1. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Renal Denervation: Overview James R. Margolis, MD Miami, FL USA INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium

2. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Disclosure Royalties Vessix Vascular/Boston Scientific Stockholder Boston Scientific INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium

3. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Teaching Points Renal denervation is an effective way to lower blood pressure. The Symplicity system works, but there is a better way. Why HTN 3 was flawed. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium

4. More than one quarter of adults in developed societies are affected by hypertension 45%30M Japan 21%182M China 21%118M India 38%78M Latin America 44%81M Europe 34%75M U.S. 2 34%75M U.S. Kearney et al. Lancet 2005;365:217-23 Lloyd-Jones et al. Circulation 2010;121:e46–e215 Wolf-Meier et al. JAMA 2003;289:2363–2369 Journal of Human Hypertension 2004;18:911-912

5. Global Burden of Hypertension is Substantial and Growing Total Hypertensive Population (M) Global Prevalence (%) Year Kearney PM: Lancet 2005;365:217–223

6. PI-136107-AE Oct 2013-6 of 43 Hypertension leads to an increased risk of death from stroke and heart disease 2x 4x4x 8x8x Systolic BP / Diastolic BP (mmHg) Cardiovascular Mortality Risk 1 Chobanian et al. Hypertension 2003;42:1206-1252 2 Lancet 2002;360:1903-1913 CV mortality risk doubles for every 20 mmHg increase in systolic blood pressure CV mortality risk doubles for every 20 mmHg increase in systolic blood pressure

7. PI-136107-AE Oct 2013-7 of 43 Systolic BP Reductionand CVD Mortality Meta-analysis of Hypertension Trials  Systolic BP (control - experimental, mm Hg) Cardiovascular Mortality Odds Ratio Staessen JA et al. Lancet. 2001;358:1305 -1315. 1.50 1.25 1. 00 0.75 0.50 0.25 -5 0 5101520 25 P =.003 MIDAS/NICS/VHAS UKPDS C vs A INSIGHT HOT L vs H HOT M vs H MRC1 MRC2 SHEP HEP EWPHE RCT70-80 Syst-Eur STONE Syst-China UKPDS L vs H HOPE PART2/SCAT ATMH STOP1 CAPPP STOP2/CCBs STOP2/ACEIs NORDIL

8. PI-136107-AE Oct 2013-8 of 43 Courtesy Adam Witkowski, MD PhD

9. Efferent Nerve Activity: Renal Artery Vasoconstriction Sodium and Fluid Retention Enhanced Renin Release Afferent Nerve Activity: Systemic Sympathetic Neural Stimulation LV Hypertrophy Systolic Heart Failure Heart Failure with preserved ejection fraction (HFpEF) Arrhythmia The Hyperactive Sympathetic Nervous System is a Driver of Hypertension HF = Heart Failure; HFpEF= HF with preserved Ejection Fraction; LV = Left Ventricle; RAS = Renin-Angiotensin-Aldosterone Doumas et al. Am J Cardiol 2010;105:570-576 Cleveland Clinic Journal of Medicine 2012; 79: 501-10

10. PI-136107-AE Oct 2013-10 of 43 Hypertension begets hypertension. Correction of hypertension resets the feedback loop. Feedback Loop

11. Surgical interruption of the sympathetic nervous system (Sympathectomy) Used to treat hypertension 75 years ago Smithwick. JAMA. 1953 Prolonged hospitalization Hypotension Blood pressure levels 10 years after Sympathectomy in 31-year-old patient Although effective, this procedure led to many adverse events: Syncope Impotence Difficulty walking 103 58 99 72 124 88 132 80 Blood Pressure Levels, mm/Hg Time in Years Operation 180 122 88 64 110 78 200 160 120 80 40

12. Chronology of Anti-hypertensive Drug Development 1940s1950s1960s1970s1980s1990s2000s Effectiveness Side Effects Peripheral Sympatholytics Ganglion Blockers Veratrum Alkaloids Direct Vasodilators Thiazide Diuretics Central Alpha 2 Agonists Non-DHP CCBs Beta Blockers Alpha Blockers DHP CCBs ACE Inhibitors ARBsDRIs Blessing, Leipzig Interventional Course, 2010 ACE = angiotensin-converting-enzyme; ARB = angiotensin receptor blocker; CCB = calcium channel blocker; DHP = dihydropyridine; DRI =direct renin inhibitors 38% of HTN population remain Uncontrolled 9% of HTN population remain resistant

13. Medtronic Symplicity System

14. PI-136107-AE Oct 2013-14 of 43 Effect of renal sympathetic denervation on muscle sympathetic nerve activity (MSNA) over 12 months of follow-up (FU). Krum H et al. Circulation 2011;123:209-215 Copyright © American Heart Association

