Renal Nerve Ablation for Resistant Hypertension: The Dust Has Not Yet Settled (2014)

Resistant hypertension represents a major clinical problem in everyday clinical practice, not only for hypertension experts but for nephrologists, cardiologists, internists, and primary care physicians alike. Resistant hypertension is frequently encountered among hypertensive patients, with a reported prevalence of approximately 10%.1, 2 Resistant hypertension is considered a condition of high cardiovascular risk. Indeed, two recent studies found that resistant hypertension was associated with a 2.2-fold increased risk for cardiovascular morbidity3 and a 50% higher risk for cardiovascular events.4 The management of resistant hypertension is challenging and requires experience and expertise. A step-by-step approach should be implemented, excluding all potential causes of “pseudo-resistance”: When all these factors are considered and adequately addressed, the percentage of true resistant hypertension is considerably lower than currently believed. Even those patients with true “true” resistant hypertension, however, are difficult to manage. Catheter-based renal nerve ablation is a minimally invasive approach that fills this gap and addresses an unmet need. Renal nerve ablation has been shown to be effective for the management of moderate and severe resistant hypertension,13-15 offering big promises for the effective management of these patients but also for patients with other disease states characterized by sympathetic overactivity (chronic kidney disease, heart failure, obstructive sleep apnea syndrome, arrhythmias).16-20 However, the recent announcement that Symplicity-3, the first sham-controlled randomized study, met its safety endpoint but failed to meet its primacy efficacy endpoint raised a lot of concerns and questions about the future of this interventional approach. Schwerg and colleagues21 in this month's issue report the effects of renal nerve ablation on ambulatory BP in patients with resistant hypertension, showing a mean reduction of 8/4 mm Hg. A major advantage of this study is that it provides information about the efficacy of renal nerve ablation in everyday clinical practice, outside the “sterile” environment of a clinical trial, better reflecting everyday medical practice. Another significant advantage is the use of ambulatory BP as a selection criterion, assuring the exclusion of patients with white-coat hypertension. A marked disparity between office and ambulatory BP reduction has been observed so far, underlining the mandatory role of ambulatory BP monitoring in studies evaluating renal nerve ablation.22 The study offered two significant pieces of information: (1) renal nerve ablation had a “Janus-like” efficacy profile, being highly effective in approximately half of studied patients (>20/10 mm Hg BP reduction), while being ineffective in the remaining other half of patients; and (2) the benefit of renal nerve ablation in responders occurred within the first month following the procedure, with no further benefits thereafter. Both findings need to be discussed within the context of available literature. The responder rate is lower in this than in previous studies. This might be attributed to differences in patient samples or procedural success (renal nerve ablation is a “blind” procedure and technical success cannot be established). It should be noted, however, that a recent larger study found that renal nerve ablation was effective only in patients with true resistant hypertension and ineffective in patients with pseudo-resistance.23 Although the exact response rate cannot be determined without any doubt, the heterogeneity in BP response is evident in all studies, with some patients experiencing marked BP reduction, and others showing moderate or minimal, if any, BP reduction. This finding highlights the importance of three factors: (1) the necessity to identify response predictors, since no clinically meaningful response predictors have been discovered up to now; (2) the necessity to identify markers of procedural success, since reliable intraprocedural success markers have not been yet identified; and (3) that device-related differences in the extent of renal nerve ablation have not been determined up to now, especially between single-electrode and multi-electrode radiofrequency ablation systems as well as with different energy sources. The same factors (sample population, procedural success) might explain the discrepancy in gradual BP response observed in this and previous studies. Prior studies have shown that initial BP reduction was further re-enforced with time both with office and ambulatory BP.13, 14, 23, 24 This gradual BP response over time might be attributed to several factors, including vessel wall remodeling and re-adjustment of mechanisms implicated in BP regulation. However, factors independent of renal nerve ablation might also contribute, such as improved adherence to lifestyle modification and drug therapy and changes in therapeutic regimen.25 The findings of the study are mainly limited by the small sample size and the short follow-up period. Moreover, the lack of office BP measurements does not allow for a more global evaluation of treatment response and the impact of white-coat hypertension. In conclusion, renal nerve ablation is associated with a much lower reduction in ambulatory BP than in office BP. The failure of Symplicity-3 to meet its primary efficacy endpoint casts doubts about the efficacy of renal nerve ablation in patients with resistant hypertension. However, three points need to be highlighted: (1) The reduction of ambulatory BP with renal nerve ablation is expected to be much lower in appropriately designed randomized, controlled, clinical trials due to an unintentional overestimation of BP reduction in uncontrolled studies26, 27; (2) even though we have to wait for the full report of the trial, it must be acknowledged that even modest BP reductions might offer significant benefits in high-risk patients, such as those with resistant hypertension; and (3) even if the trial failed to achieve its primary endpoint, the concept needs to be further evaluated, since the it may be associated with the specific device, the “learning curve” of participating centers, or other unidentified factors independent of the renal nerve ablation concept.