9.1 / IAGS 2019
Session 9: Emerging Therapies Session 2
Renal Denervation for Moderate and Severe Hypertension: Waiting for Godot?
Problem Presenter: Herbert Aronow, MD
Statement of problem or issue
According to the ACC/AHA definition, nearly 1 in 2 adults in the United States has hypertension (HTN). Epidemiologic data indicate that higher blood pressures are associated with a greater risk for ischemic heart disease mortality, stroke mortality and other vascular mortality. The SPRINT randomized controlled trial (RCT) demonstrated that when compared with standard treatment to a systolic blood pressure (SBP) goal of <140 mm Hg, intensive treatment to a SBP goal of <120 mm Hg significantly reduced the risk of cardiovascular death, myocardial infarction, other acute coronary syndromes, stroke, and heart failure, as well as the overall incidence of all-cause mortality. Nevertheless, despite these data, blood pressures are at target in only half of US adults with HTN. The reasons for uncontrolled HTN are manifold and range from true treatment failure to poor adherence to lifestyle and pharmacologic prescriptions. Non-adherence to antihypertensive agents commonly results from drug intolerance and/or the desire to avoid additional medications. Recently, device therapies (most commonly renal sympathetic denervation [RSD]) have been proposed as a method to augment if not replace antihypertensive agents. RSD has been accomplished using a variety of methods, including surgery, endovascular delivery of radiofrequency energy, ultrasound, cryotherapy, pharmacologic agents or beta radiation, renal pelvis catheter-based ultrasound delivery and external ultrasound application. The most studied of these modalities is catheter based, endovascular RSD. After promising observational and non-sham controlled RCTs evaluating catheter-based endovascular RSD, the SYMPLICITY HTN-3 RCT compared RSD to sham-therapy in patients with resistant HTN, but found no difference in blood pressure control. A number of confounding issues surrounding patient selection, operator training, device development, and endpoint ascertainment were addressed, and several recent proof-of-concept, sham-controlled pilot RCTs have yielded favorable short-term outcomes, demonstrating that RSD significantly lowers blood pressure. Despite the promising early results summarized above, important questions still remain unanswered.
Gaps in knowledge
Although larger, pivotal trials are ongoing, even if these are positive questions will remain about how to identify the ideal patient, ascertain treatment success at the time of the procedure, determine whether RSD is complementary or competitive with medical therapy, discern whether RSD can improve clinical outcomes beyond its ability to lower blood pressure, and finally, whether RSD is cost-effective.
Possible solutions and future directions
Data from earlier RSD trials have suggested that patients with isolated systolic hypertension respond less favorably than those with more sympathetically-mediated combined systolic-diastolic HTN. Accordingly, ongoing RSD trials are preferentially enrolling combined hypertensives. The currently recommended ablation approach is also more extensive than in prior trials and involves treatment of both main and accessory renal arteries as well as large sized renal artery branches. Although this modification of treatment approach will likely result in more extensive ablation of renal afferent and efferent sympathetic nerves, operators remain blind to whether the degree of ablation is satisfactory; no real-time bedside test exists to ascertain treatment success. Post-hoc analyses of clinical trial data from ongoing studies may identify technical approaches that are more favorable but a real-time method to assess sympathetic nerve activity pre- and post-ablation is greatly needed and would facilitate more efficient evolution of optimal procedural technique. To date, changes in systolic and diastolic blood pressures resulting from RSD, whether in the office or averaged over 24 hours, have been relatively small. While small changes in blood pressure are associated with large changes in cardiovascular event risk, both in epidemiologic studies and clinical trials, larger studies that are powered to detect clinical outcomes will be needed. Additionally, whether RSD will afford enough blood pressure reduction for patients to discontinue all antihypertensive agents remains to be seen. For some higher-risk patients, such as those with diabetes or atherosclerosis, discontinuation of all agents may not be desirable as many of these agents confer reductions in atherothrombotic risk beyond their ability to lower blood pressure. Finally, if clinical outcome studies demonstrate reductions in hard events with or without attendant improvements in quality of life, well-designed cost-effectiveness studies will need to be conducted from the patient, payer and societal perspectives.