Decision time for renal denervation firms as Symplicity trial yields little comfort
RIP renal denervation, 2009-2014. Full data from the pivotal trial of Medtronic’s Symplicity system – already known to have missed its primary endpoint – give the company no good reason to continue development of what was expected to be the first such device to reach the US. Worse, they cast grave doubt on the technique, intended to treat drug-resistant hypertension, as a whole.
In the absence of a good reason, Medtronic is gamely continuing development of Symplicity. But other developers, including Boston Scientific and Johnson & Johnson, must now decide whether to pursue their versions of the technology or write it off as a nice idea that simply does not work.
The denervation procedure involves using a radiofrequency catheter to disable the nerves surrounding the renal arteries from within the arteries themselves. This is intended to limit the proven hypertensive effects of the sympathetic nervous system.
And it seemed to work. The extraordinary blood pressure-lowering effects seen with renal denervation in previously untreatable patients over the past five years fuelled breathless enthusiasm for the technique, and Medtronic led the field by some distance when the blow fell. Symplicity had had the European market to itself for nearly two years before the first of seven other devices gained CE mark; it had been expected to get an even longer headstart in the US.
Medtronic’s admission in January that the 535-patient Symplicity HTN-3 study had failed did not quite come out of nowhere – some concern had already been raised that results with various renal denervation systems were simply too good to be true – but nevertheless the industry was sent reeling (Failure of Medtronic’s Symplicity trial exacerbates concerns over renal denervation, January 9, 2014).
One company, Covidien, dropped its efforts almost immediately. St. Jude Medical, interestingly, had put the pivotal US study of its EnligHTN system on hiatus a month before Medtronic announced the miss, citing expected difficulties with patient recruitment. St. Jude told EP Vantage today that it was now mulling the next steps for its renal denervation programme.
So are Boston Scientific and Cordis, a subsidiary of Johnson & Johnson. Both have previously said that they would await publication of the full Symplicity HTN-3 data before deciding whether to pull the plug on their devices, hoping to find out whether the problem was with the Symplicity system or the very concept of renal denervation.
The full HTN-3 data give little cause for hope. The remarkable thing is the scale of the change: earlier trials of Symplicity showed reductions as high as 32mmHg in systolic BP, an unheard-of achievement in drug-resistant patients. In the new trial, Symplicity could only muster a reduction from baseline systolic BP of 14.1mmHg, not significantly better than the 11.7mmHg drop seen with patients who underwent a sham procedure.
HTN-3 was the first trial of any denervation device to both be blinded and include a sham group; none was required for CE marking, partly owing to the ethical implications of putting patients through a painful procedure from which they would not benefit. If the earlier trials benefited from a placebo effect, both arms in HTN-3 will have seen this same boost.
The monitoring of the patients has also been mooted as an explanation for the failure, with those on placebo adhering more closely to their other medications thanks to greater oversight than in prior studies.
If there is still hope for the other devices, it lies in the ablation procedure. There is no way for doctors to tell definitely whether the nerves have been ablated successfully, or indeed at all. If it turns out that the Symplicity device is less able to attenuate the signals – and it is perhaps germane that Medtronic’s device has a single radiofrequency electrode, whereas almost all the others have four – its rivals could still be in with a chance.
The devices’ performance on the European market will be interesting to watch in the coming months. The enthusiasm for these products exhibited by cardiologists may mean that some are unwilling to abandon them, and there is little advantage for the developers in pulling them from the shelves.
It is in the US that work must still be done and money spent, so it is here that companies might decide to cut their losses. It could be too early to seal the tomb for renal denervation, but after the release of the HTN-3 data Covidien is unlikely to be regretting its decision.
|CE marked renal denervation systems – state of play|
|Company||Device name||CE mark date||Number of electrodes||What now?|
|Medtronic||Symplicity||April 1, 2010||One||Development continuing|
|Covidien||OneShot||February 1, 2012||One; spiral arrangement||Development halted|
|St. Jude Medical||EnligHTN||May 15, 2012||Four||Decision yet to be made – company had been waiting for Symplicity HTN-3 results|
|St. Jude Medical||EnligHTN (second generation)||August 29, 2013||Four||Decision yet to be made – company had been waiting for Symplicity HTN-3 results|
|ReCor Medical||Paradise||January 24, 2013||None; ultrasound balloon||Development continuing|
|Terumo||Iberis||April 8, 2013||One||Development continuing|
|Boston Scientific||Vessix Vascular V2||May 22, 2013||Four||Decision yet to be made – company had been waiting for Symplicity HTN-3 results|
|Medtronic||Symplicity Spyral||December 5, 2013||Four||Development continuing|
|Johnson & Johnson||Renlane||February 21, 2014||Five||Decision yet to be made – company had been waiting for Symplicity HTN-3 results|