Devices-based treatment of hypertension: the position of the European Society of Hypertension (ESH) 2023 guidelines

KEYWORDS:

• Carotid baroreceptor stimulation
• guidelines
• hypertension
• renal denervation
• resistant hypertension
• meta-analysis

1. Introduction

In this editorial, the current position of devices-based treatment of resistant and uncontrolled hypertension will be examined based on the 2023 guidelines on hypertension diagnosis and treatment issued by the European Society of Hypertension (ESH) [1]. A special focus will be given to the bilateral renal nerve ablation approach, which represents a therapeutic intervention capable of reducing elevated blood pressure values uncontrolled by multiple pharmacological treatment in specific clinical phenotypes.

Invasive procedures to cure malignant hypertension have been introduced in the clinical setting many years ago with the development of surgical interventions, such as bilateral thoraco-lumbar sympathectomy and splanchnicectomy, aimed at reducing the markedly elevated blood pressure values typical of the disease and thus at improving patients’ survival [2,3]. However, the outcome was overall disappointing due to the extensive invasivity of the procedures, unavailability of drugs capable to reduce blood pressure in the presurgical phase or during surgery, and the adverse cardiovascular consequences of procedures largely destroying the neuroadrenergic network of key organs essential for circulatory homeostasis. It should be emphasized, however, that already at that time sympathetic innervation was recognized as a potential target of the therapeutic approach finalized at obtaining a reduction in the elevated blood pressure values. This concept received renewed interest in recent years with the development of ultrasound-based bilateral renal nerves ablation for resistant hypertension [4]. Concomitantly, other therapeutic approaches beside renal denervation have been developed (Figure 1).

Figure 1. Devices evaluated by the European Society of Hypertension (ESH) 2023 guidelines for the diagnosis and treatment of hypertension (HT) [1]. AV: atrioventricular.

2. Background

Data collected in experimental animal models have clearly documented the pressor effects exerted by renal sympathetic nerve fibers, which may participate at the development and progression of elevated blood pressure and are potentially reversible by renal sympathectomy [5]. This information, together with the evidence that renal sympathetic neural outflow to the kidneys is markedly activated in hypertension, particularly in the clinical phenotype represented by drug-resistant hypertension [6], led to the development of endovascular catheter technologies. These are capable of obtaining a selective denervation of the human kidneys, with radiofrequency energy delivered in the renal artery lumen, accessing the renal nerves located in the adventitia of the renal arteries. The initial promising results of the procedure seen in the proof-of concept study Simplicity HTN-1 and in the subsequent Symplicity HTN-2 [4,7] were not confirmed, however, by the sham-controlled Symplicity HTN-3 study [8]. Results of recently published clinical trials, performed according to strict criteria for patient’s enrollment and with the use of technically optimized techniques to obtain a complete bilateral renal denervation, have provided, however, conclusive evidence on the potential usefulness of the approach [1]. Other procedures have been developed throughout the years for treating resistant and difficult-to-control essential hypertension. These include carotid baroreceptor stimulation, based on the evidence that in hypertension carotid baroreceptor restraint on sympathetic drive is reduced, thereby favoring the development as well as the progression of an adrenergic overdrive and of the consequent blood pressure increase [9]. They also include 1) iliac arteriovenous anastomoses to counteract a hallmark of the essential hypertensive state, particularly of resistant nature, namely systemic vasoconstriction, and 2) implantation of pacemakers which by shortening the cardiac atrioventricular coupling interval, reduce left ventricular filling and thus systemic blood pressure values [1].

3. The position of the 2018 ESC/ESH guidelines on hypertension

Guidelines on hypertension diagnosis and treatment issued in 2018 did not recommend renal denervation, and more in general, devices-based therapeutic interventions for the treatment of drug-resistant hypertension [10]. The reasons for this negative evaluation can be summarized as follows. As far as renal denervation is concerned, guidelines underline that, despite evidence of effectiveness in earlier uncontrolled studies, two major clinical trials with a design including a sham procedure, namely the Symplicity 3 and the ReSET trail, failed to demonstrate a blood pressure- lowering effect of the procedure on office and out-of-office blood pressure superior for magnitude to the one detected in the sham-operated placebo group of patients [8,11]. In addition, another trial, the PRAGUE-15 Study, did not reveal any superiority of renal denervation as compared to optimized pharmacotherapy, including spironolactone, in obtaining a blood pressure reduction in resistant hypertensive patients [12]. Finally, guidelines emphasize the need for optimizing blood pressure measurements in the clinical trials exploring the blood pressure-lowering effects of renal nerves ablation (and in general of device-based interventions) by systematically assessing 24-hour ambulatory blood pressure monitoring. Creation of an iliac arteriovenous fistula and stimulation of carotid baroreceptors via external or internal implantable devices represent other procedures mentioned in the 2018 ESC/ESH guidelines [10]. Also, for these approaches, however, the class of evidence was defined low, i.e. as level III [10].

