A New Era of Renal Denervation Trials for Patients With Hypertension?

Abstract

Commentary on Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised-sham-controlled, proof of concept trial. Lancet. 2017;390(10108):2160-2170. Commentary on Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised-sham-controlled, proof of concept trial. Lancet. 2017;390(10108):2160-2170. The field of renal denervation for the treatment of hypertension has undergone a substantial set of dynamics during the past decade. Early unblinded and essentially uncontrolled trials reported stunning reductions in clinic blood pressure (BP) following renal denervation in patients with uncontrolled and/or treatment-resistant hypertension.1Symplicity HTN-1 InvestigatorsCatheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months.Hypertension. 2011; 57: 911-917Crossref PubMed Scopus (736) Google Scholar, 2Esler M.D. Krum H. Sobotka P.A. et al.Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.Lancet. 2010; 376: 1903-1909Abstract Full Text Full Text PDF PubMed Scopus (1873) Google Scholar However, the field fell apart when results of the first large, randomized, observer-blinded, and sham-controlled SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial3Bhatt D.L. Kandzari D.E. O’Neill W.W. et al.(SYMPLICITY HTN-3)A controlled trial of renal denervation for resistant hypertension.N Engl J Med. 2014; 370: 1393-1401Crossref PubMed Scopus (1613) Google Scholar did not show a BP-lowering effect of renal denervation compared to sham-operator treatment. Post hoc analyses of this trial and other studies suggested a variety of factors that might have led to failure of renal denervation, including patient selection, variability in adherence to antihypertensive medications, incomplete renal denervation, or technical failure of denervation.4Kandzari D.E. Bhatt D.L. Brar S. et al.Predictors of blood pressure response in the SYMPLICITY HTN-3 trial.Eur Heart J. 2015; 36: 219-227Crossref PubMed Scopus (407) Google Scholar The heterogeneity in results from early studies in renal denervation and those from the SYMPLICITY HTN-3 trial led to an overhaul of clinical development processes for renal denervation devices similar to the approach that has been used for more than 40 years in drug development for antihypertensive agents (Fig 1).5White W.B. Galis Z.S. Heneger J. et al.Renal denervation therapy for hypertension: pathways for moving development forward.J Am Soc Hypertens. 2015; 9: 341-350Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 6Mahfoud F. Schmieder R.E. Azizi M. et al.Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future.Eur Heart J. 2017; 38: 3272-3281PubMed Google Scholar With general agreement by academicians, regulatory agencies, and device sponsors, controlled early-phase studies have been initiated by the device manufacturers. The first of these studies, the SPYRAL HTN-OFF MED (Catheter-Based Renal Denervation in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications) trial,7Townsend R.R. Mahfoud F. Kandzari D.E. et al.Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised-sham-controlled, proof of concept trial.Lancet. 2017; 390: 2160-2170Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar reports an analysis that shows a significant effect of renal denervation on both clinic BP and ambulatory BP (ABP) in patients with stages 1 to 2 hypertension who were not using antihypertensive medications. The SPYRAL HTN-OFF MED was a randomized, sham-controlled, proof-of-concept trial evaluating the effects of renal denervation on BP in the absence of antihypertensive medications. There were 80 patients randomly assigned: 38 to the renal-denervation group and 42 to the sham-control group. To evaluate study participants without antihypertensive drugs, non–treatment-resistant patients who could safely discontinue antihypertensive medications over a 3- to 4-week period were chosen as the study population. Drug surveillance using quantitative assays ensured that patients were not on therapy. The absence of antihypertensive medication use was evaluated by the use of tandem high-performance liquid chromatography and mass spectroscopy of urine and plasma by an independent laboratory (notably, adherence to remaining off treatment with antihypertensive drugs was 85.5%). An early-phase device trial in patients off antihypertensive therapies makes both clinical and regulatory sense because it avoids the confounding effects of the drugs and heterogeneity in adherence to treatment seen in SYMPLICITY HTN-3.8White W.B. Turner J.R. Sica D.A. et al.Detection, evaluation, and treatment of severe and resistant hypertension: proceedings from an American Society of Hypertension interactive forum held in Bethesda, MD, USA, October 10th 2013.J Am Soc Hypertens. 