Fallout from the surprisingly negative Symplicity HTN-3 trial in catheter-based renal artery denervation will be explored in a Symposium this afternoon. One of the Symposium’s speakers, Felix Mahfoud, descibed the findings as ‘a complete shock to many of us because the pathophysiology rationale behind renal denervation had seemed so plausible’.
In the Symposium, organised by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), Mahfoud will explain how renal denervation procedures are being improved through better understanding of the anatomy of the renal sympathetic nerves, improved use of ablation techniques and better identification of populations most likely to derive benefit.
'The field is currently being rebooted with additional trials to build a new clinical basis to allow us to move forward,’ says Mahfoud, from Saarland University Hospital in Germany. ‘We are only just starting to understand the true complexity of the sympathetic nervous system in renal denervation and are far from ready to write off this technology.’
The unmet need in hypertension, says Mahfoud, is emphasised by the fact that at best only two out of three patients are controlled by the current pharmaceutical range. ‘This means there are a huge numbers of people with uncontrolled hypertension who could benefit from different approaches to treatment.’
Renal denervation uses radiofrequency energy, ultrasound or chemical denervation to disrupt renal nerves within the renal artery wall, thereby reducing sympathetic efferent and sensory afferent signalling to and from the kidneys. It is known mechanistically that renal sympathetic fibres provide a key link between the central nervous system and the kidney, and play a role in the renal angiotensin aldosterone system.
In 2009 the landmark proof-of-concept Symplicity HTN-1 study by Henry Krum and colleagues demonstrated the feasibility of catheter-based renal denervation for resistant hypertension. The non-randomised study in 45 patients showed a mean 27/17 mmHg decrease in blood pressure at 12 months.
Since then, however, the clinical evidence for renal denervation as an effective technique in patients with resistant hypertension has been conflicting. Three randomised trials - Symplicity HTN-2, Prague 15 and DENERHTN - support both safety and efficacy of the therapy, but the sham-controlled Symplicity HTN-3 trial failed to show superiority over medical therapy alone.
However, post-hoc analysis studies of Symplicity HTN-3 are providing insight into factors that may influence efficacy. One recent analysis found greater reductions in office and ambulatory blood pressure among patients who received both a higher number of ablations (>9) and ablations delivered in all four-quadrants within the renal artery. In another post hoc analysis Mahfoud and colleagues showed that the BP-lowering effects of denervation were significantly less pronounced in patients with isolated systemic hypertension (characterised by increased vascular stiffness) compared with patients with combined systolic-diastolic hypertension.
Currently, around seven randomised controlled trials are ongoing evaluating new catheter designs, including the SPYRAL HTN-ON MED study, the SPYRAL HTN-OFF MED study, both using the SPYRAL multi-electrode denervation system with sham control, the REDUCE HTN: REINFORCE trial using the Vessix denervation system, and the RADIANCE HTN trial using a dedicated ultrasound RDN system.
‘It is to be hoped these results will be available in time for the next set of European Society of Hypertension and ESC guidelines on hypertension,’ says Mahfoud. The current 2013 guidelines, he adds, give renal denervation a IIB recommendation for treating patients with hypertension. Undoubtedly, he adds, the biggest mistake was to name the trial Symplicity. ‘They should have called it the Complexity study!’
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