-HTN investigators. The French DENER-HTN Trial: renal denervation + standardized antihypertensive treatment vs. standardized antihypertensive treatment alone in patients with resistant hypertension. J Hypertens 2014; 32(e-Supplement 1):e89. http://www.hypertension2014.org/ wordpress/wp-content/uploads/2014/06/ESH-ISH-2014- Abstract-Book-Oral.pdf.
     
  47. Widimsky J, Rosa J, Tousek P, et al. Renal denervation versus intensified medical treatment including spironolactone in patients with true resistant hypertension: 6-months results of multicenter randomized Prague. J Hypertens 2014;32(e-Supplement 1):e87. http://www.hypertension2014. org/wordpress/wp-content/uploads/2014/06/ESH-ISH-2014- Abstract-Book-Oral.pdf
     
  48. http://www.tctmd.com/show.aspx?id=126422 Accessed 2nd October 2014.
     
  49. Longland CJ, Gibb WE. Sympathectomy in the treatment of benign and malignant hypertension; A review of 76 patients. Br J Surg 1954;41:382-392.
    Crossref | PubMed
  50. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension, results in 1,266 cases. JAMA 1953;152:1501–4.
    Crossref | PubMed
  51. Persu A, Jin Y, Baelen M, et al; European Network Coordinating research on REnal Denervation (ENCOReD) Consortium. Eligibility for renal denervation: experience at 11 European expert centers. Hypertension 2014;63:1319–25.
    Crossref | PubMed
  52. Persu A, Sapoval M, Azizi M, et al. Renal artery stenosis following renal denervation: a matter of concern. J Hypertens 2014;32:2101–5.
    Crossref | PubMed
  53. Böhm M, Mahfoud F. SYMPLICITY HTN-3 trial: what is it and what does it mean? Eur Heart J 2014;35:1697–8.
    PubMed
  54. Brown MJ. Resistant hypertension: resistance to treatment or resistance to taking treatment? Heart 2014;100:821–2.
    Crossref | PubMed
  55. Brinker S, Pandey A, Ayers C, et al. Therapeutic drug monitoring facilitates blood pressure control in resistant hypertension. J Am Coll Cardiol 2014;63:834–5.
    Crossref | PubMed
  56. Chung O, Vongpatanasin W, Bonaventura K, et al. Potential cost-effectiveness of therapeutic drug monitoring in patients with resistant hypertension. J Hypertens 2014 Sep 24.
    Crossref | PubMed
  57. Kjeldsen SE, Os I. Cost-effectiveness of therapeutic drug monitoring in patients with resistant hypertension and improving patients’ adherence. J Hypertens 2014. In press.
    Crossref | PubMed