2014; 8: 743-757Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar, 9de Jager R.L. de Beus E. Beeftink M.M. et al.SYMPATHY InvestigatorsImpact of medication adherence on the effect of renal denervation: the SYMPATHY trial.Hypertension. 2017; 69: 678-684Crossref PubMed Scopus (59) Google Scholar Importantly, it makes sense to determine the efficacy and short-term safety of a new renal denervation device in a smaller well-characterized sample before it is tested in a larger heterogeneous randomized trial population with increased cardiorenal risk.6Mahfoud F. Schmieder R.E. Azizi M. et al.Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future.Eur Heart J. 2017; 38: 3272-3281PubMed Google Scholar, 10Zannad F. Stough W.G. Mahfoud F. et al.Design considerations for clinical trials of autonomic modulation therapies targeting hypertension and heart failure.Hypertension. 2015; 65: 5-15Crossref PubMed Scopus (19) Google Scholar Patients, caregivers, and those assessing BP were blinded to randomization assignments. Blinding of study patients and BP assessors was maintained for up to 12 months after randomization. Importantly, and in contrast to many prior studies of renal denervation, all interventionists performing the procedure had previous experience performing renal denervation and all procedures were proctored on the basis of detailed prespecified procedural plans involving a standardized approach to target all accessible renal arterial vessels. To minimize technical variability, the number of physicians performing the renal denervation procedure was restricted to 1 per trial center. Additionally, study patients in the sham and experimental groups both remained on the catheterization table for 20 minutes after the angiogram to prevent possible unblinding of randomization allocation. This is the approximate time that it takes to perform an ablation procedure with a multinodal catheter. The primary end point for SPYRAL HTN-OFF MED was change from baseline in 24-hour ABP at 3 months. Because of the multiple measurements obtained with ABP monitoring and removal of observer bias seen in clinical measurements, ABP is more reproducible than clinic measurements and has the ability to determine nocturnal BP values at a time when sympathetic nervous system activity is theoretically lower than while awake.10Zannad F. Stough W.G. Mahfoud F. et al.Design considerations for clinical trials of autonomic modulation therapies targeting hypertension and heart failure.Hypertension. 2015; 65: 5-15Crossref PubMed Scopus (19) Google Scholar, 11Howard J.P. Cole G.D. Sievert H. et al.Unintentional overestimation of an expected antihypertensive effect in drug and device trials: mechanisms and solutions.Int J Cardiol. 2014; 172: 29-35Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar SPYRAL HTN-OFF MED was also performed with more than 1 catheter per site, according to international consensus recommendations.5White W.B. Galis Z.S. Heneger J. et al.Renal denervation therapy for hypertension: pathways for moving development forward.J Am Soc Hypertens. 2015; 9: 341-350Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 6Mahfoud F. Schmieder R.E. Azizi M. et al.Proceedings from the 2nd European Clinical Consensus Conference for device-based therapies for hypertension: state of the art and considerations for the future.Eur Heart J. 2017; 38: 3272-3281PubMed Google Scholar Results of SPYRAL HTN-OFF MED showed that the renal-denervation group had small but both statistically and clinically significant reductions from baseline to 3 months in both clinic BPs and ABPs, whereas the sham group did not. Not surprisingly, a numerically smaller reduction from baseline was observed in ABP compared to BPs measured in the clinic.5White W.B. Galis Z.S. Heneger J. et al.Renal denervation therapy for hypertension: pathways for moving development forward.J Am Soc Hypertens. 