Medtronic (Clinical Evaluation of Anti-Hypertensive Devices)

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General Issues Panel: Clinical Evaluation of Anti-Hypertensive Devices

December 5, 2018 Medtronic Circulatory System Devices Panel Meeting CO-2

Introduction: Symplicity Spyral™ Renal Denervation System

Sidney A. Cohen, MD, PhD Senior Medical Advisor Coronary and Structural Heart Group Medtronic CO-3

Agenda

Sidney A. Cohen, MD, PhD Introduction Medtronic

Key Topics in RDN Laura Mauri, MD MSc Clinical Study Design Medtronic

Raymond Townsend, MD Safety and Imaging The University Of Pennsylvania

David E Kandzari, MD Path Forward Piedmont Heart Institute CO-4

Global Hypertension Epidemic

 Hypertension remains leading preventable cause of heart attack, stroke and death1  > 50% of patients not at blood pressure goal despite readily available and effective drugs2  Medication adherence significant issue3 . Some patients are intolerant or do not want to take daily medications  Renal denervation (RDN) could help address unmet need . Adjunctive approach to lowering blood pressure

1. Bundy JD, et al. JAMA Cardiol. 2018 Jul 1;3(7):572-581. Beaney, et al. Lancet Glob Health. 2018;6:e736-e743. 2. Muntner P, et al. J Am Coll Cardiol. 2018 ;71:109-118 2. Blaschke TF, et al. Ann Rev Pharmacol Toxicol 2012;52:275–301 CO-5

Renal Denervation as a Treatment for Hypertension

 Sympathetic nervous system plays key role in hypertension  Denervation dates to 1920’s  Medtronic Symplicity Spyral Catheter . 4 electrodes in spiral configuration . Delivers RF energy . Ablates nerves in adventitia . Treatment in main renal artery and renal artery branches CO-6

Medtronic Trials In Renal Denervation

SPYRAL SPYRAL HTN-OFF MED HTN-ON MED RCT with Sham RCT with Sham Spyral HTN HTN HTN First- 1 2 3 N=80 N=80 in-Man Pilot Study Pilot Study Complete Complete Clinical Trial Redesign CO-7 RDN Lowered Blood Pressure in 2 Sham- Controlled Pilot Trials With and Without Meds

SPYRAL HTN-OFF MED1 SPYRAL HTN-ON MED2 (change from baseline to 3 months) (change from baseline to 6 months)

24-hour SBP 24-hour DBP 24-hour SBP 24-hour DBP n=36 n=36 n=36 n=36 0 n=35 n=36 n=35 n=36 -0.5 -0.4 -2 -1.6 -1.9 Change in -4 BP from Baseline -4.8 -6 -5.5 (mmHg) -6.0 *p<0.0001 -8 *p=0.0031 *p<0.0001 -10 -9.0 RDN *p=0.0051 -12 Sham

* Between group difference 1. Townsend R, et al. Lancet. 2017;390:2160-2170; 2. Kandzari D, et al. Lancet. 2018;391:2346-2355 CO-8

Medtronic Trials In Renal Denervation

OFF MED Pivotal IDE Trial RCT with sham N≈353 SPYRAL SPYRAL Currently enrolling HTN-OFF MED HTN-ON MED RCT with sham RCT with sham ON MED Prospective Trial Spyral HTN HTN HTN RCT with sham First- 1 2 3 N=80 N=80 N≈260 in-Man Start-up phase Pilot Study Pilot Study Complete Complete Clinical Trial Redesign U.S. Patient Preference Study Under development

GLOBAL SYMPLICITY REGISTRY currently N≈2,600 patients, ~350 SPYRAL Single-arm registry evaluating safety and efficacy in real-world patients CO-9

Key Topics in Renal Denervation Clinical Study Design

Laura Mauri, MD MSc Vice President Global Clinical Research and Analytics Medtronic CO-10 SYMPLICITY HTN-3 Results Led to Discussion Among Medical Community

SYMPLICITY HTN-3 RCT1 2014 American Society of Hypertension (change from baseline to 6 months) (ASH) meeting

10 • Convened with FDA, investigators, RDN Sham N=353 N=171 and industry 0

Change in -10 • How to determine if renal BP from -11.7 denervation is effective Baseline -14.1 (mmHg) -20 p = 0.255 -30

-40

1. Bhatt DL, et al. N Engl J Med 2014;370:1393-401. CO-11 Determining if Renal Denervation is Effective • ON and OFF trial designs are needed • Run-in periods are necessary

