Renal denervation in treatment-resistant hypertension – Oslo RDN, Symplicity HTN-3 and INSPiRED randomized trials

More than 10% of patients treated for hypertension have persistently uncontrolled blood pressure (BP) despite prescription of antihypertensive drugs (1). Renal sympathetic denervation is an old concept that has been re-introduced as a new treatment for hypertension that is apparently resistant to drug treatment (2). Patients considered eligible for this procedure populate the high end of the BP spectrum, where, for whatever reason, pharmacological treatment has failed to produce adequate BP control. Recent data suggest that patients suspected of having “resistant hypertension” in fact represent a mixed group that includes those with white coat hypertension, secondary forms of hypertension, inadequate dosing of medication and poor adherence to prescribed antihypertensive treatment, as well as true resistant hypertension (3). Two out of every three patients referred for renal denervation (RDN) because of apparent resistant hypertension did not have true resistant hypertension and therefore were not considered eligible for the procedure. Non- and poor adherence to prescribed treatment occurred frequently in this referral population, leading the authors to recommend careful screening of patients with apparent resistant hypertension before undertaking RDN procedures. The main aim of such a screening program is to confirm the persistence of uncontrolled hypertension despite adequate medical treatment and to exclude secondary forms of hypertension.

The Symplicity HTN-2 study (4) was the first randomized controlled trial of renal sympathetic denervation to be reported in the literature. Symplicity HTN-2 randomized 106 patients with apparent treatment-resistant hypertension to renal sympathetic denervation or control and followed them for 6 months. Office BPs were reduced by 32/12 mmHg in the intervention group at 6 months and remained unchanged in the control group. Reductions in ambulatory BP were much smaller, suggesting a “white coat” effect. Furthermore, drug adherence was not thoroughly investigated.

Poor drug adherence is a common problem among patients with apparent treatment-resistant hypertension (5,6). For example, a study of 84 patients taking on average five antihypertensive drugs found no detectable blood levels of any antihypertensive drug in 34.5% of the patients, and that 65.5% of the patients fulfilled the criteria of non-adherence (7). It is not known to what extent the reduction in BP that is observed following RDN is caused by the denervation per se or by increased drug adherence. It is reasonable to postulate that patients with poor drug adherence who undergo RDN receive so much positive attention at follow-up that they become increasingly coherent to their antihypertensive medications and thus have enhanced BP reductions. Some patients may even discontinue their antihypertensive drugs prior to qualification procedures for RDN and then resume their medication after the procedure. This could not be detected by the methods employed in Symplicity HTN-2 (4), and these deficiencies provided an impetus for the more tightly controlled Symplicity HTN-3 study in the USA, which included a sham operated control group (8,9).

Drug adherence can be assessed in several ways, e.g. by electronic pill boxes, blood and urine measurements of prescribed drugs, or by written patient's diaries. Measurement of drugs in blood or plasma can provide valuable information (7), but is not available in most clinical practices, and neither patient's diaries as used in Symplicity HTN-2 nor electronic pill boxes are reliable enough to ensure drug intake. The only method that fully ensures true drug intake and permits documentation of the effects of the drugs that are taken, e.g. BP reducing effects, is to observe the patient taking the medications. A study of 18 patients with apparent treatment-resistant hypertension referred to a hypertension center for RDN required participants to bring their prescribed medication to the clinic visit and have the medication administered by the investigator and swallowed by the patient under continuous observation (10). A 24-h ambulatory BP device was then placed on the patient and 24-h monitoring was carried out. Strikingly, five of the participants had normalization of their ambulatory BP following witnessed intake of their medication and seven others were excluded from the procedure because of various concomitant conditions. Thus, only six of 18 patients qualified for renal sympathetic nerve ablation procedure, and only two of the six experienced reductions in both office and ambulatory BP during 6 months of follow-up. The finding that only a minority of apparently treatment-resistant hypertensive patients have true treatment resistance, are free of secondary forms of hypertension and have suitable renal arterial anatomy and thus are candidates for RDN has also been shown, on a much larger scale, in other tertiary care hypertension centers (11). Further, other open studies have reported minimal BP reductions in response to RDN (12).

In a 10-center multinational European study (13), BP was followed up 3 and 6 months after renal sympathetic denervation. Recruited patients (n = 109; 46.8% women; mean age 58.2 years) had hypertension confirmed by ambulatory BP. Office systolic/diastolic BP fell by 17.6/7.1 mmHg, and 24-h, daytime and night-time BP fell by 5.9/3.5, 6.2/3.4 and 4.4/2.5 mmHg (p ≤ 0.03 for all). In 47 patients (43%) with 3 and 6 month ambulatory measurements, systolic BP did not change between these two time points (p ≥ 0.08). Normalization was defined as a systolic BP < 140 mmHg on office measurement or < 130 mmHg on 24h monitoring and improvement as a fall of ≥ 10 mmHg, irrespective of measurement technique. For office BP, at 6 months, normalization, improvement or no decrease occurred in 22.9%, 59.6% and 22.9% of patients; for 24h BP, these proportions were 14.7%, 31.2% and 34.9%, respectively. Higher baseline BP predicted greater BP fall at follow-up. Thus, BP responses to renal sympathetic denervation are likely to include substantial regression-to-the-mean effects and therefore remain to be confirmed in randomized trials based on ambulatory BP monitoring.