2015; 9: 341-350Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 7Townsend R.R. Mahfoud F. Kandzari D.E. et al.Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised-sham-controlled, proof of concept trial.Lancet. 2017; 390: 2160-2170Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar Because a similar decline in BP was not found in the sham group, it can be concluded that the decline in BP was due to the effect of renal denervation. Clearly, the magnitude of the systolic BP reductions in the renal-denervation group, −10.0 mm Hg for clinic BP (P = 0.0004) and −5.5 mm Hg for ABP (P = 0.0031), are clinically meaningful. Similarly, there were significant reductions in clinic and ambulatory diastolic BPs in patients randomly assigned to renal denervation (sham-control–subtracted values of −4.9 and −4.4 mm Hg, respectively). This extent of BP reduction in patients with stages 1 to 2 hypertension is associated with reduced rates of cardiovascular mortality, heart failure, and stroke.12Bundy J.D. Li C. Stuchlik P. et al.Systolic blood pressure reduction and risk of cardiovascular disease and mortality: a systematic review and network meta-analysis.JAMA Cardiol. 2017; 2: 775-781Crossref PubMed Scopus (367) Google Scholar, 13Ettehad D. Emdin C.A. Kiran A. et al.Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis.Lancet. 2016; 387: 957-967Abstract Full Text Full Text PDF PubMed Scopus (1905) Google Scholar, 14Kario K. Pickering T.G. Umeda Y. et al.Morning surge in blood pressure as a predictor of silent and clinical cerebrovascular disease in elderly hypertensives: a prospective study.Circulation. 2003; 107: 1401-1406Crossref PubMed Scopus (1059) Google Scholar There are important limitations to this study. By design, SPYRAL HTN-OFF MED had a small sample size and was not powered for complete efficacy end points because of the uncertainty of the sham-subtracted BP reduction. It was a difficult study to perform; even with just 80 randomly assigned patients, it was necessary to screen more than 340 potential study participants. This large-screen failure rate was due primarily to out-of-range clinic BPs or ABPs (n = 171 and n = 49, respectively) or renal artery anatomy that was not amenable to instrumentation and radiofrequency ablation (n = 28). It is understood that a 3-month follow-up time point was short for efficacy, but deemed necessary for safety considerations. Individual responder analyses demonstrated that 20% to 30% of patients randomly assigned to renal denervation had no reduction in ABPs (20% for diastolic and 28% for systolic BP measurements). This could be explained by varying degrees of success with renal nerve ablation or differences in the underlying hypertension pathophysiology of study participants.4Kandzari D.E. Bhatt D.L. Brar S. et al.Predictors of blood pressure response in the SYMPLICITY HTN-3 trial.Eur Heart J. 2015; 36: 219-227Crossref PubMed Scopus (407) Google Scholar, 5White W.B. Galis Z.S. Heneger J. et al.Renal denervation therapy for hypertension: pathways for moving development forward.J Am Soc Hypertens. 2015; 9: 341-350Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar, 15Sakakura K. Ladich E. Edelman E.R. et al.Methodological standardization for the pre-clinical evaluation of renal sympathetic denervation.JACC Cardiovasc Interv. 2014; 7: 1184-1193Crossref PubMed Scopus (48) Google Scholar Although the SPYRAL catheter improves the ability to completely interrupt renal nerves, there is no practical method available to verify nerve destruction/disruption while the patient is undergoing the procedure. A small proportion of patients was found to be taking antihypertensive medications (<10%), but this was balanced between the 2 treatment groups and not likely to have affected efficacy results. The SPYRAL HTN-OFF MED trial differs substantially from previous renal denervation trials in terms of population enrolled, absence of antihypertensive therapy, and denervation technique. It is the first rigorously performed sham-controlled clinical trial to assess BP reductions in patients with untreated stages 1 to 2 hypertension. Virtually all prior renal-denervation trials enrolled patients with resistant1Symplicity HTN-1 InvestigatorsCatheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months.Hypertension. 