Author + information
- Received December 27, 2014
- Revision received January 16, 2015
- Accepted January 19, 2015
- Published online April 7, 2015.
- George L. Bakris, MD∗∗ (, )
- Raymond R. Townsend, MD†,
- John M. Flack, MD, MPH‡,
- Sandeep Brar, MD§,
- Sidney A. Cohen, MD, PhD†,§,
- Ralph D’Agostino, PhD‖,
- David E. Kandzari, MD¶,
- Barry T. Katzen, MD#,
- Martin B. Leon, MD∗∗,
- Laura Mauri, MD, MSc††,
- Manuela Negoita, MD§,
- William W. O’Neill‡‡,
- Suzanne Oparil, MD§§,
- Krishna Rocha-Singh, MD‖‖,
- Deepak L. Bhatt, MD, MPH¶¶,
- SYMPLICITY HTN-3 Investigators
- ∗ASH Comprehensive Hypertension Center, University of Chicago Medicine, Chicago, Illinois
- †Renal Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- ‡Division of Translational Research and Clinical Epidemiology, Wayne State University and the Detroit Medical Center, Detroit, Michigan
- §Coronary and Structural Heart Disease Management, Medtronic, Inc., Santa Rosa, California
- ‖Mathematics and Statistics Department, Harvard Clinical Research Institute and Boston University School of Public Health, Boston, Massachusetts
- ¶Interventional Cardiology, Piedmont Heart Institute, Atlanta, Georgia
- #Baptist Cardiac and Vascular Institute, Miami, Florida
- ∗∗Center for Interventional Vascular Therapy, New York Presbyterian Hospital, Columbia University Medical Center and Cardiovascular Research Foundation, New York, New York
- ††Harvard Clinical Research Institute, Division of Cardiovascular Medicine, Brigham and Women’s Hospital Heart and Vascular Center, and Harvard Medical School, Boston, Massachusetts
- ‡‡The Center for Structural Heart Disease, Division of Cardiology, Henry Ford Hospital, Detroit, Michigan
- §§Vascular Biology and Hypertension Program, University of Alabama at Birmingham, Birmingham, Alabama
- ‖‖Interventional Cardiology and Vascular Medicine, Prairie Heart Institute, Springfield, Illinois
- ¶¶Division of Cardiovascular Disease, Brigham and Women’s Hospital Heart and Vascular Center and Harvard Medical School, Boston, Massachusetts
- ↵∗Reprint requests and correspondence:
Dr. George L. Bakris, ASH Comprehensive Hypertension Center, The University of Chicago Medicine, 5841 South Maryland Avenue, MC 1027, Chicago, Illinois 60637.
Background Results of the SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) trial confirmed the safety but not the efficacy of renal denervation for treatment-resistant hypertension at 6 months post procedure.
Objectives This study sought to analyze the 12-month SYMPLICITY HTN-3 results for the original denervation group, the sham subjects who underwent denervation after the 6-month endpoint (crossover group), and the sham subjects who did not undergo denervation after 6 months (non-crossover group).
Methods Eligible subjects were randomized 2:1 to denervation or sham procedure. Subjects were unblinded to their treatment group after the 6-month primary endpoint was ascertained; subjects in the sham group meeting eligibility requirements could undergo denervation. Change in blood pressure (BP) at 12 months post randomization (6 months for crossover subjects) was analyzed.
Results The 12-month follow-up was available for 319 of 361 denervation subjects and 48 of 101 non-crossover subjects; 6-month denervation follow-up was available for 93 of 101 crossover subjects. In denervation subjects, the 12-month office systolic BP (SBP) change was greater than that observed at 6 months (−15.5 ± 24.1 mm Hg vs. −18.9 ± 25.4 mm Hg, respectively; p = 0.025), but the 24-h SBP change was not significantly different at 12 months (p = 0.229). The non-crossover group office SBP decreased by −32.9 ± 28.1 mm Hg at 6 months, but this response regressed to −21.4 ± 19.9 mm Hg (p = 0.01) at 12 months, increasing to 11.5 ± 29.8 mm Hg.
