Uncontrolled Hypertension – a new approach

1. Uncontrolled Hypertension – a new approach Charles McCreery FRCPI, FACC

2. Hypertension Epidemiology c • Single largest contributor to death worldwide • Every 20/10 mmHg increase in BP correlates with a doubling of 10-year cardiovascular mortality • Dramatically increases risk of stroke, heart attack, heart failure, & kidney failure • Only half of all treated hypertensives are controlled to established BP targets • High prevalence: • Affects 1 in 3 adults • 1B people worldwide  1.6 B by 2025 35% Treated but Uncontrolled 30% Untreated 35%Treated &Controlled Chobanian et al. Hypertension.  2003;42(6):1206–1252. 2

3. Definitions and Classification of Blood Pressure Levels Hypertension is defines as systolic blood pressure (BP) greater than 140mmHg and a diastolic BP greater than 90mmHG • Goal BP for hypertension patients2 • General Population: < 140/90 mmHg • Individuals with diabetes mellitus or chronic kidney disease < 130/80mmHg • Table modified from Carretero OA, et al. Essential hypertension, Part 1: Definition and etiology. Circulation. 2000;101(3):329-35 • Rosendorff CR, et al. Treatment of Hypertension in the prevention and management of ischemic heart disease: A scientific statement from the American Herat Association Council for High Blood Pressure Research and the Councils on Clinical cardiology and Epidemiology and prevention. Circulation. 2007;115(21):2761-88 3

4. Pharmacological Path Traditional Treatment of Hypertension Follows a Progressively More Aggressive Pharmacological Regimen The goal of pharmacotherapy is to reach a blood pressure of < 140/90 mmHg (goal pressure for diabetic and chronic kidney disease patients is < 130/80 mmHg) (See Figure).1 Patients with stage 1 hypertension are generally initiated on at least one antihypertension drug Patients with stage 2 hypertension are generally initiated on a combination drug therapy comprised of two or more antihypertension drugs * Hypertension may exist in association with other high-risk conditions in which there are compelling indications for use of a particular treatment. These additional treatments must be considered when managing BP.1 Lifestyle Modification • Not at Goal Blood Pressure (<140/90 mmHg) • Initial Drug Choices • Without Compelling Indications* • With Compelling Indications* Stage 1 Hypertension (SBP 140-159 or DBP 90-99 mmHG)Thiazide-type diuretics for most patients Stage 2 Hypertension(SBP ≥ 160 or DBP ≥ 100 mmHG)Two-drug combination for most patients Drug(s) for the compelling indications Other antihypertension drugs as needed • Not at Goal Blood Pressure • Optimize dosages or add additional drugs until goal blood pressure is achieved. Consider referring to a hypertension specialist. Reference 1. Chobanian AV, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure. Hypertension. 2003;42(6):1206-52. 4

5. Elevated Morbidity and Mortality Risk Uncontrolled Hypertension Is a Risk Factor for Cardiovascular Morbidity and Mortality Chronic uncontrolled hypertension is related to cardiovascular conditions such as stroke and heart failure1 The risk of cardiovascular death increases with rising blood pressure, every 20 mmHg rise in SBP doubles the risk of cardiovascular death (See Figure)2-4 *Measurements taken in individuals aged 40-69 years, beginning with a blood pressure of 115/75 mmHg, the data in this graph is from Lewington et al. 20022 References 1. Roger VL, et al. Heart disease and stroke statistics–2011 update: A report from the American Heart Association. Circulation. 2011;123(4):e18-e209. 2. Lewington S, et al. Age-specific relevance of usual blood pressure to vascular mortality: A meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360:1903-13. 3. Chobanian AV, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA. 2003;289:2560-2572. 4. The graph on this page includes data from sources 2 and 3 and was adapted from www.hypertensiononline.org. 5

6. Renal Sympathetic Activation: Efferent NervesKidney as Recipient of Sympathetic Signals Renal Efferent Nerves ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow 6

7. Renal Sympathetic Activation: Afferent NervesKidney as Origin of Central Sympathetic Drive Vasoconstriction Atherosclerosis Hypertrophy Arrhythmia Oxygen Consumption Sleep Disturbances Renal Afferent Nerves Insulin Resistance ↑ Renin Release  RAAS activation ↑ Sodium Retention ↓ Renal Blood Flow 7

