Year: 2018
Type: article
Abstract: The RADIANCE-HTN SOLO and the SPYRAL HTN-ON and HTN-OFF MED randomized studies suggest that the blood pressure lowering effect of renal denervation corresponds to the effect of one antihypertensive drug Renal denervation has been introduced as a new treatment modality for patients with hypertension. Until, recently, studies to test the efficacy of renal denervation in lowering blood pressure focused on patients with so-called treatment resistant hypertension; patients who had not achieved blood pressure control despite treatment with three or more antihypertensive drugs including a diuretic. The SYMPLICITY HTN-2 trial1 found a major reduction in systolic blood pressure with renal denervation in patients with treatment resistant hypertension measuring office blood pressure. However, ambulatory blood pressure is the state-of-the art technique for measuring blood pressure in patients with treatment resistant hypertension,2 and with this method blood pressure reductions were less evident.1 Furthermore, poor drug adherence is common in treatment resistant hypertension,3 and it was not monitored in SYMPLICITY HTN-2. Interpretation of the study results3 was thus confounded by the Hawthorne effect: ‘patients started taking their drugs as prescribed in response to the additional attention devoted to them’.4 The SYMPLICITY HTN-3 study5 included sham and ambulatory blood pressure measurements that balanced the Hawthorne and other patient and investigator non-specific effects, resulting in a blood pressure reduction of <2 mmHg in the renal denervation treatment group compared to control. Further, meta-analyses of the first 10 properly randomized and controlled studies of renal denervation did not show blood pressure lowering effects, whether or not SYMPLICITY HTN-3 was included in the analysis,6 or whether or not a sham control was a part of the design.7 However, these disappointments, summarized above,5–7 did not end the interest in renal denervation for several reasons. First, total abdominal sympathectomy resulting from surgical splanchnicectomy was effective blood pressure lowering treatment of severe hypertension in cohorts of patients reported in the 1930s8 and 1950s.9,10 Second, recent meta-analyses showed that renal denervation did not cause severe adverse events and could therefore be considered safe.6,7 Third, the role of the sympathetic nervous system in the pathophysiology of hypertension is well documented.11,12 Further, the procedural problems that contributed to the failure of early renal denervation trials to lower blood pressure could be resolved.13,14 Therefore, new protocols were designed to assess the antihypertensive efficacy of renal denervation. One new approach in at least two studies was to perform renal denervation in untreated hypertensive patients in order to avoid any interference of drug therapies. Hawthorne Illinois Works, Western Electric Company circa 1925. The Hawthorne effect (also referred to as the observer effect or viewing effect) is where individuals modify or improve an aspect of their behaviour in response to their awareness of being observed. The term was coined in 1950 by Henry A. Landsberger, when analysing earlier experiments from 1924–32 at the Hawthorne Works (a factory outside Chicago). The original study, which was designed to investigate the effect of different lighting levels on workers productivity, suggested that the experience of being a research subject per se could lead to productivity changes, irrespective of the lighting level. The RADIANCE-HTN SOLO study15 tested whether endovascular ultrasound renal denervation could reduce blood pressure in patients with hypertension who were untreated with antihypertensive drugs for 4 weeks, whereas the SPYRAL HTN-OFF MED16 and HTN-ON MED trials17 investigated whether renal denervation achieved by intravascular delivery of radiofrequency energy could lower blood pressure in patients off medication16 or in patients on stable antihypertensive medication.17 Similar decreases in blood pressure were obtained in RADIANCE-HTN SOLO and the SPYRAL studies (Table 1), in patients either off or on hypertensive treatment. Comparisons of the main characteristics (approximate average for the patients randomized to renal denervation and to control) and the results of three new studies of intravascular renal denervation compared with the previous DENERHTN study Primary endpoint, significant difference in DENERHTN. Except for DENERHTN, most of the differences in reductions between renal denervation and SHAM were statistically