Renal Denervation Rises From the Ashes Moderator David E. Kandzari, MD Chief Scientific Officer Director of Interventional Cardiology Piedmont Heart Institute Atlanta, Georgia

Panelists Michael Böhm, MD, PhD Franz Messerli, MD Cardiologist in Chief Director Department of Internal Medicine 3 Saarland University Homburg, Germany Franz Messerli, MD Department of Cardiology Bern University Hospital Bern, Switzerland Mount Sinai Health Medical Center New York, New York Jagiellonian University Krakow, Poland Roland E. Schmieder, MD Professor University Hospital Friedrich-Alexander-University Erlangen-Nürnberg Erlangen, Germany Panelists Layout (Title slide layout)

Program Goals Renal denervation: Where we have been and where we are heading? Important clinical trial data presented At ESC ESC = European Society of Cardiology

Hypertension HTN is a leading contributor to morbidity and mortality worldwide The prevalence has remained steady over time It is essential to lower BP however it may be achieved Typically, that BP was controlled with pharmacology Role of device therapy needs to be established BP = blood pressure HTN = hypertension Image similar to this one https://www.shutterstock.com/image-photo/cropped-image-male-doctor-checking-blood-369919787?src=ZtKIrOq48Req6JOmEifgjQ-1-3

SYMPLICITY HTN-3: Design Patient and research staff performing 1-, 3-, and 6-month follow-ups are blinded to treatment status No change in medications for 6 mo 30 days or maximum 6 wk in exceptional circumstances 2 wk Confirming Screening Office SBP ≥ 160 mm Hg Documented medication compliance Lab work 24-hr ABPM SBP ≥ 135 Home BP & Medication Confirmation Renal Angiogram If eligible anatomy, randomize "on the table" 3 mo 1 mo 6 mo Control Treatment Primary End Point 12 - 60 mo Initial Screening Full tolerated doses of ≥ 3 meds No HTN med changes in past 2 weeks No plan to change meds for 6 mo Medical history Patients with severe drug-resistant HTN (office SBP ≥ 160 mm Hg) 2:1 randomization Sham procedure in control patients included renal angiogram N = 535 (63% screen failure rate) Primary efficacy end point: Change in office SBP Primary safety end point: MAE through 1 mo, including renal artery stenosis within 6 mo ABMP = ambulatory blood pressure monitoring HTN = hypertension MAE = major adverse event SBP = systolic blood pressure MAE defined as all-cause mortality, ESRD, embolic event resulting in end-organ damage, renal artery or other vascular complication, hypertensive crisis through 30 days including new renal artery stenosis within six months 2 wk Bhatt DL, et al. N Engl J Med 2014;370:1393-1401.

SYMPLICITY HTN-3: 6-Month Results Mean change in SBP -14.13 ± 23.93 mm Hg in RDN group vs -11.74 ± 25.94 mm Hg in sham-procedure group P <.001 for both comparisons of the change from baseline Difference -2.39 mm Hg (95% CI: -6.89, 2.12; P =.26) for superiority with a margin of 5 mm Hg Bhatt DL, et al. N Engl J Med 2014;370:1393-1401.

SPYRAL HTN-OFF MED: Design Randomized, sham-controlled, single-blinded trial* The SPYRAL HTN-OFF MED trial is evaluating renal denervation in the absence of any antihypertensive medications compared to a sham-controlled population. Prior to randomization, patients will undergo an antihypertensive medication washout period of three to four weeks. Patients in both groups will be systematically titrated back into anti-hypertensive medical therapy as appropriate three months following randomization. The off-medication trial will help isolate the effect of renal denervation on blood pressure reduction, and was requested by both the FDA and many clinicians. * Only for patients discontinuing anti-hypertensive medications. Kandzari D, et al. Am Heart J. 2016;171:82-91.