Conclusions These data support no further reduction in office or ambulatory BP after 1-year follow-up. Loss of BP reduction in the non-crossover group may reflect decreased medication adherence or other related factors. (Renal Denervation in Patients With Uncontrolled Hypertension [SYMPLICITY HTN-3]; NCT01418261)
The SYMPLICITY HTN-3 (Renal Denervation in Patients With Uncontrolled Hypertension) study was a prospective, blinded, randomized, sham-controlled trial that used ambulatory blood pressure measurement (ABPM) as part of the inclusion criteria as well as a pre-specified secondary endpoint. All participants were evaluated at baseline and 6 months for changes in ambulatory, home, and office blood pressure (BP). Primary results of the trial demonstrated safety of the renal denervation procedure but failed to show a greater reduction in office or ambulatory systolic BP (SBP) than that with the sham procedure at 6 months (1). This paper presents the detailed office and 24-h ABPM results of SYMPLICITY HTN-3 after 1 year of follow-up in the original cohort randomized to the procedure as well as in those who were either not eligible to be crossed over and those who were crossed over and who underwent renal denervation at 6 months.
SYMPLICITY HTN-3 was a prospective, randomized, sham-controlled, multicenter clinical trial. Primary results and detailed methods were published previously (1). Adult subjects with uncontrolled hypertension receiving a stable antihypertensive medication regimen that included maximally tolerated doses of ≥3 medications of complementary classes, including a diuretic agent, were randomized 2:1 to undergo renal denervation or sham procedure. Subjects were required to have a seated office SBP of ≥160 mm Hg at their first screening visit with the pressure confirmed before randomization at the second screening visit. The protocol provided escape criteria to allow changes in antihypertensive medication during the 2-week period between screening visits. Subjects were also required to have a 24-h ambulatory SBP of ≥135 mm Hg before to randomization. Details of the ABPM procedures were reported previously (2).
Additional clinical exclusion criteria included known secondary causes of hypertension or more than 1 hospitalization for hypertensive emergency in the previous year. Anatomic exclusion criteria included >50% renal artery stenosis, renal artery aneurysm, prior renal artery intervention, multiple renal arteries, renal artery diameter of <4 mm, or treatable segment of <20 mm in length.
The Symplicity renal denervation system (Medtronic, Santa Rosa, California) was used to deliver radiofrequency energy within the main renal arteries to ablate surrounding efferent and afferent nerves. Subjects randomized to the sham control group received a renal angiogram and were blinded by the use of conscious sedation, blindfolding, music (to cover procedural sounds), and lack of experience regarding the procedure.
After 6-month primary safety and efficacy endpoints were ascertained, subjects were unblinded to their treatment, and those in the sham control group who still met eligibility requirements were allowed to crossover to receive the denervation procedure (crossover group). Subjects with a BP lower than required or who otherwise did not choose to undergo renal denervation were followed as the non-crossover group.
The primary efficacy and safety endpoints have been previously described and published (1). Blood pressure changes from baseline (before randomization) to 6- and 12-month follow-up are now reported for subjects in the denervation and non-crossover groups. The BP changes from pre-procedure baseline (6-month post-original randomization) to 6 months following denervation are reported for the crossover group. All denervated subjects (denervation and crossover groups) were followed biannually, and non-crossover subjects were followed annually through 5 years post-randomization. An interim protocol amendment added 12-month ABPM for non-crossover subjects; thus, these data were available only for those who consented.
Analyses were performed on the basis of intent-to-treat principle. Means and standard deviations (SD) of continuous variables were presented by treatment group. Variations in ambulatory BP at each visit were defined as SD or coefficient of variation (the SD/mean ratio). Between-group differences were compared using confidence intervals (CIs) and tested using unpaired Student t tests. Within-group differences from baseline to follow-up were tested using paired Student t tests. For categorical variables, counts and percentages were presented by treatment group and tested using the exact test for binary variables and chi-square test for multilevel categorical variables.
Role of funding source
The trial was designed by the coprincipal investigators and the sponsor, Medtronic, Inc. Data were collected and analyzed by the sponsor and independently validated by Harvard Clinical Research Institute (Boston, Massachusetts). The lead author wrote the first draft of the manuscript, and all coauthors contributed and approved the final manuscript. The corresponding author had full access to all study data and had final responsibility for the decision to submit.