15. Proof of Concept Symplicity HTN-1: Human Feasibility, Safety and Efficacy Registry Change in Office Blood Pressure Through 36 Months DBP=diastolic blood pressure; SBP=systolic blood pressure Krum, H. ESC 2013. P<0.01 for ∆ from BL all time points

16. Lancet. 2010;376:1903-1909 Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909 Study design: randomized, controlled, clinical trial Patients: 106 patients randomized 1:1 to treatment with renal denervation vs. control Clinical Sites: 24 centers in Europe, Australia, & New Zealand 16 Symplicity HTN-2

17. Primary Endpoint: 6-Month Office BP ∆ from Baseline to 6 Months (mmHg) 33/11 mmHg difference between RDN and Control (p<0.0001) 84% of RDN patients had ≥ 10 mmHg reduction in SBP 10% of RDN patients had no reduction in SBP 17 Systolic Diastolic SystolicDiastolic Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909 Symplicity HTN-2

18. From presentation by Michael Böhm

19. PI-136107-AE Oct 2013-19 of 43 SYMPLICITY HTN-2: BP Reductions Sustained to 3 Years* Sustained Reductions in the Pooled (RDN and Crossover) Group** p<0.01 at all time points ∆ from Baseline to 36 Months (mmHg) 30M n= 69 24M n= 69 6M n= 84 12M n= 80 18M n= 74 Systolic Diastolic 36M n= 40 Expanded results presented at the Transcatheter Cardiovascular Therapies annual meeting 2013 ** Only patients in the RDN group reached the 36 month follow up visit * Reference: Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension. The Lancet. 2010; 376: 1903–1909.

20. PI-136107-AE Oct 2013-20 of 43 Response Rate ≥ 10 mmHg Sustained Through 36 Months ** Expanded results presented at the Transcatheter Cardiovascular Therapies annual meeting 2013 ** Only patients in the RDN group reached the 36 month follow up visit * Reference: Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension. The Lancet. 2010; 376: 1903–1909.

21. MDT Symplicity MDT Spyral STJ EnligHTN COV OneShot ReCor Gen- 2 Paradise JNJ ThermoCool BSC Vessix CE Mark No No Catheter Design Catheter with single electrode Pigtail Catheter 4 electrodes Basket with four electrodes Balloon catheter helical electrode and cooling Balloon catheter; internal cooling; Circumferential treatment Pigtail catheter with 5 electrodes and cooling Balloon catheter 4-8 electrodes Balloon No No Guidewire No No No Energy Monopolar RF Monopolar RF Monopolar RF Monopolar RF Ultrasound Monopolar RF Bipolar RF Power 8WUnknown8W25W~12WUnknown~1W Energy Delivery Time 2 min.1 min.60 sec2 min.30 sec.Unknown30 sec. Total Treatment Time 16-24 min.2 min.4 min. 3 min.Unknown2 min. Renal Denervation Technologies None of these devices are available for sale in the US. Medtronic Website, March 2013; The New Medtronic Device, Weil, TRENDS Frankfurt 2013; Worthley, S. EuroPCR 2013; Covidien (Maya) Presentation; Ormiston et al. EuroIntv. 2013. The ReCor Device, Weil, TRENDS Frankfurt 2013; Sievert, Live Case, TRENDS, Frankfort 2013; LINC 2013, Live Case ReCor; J&J Thermocool Bertog, TRENDS Frankfurt 2013. * Vessix™ is an investigational device and not available for sale in the US. RF=Radiofrequency; W=Watt

22. Vessix™ Renal Denervation System* Technology Overview RF=Radiofrequency; TGA=Therapuetic Goods Administration, AU Regulatory Authority Balloon-based technology (4 - 7 mm diameters) Balloon-based technology (4 - 7 mm diameters) Helical pattern of bipolar radiofrequency electrodes for uniform treatment Helical pattern of bipolar radiofrequency electrodes for uniform treatment 30 second treatment time 30 second treatment time All electrodes activated simultaneously All electrodes activated simultaneously Bipolar energy delivery, ~1 Watt Bipolar energy delivery, ~1 Watt Temperature-controlled algorithm ensures energy delivery at 68°C Temperature-controlled algorithm ensures energy delivery at 68°C One button operation One button operation CE-marked and TGA-approved CE-marked and TGA-approved

23. Vessix™ Renal Denervation System Bipolar RF Energy for Renal Denervation Localized energy delivery from positive to negative poles; no grounding pad No need for cooling Reduced impact of treatment variability Low energy of ~1W delivered Energy dispersed through the body; terminates in grounding pad Cooled via blood flow and/or irrigation Increased impact of treatment variability Higher energy required Bipolar RF Monopolar RF