SPYRAL HTN-OFF MED Content no longer available Key Patient Eligibility Criteria Inclusion[a] Patient is either: Not on antihypertensive medications, OR Permitting discontinuation of drug therapy 2. Office SBP ≥ 150 and < 180 mm Hg 3. Office DBP ≥ 90 mm Hg 4. Systolic 24-hour mean ABPM ≥ 140 and < 170 mm Hg Content no longer available eGFR = estimated glomerular filtration rate HbA1c = glycated hemoglobin Exclusion[a,b] Ineligible renal artery anatomy (accessory arteries allowed) eGFR < 45 mL/min/1.73m2 Type 1 diabetes mellitus or type 2 diabetes mellitus with HbA1C > 8.0% Secondary causes of HTN a. Kandzari D, et al. Am Heart J. 2016;171:82-91; b. Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

SPYRAL HTN Clinical Program Multi-electrode catheter with quadrantic vessel contact for simultaneous ablation in up to 4 electrodes 60-second simultaneous energy delivery Vessel diameter range: 3 mm to 8 mm Flexible catheter allows branch treatment 6F guiding catheter compatible We have permission from Medtronic to use these images but they should be referenced as Bohm Study device: Symplicity Spyral™ catheter Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

SPYRAL HTN-OFF MED Medication Adherence % (n) RDN Sham Control P No anti-HTN drug identified by drug testing: At baseline 92.1% (35/38) 88.1% (37/42) .72 At 3 mo 94.3% (33/35) 92.7% (38/41) 1.00 At baseline and 3 mo 88.6% (31/35) 82.9% (34/41) .53 Patients meeting escape criteria (n) 2 4 HPLC = high-performance liquid chromatography RDN = renal denervation Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain Drug testing of urine and serum by tandem HPLC and mass spectroscopy Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

SPYRAL HTN-OFF MED Blinding Procedure and Efficacy All patients underwent renal angiography Conscious sedation Sensory isolation (eg, blindfold and music) Lack of familiarity with procedural details and expected duration Assessed by blinding questionnaire at discharge and 3 months: Time Blinding Index* 95% CI Discharge 0.65 (0.56, 0.75) 3 mo 0.59 (0.49, 0.70) *Blinding Index >0.5 indicates successful blinding. Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

SPYRAL HTN-OFF MED Results: 24-H ABPM BP Change from Baseline to 3 mo Systolic Diastolic Baseline BP (mm Hg) 154 152 100 99 n = 35 n = 36 n = 35 n = 36 Δ -5.0 mm Hg (-9.9, -0.2) P =.04 Δ -4.4 mm Hg (-7.2, -1.6) P =.002 Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

SPYRAL HTN-OFF MED Results: Office BP BP Change from Baseline to 3 mo Systolic Diastolic Baseline BP (mmHg) 162 161 100 101 n = 37 n = 41 n = 37 n = 41 Δ -4.9 mmHg (-8.5, -1.4) P =.008 Δ -7.7 mmHg (-14.0, -1.5) P =.02 Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

SPYRAL HTN-OFF MED: Conclusions Biologic proof of principle for the efficacy of RDN Clinically meaningful BP reductions at 3 months In mild to moderate patients with HTN treated with RDN in the absence of antihypertensive medications vs sham control No major safety events Despite a more complete RDN procedure that extended into renal artery branch vessels The results of this feasibility study will inform the design of a larger pivotal trial

SPYRAL HTN-OFF MED: Limitations Proof-of-concept trial, not prospectively powered for statistical significance Anti-HTN drugs were detected in the blood/urine of some patients despite off-med protocol Results in the modified ITT and PP populations were consistent Similar results observed after adjustment for baseline BP (ANCOVA) in all groups No practical methods to verify nerve destruction Results may not be generalizable to other RDN technologies ANCOVA = analysis of covariance ITT = intention to treat PP = per protocol Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

SPYRAL HTN-ON MED: Design Content no longer available Kandzari D, et al. Am Heart J. 2016;171:82-91.

Advances of SPYRAL HTN Compared to SYMPLICITY HTN-3 SPYRAL vs HTN-3 Advances of SPYRAL HTN Compared to SYMPLICITY HTN-3 Medications Patients Procedure SYMPLICITY HTN-3[a] 5.1 anti-HTN drugs at time of randomization No drug adherence testing Resistant HTN patients (Office SBP 180±16) No diastolic cutoff Mono-electrode, sequential ablation system Mostly inexperienced operators without proctoring Main artery RDN only Ablations per pt: 11.2 ± 2.8 SPYRAL HTN[b,c] No anti-HTN drugs at time of randomization Drug adherence testing by plasma and urine Moderate HTN patients (Office SBP 162±7) Excluding ISH patients (Office DBP 101±7) Four-electrode, simultaneous ablation system Highly experienced operators with proctoring Main + branches RDN Ablations/pt: 43.8 ± 13.1 ISH = isolated systolic hypertension a. Bhatt DL, et al. N Engl J Med. 2014;370:1393-13401; b. Kandzari D, et al. Am Heart J. 2016;171:82-91; c. Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

What Do the Results Mean? Will reduction in BP due to RDN ultimately translate into a reduction of stroke, heart attack, heart failure, and death?