After unblinding, 101 sham subjects who met eligibility requirements chose to undergo renal denervation, thus forming the crossover group; the remaining 70 patients, including 6 subjects who were eligible but declined the procedure, comprised the non-crossover group (Figure 1). The 6- and 12-month follow-up data were available for 319 subjects from the original denervation group and 48 subjects from the non-crossover group. Crossover subjects (n = 93) had 6 months of follow-up from the time of the denervation procedure. Baseline characteristics and antihypertensive medication used were similar across the 3 groups, although there were more men and more African-American subjects in the non-crossover group (Table 1). The non-crossover group also had significantly lower baseline pressure values than the crossover subjects (176.1 ± 14.9 mm Hg vs. 183.9 ± 19.1 mm Hg, respectively; p = 0.003).
Changes from pre-procedure baseline BP from office to 24-h ambulatory BP are displayed in the Central Illustration for the denervation and crossover subjects. The 12-month changes in office SBP were significantly greater than those observed at the 6-month visit for the denervation group (−15.5 ± 24.1 vs. 18.9 ± 25.4, respectively; p = 0.025) (Central Illustration A). However, there were no significant differences between 6- and 12-month ABPM changes (Central Illustration B). The crossover group baseline BP was on the basis of pre-procedure measurements at the 6-month crossover time point. The 6-month drop in office SBP in the crossover group was −17.7 ± 23.2 mm Hg (p < 0.001 from baseline), and the 6-month drop in 24-h SBP was −9.2 ± 13.6 mm Hg (p < 0.001 from baseline).
The non-crossover group had a mean office BP (systolic/diastolic) of 145.6 ± 24.6/82.9 ± 13.4 mm Hg at 6 months, indicating that for many of these subjects (64 of 70 [91.4%]), their ineligibility for renal denervation at 6 months was due to not meeting the SBP minimum of 160 mm Hg. Changes in office BP at 6 and 12 months for the non-crossover subjects with 12-month data available (n = 48) showed a very large SBP change from baseline to 6 months (−32.9 ± 28.1 mm Hg) with some loss of effect (an increase in SBP of 11.5 ± 29.8 mm Hg) between 6 and 12 months (p = 0.01 for the differences in 6- and 12-month SBPs) for an overall SBP drop from baseline of −21.4 ± 19.9 mm Hg at 12 months (Figure 2A).
Ambulatory data were available for only 20 of 70 non-crossover subjects (29%) at 12 months, given that ABPM was not protocol-mandated for these subjects at this time point. However, in these 20 subjects, a pattern similar to that of office readings was observed showing a larger 24-h BP reduction at 6 months compared with 12 months (−11.0 ± 19.5 mm Hg at 6 months versus −6.1 ± 14.4 mm Hg at 12 months; p = 0.272) (Figure 2B).
Composite safety data are summarized in Table 2. The safety measures were similar between 6 and 12 months among the 3 groups. One subject from the denervation group developed end-stage renal disease. The patient had a history of obesity, obstructive sleep apnea, diabetes mellitus type 2, renal insufficiency (baseline estimated glomerular filtration rate of 46 ml/min/1.73 m2), left ventricular hypertrophy, coronary artery disease, and myocardial infarction. Approximately 7 months post-denervation, he was admitted with weakness, progressive uremic symptoms, and shortness of breath. His serum creatinine concentration increased to 4.0 mg/dl, and hemodialysis was initiated.
The 1-year follow-up data for the SYMPLICITY HTN-3 trial reaffirm results of the 6-month data with regard to primary and specified secondary endpoints and indicate different BP responses in different groups following unblinding at 6 months. There was a small but significant additional drop in office BP at 12 months but no further significant reduction in ABPM at 12 months in subjects originally randomized to undergo renal denervation. Sham subjects who crossed over to renal denervation after the 6-month primary endpoint had a decrease in SBP 6 months following the procedure similar to those who originally underwent denervation (Central Illustration). More striking was the significant loss of BP control at 1 year in the non-crossover group, manifested by decreased BP reduction in both office and ambulatory readings. Last, the safety profile continued from that seen at 6 months.
