It is fair to say that the positive signs seen in a study of Medtronic’s renal denervation technology last year came as a surprise. The blood pressure-lowering technique had been roundly discredited three years earlier, but Medtronic, bolstered by the new data, immediately said it would have a second try at a pivotal US trial.
This approval study has now begun, and it is structured very differently from both Medtronic’s initial, failed, pivotal trial and the smaller study that hit last August. Jason Fontana, who leads the renal denervation commercial strategy at Medtronic, says the company is “super confident” about the new trial. But should it be?
Renal denervation was the future, once. Spectacular results were seen in single-arm trials among patients with uncontrolled blood pressure, and as this is a huge population the potential market looked enormous. Several devices were approved in Europe, including Medtronic’s Symplicity, the forerunner to Symplicity Spyral, and Spyral itself.
But disaster struck in January 2014 when the first US pivotal trial – and therefore the first to require a sham control group – failed.
|Selected CE-marked renal denervation systems|
|Company||Device||CE mark date|
|Medtronic||Symplicity||Apr 1, 2010|
|St. Jude Medical (now Abbott)||EnligHTN||May 15, 2012|
|St. Jude Medical (now Abbott)||EnligHTN (second generation)||Aug 29, 2013|
|Recor Medical||Paradise||Jan 24, 2013|
|Terumo||Iberis||Apr 8, 2013|
|Boston Scientific||Vessix||May 22, 2013|
|Medtronic||Symplicity Spyral||Dec 5, 2013|
|Johnson & Johnson||Renlane||Feb 21, 2014|
In the wake of this shock failure the companies with denervation technologies quietly wound down marketing efforts in Europe, and most shelved any plans for US trials. And this is where the situation stayed until last August, when data from the first 80 patients enrolled into the Spyral HTN Off Med trial came in positive.
A greater effect
Off Med showed a significant reduction in blood pressure over a sham procedure at three months, but this difference was so small, at 5mmHg when measured over the course of 24 hours, there were questions over its clinical utility (ESC 2017 – The corpse of renal denervation starts twitching, August 28, 2017).
The Off Med data did not have a marked effect on Spyral sales, Mr Fontana says, though they have put the company in a better position for negotiating reimbursement. Over the past few years Spyral has brought in a small amount of revenue for Medtronic, with doctors in Europe using it “as more of a last resort-type treatment”. At a cost of around $5,000 – the procedure as a whole costs $12,000-15,000 – the revenue stream from Spyral is not “something we’re counting on”, Mr Fontana says.
And the fact that the hit in Off Med was not enough to persuade European doctors to increase their use of Spyral suggests that the upcoming pivotal study will need to show a bigger effect if Medtronic is to see a decent sales bump.
As with Off Med, patients will not take antihypertensive drugs, and the two trials have the same enrolment criteria: in-office systolic blood pressure of 150-180mmHg and diastolic blood pressure over 90mmHg, and 24-hour ambulatory blood pressure of 140-170mmHg.
Measuring a patient’s blood pressure over 24 hours using a wireless monitor is considered more robust than in-office measurements since the latter can stress patients out, prompting inaccurately high readings. The failed pivotal trial used office blood pressure readings as both enrolment criteria and endpoint, possibly contributing to its failure.
With similar designs, the trials could yield similar data. The new study will take a year or two to enrol, and with a three-month endpoint it could report in 2020. Mr Fontana says results along the lines of those seen in Off Med would be good enough.
“If you look at the Spyral Off Med data and the 10mmHg [in-office] drop, we know that translates to pretty significant reductions in risk of stroke and cardiovascular disease,” he says. “The 5mmHg drop in ambulatory blood pressure is also a significant drop given that usually a 2mmHg drop has a big impact on cardiovascular outcomes.
“We feel positive about getting at least those numbers in the pivotal.”
Medtronic is spearheading the rehabilitation of renal denervation. But another, much smaller company never lost faith in the technique: Recor Medical is the only other group actively pursuing a sham-controlled trial including US patients.
Radiance-HTN is testing Recor’s Paradise device in around 300 patients, and though it is not a pivotal trial the data, expected mid-year, are hotly awaited (Interview – Recor hopes to find Paradise on the market, March 15, 2016). Paradise was CE-marked in 2013, so its safety is already accepted in Europe. Decent efficacy data – a bigger blood pressure drop than that seen in Off Med – could mean a sizeable sales jump for the Palo Alto company.
|US sham-controlled renal denervation trials|
|Company||Device||Study||Enrolment||Primary efficacy endpoint||Status||Trial ID|
|Medtronic||Symplicity||Symplicity-HTN3||535||Change in office systolic BP at 6mth||First US pivotal trial; failed Jan 2014||NCT01418261|
|Medtronic||Symplicity Spyral||Spyral HTN-Off Med||170||Change in systolic 24hr BP at 36mth||3mth interim data reported Aug 2017; full data end 2018||NCT02439749|
|Medtronic||Symplicity Spyral||Spyral HTN-On Med||106||Change in systolic 24hr BP at 36mth||3mth interim data expected May 2018; full data 2021||NCT02439775|
|Medtronic||Symplicity Spyral||Spyral HTN Pivotal Trial||433||Change in 24hr BP at 3mth||Data expected 2020||-|
|Recor Medical||Paradise||Radiance-HTN||292||Change in 24hr BP at 2mth||Data expected mid-2018||NCT02649426|
|Source: EvaluateMedTech and Clinicaltrials.gov.|
A third company was known to be conducting a US study incorporating a sham group: Boston Scientific. However, the group has confirmed to EP Vantage that it decided to stop enrolling patients into the Reinforce trial of its Vessix device late last year, though it plans to release six-month data later in 2018.
Just ahead of Recor’s readout, interim data from Medtronic’s On Med trial – Off Med’s sister study, in which patients keep taking up to three antihypertensive drugs – should appear.
Mr Fontana says the company is looking for a similar reduction to that seen in Off Med – that, “in the presence or absence of medication you still get a good, solid effect of renal denervation”. With denervation products stuck in the last-resort position, showing a benefit over drugs might move the technology up the treatment cascade.
Success in On Med would be nice for Medtronic, but it is the pivotal data that will determine whether Symplicity, and renal denervation as a whole, has a future. And then, perhaps, the technique will reach US patients – more than a decade since it was first CE-marked.