Renal Denervation After the SPYRAL HTN-OFF MED Trial
Putting a Complex Study Into Context
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Almost exactly a decade after the first patient had been subjected to catheter-based renal denervation within the framework of the symplicity HTN-1 trial,1 another proof-of-concept study was warranted to address several uncertainties pertaining primarily to the efficacy of this interventional approach to lower blood pressure (BP) in humans.2 Although Symplicity HTN-1 and HTN-21,3 demonstrated a substantial reduction in BP, Symplicity HTN-3—the largest and first study to include a sham control—failed to demonstrate a BP-lowering effect beyond that observed in the sham-control group.4 In retrospect, the unexpected neutral results from Symplicity HTN-3 may be judged to have been useful and stimulating in that they triggered an unprecedented effort by the hypertension community to better understand the clinical entity of resistant hypertension, including the pathophysiologic, as well as patient- and physician-related mechanisms contributing to the apparent resistance to prescribed pharmacological antihypertensive treatment and its management. Some of the main lessons we have learned during the past 3 years include (1) the inconvenient truth that a large proportion of patients requiring polypharmacy tend to be nonadherent with prescribed medication, (2) that objective measures of adherence are required to better appreciate the in-trial variability of BP responses, (3) that BP measurements must be highly standardized and ideally include 24-hour ambulatory assessment, (4) that a sham-control arm is warranted in device-based intervention trials, (5) that a clear understanding of the human anatomy is required to achieve optimized technical success and inform best treatment algorithms, and (6) that adequate patient selection is critical to maximize potential benefit.
Clearly, resistant hypertension is a clinically heterogenous entity, and the contribution of individual mechanisms relating predominantly but not exclusively to 3 major factors including sodium and fluid overload, activation of the renin–angiotensin–aldosterone cascade, and heightened sympathetic tone can vary substantially between hypertensive individuals, …