10. Surgical History Dr. Reginald H. Smithwick

11. Surgical Sympathectomy Grimson, Ann Surg 1941

12. BP Control Maintained Long Term Peet, Am J Surg 1948

13. Renal Nerve Anatomy • Nerves arise from T10-L2 • The nerves arborize around the artery and primarily lie within the adventitia Vessel Lumen Media Adventitia Renal Nerves 13 13

14. Renal Denervation for the Treatment of Resistant Hypertension and Other Sympathetic Driven CV Conditions Renal sympathetic nerves play a critical role in the initiation and maintenance of systemic hypertension1 Renal denervation is a catheter-based ablation procedure in which transmural lesions are delivered along the walls of the renal arteries to disrupt the sympathetic nerve network located within the arterial adventitia Emerging clinical data supports utilization of renal denervation to reduce blood pressure in patients with resistant hypertension2-3 Esler M. Am J Hypertens. 2000 Jun; 13(6 Pt 2):99S-105S Krum H, et al. Catheter-based renal sympathetic denervation for resistant hypertension: A multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-81 Esler M, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): A randomised controlled trial. Lancet. 2010;376(9756):1903-9 14

15. Renal Nerve Anatomy Allows a Catheter-Based Approach Spacing of e.g. 5 mm. • Renal artery access via standard interventional technique • 4-6 two-minute treatments per artery • Proprietary RF generator • Automated • Low power • Built-in safety algorithms 15

16. TheCatheterSystem •Disablestherenalnervesviathe deliveryofRFenergy •Reducebothefferent&afferent sympatheticeffects •A45-minuteprocedure

17. TreatmentStrategy RenalArtery Treatments Aorta Kidney Focalablations spacedalongvessel Multiplefocalablations ↑circumferentialcoverage

18. TheCatheterSystem •ReleasedEnergymaximum8Watt -Forcomparison:cardiacradiofrequencydevices: 30-55Watt •Temperaturebetween40-75° •Thegeneratorautomaticallyswitchofif temperatureishigherthan75° •Energyapplicationupto5xforeachrenal artery,dependsonlengthoftherenalartery •Amountoftime2minutesper1energy application

19. Procedure

20. Medtronic Ardian Renal Denervation • 30-40 minute procedure femoral artery access guide + ablation catheter in each renal artery 4-8 2 minute ablations each vessel painful - procedural analgesia (Fentanyl) hemostasis - groin haematoma • BP monitoring +/- medication adjustment

21. ExampleofVesselReaction Baseline AcutePost- Treatment 5Week Follow-Up

22. Boston Scientific • RF electrodes and thermistors on balloon • 4-8 gold electrode pairs • 30 sec inflation/ treatment per renal artery

23. Bipolar RF Bipolar RF systems, such as the Vessix V2, deliver energy using the electrical phenomena of ohmic resistive heating to the adjacent tissue and deliver electrical energy between two electrodes, which in the case of the V2 catheter are within a few millimetres of each other.  The V2 confines its energy delivery to an area very close to the two electrodes and moreover, thermistors mounted at each electrode pair allow for precise monitoring and temperature control at each independent electrode pair.  This delivery of energy causes thermal heat to perfuse through the artery wall into the adventitia layer of the artery and results in denervation of the target renal sympathetic nerves. The RF energy treatment, in effect, denervates the renal sympathetic nerves surrounding the renal artery without creating any flow limiting stenosis or any other deleterious effects to the renal artery. Bipolar systems do not unnecessary dissipate energy into areas further away from the electrode, and thus use energy very efficiently.  Accordingly, the V2 bipolar System uses lower voltages and power to achieve necessary depth of penetration.

