Renal denervation for resistant hypertension?

Ever since Schlaich et al.1 first reported on a patient with a blood pressure of 161/107 mm Hg (despite treatment with seven different antihypertensive drugs) that decreased to 127/81 mm Hg after renal denervation, the medical community has been enamored with this procedure. Resistant hypertension evolved into a fashionable diagnosis, and the number of publications pertaining to it grew rapidly.2 Medical-device companies fancied renal denervation as the next big innovation and as a blockbuster therapy for millions of patients. A press release from the American Heart Association even touted renal denervation as a potential “cure” for mild hypertension.3 Trials such as the SYMPLICITY HTN-14 and HTN-25 studies showed impressive decreases in blood pressure, seemingly attesting to the efficacy and safety of renal denervation. Three-year follow-up of the SYMPLICITY HTN-1 study revealed a decrease in blood pressure of 32/14 mm Hg.6 These unprecedented results seemed to surpass what was achievable with drug therapy and continued to fan the flames of renal denervation. The SYMPLICITY HTN-3 study, a blinded, sham-controlled study now reported in the Journal by Bhatt et al.,7 brings the renal-denervation train to a grinding halt. After 6 months, office systolic blood pressure decreased from baseline to a similar extent in the renal-denervation and shamprocedure groups (P<0.001 for both comparisons of the change from baseline); the difference in the change in blood pressure between the two groups was a paltry −2.39 mm Hg (Table 1). In addition, a prespecified difference in 24-hour ambulatory systolic pressure of only 2 mm Hg was not met. Thus, in the SYMPLICITY HTN-3 study, renal denervation had no significant effect on office or 24-hour ambulatory systolic blood pressure, findings that contradict most published data on renal denervation, although a recent trial even suggested inferiority of renal denervation, as compared with adjusted drug treatment.8 At first blush, the most likely explanation for the findings of the SYMPLICITY HTN-3 study is the inclusion of a sham-control group. In clinical trials testing interventional procedures and medical devices, sham procedures are seminal, analogous to the use of a placebo in pharmaceutical trials. However, for ethical reasons sham procedures are frowned upon9; neither the SYMPLICITY HTN-1 study nor the HTN-2 study had a shamcontrol cohort. For this reason, placebo effects may well explain all or most of the blood-pressure differences noted in the first two trials. Lack of efficacy could also be caused by incomplete or ineffective denervation. No reliable markers of renal denervation are available, and questions remain as to what exactly the procedure accomplishes. Nevertheless, the ablation catheter used in the SYMPLICITY HTN-3 study was no different from that used in the SYMPLICITY HTN-1 and HTN-2 studies. A decrease in systolic blood pressure was observed in both the renal-denervation group and the control group, a finding that is in marked contrast to the findings in previous trials. At 6 months, the decrease in office systolic blood pressure from baseline in the renal-denervation group in the SYMPLICITY HTN-3 study was about half that observed in the corresponding group in the SYMPLICITY HTN-2 study, despite the fact that baseline blood pressures were similar in the two studies. This is puzzling, because the degree of reduction in blood pressure is related to pretreatment blood-pressure levels (unpublished data). In addition, there was a larger decrease in blood pressure in the control group of the SYMPLICITY HTN-3 study, as compared