Editors' ChoiceHypertension

SYMPLICITY—Not as Simple as One, Two, Three

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Science Translational Medicine  30 Apr 2014:
Vol. 6, Issue 234, pp. 234ec74
DOI: 10.1126/scitranslmed.3009322

Nearly 40% of adults in developed countries have hypertension, and the incidence is growing globally. Even when patients take a combination of antihypertensive drugs, nearly 10% do not respond adequately and are considered “resistant.” In this resistant group, transection of the sympathetic innervation that courses through the renal artery adventitia has emerged as a promising treatment. First suggested as early as the 1930s, the use of surgical sympathectomy has been limited because of high morbidity and mortality and the availability of effective drugs. Within the past 5 years, however, renal denervation (RDN) performed via catheter has been shown to dramatically reduce hypertension in both preclinical animal studies as well as in early clinical trials such as SYMPLICITY HTN-1 (which had no control) and SYMPLICITY HTN-2 (which was not blinded, with an inactive control). Already approved for clinical use in Europe, RDN has been widely considered the next blockbuster cardiovascular therapy for resistant hypertension. As a result, indications ranging from a cost-effective cure for mild hypertension to a new approach in heart failure management have been on the horizon. Yet in a disappointing turn, the pivotal SYMPLICITY HTN-3 trial by Bhatt et al. demonstrated a lack of effect of RDN on hypertension over the medical control, raising questions about the fundamental value of RDN.

Avoiding many of the shortcomings of prior, smaller, nonblinded clinical studies, SYMPLICITY HTN-3 was an 88-center trial that randomized 535 patients with resistant hypertension to RDN or sham-control. The patients’ medical therapy was tightly regimented and maintained. Although the procedure did not cause any increase in adverse events, there was also no difference between groups in reduction of hypertension. At 6 months, blood pressure measured in the doctor’s office decreased in both groups to a similar extent (–14.13 ± 23.93 mmHg in RDN versus –11.74 ± 25.94 mmHg in control), as did the values after 24-hour ambulatory monitoring (–6.75 ± 15.11 mmHg in RDN versus –4.79 ± 17.25 mmHg in control). Not only were these decreases in blood pressure less pronounced than the 20- to 30-mmHg drops seen in earlier trials, but the benefit was observed even in the sham-control group. Amidst ongoing musings about the placebo effect, variability of responses, trial design, meaningful outcomes, and potential effectiveness of newer devices and techniques, we are left to contemplate an uncertain future for RDN. How do we weigh the extensive and growing body of translational evidence in support of this approach against a well-conducted and rigorously controlled randomized clinical trial that markedly tempers enthusiasm? Before turning the page on RDN, we should determine whether this trial’s outcome was a result of technology failure, an inadequacy of the trial, or our own lack of knowledge about the intervention.

D. L. Bhatt et al., A controlled trial of renal denervation for resistant hypertension. N. Engl. J. Med. 370, 1393–1401 (2014). [Full Text]

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