24. Covidien irrigated RF – single application per artery

26. Ultrasound based Non-focussed high-frequency ultrasound Low pressure balloon with cooled fluid Frictional heating of soft tissues Uniform circumferential denervation

27. “The benefit of ReCor’s ultrasound approach is three-fold,” explained Mano Iyer, CEO of ReCor Medical. “Firstly, PARADISE is designed to penetrate much deeper into the tissue, up to 8 millimeters; secondly, PARADISE delivers heat circumferentially, to target all of the renal nerves in one location; thirdly, PARADISE does this while simultaneously cooling the artery wall’s surface to protect the vessel. “Our unique approach is in stark contrast to RF, which is limited in its depth of penetration to just a few millimeters, due to inconsistent arterial wall contact, as well as its inability to heat circumferentially in any given location,” said Iyer. “In addition, RF technologies generate unnecessary heating at the level of the arterial wall. Data presented at TCT 2012 concluded that renal nerves are actually much further at depth than previously thought, and run circumferentially around the renal arteries, which underscores the PARADISE ultrasound advantage.”

28. Symplicity HTN-1 Lancet. 2009;373:1275-1281 Hypertension. 2011;57:911-917. Initial Cohort – Reported in the Lancet, 2009: • First-in-man, non-randomized • Cohort of 45 patients with resistant HTN (SBP ≥160 mmHg on ≥3 anti-HTN drugs, including a diuretic; eGFR ≥ 45 mL/min) - 12-month data \ Expanded Cohort* – This Report (Symplicity HTN-1): • Expanded cohort of patients (n=153) • 36-month follow-up *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.) 28

29. SYMPLICITY HTN-2 Systolic BP >160mmHg (>150mmHg with type II diabetes) despite 3 or more anti-hypertensive drugs Excluded • eGFR<45mL/min • type 1 diabetes • substantial valvular heart disease • MI/ unstable angina/ stroke < 6 months

30. Office BP at 1, 3 & 6 Months

31. Brief Procedure with a Low Complication rate (n=153) 38 minute median procedure time Average of 4 ablations per artery Intravenous narcotics & sedatives used to manage pain during delivery of RF energy No catheter or generator malfunctions No major complications Minor complications 4/153: 1 renal artery dissection during catheter delivery (prior to RF energy), no sequelae 3 access site complications, treated without further sequelae Symplicity HTN-1 Investigators. Hypertension. 2011;57:911-917. 31

32. Symplicity HTN-1: BP Reductions through 3 years BP change (mmHg) P<0.01 for ∆ from BL for all time points *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

33. Symplicity HTN-1: Percentage Responders Over Time Responder was defined as an office SBP reduction ≥ 10 mmHg *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

34. Symplicity HTN-1: Response Rate AmongNon-responders at 1 Month (n=45) Responder was defined as an office SBP reduction ≥ 10 mmHg *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

35. Conclusions from Symplicity HTN-1 • The magnitude of clinical response is significant and sustained through 3 years • Increasing responder rates indicate: • no loss of treatment effect out to 36 months • BP non-response at 6 months does not predict failure to respond at 12 months or later • The treatment effect was consistent across subgroups (age, diabetes status, and baseline renal function) • No late adverse events were seen *Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Krum, H.)

36. Symplicity HTN-2 Lancet. 2010;376:1903-1909. • Purpose: To demonstrate the effectiveness of catheter-based renal denervation for reducing blood pressure in patients with uncontrolled hypertension in a prospective, 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 (67% were designated hypertension centers of excellence) Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909. 36

37. Symplicity HTN-2 Trial Inclusion Criteria: Office SBP ≥ 160 mmHg (≥ 150 mmHg with type II diabetes mellitus) Stable drug regimen of 3+ more anti-HTN medications Age 18-85 years Exclusion Criteria: Haemodynamically or anatomically significant renal artery abnormalities or prior renal artery intervention eGFR < 45 mL/min/1.73m2 (MDRD formula) Type 1 diabetes mellitus Contraindication to MRI Stenotic valvular heart disease for which reduction of BP would be hazardous MI, unstable angina, or CVA in the prior 6 months • Treatment-resistant HTN population • BL OBP 178/97 mmHg • 49 RDN, 51 Control • Age 58 years • BMI 31 kg/m² • 40% with Diabetes • eGFR 77* • Avg # meds 5.2 • RDN and Control groups generally well-matched *MDRD, ml/min/1.73m2 Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909.

