SYMPLICITY HTN-3: A Prospective, Randomized, Sham-Controlled Trial of Renal Sympathetic Denervation in Patients with Refractory Hypertension: Post Hoc Analyses of 12-Month Results Deepak L. Bhatt, MD, MPH, and George L. Bakris, MD on behalf of the SYMPLICITY HTN-3 Trial Investigators

Disclosures for Dr. Bhatt Advisory Board: Elsevier Practice Update Cardiology, Medscape Cardiology, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care; Chair: American Heart Association Get With The Guidelines Steering Committee; Data Monitoring Committees: Duke Clinical Research Institute; Harvard Clinical Research Institute; Mayo Clinic; Population Health Research Institute (including EnligHTNment); Honoraria: American College of Cardiology (Editor, Clinical Trials, Cardiosource), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), Harvard Clinical Research Institute (clinical trial steering committee), HMP Communications (Editor in Chief, Journal of Invasive Cardiology); Population Health Research Institute (clinical trial steering committee), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), WebMD (CME steering committees); Research Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic (co-PI of SYMPLICITY HTN-3), Roche, Sanofi Aventis, The Medicines Company; Unfunded Research: FlowCo, PLx Pharma, Takeda. This presentation discusses off-label and investigational uses of various devices. The SYMPLICITY HTN-3 trial was funded by Medtronic, Inc.

Background SYMPLICITY HTN-3 is the first randomized, blinded, sham-controlled clinical trial of renal denervation for treatment resistant hypertension. Initial results confirmed the safety of renal denervation but did not achieve the 6-month primary efficacy endpoint. Besides blinding and sham control, post hoc analyses have identified potential factors to explain the negative results of the trial including: Patient population Procedural variability

SYMPLICITY HTN-3 Trial Design 2 weeks 2 weeks 1 M 3 M Home BP & HTN med confirmation 6 M Home BP & HTN med confirmation Sham Procedure Renal angiogram; Eligible subjects randomized Primary endpoint Cross- over Screening Visit 1 Screening Visit 2 Office SBP ≥160 mm Hg Full doses ≥3 meds No med changes in past 2 weeks No planned med changes for 6 M Office SBP ≥160 mm Hg 24-h ABPM SBP ≥135 mm Hg Documented med adherence Renal Denervation Home BP & HTN med confirmation 1 M 3 M 6 M 12-60 M 2 weeks Patients, BP assessors, and study personnel all blinded to treatment status No changes in medications for 6 M Bhatt DL, Kandzari DE, O’Neill WW, et al...Bakris GL. N Engl J Med 2014

Primary Efficacy 6-Month Endpoint: Office Systolic BP Baseline – Denervation 179.7 ± 16.1 6 Mo – Denervation 165.6 ± 23.6 Baseline – Sham 180.2 ± 16.8 6 mo – Sham 168.4 ± 28.6

Methods All clinicians and subjects were un-blinded to randomization following the primary 6-month endpoint evaluation. Sham control subjects were allowed to crossover to RDN following the 6-month primary endpoint evaluation if they continued to satisfy study inclusion and exclusion criteria. Follow-up of the study will continue for up to 5 years.

Patient Disposition: 6 Months to 1 Year Crossover subjects were denervated after unblinding at 6 months if blood pressure criteria for treatment were met and subjects elected to proceed. Sham Control Group 171 subjects Denervation Group 361 Subjects Crossover Group 101 Subjects   Non-Crossover Group 70 Subjects   4 died 3 withdrew 2 died 3 withdrew 2 died 6 withdrew 354 eligible for 12M follow-up   96 eligible for 6M post-RDN follow-up 62 eligible for 12M follow-up   Patients that crossed over were not necessarily similar to patients that did not crossover. The two subgroups of the original sham control group were not randomized and so their inclusion in either group is biased. Also note that many non crossover pts, by comparison, missed the 12 month follow up. It was difficult to remain engaed with many non crossover patients who have improved but not received RDN therapy. 322 Subjects (91%) 12M post-RDN follow-up 93 Subjects (96.9%) 6M post-RDN follow-up  48 Subjects (77%) 12M follow-up

Change in Office Blood Pressure through 12 Months Post-Procedure Both the original RDN group and the crossover patients show significant reductions in office BP 6 months post treatment. This decrease was maintained in the original RDN group out to 12 months. Although it’s tempting to note that the 6 month drop in BP was nominally larger for crossover patients, note also that the baseline pressure for this group was higher. Non Crossover patients are not shown in this comparison since they are no longer a legitimate control group eligible for comparison. (Error bars are 1.96 x the Standard error of the mean. This is equivalent to the 95% CI range.)

