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Our article provides an overview of the treatment for resistant hypertension, a problem rarely addressed in research. We therefore consider the information provided by our colleagues a welcome addition. Reversible causes should be identified before any pharmacological or interventional therapy is provided (see Figure 1). Table 1 of the publication contains an overview of the available pharmacological treatment strategies. Substances have been selected according to current guidelines (1). Evaluation of blood pressure-reducing properties within the groups was deliberately omitted. Aldosterone antagonist therapy is particularly important, because its efficacy in reducing blood pressure in patients with resistant hypertension has been demonstrated in studies (2). Minoxidil causes extremely high levels of side effects, which leads to poor compliance and so considerably restricts widespread clinical use. More detailed discussions of drugs are available and were not the subject of this article. For reasons of space it was only possible to examine common secondary causes of hypertension.

Particular emphasis was placed on interventional renal sympathetic denervation. This procedure is a new, promising treatment option for patients with resistant hypertension for whom pharmacological treatment options have been exhausted. It is important to state again that to date there are no clinically proven pharmacological or non-pharmacological treatment procedures for these patients with high cardiovascular risk. Our article clearly indicates that renal denervation is currently not a standard procedure, but rather an alternative option for the treatment of hypertension in cases of confirmed resistance to treatment. We therefore strongly recommend that our critical correspondents reread our publication.

As mentioned in the article, 206 patients, 106 as part of the randomized Symplicity HTN2 trial, have so far undergone systematic research in clinical trials, and follow-up for a period of 24 months (3, 4). The effects of renal denervation over longer follow-up times (36 months) in the Symplicity HTN1 trial show a sustained drop in blood pressure and do not provide any evidence of renal arterial stenosis or aneurysms (manuscript submitted for publication). In the USA the first patients have been enrolled in the Symplicity HTN3 trial in which randomization is performed after renovasography in a catheterization laboratory and placebo treatment is started. Due to intraprocedural pain, the extent to which blinding and placebo treatment is really possible remains to be seen, as do the ethical and legal considerations arising from this. It is more than unlikely to ascribe a drop in blood pressure over 24 to 36 months to a placebo effect.

Large, randomized trials have shown clearly that reductions in blood pressure over 24 hours during antihypertensive treatment are less marked than office blood pressure values. It is therefore not surprising that this is also the case following renal denervation. The analysis of the effects of renal denervation on 24-hour blood pressure will provide important information on the effect of renal denervation on day and night blood pressure values (manuscript submitted). The international registry, allowing scientific analysis of up to 5000 patients following renal denervation, will provide a valuable contribution to the evaluation of long-term effects and safety and represents a significant addition to randomized trials. In other, ongoing clinical trials, patients with advanced and terminal renal failure, chronic heart failure, milder forms of hypertension, and other cardiovascular diseases with high sympathetic activity are also undergoing systematic research. In the authors’ opinion, endpoint trials are needed for these indications, because unlike hypertension no confirmed surrogate parameters for clinical endpoints exist. For now the procedure should remain restricted to patients following the criteria used in the Symplicity trials (see Box 3).

Baroreflex stimulation is a pathophysiologically interesting concept for the treatment of resistant hypertension. However, it requires long-term pacemaker implantation, which currently requires vascular surgery under general anesthesia. Further development involving unilateral carotid stimulation and therefore longer battery life is currently undergoing clinical testing. It remains to be seen whether this surgery can regularly be performed under local anesthesia and so also reduce the complication rate associated with the procedure.

DOI: 10.3238/arztebl.2012.0313b

Dr. med. Felix Mahfoud, Dr. med. Christian Ukena
Prof. Dr. med. Michael Böhm,
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, felix.mahfoud@uks.eu

Dr. med. Frank Himmel, Prof. Dr. med. Heribert Schunkert

Prof. Dr. med. Joachim Weil, Medizinische Klinik II, Universitätsklinikum Schleswig-Holstein, Campus Lübeck

Conflict of interest statement

The authors of the article received research funding from Ardian/Medtronic Inc., Palo Alto, USA to finance the conduct of clinical trials.

Dr. Mahfoud, Dr. Ukena, and Prof. Böhm are supported by the Ministry for Economics and Science of the Saarland and by the German Research Foundation (DFG; Clinical Research Group KFO 196).

Dr. Mahfoud is supported by the German Hypertension League (Deutsche Hochdruckliga) and has received fees for lectures and consultancy from Berlin-Chemie, Boehringer Ingelheim, Medtronic, Novartis, and Takeda Pharm.

Dr. Himmel is supported by Medtronic within the scope of the AF grant program and has received fees for lectures and consultancy from Medtronic and St. Jude Medical.

Dr. Ukena has received fees for lectures and consultancy from Boehringer Ingelheim and Medtronic.

Prof. Schunkert has received fees for lectures and consultancy from Astra Zeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, Novartis, Pfizer, Sanofi-Aventis, Berlin-Chemie, MSD, Takeda, and Servier.

Prof. Böhm has received fees for lectures and consultancy from Astra Zeneca, Boehringer Ingelheim, Novartis, Sanofi-Aventis, Servier, Medtronic, and Pfizer.

Prof. Weil has received fees for lectures and consultancy from Actelion, Astra Zeneca, Bayer, Daiichi-Sankyo, Novartis, Medtronic, and Pfizer.

1.
Mancia G, De Backer G, 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: 1105–87. CrossRef MEDLINE
2.
Vaclavik J, Sedlak R, Plachy M, et al.: Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 2011; 57: 1069–7. CrossRef MEDLINE
3.
The Symplicity HTN-1 Investigators: Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011; 57: 911–7. CrossRef MEDLINE
4.
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 MEDLINE
5.
Mahfoud F, Himmel F, Ukena C, Schunkert H, Böhm M, Weil J: Treatment strategies for resistant arterial hypertension. Dtsch Arztebl Int 2011; 108(43): 725–31. VOLLTEXT
1.Mancia G, De Backer G, 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: 1105–87. CrossRef MEDLINE
2.Vaclavik J, Sedlak R, Plachy M, et al.: Addition of spironolactone in patients with resistant arterial hypertension (ASPIRANT): a randomized, double-blind, placebo-controlled trial. Hypertension 2011; 57: 1069–7. CrossRef MEDLINE
3.The Symplicity HTN-1 Investigators: Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011; 57: 911–7. CrossRef MEDLINE
4.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 MEDLINE
5.Mahfoud F, Himmel F, Ukena C, Schunkert H, Böhm M, Weil J: Treatment strategies for resistant arterial hypertension. Dtsch Arztebl Int 2011; 108(43): 725–31. VOLLTEXT