A review of subject characteristics among the 3 groups demonstrated no differences in follow-up of subgroups thought to detract from the effects of renal denervation in the 6-month primary analyses, such as race or older age (>65 years of age) of subjects (1). At 1 year, we found no differences in proportion of African Americans, which ranged from 25% to 31%, among groups. Likewise, there were no differences among the proportions of people 65 years of age and older in any single group.
There were no differences in safety outcomes among the groups, and this included progression to end-stage kidney failure or cardiovascular-associated deaths. Moreover, there were no differences in episodes of hypertensive urgency or emergency. There was 1 subject from the initial denervation group, however, who developed end-stage renal disease requiring chronic dialysis therapy, but that subject entered the trial with stage 3 chronic kidney disease.
Why these results differ from earlier SYMPLICITY trial follow-up data at 1 year is unclear. Of course, it may have to do with the more rigorous trial methodology of SYMPLICITY HTN-3 (blinding, sham control, and other factors). There are other potential explanations for these results, the 2 most prominent being an increase in early medication adherence that decreased over time (although it is unclear why this would differ among arms) as well as a failure to provide complete denervation in the renal arteries using a predefined pattern (3). Recent preclinical data support the concept that all main renal arteries as well as distal segments of the main renal arteries and, when feasible, the arterial branch vessels and accessory arteries should be targeted for complete denervation (4).
Another possible factor is the Hawthorne effect that was expressed initially as strong patient adherence to medications (5). The improved adherence to medications in the group that initially or subsequently received the procedure is seen at 1 year with similar BP reductions. In contrast, the non-crossover group had a significant loss in BP control following unblinding compared with that in the denervated groups, a result that may relate to reduced medication adherence. These results are consistent with known factors impacting medication adherence such as medication complexity, social support, and lack of clear benefit in chronic disease (6).
Additionally, a less likely scenario is the statistical phenomenon, regression to the mean, in which multiple measurements tend to return to a true mean (7). This has been suggested as a possible explanation for the observed results and highlights the importance of continued follow-up of all subjects to document BP trajectory. The significant reduction in office SBP between 6 and 12 months that is not seen with 24-h ambulatory SBP over the same period may be consistent with a reduction in the white coat effect. A study examining the relationship over time between office and ambulatory BP in 2,722 patients found that the differences between office and ambulatory BP measurements, termed the “white coat effect,” were less at 1-year follow-up after intensive pharmacotherapy (8). The degree of BP change was related to the pretreatment BP level that has also been consistently observed in the renal denervation trials (3,9). The current trial required a baseline ambulatory SBP of ≥135 mm Hg, which was intended to eliminate white coat-resistant hypertension; however, differences in the mean baseline SBPs taken in the office versus those by ABPM were 20.6 ± 16.1 mm Hg for the denervation group. This may indicate that white coat-resistant hypertension was not entirely eliminated from the study population. This difference was only 9.2 ± 18.9 mm Hg at 12 months, which is consistent with the observation of less white coat effect after intensive treatment; a similar smaller white coat effect was also observed in the untreated non-crossover group (20.9 ± 17.0 mm Hg SBP at baseline and 10.1 ± 16.5 mm Hg at 12 months).
Finally, in the SYMPLICITY HTN-1 trial, BP continued to drop over 3 years of follow-up following renal denervation (9). The small but significant increase in BP change seen at 12 months for the denervation group in the current trial was not duplicated in the ABPM data, but longer follow-up may clarify whether these early observations will be meaningful.
A second randomized, blinded, sham-controlled trial of renal denervation in patients with less severe hypertension also did not show a significant benefit of denervation in the intent-to-treat population at 6 months (10). That study had a number of limitations, including a small sample size and 2 patients allocated to the wrong treatment group, but it confirmed the importance of a sham control for future clinical trials of renal denervation.
Limitations of this analysis include incomplete follow-up in patients in the non-crossover group due primarily to withdrawal of consent (n = 6) and missed visits at 12 months (n = 14). Thus, the observations in that group need to be interpreted cautiously. The safety of renal denervation beyond 12 months was not addressed in the present analysis, however, longer-term follow-up is ongoing.
