Lessons Learned From the Results of the SYMPLICITY

Lessons Learned From the Results of the SYMPLICITY HTN 3 Trial Industry View Sandeep Brar, M. D. Director, Clinical Research Medtronic, Santa Rosa, CA Sandeep. brar@medtronic. com

Symplicity HTN-3: severe drug-resistant HTN SBP >160 • • Randomized 2: 1, Sham Control, 535 subjects Randomized, 1441 Enrolled (63% Screen Failure Rate) Complex Screening Process including maximum tolerated doses of antihypertensive meds No check for medication compliance 8 touch points prior to pr EP 2 weeks 6 M Large SD in OSBP and ABPM 1 M 3 M Home BP & Pts on >5 meds Control Confirmatory Med Confirmation Screening Initial Screening • Office SBP ≥ 160 mm. Hg • Full tolerated doses of ≥ 3 meds • No HTN med changes in past 2 weeks • No plan to change meds for 6 M • Medical Hx Renal Angiogram 2 weeks Home BP & Med Confirmation • Office SBP ≥ 160 mm. Hg • Documented compliance on meds • Lab work Primary Endpoint • If eligible anatomy, randomize “on the table” • 24 hr ABPM SBP ≥ 135 30 days or maximum 6 weeks in exceptional circumstances 1 o Endpoint: Change in Office Systolic Blood Pressure 2 o Endpoint: MAE through 1 month, Stenosis to 6 m 2 | MDT Confidential and Proprietary; Do Not Copy or Distribute 2 weeks Treatment 1 M 3 M Home BP & Med Confirmation • Patient and Research staff performing 1, 3 & 6 month follow-ups are blinded to treatment status • No changes in medications for 6 M 6 M 1260 M

Primary Efficacy Endpoint Δ = -2. 39 (95% CI, -6. 89 to 2. 12) P=0. 26* Δ = -14. 1± 23. 9 Δ = -11. 7± 25. 9 P<0. 001 Office SBP (mm Hg) 200 150 180 mm Hg 168 mm Hg 166 mm Hg Baseline 6 Months 100 50 0 (N=364) (N=353) Denervation 3 | MDT Confidential and Proprietary; Do Not Copy or Distribute (N=171) Sham *P value for superiority with a 5 mm Hg margin; bars denote standard deviations

Powered Secondary Efficacy Endpoint Δ = -1. 96 (95% CI, -4. 97 to 1. 06) P=0. 98* 24 hour mean systolic ABPM (mm Hg) 180 150 Δ = -6. 8± 15. 1 Δ = -4. 8± 17. 3 P<0. 001 159 mm Hg 120 152 mm Hg 160 mm Hg 154 mm Hg Baseline 6 Months 90 60 30 0 (N=360) (N=329) Denervation 4 | MDT Confidential and Proprietary; Do Not Copy or Distribute (N=167) (N=162) Sham *P value for superiority with a 2 mm Hg margin; bars denote standard deviations

Multivariate predictors of systolic blood pressure change at 6 months Covariate RDN group (N=318) Estimate (mm Hg/attempt) P value Baseline Office SBP at ≥ 180 -14. 31089 <0. 0001 Total Number of Attempts -0. 93574 0. 040 Aldosterone Antagonist -9. 77411 0. 002 Vasodilator 7. 55107 0. 005 Baseline Office SBP at ≥ 180 -8. 00441 0. 064 African American race -11. 97485 0. 003 Alpha-1 blocker use -12. 00325 0. 044 Control group (N=169) All covariates are positive predictors for increasing SBP reduction except vasodilator use at baseline which is a negative predictor for SBP drop from baseline Univariate P <0. 2 required to enter the model Kandzari et al, Eur Heart J 2014

