Renal sympathetic denervation as a potential treatment for hypertension

Transcription

1 Renal sympathetic denervation as a potential treatment for hypertension (Why we must keep going) Dr Andrew SP Sharp Consultant Cardiologist and Honorary Senior Lecturer Royal Devon and Exeter Hospital and Exeter Medical School

2 Conflicts of Interest Consultant: Medtronic, Philips Volcano Research Funding: Medtronic

3 Let s get this out of the way

4 Let s get this out of the way Renal Denervation may not work.at all Particularly with radiofrequency technology, which has design strengths but also limitations in current iterations

5 Now. I will detail why we require more research in this area

6 Why bother?

7 The procedure doesn t work you ve had years to prove it. Move on! Trial design and technology used are key to proving whether a technology works or not Trials of catheter intervention for acute stroke failed until the right trial design deployed the right technology Now a Class 1A indication a year later

8 Background 1.1 billion hypertensives worldwide Fewer than half at recommended target Drug-based strategies are currently not getting >500 million people to target This represents a failure of current therapeutic strategies 30% Untreated 35% Treated and controlled 35% Treated but uncontrolled*

9 Why are drugs not getting patients to target? Compliance Physician treatment inertia Side effects from drugs Drug Resistance Patients not diagnosed

10 Who on earth would want their kidneys ablated?

11 People (%) 8% of adults would rather die two years early than take drugs forever Number of Weeks Willing to Trade Hutchins et al. Circ Cardiovasc Qual Outcomes. 2015;8:00-00.

12 Case Study from Exeter 42 yr old diabetic male Elevated BMI (35) Taking: Indapamide 2.5, Spironolactone 25, Ramipril 10, Amlodipine 10 BP: Office: 188/98 DABP 188/94, NABP 177/88

13 Home BPs before RDN

14 ABP before RDN

15 ABP before RDN

16 Original Technique

17 1 wk post RDN Post procedure home BPs

18 Post procedure ABP at 1 year

19 Post procedure ABP

20 Ambulatory BP response Fall of Day ABP of 42/14 Fall of Night ABP of 38/11 Drugs at time of 1 year ABP were: Indapamide 2.5, Ramipril 10, Amlod 10, Eplerenone 25 (switched due to S/E) Three year follow-up BP controlled on four agents

21 ECG before RDN

22 ECG at 1 year regression of LVH and strain pattern

23 What this case tells us: There is no doubt that blood pressure has fallen Dramatically How and why?

24 What is the sympathetic nervous system? Fight or flight Conserves salt and water Tightens Arteries Increases blood pressure Elevates heart rate Increases alertness Designed to help you run away from this About 30% of the SNS involves the kidneys

25 The effects are mostly bad for CV health

26 The aim of RDN M Leon, TCT 2013

27 How can we disrupt the SNS? M Leon, TCT 2013

28 Doesn t it damage the wall? Heat the adventitia to 80 degrees Blood flow cools the near field Enough energy to permanently disrupt the nerves Not enough to cause significant lasting damage to the renal arterial wall

29 Virmani, TCT 2013

30 How do we know that RDN really does persistently reduce sympathetic activity?

31 Peroneal nerve sympathetic firing can be quantified and is reduce by RDN Schlaich M et al. NEJM. 2009;36(9):

32 Kidney norepinephrine spillover is reduced by RDN Esler et al. J Htn. 2009;27(suppl 4):s167. Schlaich et al. J Htn. 2009;27(suppl 4):s154.

33 How will the kidney function without sympathetic control? Transplanted kidneys: Lack innervation Effectively maintain fluid and electrolyte balance Supports that sympathetic component of control represents overdrive system, rather than foundation of basic renal function Blaufox et al. N Engl J Med. 1969;280(2):62 66.

34 We have known that the process of sympathectomy markedly reduces blood pressure for a long-time

35 Sympathectomy: An Early Surgical Precedent Dr. Reginald H. Smithwick 1952

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37 % Survivals Surgical Sympathectomy in Essential Hypertension Provided Beneficial Effect on Survival Medical 2 Medical Time in Years Survival rate of normal population Age 43 Sympathectomy 2 Sympathectomy 1 Surgical n=1266 Medical n=467 However, surgical sympathectomy was associated with significant morbidity 2 Sources: 1. Adapted from Smithwick RH, Thompson JE. JAMA. 1953;152: Gewirtz JR, Bisognano JD. Cardiol J. 2011;18:

38 Catheter based, selective sympathectomy is the endpoint of an 80 year research programme M Leon, TCT 2013

39 Observational studies

40 UK Renal Denervation Affiliation - results

41 UK Renal Denervation Affiliation Investigator-led Initiative 18 of 21 UK centers with RDN experience All performed 5+ RDN cases at time of conception All cases performed for treatment-resistant hypertension

42 UK Renal Denervation Affiliation Birmingham Heartlands Birmingham QE Bournemouth Bristol Dundee Exeter Glasgow Hastings Hull Kent and Canterbury London Barts London Brompton London Imperial London St Georges London St Thomas Sheffield Southampton Wycombe

43 Pre-procedural BP data

44 Follow-up Office BP data

45 ABP follow-up

46 Do we harm the kidneys? Anatomically, there are few cases of renal artery stenosis (>10,000 cases done worldwide) What about physiologically?

47 Change in GFR over time

48 4ml/min/yr in GLOBAL Renal function declines year on year in hypertension RDN effect? Bakris. Am J Kid Disease

49 What about other trial data?

50 HTN-2 Randomised trial RDN (n = 52) Control (n = 54) p-value Baseline systolic BP (mmhg) 178 ± ± Baseline diastolic BP (mmhg) 97 ± ± Number anti-htn medications 5.2 ± ± * 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.)

