The NephJC offering this week is the SYMPLICITY HTN-3 renal denervation trial reported in the NEJM. SYMPLICITY HTN-3 was the definitive randomized placebo controlled (sham) trial that was supposed to get renal denervation for resistant hypertension FDA approval and open up the money gates for Medtronic the manufacturer of the device. The results represented the most anticipated trial in the field of hypertension and nephrology in a very long time. This was my tweet from the day the press release came out (I can remember exactly where I was then)

RT @kidney_boy: “@MillenniuMRG: SYMPLICITY HTN-3 failed to meet its primary efficacy endpoint http://t.co/YStzgiSDIi” Too bad!!!

— Matt Sparks (@Nephro_Sparks) January 9, 2014

Why was this trial so anticipated? for one, resistant hypertension is difficult to treat and associated with considerable mortality and morbidity. Secondly, the addition of a non-pharmacological intervention to the armamentarium is attractive in a field in need of innovative therapy. Lastly,  the predecessor SYMPLICITY trials showed, what was thought to be, impressive BP lowering effects from the procedure (on the magnitude of 30 mmHg SBP reduction!). However, several problems were readily apparent with these trials. They lacked a proper control group (no blinding or sham procedure). This didn’t stop renal denervation from being performed in over 80 countries before the SYMPLICITY HTN-3 trial.

The story of renal denervation has been around for a long time. The sympathetic innervation to the kidney is important to maintaining BP homeostasis. Efferent and afferent nerves provide rich innervation to many parts of the kidney including the renal tubules, vasculature, and juxtaglumerular apparatus and each of these compartments can impact blood pressure. Disruption of the nerve supply of the kidney was first employed back in the 1950s where splanchnicectomy was performed in patients with essential hypertension. However, considerable side effects such as postural hypotension, syncope and impotence limited its use. This novel catheter based technique in which the efferent nerves of the kidney were selectively ablated was a resurrection of this abandoned idea.

Let’s take a look at the SYMPLICITY HTN-3 trial design.

• Symplicity-3 screened 1441 patients and enrolled 535 from 88 sites in the US
• Patients were required to have a SBP of 160 mmHg and to be taking maximally tolerated doses of three or more BP meds, one of which had to be a diuretic
• There were no significant differences between the two groups
• Patients were receiving an average of 5 BP meds (4 of which were at max dose)
• The majority of patients were receiving hydrochlorothiazide
• The numbers and types of antihypertensive medications at 6 months were similar to those at baseline in both groups
• Patients underwent renal angiography before randomization
• The participants were randomized to either denervation or sham in a 2:1 fashion. (this is important, as it represents the only renal denervation trial using sham)
• Patients in the treatment group underwent renal-artery denervation with the use of radiofrequency energy delivered by the Symplicity renal-denervation catheter (Medtronic).
• Patients were unaware of whether they underwent renal-artery denervation or renal angiography only (sham control).
• BP assessors were unaware of the study-group assignments
• Demographics (table 1): average age of ~57, ~60% male, ~70% white, ~9% with eGFR <60, ~45% with DM2, ~99% on ACEi or ARB, ~25% on aldactone, ~100% diuretic

SYMPLICITY HTN-3 End Points

The primary efficacy end point was the mean change in office systolic BP from baseline to 6 months in the denervation group, as compared with the mean change in the sham control group, with a superiority margin of 5 mm Hg.

The study was also powered for assessment of a secondary efficacy end point: the change in mean 24-hour ambulatory systolic BP at 6 mo.

The primary safety end point was a composite of major adverse events, defined as death from any cause, ESRD, an embolic event resulting in end-organ damage, renal-artery or other vascular complications, or hypertensive crisis within 30 days or new renal-artery stenosis of more than 70% within 6 months.

Safety Data

• 5 major adverse events in the denervation group
• 1 in the sham-procedure group
• No significant differences between the two groups in kidney function at any time point

These results indicate that renal denervation in a well-conducted, multicenter, sham-controlled, blinded, randomized controlled trial in a population of patients with resistant hypertension did not result in a significant reduction in BP at 6 months compared to sham-control.

Why was there such a lowering of BP in the sham control group? Could the statistical phenomenon termed “regression toward the mean” be a factor in this study? The definition of this phenomenon is that if a variable is extreme on its first measurement, it will tend to be closer to the average on its second measurement. The possible scenario in this study is that the selection criteria selected participants who happened to be at the extreme of their usual measure upon entry to the study protocol and hence as the study progressed they regressed to the mean. Another possibility is that the decrease in BP seen in both groups represents the placebo effect and this effect was amplified on the basis of this being an invasive intervention. It is possible also that the earlier trials were complicated by the Hawthorne effect (i.e. more attention meds and adherence).

Could this negative result be secondary to ineffective nerve ablation? This is a possibility and I have seen this theory propagated in the literature. There was evaluation of the efficacy of nerve ablation by measuring norepinephrine in the urine, renin activity and muscle sympathetic nerve activity in prior studies.  However, this was not performed in the SYMPLICITY HTN-3 patients. This is a possibility and I wonder if they saved urines on these participants.

Is there a patient population that could benefit from such a procedure? This is the million dollar question. Maybe CKD (with higher sympathetic tone) is a prerequisite for renal denervation to work. Interestingly the subgroup analysis was skewed the opposite direction towards benefit in higher eGFR.  However, only a small proportion of patients had a eGFR of less than 60. Maybe urinary norepinephrine levels could determine a subset of patients that would benefit from such a procedure as they might have enhances efferent tone to the kidney.

Check out all of the discussion next Tuesday, May 27th at 9pm EDT. Follow @NephJC and use the hashtag #NephJC. Go to NephJC.com to follow the discussion.

Dr. Matthew A. Sparks
eAJKD Advisory Board member