2011; 57: 911-917Crossref PubMed Scopus (736) Google Scholar, 2Esler M.D. Krum H. Sobotka P.A. et al.Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.Lancet. 2010; 376: 1903-1909Abstract Full Text Full Text PDF PubMed Scopus (1873) Google Scholar, 3Bhatt D.L. Kandzari D.E. O’Neill W.W. et al.(SYMPLICITY HTN-3)A controlled trial of renal denervation for resistant hypertension.N Engl J Med. 2014; 370: 1393-1401Crossref PubMed Scopus (1613) Google Scholar or moderately severe hypertension16Mahfoud F. Bakris G. Bhatt D.L. et al.Reduced blood pressure-lowering effect of catheter-based renal denervation in patients with isolated systolic hypertension: data from SYMPLICITY HTN-3 and the Global SYMPLICITY Registry.Eur Heart J. 2017; 38: 93-100PubMed Google Scholar, 17Azizi M. Pereira H. Hamdidouche I. et al.Adherence to antihypertensive treatment and the blood pressure-lowering effects of renal denervation in the renal denervation for hypertension (DENERHTN) trial.Circulation. 2016; 134: 847-857Crossref PubMed Scopus (116) Google Scholar using a multitude of antihypertensive drugs and did not exclude those with isolated systolic hypertension. Patients with both systolic and diastolic hypertension were enrolled in SPYRAL OFF-HTN MED, which likely increased the response rate because patients with diastolic BP elevations are younger, have more arterial elasticity, and have a greater chance that sympathetic nervous system activity plays a role in their hypertension. Earlier SYMPLICITY trials1Symplicity HTN-1 InvestigatorsCatheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months.Hypertension. 2011; 57: 911-917Crossref PubMed Scopus (736) Google Scholar, 2Esler M.D. Krum H. Sobotka P.A. et al.Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.Lancet. 2010; 376: 1903-1909Abstract Full Text Full Text PDF PubMed Scopus (1873) Google Scholar, 3Bhatt D.L. Kandzari D.E. O’Neill W.W. et al.(SYMPLICITY HTN-3)A controlled trial of renal denervation for resistant hypertension.N Engl J Med. 2014; 370: 1393-1401Crossref PubMed Scopus (1613) Google Scholar used a single-node renal denervation catheter in the main renal arteries (ie, before any bifurcation or in branch renal arteries), which may have affected the success of renal nerve ablation, particularly in the distal portion of the artery, where nerve density has been found to be substantially greater than in the proximal renal artery.15Sakakura K. Ladich E. Edelman E.R. et al.Methodological standardization for the pre-clinical evaluation of renal sympathetic denervation.JACC Cardiovasc Interv. 2014; 7: 1184-1193Crossref PubMed Scopus (48) Google Scholar The SPYRAL HTN-OFF MED trial used a multinodal catheter that delivered 4 simultaneous radiofrequency ablations in a helical pattern and included branch vessel treatment. An average of 17.9 ablations were performed in the main renal arteries, and 25.9, in branch vessels, compared with 11.2 ablation attempts and 0 branch vessel treatments in the SYMPLICITY HTN-3 trial.4Kandzari D.E. Bhatt D.L. Brar S. et al.Predictors of blood pressure response in the SYMPLICITY HTN-3 trial.Eur Heart J. 2015; 36: 219-227Crossref PubMed Scopus (407) Google Scholar Hence, the increased number of ablations delivered in a circumferential pattern within the main renal artery, renal artery branches, and larger accessory arteries (>3 mm and <8 mm in diameter), may have led to a more complete denervation procedure. The variance for BP changes was notably tighter in SPYRAL HTN-OFF MED compared with previous trials and attributed to the removal of nonstandardized BP measurement and confounding antihypertensive drug therapy along with improved patient selection, greater consistency in the delivery and implementation of renal nerve energy/ablation, and the distal and branch vessel treatment. SYMPLICITY HTN-1 reported significant BP reductions in patients with resistant hypertension, which were evident by 1 month and sustained for 3 years, but this was an uncontrolled study and contaminated in the later observation period by the introduction of new and increased doses of antihypertensive drug therapy.2Esler M.D. Krum H. Sobotka P.A. et al.Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.Lancet. 