Renal Denervation for Hypertension

Motivation: Yes, the blog is not dead.  It has been moribund for a while under pressure from residency. Apologies.

A previous blog post here on July 2012 had considered kidney denervation for treatment of hypertension. Recently, there was a larger trial of this technique (SYMPLICITY HTN-3) was reported. So, should be all be considering this treatment for refractory hypertension?

Paper: Bhatt, D.L., Kandzari, D.E., O'Neill, W.W. et. al. "A Controlled Trial of Renal Denervation for Resistant Hypertension." NEJM (2014); 370: 1393-401

Method: Prospective blinded randomized sham-controlled trial in adult patients with severe resistant hypertension. Subjects were randomized in 2:1 ratio to undergo renal denervation or a sham procedure. Severe resistant hypertension was defined as three drugs at maximum doses. Primary endpoint was change in systolic blood pressure at six months.Of note, patients with renal artery stenosis were excluded.

Results:
Cohort: Total of 535 patients were randomized in this trial (364 to renal denervation group and 171 to sham procedure). The average age was about 57 years with roughly 60% of male patients. Baseline characteristics including body mass index, race, kidney disease, cardiovascular disease, and rate of smoking were not different between the two groups. On average, subjects took five antihypertensive medications.

Primary outcome: At six months, the intervention group had 14.13 mmHg decrease in SBP compared to 11.74 mmHg decrease in the sham group. This difference was not statistically significant.

Safety: There were five adverse effects in the intervention group compared to one in the sham group. There was no difference kidney function in the intervention group.

Discussion: This trial shows that renal denervation is not worth pursuing in the severely refractory hypertensive group of patients. The question remains why the therapy appeared so promising in the smaller trial but failed now.  One possible reason is that in the smaller previous trial, the placebo and the intervention groups were not well matched while the two groups are well matched in this trial. While this trial did not have promising results, one wonders whether this same procedure might benefit patients with early hypertension who may still respond to renal denervation. However, for now, I would not recommend this therapy.

New Way for Hypertension

Motivation: Last weekend, I was flipping through an old issue of TIME magazine when I noticed an article with large picture of pink kidneys.  Wondering why TIME magazine would be concerned with urine production, I read a little more and learnt about a "revolutionary" new treatment for hypertension discovered in England in 2010.  The article refers to amazing results published in a trial in Lancet in 2010 from renal sympathetic ablation.  Throughout intern year, we had never seriously considered this therapy.  Why? How good is the data?

Paper: Symplicity HTN-2 Investigators. "Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial" Lancet (2010); 376: 1903-09.

Methods: Multicenter randomized unblinded trial of renal denervation with treatment resistant hypertension, defined as SBP > 160 mmHg (SBP > 150 with DM2) despite compliance on 3 or more anti-hypertensives.  Important exclusion criteria were GFR < 45 and history of MI, unstable angina, or stroke.  Study conducted at Europe, Australia, and New Zealand.  Patients randomized to renal denervation had endovascular catheter directed radioablation through renal artery access.  Primary endpoint was change in average office-based SBP from baseline to 6 months.

Results:
Cohort: In total, 52 patients were randomized to renal denervation while 54 were in the control group.  The two groups were overall similar except for differences in gender (35% female in intervention vs. 50% in control group) and difference in baseline GFR (77 ml/min in intervention vs. 86 in control group). Three patients were lost to follow-up in each group.

Efficacy: In per-protocol analysis, at six-months, renal denervation resulted in mean decrease in BP of 33/11 mmHg compared to no changed in the control group.  The baseline was 178/96 in the intervention group and the same in the control group.  The result is statistically significant, p < 0.0001.  Similar changes were noted in BP measurements at home-based and 24 hour ambulatory measurements.  At least 84% of patients in intervention group had >10 mmHg decrease in SBP at 6 months.

Secondary End Points: There were no differences in serum creatinine, eGFR, and cystatin C between baseline and 6 months in both groups.  There were no differences in composite cardiovascular between the two groups.

Safety: No serious procedure-related or device related complications noted in the six month follow-up.

Discussion: In this preliminary phase trial of renal denervation, the procedure appears remarkably efficacious.  The degree of BP measurement is clearly better than any other current medicinal or lifestyle approach.  Yet, before adopting this intervention, the paper has multiple limitations that need to be clarified.  First, the control and intervention groups were different some important baseline parameters such as gender distribution and GFR.  Second, there were no hard endpoints used in the paper such as MI or long-term cardiovascular outcomes.  It is unclear whether renal denervation has any long-term risks that may outweigh short-term benefits in BP reduction.  Finally, this entire study was funded, designed, and analyzed by Ardian, the maker of the denervation catheter.  The data would gain more integrity if the trial was designed and analyzed independently.  Thus, this therapy is promising but needs a larger follow-up trial before widespread use.