The Return of Renal Denervation - Promedica International · 2019. 5. 24. · The Return of Renal...
Transcript of The Return of Renal Denervation - Promedica International · 2019. 5. 24. · The Return of Renal...
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The Return of Renal Denervation
Florian Rader, M.D., M.Sc. Co-Director, Clinic for Hypertrophic Cardiomyopathy and Aortopathies
Assistant Director, Non-invasive Laboratory Hypertension Center of Excellence
Cedars-Sinai Heart Institute
Disclosures: Renal Denervation is investigational and not FDA-approved
PI/Co-PI of Symplicity-HTN-3, Radiance, Reduce-HTN Consultant for MyoKardia, ReCor Medical
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Naïve Day 7 Day 60
Viable Nerves Ablated Nerves
Intraluminal renal denervation
Radiofrequency Energy Ultrasound Energy
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Overactive SNA in HTN
Normotensive HTN PG Guyenet Nature Reviews Neuroscience, 2006
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Age dependency of SNA- conflicting data
Ng et al. Hypertension.1993 Parati G et al., Eur Heart J 2012
Mean age in Simplicity 58 years
Only mild increases
Hypertension
N=9 N=8
N=7 N=8
24y 26y 63y 66y
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SNA is increased in obesity
Lambert et al. Hypertension 2007 50:862
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SNA is increased in moderate CKD
Grassi et al. Hypertension. 2011;57:846-851
Quartiles of GFR 95 68 48 31
HR NE MSNA
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vagal efferents
sympathetic efferents
NE
NE
Ach
EPI
Stress
Renal afferents
Chemoreceptors
Cardiac afferents
NTS
Baroreceptors
Ang II
renin
NE
Muscle afferents
Courtesy of Ron Victor
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sympathetic efferents NE
NTS
Renal efferent nerves>>Renal afferent nerves
- Decrease of Renin release - Less tubular Na and H2O
resorption - Increase of renal blood flow
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What causes of uncontrolled HTN can be (potentially) addressed by RDN&Co?
• Non-adherence • Physician inertia to intensify antihypertensive
regimen • HTN driven by sympathetic overactivity
– Still learning-Young?, CKD?, OSA?, LVH? • Non-tolerance (or patient’s refusal) of multi-
drug regimens for HTN
Consider what the patient wants not only what physicians think is right!
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Symplicity HTN-2 (N=100)
6 month endpoint Denervation group (n-49)
Control group (n=51)
systolic
diastolic
chan
ge fr
om b
asel
ine
[mm
Hg]
p < 0.00001 vs. control
Symplicity HTN-2 Investigators. Lancet 2010; 376: 1903–09
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Symplicity HTN-3 (N=535)
Symplicity HTN-3 Investigators. NEJM 2014;370:1393-401
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“Why was Symplicity HTN-3 negative?”
Option #1 RDN does not lower BP: all animal data, our understanding of the sympathetic control of the kidney and all positive trials are wrong
Option #2 HTN-3 had issues
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Explanation #1 Inclusion of White-Coat HTN & Large
variability of treatment effect
• ABPM >135/85 for inclusion (>150 in the office) white-coat tendency in the trial by design
• Variability of BP response in Symplicity HTN-3:
– RDN: -14 +/- 24 mmHg – Control: -12 +/- 26 mmHg super-responders, responders, non-responders a statistical nightmare!
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Age <65 (RDN: 246; sham: 128) Age >65 (RDN: 104; sham: 41)
RDN better control better
Age predicts response
Symplicity HTN-3 Investigators. NEJM 2014;370:1393-401
Explanation #2 Patient selection
Mean age in Symplicity-HTN 3: 58 years
Hypertension
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Explanation #3 Patient selection
control better
Black (RDN: 85; sham: 49) Non-Black (RDN: 264; sham: 120)
RDN better
Race/ethnicity – an adherence issue?
Symplicity HTN-3 Investigators. NEJM 2014;370:1393-401 J Am Soc Hypertens 2015;9(10):769–779
-Black participants on tid and qid drugs had a placebo effect of -26 mmHg!! -This does not explain why the trial was negative, but points out that adherence was a major confounder
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Explanation #4 Incomplete denervation
• Operator experience
How would have TAVR or MitraClip faired if most participating centers would have performed one or two TAVRs?