2010; 376: 1903-1909Abstract Full Text Full Text PDF PubMed Scopus (1873) Google Scholar The randomized openly controlled DENERHTN (Renal Denervation for Resistant Hypertension) Study reported a significant difference in reduction in daytime systolic ABP after renal denervation plus antihypertensive medication compared to antihypertensive medication alone.17Azizi M. Pereira H. Hamdidouche I. et al.Adherence to antihypertensive treatment and the blood pressure-lowering effects of renal denervation in the renal denervation for hypertension (DENERHTN) trial.Circulation. 2016; 134: 847-857Crossref PubMed Scopus (116) Google Scholar A meta-analysis of heterogeneous randomized controlled trials concluded that the safety of renal denervation but did not show a significant reduction in BP.18Fadl Emula F.E. Feng Y.M. Jacobs L. et al.Sham or no sham control: that is the question in trials of renal denervation for resistant hypertension. A systematic meta-analysis.Blood Press. 2017; 26: 195-203Crossref PubMed Scopus (28) Google Scholar Hence, it is difficult to interpret whether a lack of safety findings is due in part to a lack of efficacy of the procedure. Hence, SPYRAL HTN-OFF MED could be viewed as the first sham-controlled renal denervation trial that demonstrated both efficacy and short-term safety in clinical hypertension. Results of this proof-of-concept trial provided evidence that renal denervation, in the absence of antihypertensive medications, can lower clinic BP and ABP by approximately 8/5 mm Hg and 6/4 mm Hg, respectively, in patients with stages 1 to 2 hypertension. This moderate reduction in BP after renal denervation is apparent as early as 3 months. Importantly, the rate of procedural complications was low. Serial biochemical assays have not demonstrated deterioration in kidney function, although for only a rather short-term follow-up period. The study provides physiologic proof of principle for the efficacy of catheter-based renal denervation that would encourage further development for patients with treatment-resistant hypertension. The BP results of SPYRAL HTN-OFF MED are fairly modest and similar or less than one might expect following treatment by a single antihypertensive agent in patients with untreated stage 2 hypertension. However, the possibility exists that the efficacy of this catheter in patients with treatment-resistant hypertension could be more substantial and deserves further evaluation, particularly for patients who find it difficult to tolerate more than 3 classes of antihypertensive agents. For example, studies of eplerenone and spironolactone in resistant hypertension demonstrated much larger reductions in BP compared to when these drugs are used in untreated stages 1 to 2 hypertension.19Calhoun D.A. White W.B. Effectiveness of the selective aldosterone blocker, eplerenone, in patients with resistant hypertension.J Am Soc Hypertens. 2008; 2: 462-468Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar, 20Williams B. MacDonald T.M. Morant S. et al.Spironolactone versus placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial.Lancet. 2015; 386: 2059-2068Abstract Full Text Full Text PDF PubMed Scopus (682) Google Scholar In conclusion, Townsend et al7Townsend R.R. Mahfoud F. Kandzari D.E. et al.Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised-sham-controlled, proof of concept trial.Lancet. 2017; 390: 2160-2170Abstract Full Text Full Text PDF PubMed Scopus (475) Google Scholar have successfully carried out an important device study in hypertension that has provided evidence regarding the effectiveness of renal denervation that yields an important platform for the next step of evaluating the efficacy and safety of this catheter in a larger randomized sham-control trial in drug-treatment resistant hypertension. Future phase 3 or pivotal studies could use more than 1 design to gain approval by regulatory bodies, but should incorporate sham-control with skilled operators, improved patient selection, and standardization of antihypertensive regimens with quantitative screening for antihypertensive drug levels to avoid potential confounding of drug nonadherence.5White W.B. Galis Z.S. Heneger J. et al.Renal denervation therapy for hypertension: pathways for moving development forward.J Am Soc Hypertens. 2015; 9: 341-350Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar