From SYMPLICITY HTN-1 to SPYRAL HTN-OFF MED: The story of renal denervation

It is now almost a decade since the first patient underwent catheter-based renal denervation as a participant in a safety and proof-of concept study (SYMPLICITY HTN-1).¹ Since then, SYMPLICITY HTN-3 has indicated that renal denervation does not provide benefit for patients with resistant hypertension and the recently published SPYRAL HTN-OFF MED has shown that it does provide benefit for patients who are not receiving antihypertensive medication. In this commentary, Markus P Schlaich reviews the evidence for renal denervation.

The publication of SYMPLICITY HTN-1 triggered substantial interest and enthusiasm in the hypertension community. While relatively small in size, the study suggested that catheter-based renal denervation using a first-generation single electrode catheter appeared safe and was associated with a significant reduction in office blood pressure at  six, 12, and 36 months post-intervention, respectively.

The subsequent SYMPLICITY-HTN-2 was designed as a prospective randomised, controlled clinical trial.² The blood pressure lowering effect observed in this study, in the renal denervation group, was -32±23/12±11 mmHg at six months post-procedure. Sustained blood pressure effects were subsequently demonstrated at 12 months.³

While SYMPLICITY HTN-1 and HTN-2 found a substantial reduction in blood pressure with renal denervation, SYMPLICITY HTN-3—the largest and first study to include a sham control—failed to demonstrate a blood pressure lowering effect beyond that observed in the sham control group.⁴ Potential shortcomings in the execution of the study, including limited operator experience and insufficient denervation among other factors, are now considered likely contributors to these neutral findings. Also, from a technical perspective, the failure of SYMPLICITY HTN-3 sparked renewed interest and investigations in renal nerve anatomy and physiology, the development of more sophisticated catheter designs, and adjustment of treatment algorithms aimed at achieving more complete and reliable renal denervation.

Against this background and with additional insights obtained from relevant preclinical models, the recently published SPYRAL HTN-OFF MED trial⁵ was conducted as a renewed proof-of-concept study. It showed a significant difference, at three months, in 24-hour ambulatory blood pressure (the primary endpoint) and office blood pressures from baseline with renal denervation.

Importantly, a more aggressive treatment approach was applied in SPYRAL HTN-OFF MED; both in terms of the average number of ablations performed per patient (43.8±13.1 vs. 11.2±2.8 in SYMPLICITY HTN-3) and in terms of how many arteries were treated (both the main arteries and smaller branches). Therefore the study, with its more aggressive approach, confirms the general safety of catheter-based renal denervation.

Overall, the findings provide unequivocal evidence for biological proof-of-principle for the efficacy of catheter-based renal denervation to reduce blood pressure in patients with hypertension not treated with antihypertensive medications and absence of other confounders. The challenge now is to determine which patient cohorts may benefit most from this approach.⁶

To this end longer term safety is an important aspect that needs to be addressed to provide more robust assurance that the substantially more aggressive treatment algorithm does not cause major reno-vascular or other adverse consequences. Identification of the most appropriate patient cohort that may benefit from renal denervation, as well as those who may not be suitable candidates for such an approach is crucial. Patients with resistant hypertension in whom sympathetic activity has been shown to be particularly elevated have been studied most extensively, but data on efficacy with the more aggressive treatment approach are scarce. One recent study with a head-to-head comparison of the conventional (main renal artery only) vs a more aggressive (distal main artery + branches ) treatment approach did demonstrate a clear signal for more efficacy with the latter.⁷ Several studies are ongoing, including the SPYRAL HTN-ON MED trial, which will provide some more insights using renal denervation in the context of resistant hypertension. Patient cohorts characterised by increased sympathetic activation such as those with heart failure, chronic- and end-stage renal disease, and obstructive sleep apnoea accompanying hypertension may be particularly well suited. However, studies in all these patient groups would have to be conducted to assess the potential utility of renal denervation, given that technical advances and the described more aggressive treatment approach have not previously been applied in these cohorts and may provide different results compared to those available from studies using previous generation catheters and less aggressive ablation algorithms.

With SPYRAL HTN-OFF MED renal denervation has been rehabilitated as therapeutic approach to lower blood pressure but the ideal clinical scenarios for its clinical application remain to be determined.

References

1. Krum et al. Lancet 2009; 373(9671): 1275–81.
2. Esler et al. Lancet 2010; 376(9756): 1903–09.
3. Esler et al. Circulation 2012; 126: 2976–82.
4. Bhatt et al. N Engl J Med 2014; 370(15): 1393–401.
5. Townsend et al. Lancet 2017. Epub.
6. Am J Hypertens 2017; 30(9): 847–56.
7. Pekarskiy et al. J Hypertens 2017; 35(2): 369-75.

Markus P Schlaich is Head of the  Dobney Hypertension Centre, School of Medicine – Royal Perth Hospital Unit, University of Western Australia; Departments of Cardiology and Nephrology, Royal Perth Hospital, Perth, Australia; and the Neurovascular Hypertension & Kidney Disease Laboratory and Human Neurotransmitter Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.