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.
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.
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| 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’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:
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
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.
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…
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!
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
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.
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?
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.
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.
activation that is being
actively studied for treatment of resistant hypertension.
I agree 1000% with Veeraish, but there may be more to the story.
If you look at the S3 end points. Younger patients and non AA patients actually did have a statistically significant improvement.
These patients tend to be hyper-reninemic, or salt resistant hypertensives, and hence respond better to sympathetic blockers and vasoactive agents.
AA patients on the other hand tended not to have any response, and they tend to be salt sensitive and hyporeninemnic and respond best to diuretic therapy.
Similar to ACCOMPLISH trial results were, (different from ALLHAT) – when the same investigators looked at the population according to the BMI, the high BMI patients(that tend to be salt sensitive) tended to have better response to thiazide/ACEi combination compared to leaner population which tend to be salt resistant, besides they used HCTZ which is not Chlorthalidone used in ALLHAT and may have contributed to the difference in outcome compared to
Now objective measurements using salt excretion, renin profiling may have had an additional role in finding which population may benefit from renal denervation.
Second problem is that there was no criteria set looking at at the response to renal denervation, to, like MSNA etc, to look at effective denervation.
Although device therapy of resistant hypertension – renal denervation in this case – may not revive but, what I gather is that treatment of hypertension is differ individually and we need objective measures to see what will work for whom.