Resistant hypertension and renal sympathetic denervation—what does the future hold?

Abstract

Hypertension is a major public health problem and despite adequate pharmacological treatment, blood pressure remains uncontrolled in a subset of patients with hypertension. Renal sympathetic denervation is a percutaneous catheter-based treatment for select patients with resistant hypertension. In this article, we discuss the development of this intervention, its role in patients with resistant hypertension and the need for guarded optimism in the future of device-directed renal sympathetic denervation.

Keywords::

• Hypertension
• renal artery denervation

Hypertension is a burgeoning public health problem with prevalence of about 30% in United States. Adequate blood pressure control is important in reducing adverse cardiovascular events in patients with hypertension. However, despite treatment, in more than 10% of patients, blood pressure control remains inadequate (1). Resistant hypertension is defined as blood pressure that remains above the goal despite adhering to optimal doses of three different classes of antihypertensive medications, one of which is a diuretic (2). For this group of patients, renal sympathetic denervation could be a treatment option. Since sympathetic nervous system activation can contribute to various comorbidities associated with hypertension like metabolic syndrome, obesity and insulin resistance, the role of renal sympathetic denervation might also go beyond control of hypertension (1).

In renal sympathetic denervation, a specially designed catheter is percutaneously inserted into the renal arteries and radiofrequency energy is used to denervate the renal sympathetic nerves (3). Various new catheter systems for renal sympathetic denervation that use ultrasound energy, cryoablation techniques, radiation, etc. are under development (3).

The clinical evidence in support of renal sympathetic denervation first came from Symplicity HTN-1 trial, which involved 45 patients in an observational, first-in-human trial (3). Efficacy analysis showed a significant 6 and 24 months reduction in blood pressure readings and a durable reduction in blood pressure at three-year follow-up. Symplicity HTN-1 trial had major limitations but paved its way to the Symplicity HTN-2 trial, which was a 1:1, randomized controlled trial in which 106 patients were randomized to receive percutaneous renal denervation or to control group (4). Patients that received renal sympathetic denervation demonstrated a statistically significant reduction in blood pressure at each follow-up point (6, 12 and 18 months). Two-year follow-up data showed a sustained, significant reduction in both systolic and diastolic blood pressure at one-year follow-up (change from baseline SBP and DBP –28.87 ± 21.6 and –10.4 ± 11.2, P < 0.011, respectively). Renal sympathetic denervation trials showed that the procedure was generally safe. Although not without potential complications, femoral artery pseudoaneurysm and renal artery dissection were reported, however, the occurrence of such an adverse effect was noted to be low. In terms of renal sympathetic denervation cost-effectiveness, a complex analysis of Symplicity HTN-2 trial suggested that this procedure is cost-effective for patients with resistant hypertension. According to the study renal denervation reduces cardiovascular mortality by 30% and all-cause mortality by 15% compared with standard therapy over 10 years while increasing quality-adjusted life expectancy from 12.07 to 13.17 quality-adjusted life-years (5). The statistical model assumed that the renal denervation reduced undiscounted costs by US$1769 over a lifetime but increased discounted costs by US$2013, reflecting the fact that the costs of the procedure are incurred up front while the resulting savings are reaped over a lifetime. The discounted lifetime incremental cost-effectiveness ratio (incremental direct medical costs of treatment and consequences divided by the incremental health benefits in quality-adjusted life-years) for renal denervation was US$2715 per life-year gained and US$3071 per quality-adjusted life-year.

With the experience from Symplicity HTN-1 and 2 trials, patient selection for renal sympathetic denervation was noticed to be of great importance (6). With intention of more stringent patient selection, a much larger Symplicity HTN-3 trial was planned which was to include, for the first time in renal sympathetic denervation trials, a sham-control group.

The Symplicity HTN-3 trial (NCT01418261) is a phase 3, multi-center, prospective, single-blinded, randomized, controlled study of the safety and effectiveness of renal denervation in subjects with uncontrolled hypertension. This trial is the largest trial for renal sympathetic denervation, which randomized 535 treatment-resistant hypertension patients. All patients randomized to the control arm, as mentioned earlier, underwent a sham procedure. Enrollment criteria to this study were more stringent including the use of maximally tolerated doses of diuretics and a change in the blood pressure assessed by ambulatory blood pressure monitoring. The primary efficacy endpoint was the change in office blood pressure from baseline to six months and the primary safety endpoint was incidence of major adverse events. Before the results of trial were published, Medtronic Inc. announced that Symplicity HTN-3 trial failed to meet its primary efficacy endpoint. The trial met its primary safety endpoint, and the trial's data safety monitoring board concluded that there were no safety concerns in the study.

Although long-term data on durability of blood pressure response, safety, as well as data on the role of renal sympathetic denervation on prevention of hypertension related end organ complications and on comorbidities associated with hypertension like metabolic syndrome and obesity is lacking, renal sympathetic denervation has a pathophysiological rationale. While earlier trial results were promising, the recent report of the Symplicity HTN-3 trial is disappointing in terms of impact on blood pressure control. Given the clear positive effect that renal denervation had in the earlier trials, the result of Symplicity HTN-3 trial underscores the fact that positive treatment effects observed in unblinded studies can be unreliable and that rigorous trials are essential to derive meaningful conclusions.

At this juncture, we will have to wait to see if other sympathetic denervation modalities will be studied in the future and, at best, keep a guarded optimism on device-directed renal sympathetic denervation as a treatment option for patients with true resistant hypertension.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.