6 Learnings from HTN-3 • Procedure • Medication Adherence • Population

Impact of number of ablations on difference in 6 month office SBP change between denervation and propensity matched sham subjects 7 ≤ 9 15 =10 =11 =12 or 13 -5. 0 -4. 1 ≥ 14 12. 1 10 5 0 -0. 4 -5 -10 -15 P value for trend = 0. 01 -14. 1 -20 95% CI 12. 09 [-0. 33, 24. 51] P* 0. 056 RDN SBP -6. 38 ± 23. 04 (33) change (n) Sham SBP -18. 47 ± 27. 85 (35) change (n) -0. 42 [-12. 24, 11. 40] -4. 97 [-15. 32, 5. 38] 0. 943 0. 342 0. 465 0. 061 -14. 99 ± 24. 60 (33) -12. 58 ± 20. 97 (37) -9. 69 ± 16. 49 (35) -24. 27 ± 26. 84 (26) -14. 57 ± 23. 84 (34) -7. 61 ± 23. 62 (37) -5. 56 ± 29. 25 (36) -10. 22 ± 26. 49 (27) Kandzari et al. European Heart Journal: 2014 -4. 13 [-15. 38, 7. 12] -14. 05 [-28. 76, 0. 66] *P value change in SBP for RDN compared with sham

Procedural Variability 8 Goal: To achieve 4 -quadrant ablation pattern for optimal denervation Cross-section of artery Inferior Anterior Superior Lesion 4 quadrant ablation pattern Bhatt, TCT 2014 Posterior

HTN-3: Ablation Pattern Led to Considerable Variation in 6 M SBP Changes RDN Only Office ABPM Home 0 n=253 n=68 n=19 n=236 n=62 n=17 n=248 n=66 n=19 Change in Blood Pressure (mm Hg) -10 -20 -6. 3 -14. 2 -7. 7 -10. 3 -7. 3 -8. 2 -17. 2 -9. 0 -24. 3 -30 RDN + Crossover Office 0 ABPM n=314 n=83 n=27 n=289 n=76 n=24 n=308 n=82 n=27 -6. 4 -10 -20 Home -14. 6 -7. 50 -8. 2 -12. 1 -8. 2 -16. 7 0 Four-quadrant ablations -30 -27. 3 1 Four-quadrant ablation (Right or Left) Four quadrants = 1 superior, 1 inferior, and 2 posterior -10. 60

New View of Renal Nerve Distribution 10 Renal nerves have a positional bias on radial distance from the arterial lumen: distal nerves are closer Distal Proximal Prior concept – Uniform radial distribution Distal Proximal Current concept – Non-uniform radial distribution

Summary of Knowledge Gained 11 • Procedural variability impacts efficacy of denervation procedure • 4 -quadrant ablation pattern appears to correlate with more consistent reduction in blood pressure • Renal nerves are closest to the lumen at the distal portion of the renal artery • Pre-Clinical & Clinical data suggest that a combination of branch & main renal artery treatments will produce a larger and more consistent decrease in blood pressure

12 Learnings from HTN-3 • Procedure • Medication Adherence • Population

Medication Adherence Issues 13 • Medications were a potential confounder in HTN-3 – Protocol required patients be on maximum tolerated doses of at least 3 hypertension medications – Patients were on an average of 5 antihypertensive medications – Despite the protocol requirement, many patients changed medications during the study – Drug adherence not measured but believed a key uncontrolled variable

HTN 3: Medication Changes to 12 Months Baseline to 6 -Months Patients With Medication Changes (%) 60 50 40 44% 39% 60 53% 50 51% 39%* 40 30 30 20 20 10 10 0 0 RDN 6 Months to 12 Months Sham N = 139 RDN Crossover N = 72 Non-Crossover *p=0. 036 for difference from RDN group

Changes in Antihypertensive Medication Denervation group (n=364) Sham group (n=171) Baseline number of medications 5. 1 ± 1. 4 5. 2 ± 1. 4 6 month number of medications 5. 0 ± 1. 4 5. 2 ± 1. 6 Medication change SV 1 to SV 2 18 (4. 9%) 13 (7. 6%) Any medication change between baseline and 6 months 139 (38. 2%) 72(40. 3%) >1 change between baseline and 6 months 67 (18. 4%) 38 (22. 2%) Decreased number of medications or doses 52(14. 3%) 23 (12. 8%) Increased number of medications or doses 31 (8. 5%) 17 (9. 9%) Combination of increases and decreases in medication and/or dose 56 (15. 3%) 32 (18. 7%) Medication change related to an adverse event or symptom change 65 (17. 9%) 29 (17. 0%) Medication change related to SBP <115 mm Hg 75 (20. 6%) 45 (26. 3%) Medication change related to SBP increase >15 mm Hg 14 (3. 8%) 5 (2. 9%) Reasons for Medication Changes * Data are mean (SD) or n (%); SV = screening visit * More than 1 reason for a change could be documented