4. The position of the 2023 ESH guidelines on hypertension

Since 2018, publication of the main results of a number of relevant clinical trials, performed in the absence (off-medication studies) or in the presence (on-medication studies) of antihypertensive drug treatment, has provided conclusive data in favor of the blood pressure lowering effects of renal denervation [13]. The meta-analyzes performed during the years have shown 24-hour ambulatory blood pressure reduction amounting on average to about 3.9–7.0 mmHg for the systolic and 3.7–6.9 mmHg for the diastolic component [14]. Meta-analyzes have also provided large scale information on the safety profile of the procedure both in the short-term and in the long-term (3–4 years) period. This is particularly the case for the very rare occurrence post-procedure of a de-novo renal artery stenosis, an endothelial vascular damage at the level of the renal arteries, and a deterioration of renal function. Based on these data, ESH guidelines modified substantially the evaluation of the renal denervation procedure made in 2018, recognizing the effectiveness and safety of the approach with class of evidence I or II [1]. One element of important clinical relevance addressed by 2023 ESH guidelines refers to the detection of the clinical hypertensive phenotypes, which may be the preferred targets of the procedure. The document includes as recommended clinical conditions not only resistant but also uncontrolled hypertension. Guidelines also emphasize the need for a special attention in the selection 1) of the patients for the procedure, including the presence of an estimated glomerular filtration rate > 40 ml/min/1.73 m², and 2) of the specialized clinical centers with a large experience on the procedure, most suited for performing renal denervation, and guaranteeing an adequate follow-up to the patients [1].

The ESH guidelines also provide recommendations concerning other device-based interventions. As far as carotid baroreceptor stimulation, arteriovenous anastomoses, and pacemaker-induced cardiac neuromodulation is concerned, the position of the 2023 document remains the same expressed in 2018, not recommending their use in current clinical practice [1]. The hope is to obtain more conclusive information on the long-term clinical efficacy and safety of these procedures in the near future.

5. Expert opinion

The evolution during the years of the recommendations expressed by guidelines on renal denervation in hypertension represents a classic example on how implementation of information on a specific diagnostic and/or therapeutic approach to a given disease may modify the indications expressed by a guidelines document. The ESH hypertension guidelines published last year clearly recognize the potential usefulness of the renal denervation approach for treatment of some clinical phenotypes characterized by a blood pressure elevation resistant to traditional antihypertensive drug treatment [1]. However, main elements of novelty of the 2023 document in this regard are represented by 1) the observation that the clinical application of the procedure can be expanded by including uncontrolled hypertension, beside resistant hypertension, 2) the need for a careful selection of the patients eligible for the procedure, taking particular care for the assessment of drug adherence of the patients prior to their selection for the procedure, 3) the crucial role of ambulatory blood pressure monitoring for determining the blood pressure lowering effects of the intervention and 4) the need to plan an accurate and well organized follow-up of the patients underwent the procedure.

2023 ESH guidelines also highlight some shadows and uncertainty related to the procedure. These include the observation that other mechanisms beside the sympathetic deactivation may participate at the blood pressure lowering effects of the approach [13–15]. They may also include the inability to employ a marker useful for predicting the clinical efficacy of the intervention, which remains at present extremely variable in its blood pressure lowering effects between patients and impossible to forecast. They finally comprise the difficulty in the current clinical practice to correctly perform the selection of the ‘gold standard’ candidate for the procedure [1].

A final comment deserves to be made regarding the guidelines position on other devices beyond renal denervation for treatment of resistant hypertension. The need for further evaluation of the different approaches recommended by the ESH guidelines is crucial, taking into account that in the case of carotid baroreceptor stimulation, arteriovenous anastomoses and pacemaker-induced cardiac neuromodulation, the invasivity, economic burden and lack of long-term safety information represent important barriers for their clinical use.

Declaration of interest

The author has no relevant affiliation or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. The author has no conflict of interest to disclose relative to the current manuscript.

Reviewers disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.