This further analysis of data from SYMPLICITY HTN-3 demonstrates a further reduction in office BP at 12 months, but renal denervation failed to reduce 24-h ambulatory BP to a greater extent at 1 year than at 6 months. There was no difference in the safety profile among the groups. As a result of further detailed research into the renal denervation process itself and the evaluation of medication adherence, we conclude that renal denervation is safe but, by the method applied in SYMPLICITY HTN-3, does not clearly reduce BP to a greater extent than medication. Future randomized, blinded, and sham-controlled studies will be necessary to determine if renal denervation performed differently will provide substantial BP reduction.
COMPETENCY IN MEDICAL KNOWLEDGE: Renal denervation did not lower BP more than a sham procedure plus medication in subjects with resistant hypertension after 12 months in the SYMPLICITY HTN-3 clinical trial.
COMPETENCY IN PATIENT CARE: Renal denervation as used in this trial is not approved for clinical use in patients with resistant hypertension.
TRANSLATIONAL OUTLOOK: More research is needed to clarify whether other renal denervation techniques could be more effective than adherence to medication therapy in patients with hypertension.
The authors thank Xiaohua Chen, MS, and Lanyu Lei, MS, Harvard Clinical Research Institute, for statistical analyses, funded by Medtronic, and Colleen Gilbert, PharmD, Medtronic, for help with collating coauthor comments and document, table, and figure formatting and coordinating revisions. We also thank Juan Wu, MS, for data analysis support and Vanessa DeBruin, MS, Denise Jones, RN, BSN, Dan Jolivette, MD, and the SYMPLICITY HTN-3 study team for dedicated research support. Investigators in the SYMPLICITY HTN-3 trial are listed in the supplement of the prior publication.
Dr. Bakris is a consultant for Medtronic, Relypsa, Novartis, Janssen, Bayer, Daichi-Sankyo, GlaxoSmithKline, and AstraZeneca. Dr. Townsend has received grant support from NIH, consultant fees from Medtronic and Janssen, and travel support from the American Society of Nephrology, North American Artery, and the National Kidney Foundation. Dr. Flack is a consultant for and member of the steering committees for Medtronic, BackBeat Medical, and Forest Laboratories, LLC. Dr. Brar is Director of Clinical Research, Medtronic. Dr. Cohen is an employee of and holds stock options in Medtronic. Dr. Kandzari has received research grant support and consulting honoraria from Medtronic and Boston Scientific. Dr. Katzen is Chief Medical Executive and member of the steering committee for Medtronic Vascular. Dr. Mauri has received institutional grants from Abbott Vascular, Boston Scientific, Cordis, and Medtronic; and is a consultant for Medtronic, St. Jude Medical, and Biotronik. Dr. O'Neill is a consultant for Medtronic. Dr. Oparil has received grant support from Medtronic, Merck, and Bayer; and personal fees from Medtronic, Daiichi Sankyo, and Bayer. Dr. Rocha-Singh is a consultant for Medtronic, Boston Scientific, Cardiosonic, and Cordis. Dr. Bhatt is an advisory board member of, has financial relationships with, and has received honoraria from the American College of Cardiology, American Heart Association Get With The Guidelines Steering Committee, Belvoir Publications, Boston VA Research Institute, Cardax Cardiology, Cardiovascular Patient Care, Clinical Cardiology, Data Monitoring Committees of Duke Clinical Research Institute and Harvard Clinical Research Institute, Duke Clinical Research Institute, Elsevier, Harvard Clinical Research Institute, HMP Communications, Journal of the American College of Cardiology, Mayo Clinic, Medscape Cardiology, Population Health Research Institute, Practice Update Cardiology, Regado Biosciences, Slack Publications, and WebMD; and has received research funding from Amarin, Harvard Clinical Research Institute, HMP Communications, Journal of the American College of Cardiology, Population Health Research Institute, Slack Publications, WebMD, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Forest Laboratories, Ischemix, Medtronic, Pfizer, Roche, Sanofi, and The Medicines Company. Dr. Negoita is an employee of Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Stanley S. Franklin, MD, has served as Guest Editor for this paper.
- Abbreviations and Acronyms
- ambulatory blood pressure monitoring
- diastolic blood pressure
- systolic blood pressure
- Received December 27, 2014.
- Revision received January 16, 2015.
- Accepted January 19, 2015.
- American College of Cardiology Foundation
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