Renal Denervation in Patients With Uncontrolled Hypertension - SYMPLICITY HTN-3

Contribution To Literature:

Highlighted text has been updated as of September 18, 2022.

The SYMPLICITY HTN-3 trial indicated that renal arterial denervation with the Symplicity denervation system was not superior to a sham procedure and medical therapy in reducing office and ambulatory blood pressure at 6 months in patients with severe resistant hypertension.


Renal denervation has shown promising results for the treatment of resistant hypertension in phase I and II trials. The current phase III trial sought to evaluate the safety and efficacy of renal artery denervation in patients with severe resistant hypertension.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Age ≥18 and ≤80 years at time of randomization
  • Stable medication regimen including full tolerated doses of three or more antihypertensive medications of different classes, including a diuretic (with no changes for a minimum of 2 weeks prior to screening) and no expected changes for at least 6 months
  • Office systolic blood pressure (SBP) ≥160 mm Hg based on an average of three blood pressure readings measured at both an initial and a confirmatory screening visit

    Number screened: 1,441
    Number of enrollees: 535
    Duration of follow-up: 6 months, 12 months
    Mean patient age: 57 years
    Percentage female: 39%


  • Ambulatory BP monitoring (ABPM) 24-hour average SBP <135 mm Hg
  • Estimated glomerular filtration rate (eGFR) of <45 ml/min/1.73 m2
  • Main renal arteries <4 mm diameter or <20 mm treatable length
  • Multiple renal arteries where the main renal artery is estimated to supply <75% of the kidney
  • Renal artery stenosis >50% or aneurysm in either renal artery
  • History of prior renal artery intervention

Primary Endpoints:

  • Safety: Major adverse events
  • Efficacy: Comparison of office SBP change from baseline to 6 months in renal denervation arm compared with change from baseline to 6 months in control arm

Secondary Endpoints:

Comparison of mean 24-hour ABPM SBP change from baseline to 6 months in renal denervation arm compared with change from baseline to 6 months in control arm

Drug/Procedures Used:

Patients were randomized in a 2:1 fashion to renal denervation or a sham procedure. Randomization was performed after renal artery angiography. Patients in the treatment group underwent renal artery denervation with the use of radiofrequency energy delivered by the Symplicity renal-denervation catheter. All patients underwent renal angiography.

Concomitant Medications:

Diuretics (99.8%), beta-blockers (86%), angiotensin-converting enzyme inhibitor (46%), angiotensin-receptor blocker (51%), and aldosterone antagonists (25%)

Principal Findings:

A total of 535 patients were randomized, 364 to renal denervation and 171 to a sham procedure. Baseline characteristics were similar between the two arms. Approximately 45% had diabetes mellitus, and 9% had prior stroke. The mean SBP was 180 mm Hg, and the mean 24-hour ambulatory BP was 159 mm Hg. These patients were on a mean of 5.1 antihypertensive medications at baseline.

There were significant reductions in office SBP in both the renal denervation (-14 mm Hg) and sham procedure (-11.7 mm Hg) arms. However, the primary efficacy endpoint of difference in office SBP at 6 months between the renal denervation and sham arms was nonsignificant (absolute difference = -2.39, 95% CI -6.89 to 2.12, p = 0.26). Similar results on 24-hour ABP monitoring (ABPM): mean SBP decreased in both the renal denervation (-6.8 mm Hg) and sham procedure (-4.8 mm Hg) arms, with no difference between the two arms at 6 months (absolute difference = -1.96, 95% CI -4.97 to 1.06, p = 0.98). The daytime ambulatory SBP change difference between groups was -1.1 (95% CI -4.3 to 2.2; p = 0.52). The nocturnal ambulatory SBP change difference between groups was -3.3 (95% CI -6.7 to 0.1; p = 0.06).

The primary safety endpoint was met: Major adverse events were observed in 1.4% of patients in the denervation arm compared with 0.6% in the sham procedure arm (p = 0.67; performance goal based on historical controls of 9.8%). Outcomes including mortality (0.6% in each arm), serum creatinine elevation >50% (1.4% vs. 0.6%), and new renal artery stenosis >70% (0.3% vs. 0%) were similar at 6 months.

Twelve-month follow-up: Following the initial 6-month follow-up duration, clinicians and patients were unblinded, and crossover to renal denervation was permitted from the sham arm. There were 364 patients from the original renal denervation arm, 101 crossovers, and 70 non-crossovers at 12 months. The number of prescribed antihypertensive medications was similar at the end of 12 months. Significant decreases from baseline were again observed for SBP in the renal denervation, crossover, and non-crossover groups, but no difference was observed between the groups themselves (-18.9 mm Hg vs. -17.7 mm Hg vs. -21.4 mm Hg, p < 0.001 for all compared with baseline). Changes in ambulatory SBP were -6.8 mm Hg vs. -9.2 mm Hg vs. -6.1 mm Hg. Renal artery reintervention was necessary in 0.6% of the renal denervation arm patients at 12 months; the presence of new renal artery stenosis was only assessed at 6 months.