significant in the three new trials.15–17 SBP, systolic blood pressure; DBP, diastolic blood pressure. Comparisons of the main characteristics (approximate average for the patients randomized to renal denervation and to control) and the results of three new studies of intravascular renal denervation compared with the previous DENERHTN study Primary endpoint, significant difference in DENERHTN. Except for DENERHTN, most of the differences in reductions between renal denervation and SHAM were statistically significant in the three new trials.15–17 SBP, systolic blood pressure; DBP, diastolic blood pressure. However, the Hawthorne effect was not ruled out in RADIANCE-HTN SOLO,15 as investigators relied on antihypertensive drug use reported by the patients themselves. Reported medication use was more common in the sham groups in the RADIANCE-HTN SOLO study15 and in SPYRAL HTN-ON MED,17 with a mean drug adherence of 60%. However, hidden use of drugs was not evaluated by direct measurements in blood or urine. Thus, assuming that hidden drug use was not more common in the treatment group, RADIANCE-HTN SOLO, together with the SPYRAL HTN-OFF16 and HTN-ON MED trials,17 show that renal denervation lowers blood pressure. Interestingly, the designs, inclusion and exclusion criteria, baseline characteristics, and results expressed as ambulatory and office blood pressure lowering were similar in all of the new trials (Table 1). This standardization of design of the recent renal denervation research studies likely relates to the same investigators being involved and to improvements in procedures, as indicated in Table 1, in which we have compared with DENERHTN as an example of previous studies—leading to similar statistically significant blood pressure reductions compared with control.18 The RADIANCE-HTN SOLO and the SPYRAL HTN-OFF and HTN-ON MED trials open a new chapter in renal denervation research6,7 and take the renal denervation field into a new era. Together, these trials suggest that a renal denervation class effect may apply. Renal denervation achieved by intravascular delivery of radiofrequency energy or ultrasound energy may produce similar blood pressure lowering effects. What is the clinical benefit of renal denervation? The net reduction in ambulatory systolic blood pressure of 6 mmHg reported in the new studies15–17 approximates the effect of one antihypertensive drug.19 However, there may be responders and non-responders, as shown in RADIANCE-HTN SOLO, and some subgroups of patients may benefit more than others. Further research is needed to identify the patients who will most likely benefit from renal denervation20 and to confirm a sustained long-term blood pressure lowering effect, which could then make renal denervation cost-effective, at least for the treatment of resistant hypertension.21 Long-term safety must also be established beyond the initial 6 months post-procedure.6,7 Future research needs to show that blood pressure reduction following renal denervation protects the brain, heart, kidneys, and large arteries and that renal denervation lowers cardiovascular morbidity and mortality. RADIANCE-HTN SOLO and the SPYRAL studies inject new optimism into this field of research by demonstrating successful blood pressure reduction following renal denervation with both radiofrequency energy and ultrasound energy. After overcoming multiple problems with renal denervation in clinical research, with a dramatic fall in expectations from extremely high1 down to almost nothing,5–7 we may again be at the foot of an uphill spiral.16–18,22 A previous version of this commentary has been published in Blood Pressure23 and this subsequent publication in European Heart Journal has been approved by the administrative editor of Blood Pressure. Conflict of interest: S.E.K., K.N., and M.B. are the editors of Blood Pressure and report no relevant conflicts of interest to disclose related to this article. Outside the present work, S.E.K. has received ad hoc honoraria for lecturing from Bayer, Merck & Co., Sanofi, and Takeda, and honoraria from Takeda for study committee work within the past 3 years. S.O. is also editor of Blood Pressure and declares the following COI: ROX Medical, Inc. (Rox Control HTN 2 Study—US IDE Steering Committee Member); (multicenter study/ROX coupler-HTN); Vascular Dynamics, Inc. (site investigator, multicenter pivotal study/PMA for resistant HTN). The list of references is available on the online version of this paper.
Source: European Heart Journal
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2889993707