Two recently published trials, the Oslo RDN Study (14) and the Symplicity HTN-3 Trial (9), employed novel design features that addressed some of the deficiencies of the earlier trials.

The Oslo RDN Study tested the hypothesis that RDN lowers BP better than intensified drug treatment guided by non-invasive hemodynamic assessments measured by impedance cardiography (14,15). The study randomized patients with true treatment-resistant hypertension to RDN with the Symplicity^™ Catheter System vs medical treatment as above. A novel aspect of the Oslo RDN study was that patients could only qualify if ambulatory BP remained elevated after witnessed intake of the antihypertensive drugs prescribed. A number of additional steps were taken to further ensure that patients enrolled in the Oslo RDN Study had true resistant hypertension. First, patients were referred for the study by specialists and other care providers, who had been instructed to use Symplicity HTN-2 inclusion and exclusion criteria as the basis for referral (4). Second, potential participants were evaluated by the study investigators, and baseline drug therapy was optimized. Third, potential participants were required to have elevated ambulatory daytime SBP following intake of their prescribed antihypertensive drugs under the observation of the study investigators. From the 65 patients who would apparently qualify for RDN according to HTN-2 criteria (4), as many as 46 patients were excluded because they could not any longer be characterized as treatment-resistant hypertensive patients. The number of true treatment-resistant hypertensive patients was reduced to 19 patients, or less than 30%.

The Oslo RDN Study (14) revealed a lack of meaningful BP lowering effects of RDN in these “true” treatment-resistant hypertensive patients. Their office and ambulatory BPs remained elevated at 6 months, and according to a pre-specified decision (10) relating to the high cardiovascular risk of these patients, it was considered unethical to continue recruitment to the study. In contrast, the reduction in BP seen in patients randomized to further adjusted drug treatment guided by non-invasive hemodynamic assessments measured by impedance cardiography (15) was significantly greater compared to RDN and BP normalized in almost all patients (14).

Symplicity HTN-3 (15) was a prospective, single-blind, randomized, sham-controlled trial. Patients with severe resistant hypertension were randomly assigned in a 2:1 ratio to undergo RDN or to a sham-procedure. Before randomization, patients were receiving a stable antihypertensive regimen involving maximally tolerated doses of at least three drugs, including a diuretic. The primary efficacy end point was the change in office SBP at 6 months; a secondary efficacy end point was the change in mean 24-h ambulatory SBP. The primary safety end point was a composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis of more than 70% at 6 months. A total of 535 patients underwent randomization. The mean (± SD) change in SBP at 6 months was − 14.13 ± 23.93 mmHg in the denervation group compared with − 11.74 ± 25.94 mmHg in the sham-procedure group (p < 0.001 for both comparisons of the change from baseline), for a difference of − 2.39 mmHg (95% confidence interval [CI] − 6.89 to 2.12; p = 0.26 for superiority with a margin of 5 mmHg). The change in 24-h ambulatory SBP was − 6.75 ± 15.11 mmHg in the denervation group and − 4.79 ± 17.25 mmHg in the sham-procedure group, for a difference of − 1.96 mmHg (95% CI − 4.97 to 1.06; p = 0.98 for superiority with a margin of 2 mmHg). There were no significant differences in safety between the two groups. Thus, this blinded trial did not show a significant reduction of SBP in patients with resistant hypertension 6 months after renal-artery denervation compared with a sham control.

These trials (9,14) have changed our assessment of the benefits of RDN, at least when performed with current technology and choice of treatment targets. The trials (9,14) throw doubt whether RDN lowers BP but the results (9,14) are up against the results of the first randomized study (4), which showed a large benefit, and numerous reports from open studies of similar good BP lowering effects. It is therefore unlikely that RDN will instantly halt on clinical indications and further rigorous research projects are needed in order to detect whether there are patients who respond with BP lowering in respond to RDN and whether predictors of who will respond can be identified.

One of these projects, INSPiRED, is presented in this issue of Blood Pressure (16). INSPiRED is a randomized controlled trial enrolling 240 treatment-resistant hypertensive patients at 16 expert centers in Belgium. Eligible patients have a 24h ambulatory BP of 130 mmHg systolic or 80 mmHg diastolic or more, while taking at least three antihypertensive drugs. They are randomized to RDN (EnligHTN^TM, SJM system) plus usual care (intervention group) or usual care alone (control group) in a ratio of 1:1. The primary endpoints for efficacy and safety, measured after 6 months, are the baseline-adjusted between-group differences in 24h systolic BP and in glomerular filtration rate. Follow-up will continue for up to 36 month after randomization. INSPiRED is powered to demonstrate a 10mmHg difference in systolic BP between randomized groups with a two-sided p-value of 0.01 and 90% power. It will generate long-term efficacy and safety data, identify the subset of treatment-resistant hypertensive patient responsive to RDN, provide information on cost-effectiveness, and by doing so INSPiRED will inform guideline committees and health policy makers.

Declaration of interest: SEK, TH and KN report no relevant conflicts of interest to disclose related to this Editorial. SO serves as a consultant for Medtronic and on the Steering Committee of Symplicity HTN-3. The authors alone are responsible for the content and writing of the paper.