51 mm Hg Office SBP through 30 Months* 6m Primary Endpoint Control Crossover Randomization 6m post procedure 12m post procedure 18m post procedure 24m post procedure 6m post randomization 12m post randomization 18m post randomization 24m post randomization 30m post randomization Esler M, ASH 2013

52 Enlightn 1 results (176/96 starting BP)

53 Then came Symplicity HTN-3

54 Symplicity HTN-3 Substantial BP falls Occurred in BOTH groups Difference between groups 2.4mmHg only

55 So what happened in HTN-3? Well, the technology might not work The alternative explanations are The RDN BP lowering effect is much less powerful than that observed in open label studies The study design masked the measured clinical benefit The study procedure was not conducted properly

56 The crucial issue of renal nerve anatomy and catheter design

57 We thought that most of the nerves were within range of a 3mm burn depth

58 s distal ease the sful Distribution of nerves proximal renal artery vs distal egies can th ers y. ry Superior Inferior Nerves more frequently make a close approach in the distal segment Distribution of renal nerves around renal artery ahfoud F. Sakakura et al. JACC 2014

59 Can we reliably get the nerves? Distal Proximal Prior concept uniform radial distribution Distal Proximal Current concept nonuniform radial distribution Sakakura K et al. JACC :

60 Therefore With a proximal ablation strategy, the technique is relying on randomly hitting where nerves dip down towards the vessel This was the recommended ablation strategy at the time A distal ablation strategy should ensure more reliable denervation

61 Has a distal ablation strategy been demonstrated to be more effective? IVY study. Melder et al. TCT Note: Each animal served as its own control in this study

62 Are there any signals within HTN-3 to support this?

63 Ablation attempts and change in BP in HTN-3 MORE ABLATIONS = MORE BP REDUCTION OFFICE 24 hr ambulatory SBP

64 Were there other technical issues in the HTN-3 trial? The trial was a sham-controlled RCT of Renal denervation versus placebo The recommended RDN technique is to ablate the four points of a compass in a retrograde spiral fashion Four quadrant ablation Animal data suggests we need to get >70% of the nerves to produce a BP lowering effect We therefore need all four quadrants to be ablated

65 What proportion of patients had the recommended (and required) four quadrant ablation in the HTN- 3 trials? 5%

66 Four-quadrant ablations in HTN-3 Procedural Variability Correlation with # of ablations Correlation with 4-quadrant ablation pattern Cross-section of artery Inferior Anterior Superior Posterior

67 Four quadrant ablations Procedural Variability Operators performed their 1 st procedure within the trial Correlation with # of ablations Correlation with 4-quadrant ablation pattern >50% cases were performed by operators with a cumulative experience of 2 procedures by the end of the trial Cross-section of artery Inferior Anterior Superior Posterior

68 Patients With Medication Changes (%) Medication changes Medication Changes During Trial Medication changes were permitted between procedure and primary endpoint assessment in cases of hypertensive urgency ~40% (n = 211) of trial subjects required medication changes between baseline and primary efficacy endpoint assessment: 69% of first medication changes were medically necessary 121 patients had a med change due to an adverse event 80 patients had a med change due to a drug side-effect What proportion of patients with hypertension under your care meet such a criteria during 6 month follow-up? ~69% were changes in drugs at maximally-tolerated dose % RDN 40% N = 139 N = 72 Control Drug changes during the trial

69 Current state of play We know: Surgical sympathectomy reduces blood pressure RDN appears to perform selective sympathectomy in animals if correct technique and technology is deployed Blood pressure fell after RDN in >5000 (observational) published cases Early serious side effects (<3 yrs) appear few

70 Current state of play We don t know: The true magnitude of effect in a real-world population (is it real and meaningful?) Long-term outcomes (>7 years) Whether any BP reduction from RDN has same magnitude of effect as seen with BP reduction with drugs

71 RCTs currently active

72 SPYRAL research programme Medtronic dominate the field This is their flagship research programme Two centres in the UK, 22 globally

73 SPYRAL RDN catheter Four electrode RFA catheter Monitor tracks impedance and temp changes during delivery Delivers simultaneously for 60 seconds

74 A lot of thought has gone into these trials

75 Trial 1: SPYRAL OFF Office BP Diastolic >90 ABP on no drugs

76 SPYRAL OFF Uncontaminated RDN Week 1: Four week washout if on drugs If BP >180 exit trial and re-start drugs Week 4: final screen Week 6: RDN treatment or sham Week 18: Begin drug-titration schedule (ARB/CCB/Diuretic) One year unblinded

77 Trial 2: SPYRAL ON Age BP on office despite between 1 and 3 drugs (A-B-C-D) BP on ABPM DOT with urine testing to confirm compliance RDN:Sham in 1:1 ratio

78 Trials 3&4: RADIANCE ON/OFF Sham-controlled trial programme Similar concept to SPYRAL Instead of RF energy, uses ultrasound to denervate Delivered percutaneously via catheter approach Reliably reaches 6mm depth so appears well designed for task

79 Conclusions Hundreds of millions of patients with hypertension have uncontrolled blood pressure A 2mmHg reduction in systolic BP would be expected to reduce the risk of the stroke by 10% Some people would, unfortunately and literally, rather die than take pills New methods of BP control are required

80 Conclusions Proving efficacy when the primary endpoint is as variable as BP is extremely challenging I often get asked whether I believe in renal denervation Its not a religion! We must know whether RDN reduces BP before we give up on it through sound scientific research Those trials are now active in the SW of England

81 If you have interested patients... me on Ask your patient to register via my research website:

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