38. Symplicity HTN-2: Patient disposition Assessed for Eligibility (n=190) Screening • Excluded During Screening, • Prior to Randomisation (n=84) • BP < 160 at Baseline Visit (after 2-weeks of medication compliance confirmation) (n=36; 19%) • Ineligible anatomy (n=30; 16%) • Declined participation (n=10; 5%) • Other exclusion criteria discovered after consent (n=8; 4%) Randomised (n=106) 6-month Primary End-Point Allocated to RDN n=52 Treated n=49 Analysable Allocated to Control n=54 Control n=51 Analysable Crossover n=46 12-month Post- Randomisation 2 LTFU Per protocol, 6-mo Post-RDN (Crossover) n=35 Not-per-protocol*, 6-mo Post-RDN (Crossover) n=9 12-month post-RDN n=47 * Crossed-over with ineligible BP (<160 mmHg)

39. RDN and Control Populations Well-matched, Severe Treatment Resistant Hypertensives * n = 42 for RDN and n = 43 for Control. Wilcoxon rank-sum test for two independent samples used for between-group comparisons of UACR. † n = 39 for RDN and n = 42 for Control. Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)

40. Symplicity HTN-2: Primary Endpoint and Latest Follow-up Primary Endpoint (6M post Randomisation) Latest Follow-up (12M post Randomisation) RDN (n= 47) ∆ from Baseline to 6 Months (mmHg) ∆ from Baseline to 12 Months (mmHg) Systolic Diastolic Diastolic Diastolic p <0.01 for difference between RDN and Control Systolic Systolic p <0.01 for  from baseline Primary Endpoint: • 84% of RDN patients had ≥10 mmHg reduction in SBP • 10% of RDN patients had no reduction in SBP Latest Follow-up: • Control crossover (n = 35): -24/-8 mmHg (Analysis on patients with SBP ≥ 160 mmHg at 6 M) Expanded results presented at the American College of Cardiology Annual Meeting 2012 (Esler, M.)

41. Symplicity HTN-2: Lancet Conclusions Catheter-based renal denervation, done in a multicentre, randomised trial in patients with treatment-resistant essential hypertension, resulted in significant reductions in BP. The magnitude of BP reduction can be predicted to affect the development of hypertension-related diseases and mortality The technique was applied without major complications. This therapeutic innovation, based on the described neural pathophysiology of essential hypertension, affirms the crucial relevance of renal nerves in the maintenance of BP in patients with hypertension. Catheter-based renal denervation is beneficial for patients with treatment-resistant essential hypertension. Symplicity HTN-2 Investigators. Lancet. 2010;376:1903-1909. 41

43. H-FIB

47. Objectives • The aim of this prospective randomized study was to assess the impact of renal artery denervation in patients with a history of refractory atrial fibrillation (AF) and drug-resistant hypertension who were referred for pulmonary vein isolation (PVI). • Background • Hypertension is the most common cardiovascular condition responsible for the development and maintenance of AF. Treating drug-resistant hypertension with renal denervation has been reported to control blood pressure, but any effect on AF is unknown. • Methods • Patients with a history of symptomatic paroxysmal or persistent AF refractory to ≥2 antiarrhythmic drugs and drug-resistant hypertension (systolic blood pressure >160 mm Hg despite triple drug therapy) were eligible for enrolment. Consenting patients were randomized to PVI only or PVI with renal artery denervation. All patients were followed ≥1 year to assess maintenance of sinus rhythm and to monitor changes in blood pressure. • Results • Twenty-seven patients were enrolled, and 14 were randomized to PVI only, and 13 were randomized to PVI with renal artery denervation. At the end of the follow-up, significant reductions in systolic (from 181 ± 7 to 156 ± 5, p < 0.001) and diastolic blood pressure (from 97 ± 6 to 87 ± 4, p < 0.001) were observed in patients treated with PVI with renal denervation without significant change in the PVI only group. Nine of the 13 patients (69%) treated with PVI with renal denervation were AF-free at the 12-month post-ablation follow-up examination versus 4 (29%) of the 14 patients in the PVI-only group (p = 0.033). • Conclusions • Renal artery denervation reduces systolic and diastolic blood pressure in patients with drug-resistant hypertension and reduces AF recurrences when combined with PVI. (Combined Treatment of Resistant Hypertension and Atrial Fibrillation; NCT01117025)

48. Conclusions •Trans-catheterRenalDenervation resultedinsignificantreductionsinBP •Nomajorcomplicationsoccurred 25

49. Ultimate Rehab