Since the advent of minimally invasive renal denervation procedures about a decade ago, the nephrology community had been eagerly awaiting conclusion of the SYMPLICITY 3 trial. As many of you might already know, Medtronic, the device’s company issued a press release on January 9th about the procedure failing to meet the primary efficacy endpoint. To a lot of us, this result has been surprising, and disappointing to a certain extent.
|1952 paper from Mayo: Renal denervation/sympathectomy is not a new concept and has been around for almost a century.|
To understand the context, let’s review the background of renal denervation’s role in treatment of resistant hypertension briefly. Per NHANES data from the period 2003-2008, the prevalence of resistant hypertension is 8.9 ± 0.6% of the US hypertensive population, and continues to increase. I am guessing the prevalence could theoretically be a little lower if the new, more relaxed, hypertension treatment goals of JNC 8 are considered. This was discussed by Matt earlier.
Renal denervation is supposed to work on the premise that the sympathetic nervous system is hyperstimulated in patients with treatment resistant high blood pressure, and the kidneys modulate that to a large extent. Afferent signaling from the kidneys increases central sympathetic drive, while efferent signals to the kidneys increase renin release and sodium retention, while reducing renal blood flow. Hence, if you could cut off this two way traffic between the kidneys and the sympathetic nervous system, you should be able to bring the blood pressure down. Here is a picture that explains this. And below is a video of how the procedure is performed:
Renal sympathetic afferent and efferent fibers run circumferentialy in the wall of the renal artery, and ablation reduces both pathways
We have seen a succession of studies done to validate this hypothesis. Earlier, Matt had talked about the SYMPLICITY-1 trial, which was a non-randomized pilot study. Then we had SYMPLICITY-2 trial in 2010 which was a larger randomized study with 106 patients. This was conducted in Europe, Australia, and New Zealand. This showed significant reduction in office based blood pressures at 6 months, with no serious side effects. And so, with much fanfare and hype, the SYMPLICITY-3 trial was initiated in August 2011. While the study has not been published, the authors chose to communicate the procedure’s lack of efficacy (in meeting the primary end point) via a press release. There was no mention about the status of secondary end points (which included ambulatory BP changes) in the statement.
WHICH BRINGS US TO THE QUESTION…
Why did the trial fail to meet the primary efficacy end point, in spite of the prior data that looked promising? It appears to be the best designed trial till date to study this issue. SYMPLICITY-3 was bigger (535 patients) and better designed (control patients underwent a sham procedure) than its predecessors. I wonder if that itself could have been the reason for us seeing the lack of any benefit. That in fact, the prior trials were outliers given smaller size of the studies, or lack of randomization. Or, could it have something to do with anatomical and functional regrowth of sympathetic nerves that can happen after they are ablated (as can happen post transplant)? Let us know your thoughts about what you think could have been the reasons!
IMPLICATIONS FOR CKD PATIENTS
Something that I have always wondered about (and which has nothing to do with this press release) is the safety and efficacy of this procedure in CKD patients. It is plausible that if you are tinkering with the renin angiotensin system, you could adversely affect renal function. Just like you could be leery of giving ACE inhibitors to an advanced CKD-4 patient with hypertension, would you consider not doing this procedure as well? Could we see hyperkalemia develop? In the absence of adequate data, I would say that I don’t know, but we did see a study that tried to answer this question. However, it was a small study (15 patients, and even those didn’t complete follow up), and a short follow up period.
IF ALL YOU HAVE IS A HAMMER, EVERYTHING LOOKS LIKE A NAIL?
So is this development the beginning of the end of renal denervation procedure? Maybe; or maybe not. Medtronic has already suspended further enrollment in other renal denervation trials in the US (SYMPLICITY-4), Japan, and India. However, the device will still remain available for “discretionary use” by physicians (good luck convincing insurance companies to pay for a procedure that is about as good as sham!). But, we still have other potential indications under the sun which could be a breath of life for the device/procedure. These include heart failure, metabolic syndrome, and obstructive sleep apnea.
Finally, we also have another device that works on the principle of baroreceptor activation that is being actively studied for treatment of resistant hypertension.