By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
SYNOPSIS: Three-year follow-up data from the SYMPLICITY HTN-3 trial of renal denervation provide support for long-term safety of this technique and suggest blood pressure benefit.
SOURCE: Bhatt DL, Vaduganathan M, Kandzari DE, et al. Long-term outcomes after catheter-based renal artery denervation for resistant hypertension: Final follow-up of the randomised SYMPLICITY HTN-3 trial. Lancet 2022;400:1405-1416.
Treatment of resistant hypertension has been a thorny problem in cardiovascular care. The authors of the first reported trial of the Symplicity catheter system (SYMPLICITY HTN-1) noted a nearly unbelievable 25 mmHg reduction in systolic blood pressure at 12 months.1 The SYMPLICITY HTN-3 trial was designed as a sham-controlled, single-blind trial to demonstrate the efficacy of this technique. Instead, treated patients did not show a significant reduction in systolic blood pressure at six months compared with a sham control.2 This negative result squelched the entire field of renal denervation.
The authors of the SYMPLICITY HTN-3 trial enrolled 535 patients and randomly assigned them in a 2:1 fashion to either renal artery denervation using the Symplicity system or to a sham procedure. The mean age of enrolled patients was 57.9 years, and 39% were women. Patients qualified by recording a systolic blood pressure of 160 mmHg or higher at an office visit and were required to be taking maximally tolerated doses of three or more classes of antihypertensive medications. The trial failed to meet its primary endpoint of a significant reduction in systolic blood pressure at six months.
After completion of the six-month primary trial, patients were unblinded. Of the 171 patients initially randomized to the sham treatment arm, 101 patients continued to meet eligibility requirements (i.e., their blood pressures remained higher than the 160 mmHg threshold) and crossed over to undergo denervation treatment. Only six patients who met criteria declined to cross over. For the long-term analysis, Bhatt et al imputed 12- to 36-month information for the crossover patients fusing six-month data (before unblinding and intervention) using the last observation carried forward (LOCF) method. In the final analysis, 36-month data were available for 219 patients in the renal artery denervation group, 63 patients in the crossover group, and 33 patients in the non-crossover group.
At 36 months, the renal artery denervation group showed significantly better reductions in both office and ambulatory blood pressures vs. the sham control. Change in office systolic blood pressure was reported as -26.4 mmHg in denervation patients vs. 5.7 mmHg in control. These values were -15.6 mmHg vs. -0.3 for ambulatory pressures). Similar results were obtained in a post-hoc sensitivity analysis in which all missing data were imputed up to 36 months. Medication use was similar between groups at the final endpoint, although no measures of medication adherence were undertaken. The composite safety endpoint was similar between groups. Bhatt et al also examined the crossover and non-crossover groups specifically. This showed crossover patients exhibited no significant reduction in blood pressure during the first six months while masked but showed persistent blood pressure drops out to 36 months after intervention. In contrast, blood pressure of patients in the non-crossover group increased after unmasking. Bhatt et al concluded SYMPLICITY HTN-3 adds to the evidence supporting the safety of renal artery denervation out to 36 months. They added that between 12 and 36 months after the procedure, patients undergoing renal artery denervation demonstrated better reductions in blood pressure compared to patients who underwent sham control.
COMMENTARY
At first glance, this publication appears to represent a huge win for renal artery denervation. Subjects who initially did not show a significant reduction in blood pressure at six months vs. sham controls exhibited significant blood pressure improvements at 36 months. An incautious reading might lead one to believe significant blood pressure effects of denervation simply caught up over time. The reported average reduction in office systolic blood pressure measurement (26 mmHg) is huge and is similar in magnitude to some of the early non-blinded, non-sham-controlled studies, including SYMPLICITY HTN-1. More recent sham-controlled studies of improved systems have shown significant reductions in blood pressure, but not to this degree. For example, the authors of the SPYRAL HTN-ON study reported a (relative to sham) 7 mmHg reduction in systolic blood pressure at six months and a 10 mmHg reduction at 36 months.3
An essential point to recognize in the Bhatt et al study is the results do not represent 36-month data from a randomized, blinded, sham-controlled trial that was designed to be of this duration. Rather, these patients were unblinded at the end of the initial observation period at six months. This longer-term analysis has lost the benefits of blinding and randomization and introduces some of the biases of an observational study. Of the 171 patients in the sham group, 101 were allowed to cross over and receive denervation therapy. The control group in this case used imputed data from the six-month point before unmasking, which introduces a host of uncertainties, and likely overestimates the treatment effect.Perhaps the most significant finding from the Bhatt et al study is the confirmation of the longer-term safety of renal artery denervation, which appears robust and reassuring. More work will be required to demonstrate the long-term effectiveness of this therapy and to define which patients are most likely to benefit.
REFERENCES
1. Krum H, Schlaich MP, Sobotka PA, et al. Percutaneous renal denervation in patients with treatment-resistant hypertension: Final 3-year report of the Symplicity HTN-1 study. Lancet 2014;383:622-629.
2. Bhatt DL, Kandzari DE, O’Neill WW, et al. A controlled trial of renal denervation for resistant hypertension. N Engl J Med 2014;370:
1393-1401.
3. Mahfoud F, Kandzari DE, Kario K, et al. Long-term efficacy and safety of renal denervation in the presence of antihypertensive drugs (SPYRAL HTN-ON MED): A randomised, sham-controlled trial. Lancet 2022;399:1401-1410.
Three-year follow-up data from the SYMPLICITY HTN-3 trial of renal denervation provide support for long-term safety of this technique and suggest blood pressure benefit.
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