Renal Denervation: Back From The Dead Or Deja Vu All Over Again?

  Renal denervation is back. Or not.

The failure of renal denervation (RDN) was one of the most spectacular failures in cardiovascular medicine in recent years. Great expectations for RDN appeared to die with the Simplicity-3 HTN trial, the first rigorous test of the technology, which showed that it was ineffective in the treatment of resistant hypertension.

Following the failure of the trial Medtronic and the research community probed the data for clues to what went so wrong and went back to the drawing board and developed a new device they hoped would overcome the limitations of the first device. Now the cardiovascular community is about to get an early, highly preliminary look at the new device, the Symplicity Spyral multielectrode renal denervation catheter. Results of an interim analysis of an ongoing trial, the Spyral-HTN-OFF-Med, will be presented on August 28 at the European Society of Cardiology meeting in Barcelona.

Spyral-HTN-OFF-Med is testing the effect of RDN in hypertensive patients after withdrawal of antihypertensive therapy. It is one of two ongoing initial trials with the device. The second trial, Spyral-HTN-ON-Med, has a similar design but is testing the device in patients treated with antihypertensive drug therapy. In both trials patients will be followed for three years, but they will be unblinded after a year.

The presentation in Barcelona will present details on blood pressure reduction and major safety events at the 3 month evaluation of the first 80 patients randomized into the trial.

One influential Wall Street analyst, Larry Biegelsen at Wells Fargo, wrote that renal denervation may be “back from the dead.” He said that he was “optimistic that the Spyral HTN Off Med study will be positive.” But it is important to interject a strong note of caution, and, to be fair, Biegelsen was clear that he was only speculating. Importantly, even if this first presentation is highly positive there is still a very long way to go before it will be possible to say that the technology has indeed been redeemed.

Biegelsen offered a number of reasons why he thinks the trial may be positive. First, he cited as evidence the fact that Medtronic scheduled a satellite symposium and an investor event following the ESC presentation at ESC. I am reluctant to read too much into this. It’s quite possible that the company was not aware of the results before it scheduled the meetings. It’s also plausible that the company events are an indication that the company is aggressively trying to spin a marginal or mediocre result.

Biegelsen also points to the fact that the sample size was recently increased from 120 patients to 170 patients. “We doubt MDT would continue the study if the results from the initial 120 patients were negative.” Again, I would urge caution. A Medtronic spokesperson told me that “in order to avoid a pause in enrollment momentum as we consider next steps toward pivotal trial design, we have agreed with the FDA to extend the OFF MED trial enrollment by an additional 50 patients.” But it should also be pointed out that increasing the sample size is not necessarily a sign of strength. An alternative explanation is that the original sample size resulted in a weaker effect than originally posited and the company hopes that a larger sample size will lead to greater statistical power.

I completely agree with Biegelsen that “the bigger question is, does RDN work on patients still taking meds?” The OFF trial was designed to demonstrate the precise effect of renal denervation, but Biegelsen is right that the trial with people still taking antihypertensive medications, the Spyral HTN-On Med trial, “is more important… from a commercial standpoint… because if RDN were to be approved, its initial clinical use would most likely be as adjunctive therapy for uncontrolled hypertensive patients still on medication. We think clinicians will be reluctant (at least early on) to use RDN in newly diagnosed patients or in patients who want to come off their medications.”

We will need to wait before we will have a clear idea of the new technology’s worth. Both trials, however, are far too small to provide a reliable evaluation of renal denervation. The trials were only designed to inform the design of a pivotal trial.

It’s also important to emphasize that, as the company told me, this is only a prespecified interim analysis of the first 80 patients in the trial. (This raises the separate question of whether this should really be presented at a major meeting as a late-breaking clinical trial.) So more caution is warranted. “Interim analysis of such low numbers are often uninformative and potentially misleading unless they are being utilized to guide final trial design, which appears to be the case,” Sanjay Kaul (Cedars-Sinai) told me.

I take some comfort from the fact that both the OFF and ON trials use sham procedures in the control arms. Remember, the first generation device was wildly successful in a series of early trials. These trials lacked rigorous controls. It was only when the device was tested in the pivotal trial against sham procedures that it was shown to be ineffective.

On the other hand, I take no comfort from the fact that the bar to RDN acceptance is being lowered. The most compelling aspect of the development of the original device was the focus on resistant hypertension, since it seemed clear that the case for an invasive procedure to treat hypertension could best be made in the population of people who had tried and failed multiple attempts at drug therapy. It turned out that it may not be so easy to define or study this population. But I find it hard to accept the case that RDN should be developed as an alternative to drug therapy. I suppose our views on this may evolve over time, but for now it seems an extreme case of over-treatment to contemplate an invasive procedure like RDN over drug therapy. On the other, other hand, Sripal Bangalore (NYU) told me that “if the trial is positive (we of course need to see the full results and the long term durability) it likely will shake up the way we approach patients with hypertension.”

Related reading:

• MedPage Today: Time to Say Goodbye to Renal Denervation? Not quite, some say, with an eye towards 2017
• No Benefit Found in First Real Test of Renal Denervation
• Study Shows Why Sham Controls Are Necessary For Device Trials
• The Uncertain Future Of A Once Highly Promising Device For Lowering Blood Pressure
• Wall Street Journal Op-Ed On Sham Surgery Gets It Wrong
• Pivotal Medtronic Trial For ‘Breakthrough’ Blood Pressure Device Goes Down The Tubes
• Realistic Expectations For New ‘Breakthrough’ Blood Pressure Technology