Summary of Knowledge Gained 16 • Medication adherence likely impacted the HTN-3 results • Complexity of medication regimen impacts adherence • Maximum tolerated dose of 3+ medications is not sustainable as a large % of patients required modifications to their medication

17 Learnings from HTN-3 • Procedure • Medication Adherence • Population

Change in SBP at 6 M Within Pre-specified Subgroups 18

A Large SBP Drop occurred in the African American Control Group Change in Office SBP at 6 Months (mm Hg) 0 Non-African American N=264 N=120 N=85 N=49 -5 -8. 6 -10 -15 -20 -15. 2 -15. 5 -6. 6 [-11. 8, -1. 4] P=0. 01 Baseline 179. 5 SBP, mm. Hg RDN Sham 178. 6 -17. 8 2. 3 [-7. 3, 11. 8] P=0. 64 180. 6 183. 9 Flack, TCT 2014

Systolic blood pressure change, mm Hg African American Control Subjects on Vasodilators had a Large BP Drop: Is Regimen Complexity and Change in Adherence a Confounding Factor? 0 Non-African American on Vasodilators Not on Vasodilators N=92 N=49 N=42 N=28 N=181 N=72 N=48 N=22 -5 -5. 9 -10 -15 -10. 3 -10. 4 -12. 3 -12. 7 Sham -4. 4 [-12. 9, 4. 1] p=0. 30 -17. 6 -20 -21. 9 -25 Baseline SBP, mm. Hg -18. 2 -7. 1 [-13. 7, -0. 6] p=0. 03 -5. 6 [-19. 2, 8. 1] p=0. 42 9. 6 [-4. 0, 23. 2] p=0. 16 -30 178. 9 180. 9 RDN 180. 6 187. 1 179. 8 177. 1 180. 6 179. 9

HTN 3 -Regional Variability: Systolic office and ambulatory blood pressure change at 6 months by Region Social-economic factors may have had an effect on the level of compliance Office -4. 5 -5. 3 -15. 8 -4. 4 Northeast -10. 0 -16. 6 Midwest Southeast 2. 2 -1. 3 Office -8. 4 -4. 5 ABPM -8. 3 West ABPM Office ABPM -5. 0 South -8. 1 -12. 7 -7. 6 -15. 6 -8. 4 ABPM -14. 2 -16. 1 RDN Control

True Population Difference With African Americans? 22 • Other factors beyond ethnicity may have played a role in the different outcomes in African Americans vs non-African Americans – Important to note the RDN groups responded similarly • Large sham response observed in the South and South East where there was a higher proportion of African Americans – However, Non-African Americans also saw a similar sham response in those regions implying regional treatment or behavior differences • Certain medications (complex daily regimens, vasodilators) were more often prescribed in African Americans creating the potential for increased adherence issues in specific subgroups

Summary of Knowledge Gained 23 • Perceived population differences (AA vs non-AA) likely related to factors other than race (i. e. patient behavior, specific drugs prescribed, complexity of drug regimen) • Future renal denervation studies should study a less severe resistant hypertension population

Many Learnings from HTN-3, But Questions Remain 24 • Is there a synergistic, neutral, or antagonistic relationship between RDN and antihypertensive drugs? • Will taking an “off-meds” approach lead to a greater drop in blood pressure? – Study populations ON and OFF medications? • What is the impact of branch treatment on blood pressure? – Assess the impact of branch treatment • Can we minimize the issue of drug adherence? – Enroll stable patients on less complex medication regimes that could lead to increased adherence