“A Controlled Trial of Renal Denervation for Resistant Hypertension”
N Engl J Med. 2014 Apr 10;370(15):1393-401. [free full text]
Approximately 10% of patients with hypertension have resistant hypertension (SBP > 140 despite adherence to three maximally tolerated doses of antihypertensives, including a diuretic). Evidence suggests that the sympathetic nervous system plays a large role in such cases, so catheter-based radiofrequency ablation of the renal arteries (renal denervation therapy) was developed as a potential treatment for resistant HTN. The 2010 SYMPLICITY HTN-2 trial was a small (n=106), non-blinded, randomized trial of renal denervation vs. continued care with oral antihypertensives that demonstrated a remarkable 30 mmHg greater decrease in SBP with renal denervation. Thus the 2014 SYMPLICITY HTN-3 trial was designed to evaluate the efficacy of renal denervation in a single-blinded trial with a sham-procedure control group.
Population: adults with resistant HTN with SBP ≥ 160 despite adherence to 3+ maximized antihypertensive drug classes, including a diuretic
pertinent exclusion criteria: 2º HTN, renal artery stenosis > 50%, prior renal artery intervention
(Note – all patients received angiography prior to randomization.)
Intervention: renal denervation with the Symplicity (Medtronic) radioablation catheter
Comparison: renal angiography only (sham procedure)
1º – mean change in office systolic BP from baseline at 6 months (examiner blinded to intervention)
2º – change in mean 24hr ambulatory SBP at 6 months
primary safety endpoint – composite of death, ESRD, embolic event with end-organ damage, renal artery or other vascular complication, hypertensive crisis within 30 days, or new renal artery stenosis of > 70%
535 patients were randomized. There were no differences in baseline characteristics among the two groups. On average, patients were receiving five antihypertensive medications.
There was no significant difference in reduction of SBP between the two groups at 6 months. ∆SBP was -14.13 ± 23.93 mmHg in the denervation group vs. -11.74 ± 25.94 mmHg in the sham-procedure group, for a between-group difference of -2.39 mmHg (95% CI -6.89 to 2.12, p = 0.26 with a superiority margin of 5 mmHg). The change in 24hr ambulatory SBP at 6 months was -6.75 ± 15.11 mmHg in the denervation group vs. -4.79 ± 17.25 mmHg in the sham-procedure group, for a between-group difference of -1.96 mmHg (95% CI -4.97 to 1.06, p = 0.98 with a superiority margin of 2 mmHg). There was no significant difference in the prevalence of the composite safety endpoint at 6 months with 4.0% of the denervation group and 5.8% of the sham-procedure group reaching the endpoint (percentage-point difference of -1.9, 95% CI -6.0 to 2.2).
In patients with resistant hypertension, renal denervation therapy provided no reduction in SBP at 6-month follow-up relative to a sham procedure.
This trial was an astounding failure for Medtronic and its Symplicity renal denervation radioablation catheter. The magnitude of the difference in results between the non-blinded, no-sham-procedure SYMPLICITY HTN-2 trial and this patient-blinded, sham-procedure-controlled trial is likely a product of 1) a marked placebo effect of procedural intervention, 2) Hawthorne effect in the non-blinded trial, and 3) regression toward the mean (patients were enrolled based on unusually high BP readings that over the course of the trial declined to reflect a lower true baseline).
Currently, there is no role for renal denervation therapy in the treatment of HTN (resistant or otherwise). However, despite the results of SYMPLICITY HTN-3, other companies and research groups are assessing the role of different radioablation catheters in patients with low-risk essential HTN and with resistant HTN (for example, see https://www.ncbi.nlm.nih.gov/pubmed/29224639).
1.. NephJC, SYMPLICITY HTN-3
2. UpToDate, “Treatment of resistant hypertension,” heading “Catheter-based radiofrequency ablation of sympathetic nerves”
Summary by Duncan F. Moore, MD