Meta-Analysis: Intensive BP Lowering Patients in the more intensive BP-lowering treatment group had a mean BP level of 133/76 mm Hg vs 140/81 mm Hg in the less intensive treatment group Intensive BP-Lowering Treatment RR Reductions   RR 14% (95% CI: 4, 22) RR 13% (95% CI: 0, 24) RR 22% (95% CI: 10, 32) Risk Reduction,% MACE = major adverse cardiovascular events MI = myocardial infarction RR = relative risk Xie: Intensive blood pressure-lowering treatment achieved RR reductions for major cardiovascular events (14% [95% CI 4-22]), myocardial infarction (13% [0-24]), stroke (22% [10-32]), Xie X, et al. Lancet. 2016;387:435-443.

SPYRAL HTN-OFF MED Medication Adherence % (n) RDN Sham Control P No anti-HTN drug identified by drug testing: At baseline 92.1% (35/38) 88.1% (37/42) .72 At 3 mo 94.3% (33/35) 92.7% (38/41) 1.00 At baseline and 3 mo 88.6% (31/35) 82.9% (34/41) .53 Patients meeting escape criteria (n) 2 4 Drug testing of urine and serum by tandem HPLC and mass spectroscopy Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

Antihypertensive Medication Patients often not willing to take medications, adherence rates in trials is often around 50% RDN could be a third option to manage HTN beyond lifestyle and medications It may delay the need for medication HTN is a progressive disorder and many patients undergoing RDN may eventually need medication RDN may enable a reduction in the number/dose of medication Need more data  Something similar, multiple RXs https://www.shutterstock.com/image-photo/conceptual-shot-taking-many-drugs-drug-924822?src=pQABwLezFUX1MOGw3NVFVQ-1-12

Antihypertensive Medication (cont) Patients who may remain normotensive without medication include those with: Young age Normal body weight Low salt intake No alcohol consumption Low pretreatment BP Successful therapy with one drug only No/minimal signs of target organ damage  Schmieder RE, et al. JAMA. 1991;265:1566-1571.

Device Therapy Device therapy is complimentary to medical therapy not instead of it Getting to BP goal, whatever that goal maybe, is important and meaningful for the patient Patient preference is important, many do not want a pill burden for the rest of their lives Device therapy may allow reduction, or, in some cases be an alternative to medication RD vs medication will be investigated in SPYRAL HTN- ON MED[a] a. Kandzari D, et al. Am Heart J. 2016;171:82-91.

Patients in Trials Patients who enroll in trials tend to be open-minded and more interested in medical interventions In heart failure trials, patients agreeing to take part in a trial compare to a matched population, who did not take part in the trial, have a better survival Registry will determine how the procedure is doing in real life practice Importantly, patients who are not adherent to the protocol and took other medication were equally distributed in the sham group and in the treatment group

Study device: Symplicity Spyral™ catheter SPYRAL Program Procedures were done with a different technology and in a very different way RDN was extended into the branch vessels of the renal architecture of the vasculature May not be a class effect, rather this specific approach is the one that is effective Study device: Symplicity Spyral™ catheter Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

Conclusions SPYRAL HTN-OFF Med demonstrated that RDN is effective in reducing BP as measured by 24-hour ABPM Considered to be the gold standard to analyze any anti-HTN efficacy Next step: more patients, broader inclusion criteria Which other patients will profit most from RDN? BP reduction with pharmacological therapy remains a focus of interest

SPYRAL HTN-OFF MED Safety Results at 3 Months RDN (n = 38) Adverse Events, % RDN (n = 38) Sham Control (n = 42) Death New MI Major bleeding (TIMI) New onset ESRD Serum creatinine elevation >50% Significant embolic event resulting in end-organ damage Vascular complications Hospitalization for HTN crisis/emergency New stroke TIMI = Thrombolysis In Myocardial Infarction ESRD = end-stage renal disease Data presented by Böhm M, et al. European Society of Cardiology Congress, Late-Breaking Clinical Trials 2, August 28, 2017, Barcelona, Spain.

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