Change in Office Blood Pressure at 6 and 12 Months for Matched Subjects Both the original RDN group and the crossover patients show significant reductions in office BP 6 months post treatment. This decrease was maintained in the original RDN group out to 12 months. Although it’s tempting to note that the 6 month drop in BP was nominally larger for crossover patients, note also that the baseline pressure for this group was higher. Non Crossover patients are not shown in this comparison since they are no longer a legitimate control group eligible for comparison. (Error bars are 1.96 x the Standard error of the mean. This is equivalent to the 95% CI range.)

Change in 24-h Ambulatory Blood Pressure at 6 and 12 Months for Denervation Subjects Both the original RDN group and the crossover patients show significant reductions in office BP 6 months post treatment. This decrease was maintained in the original RDN group out to 12 months. Although it’s tempting to note that the 6 month drop in BP was nominally larger for crossover patients, note also that the baseline pressure for this group was higher. Non Crossover patients are not shown in this comparison since they are no longer a legitimate control group eligible for comparison. (Error bars are 1.96 x the Standard error of the mean. This is equivalent to the 95% CI range.)

Change in Office Blood Pressure through 12-Months Post-Procedure for Non-Crossover Subjects The non crossover subgroup of the original sham control group had large drops in pressure at 6 months. Hence most of these subjects did not meet RDN inclusion criteria and could not crossover. The drop in blood pressure at 12 months, although not as large as at 6 months was still significant.

Procedural Variability Correlation with # of ablations Correlation with 4-quadrant ablation pattern Inferior Anterior Superior Posterior Cross-section of artery 4-quadrant ablation pattern

Relationship Between SBP Changes and Number of Ablations Attempted for Denervation Group at 6 Months Error bars = ± 1 SE Baseline SBP (mm Hg) 180 181 182 183 186 188 185 Number of ablations remains significant after adjustment for baseline blood pressure

*Denervation and crossover subjects combined Relationship Between Office SBP Changes and Number of Ablations Attempted for Combined* RDN Subjects at 6 Months 440 400 334 249 161 112 71 48 31 18 11 n 6 month data expanded cohort includes crossover *Denervation and crossover subjects combined Baseline SBP (mm Hg) 181 180 182 184 187 186

*Denervation and crossover subjects combined Relationship Between 24-Hr Ambulatory SBP Changes and Number of Ablations Attempted for Combined* RDN Subjects at 6 Months 406 367 304 226 145 98 63 41 27 15 8 n 6 month data expanded cohort includes crossover *Denervation and crossover subjects combined Baseline SBP (mm Hg) 160 159 161 162 165 168

Systolic Blood Pressure Change at 6 Months According to Ablation Pattern Analysis tables: see Q132

Limitations These are post hoc analyses, so the results can only be viewed as hypothesis generating and need to be confirmed in prospective, randomized, blinded, sham-controlled studies. Protocol did not specify ABPM for the non-crossover patients at 12 months.

Conclusions The 12-month results of SYMPLICITY HTN-3 are consistent with the 6-month findings previously reported. The safety of the procedure is maintained but blood pressure reductions are similar to a sham procedure. The positive correlation of the total number of ablations and the circumferential pattern of ablations on systolic BP drop is maintained and enhanced when the 6-month data from the crossover subjects are added. These post hoc observations suggest hypotheses concerning optimization of the denervation procedure that may inform the design of future renal denervation trials.

Thank You! Deepak L. Bhatt, MD, MPH Executive Director of Interventional Cardiovascular Programs, BWH Heart & Vascular Center Professor of Medicine, Harvard Medical School 1 (857) 307-1992 dbhatt@partners.org www.brighamandwomens.org/heart