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Explanation #5 Incomplete denervation
1. Number of nerves: Proximal>distal
2. Distance from arterial wall: Proximal>distal
1. Distal ablations were discouraged (RAS)
2. Proximal ablation may not have reached nerves
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Explanation #5 Incomplete denervation
More ablations greater BP reduction
Kandzari et al. Eur Heart J. 2015 Jan 21;36(4):219-27
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Explanation #6… Trial Design Issues
• Confounders: – Compliance not measured (~5 BP meds) – High rate of Central sympatholytics (49% vs.
44%) which increase BP variability and with non-compliance give very labile BP estimates
• Medication changes: – 40% of patients had medication changes prior to
the primary outcome – 69% of those were deemed medically necessary
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THE NEW CHAPTER
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Optimal care plus RDN (N=106) • Open-label trial of 106 patients randomized stepped
protocolized treatment intensification vs. RDN plus stepped care
• Treatment effect of RDN was 6 mmHg reduction of 24-hour SBP (p=0.03)
Azizi M et al. Lancet 2015; 385: 1957–65
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Optimal care plus RDN (N=71) • Sham-controlled trial of 71 patients randomized
stepped protocolized treatment intensification vs. RDN plus stepped care
• In the per-protocol cohort, RDN group had greater ambulatory BP reduction
• Kidney function as estimated by the glomerular filtration rate remained
unchanged at 6 months
Desch et al. Hypertension. 2015;65:1202-1208
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SPYRAL OFF-MEDS (N=71)
Townsend RR, et al. Lancet. 2017;390(10108):2160-2170.
Trial design
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ASBP = ambulatory systolic blood pressure; DBP = diastolic blood pressure
Townsend RR, et al. Lancet. 2017;390(10108):2160-2170.
24-hour ASBP 24-hour ADBP
Office SBP Office DBP
3-m
onth
cha
nge
in B
P
3-m
onth
cha
nge
in B
P
SPYRAL OFF-MEDS (N=71)
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Kandzari DE et al. Lancet. 2018 Jun 9;391(10137):2346-2355
Patients
SPYRAL ON-MEDS (N=75)
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Kandzari DE et al Lancet. 2018 May 22. pii: S0140-6736(18)30951-6. doi: 10.1016/S0140-6736(18)30951-6. [Epub ahead of print]
Asleep Awake
Results
SPYRAL ON-MEDS (N=75)
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RADIANCE-HTN-SOLO (N=146)
Azizi M, et al. Lancet. 2018. Published online May 23, 2018. http://dx.doi.org/10.1016/S0140-6736(18)31082-1. Accessed May 23, 2018. DAIC [website]. News. February 20, 2012. ReCor medical granted CE mark for transcatheter renal denervation system. https://www.dicardiology.com/content/recor-medical-granted-ce-mark-transcatheter-renal-denervation-system. Accessed May 23, 2018.
N=74
N=72
2 month results
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RADIANCE-HTN-SOLO
Unpublished-submitted to ACC 2019
6 month results
• Stepped care if BP >135/85 mmHg at 2 months: 1. amlodipine 5 2. ACEi/ARB 3. HCTZ 12.5->25
• Embargoed results BUT we are HAPPY
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Other pending trials
• RADIANCE-HTN TRIO: uncontrolled on triple combination pill, 50% enrolled
• RADIANCE-HTN 2: extension of SOLO for FDA approval
• SPYRAL: pivotal trials are being designed
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RDN in summary • Despite the disappointing Symplicity-HTN 3 trial (which
had flaws), new rigorous data demonstrates a significant and clinically meaningful BP reduction in patients with or without medications
• Don’t forget: a sustained 10 mmHg SBP reduction lowers risk of stroke by 30%, MI by 23%, CV mortality by ~25%!
• The magnitude of BP reduction was grossly
overestimated in uncontrolled trials. RDN will not replace medications in most (it does in a few)
• Pivotal trials for FDA approval are currently underway: RADIANCE 2 (start 12/2018)
Staessen JA et al. Lancet 2001; 358: 1305–15
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RADIANCE-TRIO: enrolling RADIANCE 2: start in December 2018 PI: Florian Rader Co-PI: Raj Makkar, Suhail Dohad Coordinator: Mo Rashid [email protected] Hoonie Kim [email protected]
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Parked slides
32
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Nifedipine for 2 weeks
Hu et al. Drug Design, Development and Therapy. Volume 11. 3179-3186.