24. RF treatment can be tailored to length of the artery landing zone RF treatment can be tailored to length of the artery landing zone Electrodes that are unapposed to vessel wall are automatically deactivated Electrodes that are unapposed to vessel wall are automatically deactivated Vessix™ System RF Balloon Catheter RF=Radiofrequency

25. Boston Scientific Renal Denervation Program REDUCE-HTN Clinical Series Studies evaluating the Vessix System technology in the currently defined hypertension space: REDUCE-HTN FIM Study REDUCE-HTN Post Market Study REDUCE-HTN Global Pivotal Study REDUCE-HTN Regional Reg. Approval Studies REDUCE-HTN EU Post Market Trial RELIEVE Clinical Series Includes pre-clinical, clinical and investigator initiated research evaluating the Vessix System technology in additional disease states: RELIEVE - End Stage Renal Disease RELIEVE - Heart Failure RELIEVE - Atrial Fibrillation RELIEVE - Diabetes Vessix™ Global Clinical Program > 1200 patients planned worldwide * Vessix™ is an investigational device and not available for sale in the US.

26. REDUCE HTN FIM – CE Mark and TGA Approval Multicenter, Non-randomized, feasibility N = 18 REDUCE HTN Post Market Study Multicenter, Non-randomized, post market surveillance N = 128 Boston Scientific Renal Denervation REDUCE-HTN Clinical Series Enrollment Complete / In Follow-Up Year 1 Global Pivotal Study Multicenter, randomized (2:1), superiority N = 550 European Post Market Trial Multicenter, Non-randomized, post market N = 500 Planning / Target Enrollment to begin Q4 2013 Regional Regulatory Approval Studies Multicenter, Non-randomized, prospective, single cohort N = TBD

27. Efficacy Endpoint – Reduction of SBP and DBP (Office Based and ABPM) at six months post procedure compared to baseline Safety Endpoint – Acute Safety Renal artery dissection or perforation during the procedure that requires stenting or surgery Renal artery infarction or embolus Cerebrovascular Accident (CVA) at time of procedure Myocardial infarction at time of procedure Sudden cardiac death at time of procedure – Long-term Safety Renal stenosis requiring an intervention documented by angiography Absence of flow limiting stenosis in the renal artery at six (6) months measured by duplex ultrasound core laboratory SBP=Systolic Blood Pressure; DBP=Diastolic Blood Pressure; ABPB=Ambulatory Blood Pressure Monitoring; PMS=Post Market Study. REDUCE-HTN PMS Study Endpoints

28. REDUCE-HTN Case Bipolar RF Technology on a Balloon for the treatment of smaller arteries Small diameter renal arteries and accessory renal arteries treated with the Vessix™ system RF=Radiofrequency Images of REDUCE-HTN case. Results from case studies are not predictive of results in other cases. Results in other cases may vary.

29. REDUCE-HTN Case Bipolar RF Technology on a Balloon for the treatment of smaller arteries RF=Radiofrequency Right accessory renal artery pre treatment Distal balloon placemetn – 5mm Proximal balloon placement – 5mm Images of REDUCE-HTN case. Results from case studies are not predictive of results in other cases. Results in other cases may vary.

30. REDUCE-HTN Case Continued Patency, No spasm RF=Radiofrequency Images of REDUCE-HTN case. Results from case studies are not predictive of results in other cases. Results in other cases may vary. Right accessory renal artery pre treatment Right accessory renal artery post treatment

31. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium P<.0001 for each timepoint vs baseline. Error bars represent 95% confidence bounds. Significant Office Blood Pressure Reductions Over Time BP=blood pressure Sievert, H. CRT 2014. * Vessix™ is an investigational device and not available for sale in the US. Mean reduction in office-based BP was 24.7/10.3 mmHg at 6 months (P<.0001)

32. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium P<.0005 for each timepoint vs baseline. Error bars represent 95% confidence bounds. Significant Office Blood Pressure Reductions for Patients with Treated Accessory Renal Arteries (n=24) BP=blood pressure Sievert, H. CRT 2014. * Vessix™ is an investigational device and not available for sale in the US.

33. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Most Bets Are Won and Lost on the First Tee My shoulder hurts. I was up all night. I haven’t played in a long time. I never played this course before. I need extra strokes.

34. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Results of Clinical Studies are Highly Dependent on Their Protocols

35. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium The SYMPLICITY HTN-3 Clinical Trial Medtronic is sponsoring a clinical trial that will involve more than 500 patients at up to 90 hospitals in the United States. The purpose of this study is to provide additional information about a medical device intended to help treat high blood pressure in people whose blood pressure is not controlled despite treatment with multiple blood pressure medications. The study is "Controlled", meaning some of the patients will be treated with the device (the "Treatment Group") and some will NOT be treated with the device (the "Control Group"), and the results of the two groups will be compared. This study is "Randomized" meaning that patients who are confirmed to be eligible will be randomly assigned to one of two groups. Each patient has a 2 to 1 chance of being assigned to the treatment group. This means you are twice as likely to be in the treatment group rather than the control group. At 6 months, those who were in the control group and remain eligible may be able to have the treatment if they wish. This study is also "Blinded" meaning that patients will not be told which group they are assigned to, and certain procedures will be followed to prevent patients from knowing which group they are in. This study design is necessary to properly evaluate the safety and effectiveness of the investigational device and procedure.

36. PI-136107-AG Feb 2014-36 of 43 Superiority Margin A superiority by a margin tests that the treatment mean is better than the reference mean by more than the superiority margin. Most clinical trials designed to demonstrate superiority assume the margin is zero. That is, the goal is to prove that any significant difference exists. SYMPLICITY HTN-3 was designed to demonstrate that RDN was much better than control. Therefore, chose to perform a more stringent and rigorous comparison and selected a superiority margin of 5 mm Hg. Courtesy I Patrick Kay, MD PhD

37. PI-136107-AG Feb 2014-37 of 43 Illustrative examples of endpoint scenarios, either meeting or not meeting the set assumptions for the primary endpoint (PE) Primary Efficacy Endpoint Assumptions 15 0 5 10 Does Not Meet Meets PE Does Not Meet Relative drop in office systolic blood pressure between treatment and control Courtesy I Patrick Kay, MD PhD

38. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium SYMPLICITY HTN-3 fails to meet primary efficacy endpoint Thursday, 09 Jan 2014 12:24

39. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Symplicity HTN 2 vs 3 Symplicity 2 190 assessed 106 patients enrolled Enrollment one year 24 Centers Average enrollment/center 4 patients Symplicity 3 1000+ assessed 535 patients enrolled Enrollment 2+ years 89 centers Average enrollment/center 6 patients

40. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Primary Endpoint: 6-Month Office BP ∆ from Baseline to 6 Months (mmHg) 33/11 mmHg difference between RDN and Control (p<0.0001) 84% of RDN patients had ≥ 10 mmHg reduction in SBP 10% of RDN patients had no reduction in SBP 40 Systolic Diastolic SystolicDiastolic Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909 Symplicity HTN-2

41. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Why Did HTN-3 Fail to Meet Primary Endpoint? Do not know. Control group not truly refractory? Insufficient drop in BP in treated group? – Operators inexperienced? – Treated patients stopped their meds? Endpoint too ambitious? Maybe we will know in 2½ weeks.

42. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Pneumococcal Pneumonia Study 1942 Untreated pneumococcal pneumonia carried 80% mortality. Treated with Penicillin, expected mortality 20%. Using these numbers as results, a 10 patient study (5 treated, 5 placebo) would be positive in favor of PCN at p <.0000001

43. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Hypothetical study for FDA approval of PCN for Pneumococcal Pneumonia Indication 1942 500 patient RCT drug vs. placebo. Cannot consent placebo patients, because they have heard about “wonder drug.” Penicillin supplies preferentially shipped to soldiers in Europe. Patients (placebo and control) obtain their own PCN on the black market, but not in time for early treatment. 50% mortality in both groups. Conclusion: no benefit from PCN for pneumococcal pneumonia. Result: PCN never approved for this indication.

44. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium How Do We Avoid Repeat of HTN-3 Debacle? Smaller study – Bigger is not necessarily better. – HTN-2 was positive at.0001 level with only 100 patients. No sham procedure. – Unethical in my opinion. – No rationale to include it. – Seriously hampers patient enrollment. More careful patient selection and monitoring. – Assure patients in both groups are truly refractory. – Make sure treated patients do not stop their medications. Test for superiority as opposed to superiority margin.

45. INTERVENTIONAL CARDIOLOGY 2014 29TH ANNUAL International Symposium Summary Renal denervation is an effective treatment for refractory hypertension. To date, every study with every system has achieved systolic BP reductions of 20-30 mmHg at six to 12 months. Why HTN-3 did not reach its primary endpoint remains a mystery until all of the data is presented. Future studies should have a simpler design: – As with penicillin for pneumococcal pneumonia, we do not need a 500 patient RCT to prove effectiveness. – A 100 patient RCT is already overkill.

46. Thank you