Analysis of covariance was performed on the 6-month change in SBP, estimating a mean treatment difference of -4.11 mm Hg (95% CI -8.44 to 0.22, p = 0.064), similar to the unadjusted difference, but with a smaller CI. Regression to the mean occurred in both arms, but had a negligible effect on the observed treatment difference.

Three-year follow-up (n = 315, 59%): After 6 months, 101 (59%) patients in the sham control group crossed over to renal artery denervation. Change in office SBP from baseline for renal denervation vs. sham: -26.4 vs. -5.7 mm Hg (p < 0.0001); change in ambulatory SBP: -15.6 vs. -0.3 mm Hg (p = 0.0001). Results were similar on sensitivity analyses accounting for BP imputations. Time in therapeutic BP range: 18% vs. 9% (p < 0.0001). Change in number of prescribed medication classes: -0.3 vs. -0.2 (p = 0.22).

Composite safety endpoint (all-cause death, new-onset end-stage renal disease, significant embolic event resulting in end-organ damage, vascular complication, renal artery re-intervention, or hypertensive emergency) at 48 months for renal denervation vs. crossover vs. sham, was: 15% vs. 14% vs. 14% (p > 0.05).


The results of the SYMPLICITY HTN-3 trial indicate that renal arterial denervation with the Symplicity denervation system was not superior to a sham procedure and medical therapy in reducing office and ambulatory BP at 6 months in patients with severe resistant hypertension. Regarding safety, there was no excess increase in new significant renal artery stenosis at 6 months. This is the first phase III trial on this topic, and follows very impressive phase I and phase II results with this technology. Thus, these results are very surprising, but highlight the utility of sham controls in device-based trials, a practice that is not commonly followed.

Crossover to renal denervation in the sham arm at 6 months was permitted, and interestingly, on 3-year follow-up, there appeared to be a large BP benefit with renal denervation despite medication use being similar. These results are hypothesis generating and will need to be confirmed in further trials. There also appeared to be a large placebo effect in this trial (larger than recent renal denervation trials); following unmasking, BP increased in the non-crossover group after the primary endpoint evaluation at 6 months and stayed consistently above the 6-month values.

Several issues deserve comment. First, the investigators tried very hard to ensure that only patients with true treatment-resistant hypertension were enrolled. There were rigorous inclusion criteria, including 24-hour ABPM, and also a screening phase to assess for medication compliance. Only one third of patients with perceived treatment-resistant hypertension could be enrolled, however. This implies that true treatment-resistant hypertension may be far less common than previously believed.

Second, the BP reduction observed in the denervation arm in this trial was lower (14 mm Hg) than reported in earlier trials (20-25 mm Hg). While the efficacy of renal denervation was explicitly not measured in this study, this is the same catheter that has been used in earlier phase II trials. Thus, it is unknown if this represents a “regression to the mean” effect in a larger sample size or inadequate ablation. It remains to be seen if newer-generation multipoint ablation catheters can achieve more complete denervation, and perhaps better results.

A detailed subanalysis indicated that regression to the mean occurred in the both arms, but likely had a negligible effect on the primary outcome. Commensurate with a lower than expected reduction in BP in the denervation arm, there appeared to be a higher than expected response in the sham procedure arm. Some of this may be due to the higher utilization of aldosterone antagonists in this arm. The utility of renal denervation in patients with a higher sympathetic tone such as those with concomitant chronic heart failure or atrial fibrillation will need to be assessed in future trials.


Presented by Dr. Deepak Bhatt at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2022), Boston, MA, September 18, 2022.

Bhatt DL, Vaduganathan M, Kandzari DE, et al., on behalf of the SYMPLICITY HTN-3 Steering Committee and Investigators. Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: final follow-up of the randomized SYMPLICITY HTN-3 Trial. Lancet 2022;400:1405-16.

Editorial Comment: Fanelli E, Persu A. SYMPLICITY HTN-3: failure at 6 months, success at 3 years? Lancet 2022;400:1382-3.

Pocock SJ, Bakris G, Bhatt DL, Brar S, Fahy M, Gersh BJ. Regression to the Mean in SYMPLICITY HTN-3: Implications for Design and Reporting of Future Trials. J Am Coll Cardiol 2016;68:2016-25.

Presented by Dr. George Bakris at the European Society of Cardiology Congress, Barcelona, Spain, September 1, 2014.

Bakris GL, Townsend RR, Liu M, et al. Impact of renal denervation on 24-hour ambulatory blood pressure: results from SYMPLICITY HTN-3. J Am Coll Cardiol 2014;64:1071-8.

Bhatt DL, Kandzari DE, O’Neill WW, et al., on behalf of the SYMPLICITY HTN-3 Investigators. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:1393-1401.

Presented by Dr. Deepak L. Bhatt at the American College of Cardiology Scientific Session, Washington, DC, March 29, 2014.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Acute Heart Failure, Hypertension

Keywords: Stroke, Denervation, Mineralocorticoid Receptor Antagonists, Diuretics, Blood Pressure, Creatinine, Systole, Medication Adherence, Renal Artery, Renal Artery Obstruction, Research Personnel, Heart Failure, Kidney, Hypertension, Diabetes Mellitus, ESC Congress, TCT22, Transcatheter Cardiovascular Therapeutics

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