Renal Denervation for the Treatment of Hypertension: Making a New Start, Getting It Right Michael A. Weber, MD; Ajay Kirtane, MD; Laura Mauri, MD; Raymond R. Townsend, MD; David E. Kandzari, MD; Marin B. Leon, MD

Renal Denervation Therapy for Hypertension: Pathways for Moving Development Forward William B.White, MD; Zorina S.Galis, PhD; Jeffrey Henegar, PhD; David E. Kandzari, MD; Ronald Victor, MD; Domenic Sica, MD; Raymond R. Townsend, MD; J. Rick Turner, PhD; Renu Virmani, MD; Laura Mauri, MD CO-12 Blood Pressure Reduction in 3 Sham-Controlled Studies Medtronic ReCor

SPYRAL HTN-OFF MED1 SPYRAL HTN-ON MED2 RADIANCE-HTN SOLO3 (change from baseline to 3 months) (change from baseline to 6 months) (change from baseline to 2 months)

24-hour SBP 24-hour DBP 24-hour SBP 24-hour DBP 24-hour SBP 24-hour DBP n=35 n=36 n=35 n=36 n=36 n=36 n=36 n=36 n=74 n=72 n=74 n=72 0 0 0 -0.5 -0.4 -2 -2 -2 -1.6 -1.9 Change -4 -4 -4 -3.1 -3.0 in -4.4 -4.8 BP from -6 -5.5 -6 -6 Baseline -6.0 *p<0.0001 *p=0.07 (mmHg) -8 *p=0.003 -8 -8 -7.0 *p<0.0001 *p=0.006 -10 -10 -9.0 -10 RDN RDN *p=0.005 -12 -12 Sham -12 Sham

* Between group difference 1. Townsend R, et al. Lancet. 2017;390:2160-2170; 2. Kandzari D, et al. Lancet. 2018;391:2346-2355 3. Azizi M, et al. Lancet. 2018;391.2335-2345 CO-13 Key Topics in Renal Denervation Clinical Study Design

• Study design • Controlling bias and medication use • Evolution of study population • Evaluating effect in absence of medications • Measuring efficacy • What reduction in blood pressure is meaningful to patients? • Beyond feasibility and pivotal studies • Questions for future investigation CO-14 Sham Controls Necessary to Determine Valid Treatment Effect

Medtronic SYMPLICITY HTN-2 RCT1 SYMPLICITY HTN-3 RCT2 (change from baseline to 6 months) (change from baseline to 6 months) RDN Standard of Care RDN Sham 10 N=49 N=51 10 N=353 N=171 1 0 0 Change in Systolic BP -10 -10 from -11.7 -14.1 Baseline -20 -20 (mmHg) p = 0.255 -30 -30 -32 -40 *p < 0.0001 -40

*Between group difference 1. Esler MD, et al. Lancet 2010;376:1903-9; 2. Bhatt DL, et al. N Engl J Med 2014;370:1393-401. CO-15 Sham Controls May Be Necessary: Randomized Trials of Laser Myocardial Re-Vascularization

Initial non-sham-controlled trials showed benefit1 Subsequent sham-controlled trial showed no benefit2

Patients (%) with p < 0.001 % Canadian CV Society Angina p=NS Improvement in Angina Class III or IV

1. Allen K, et al. N Engl J Med 1999;341:1029-1036; Leon M, et al. J Am Coll Cardiol 2005;46:1812–9 CO-16 Randomization and Sham Design Do Not Prevent Hawthorne Effect

• Behavioral experiments show productivity improved regardless of light intensity • Being “observed” led to changes in performance • Principle applies to medication adherence • Adherence improves under observation *Behavioral experiments (1924-1932) conducted by • Hawthorne Effect observed in trials of Elton Mayo of Harvard Business School at Western hypertension, diabetes etc. Electric factory outside of Chicago CO-17 Attention to Medication Use Necessary To Determine Effectiveness

100 HTN-3 Trial 80 • ~40% reported changing Patients medications between 60 with baseline and primary Medication Changes 40 efficacy endpoint 40 38 (%) assessment 20

N = 139 N = 72 0 RDN Sham N=139 N=172

Kandzari D, et al. Eur Heart J 2014;Nov16 CO-18 Subsequent Trials Included Run-In and Medication Testing

Medication Testing (at randomization and Sponsor Trial Run-in Period follow-up)

SPYRAL HTN-ON MED 4 weeks Medtronic SPYRAL HTN-OFF MED 4 weeks

RADIANCE-HTN SOLO 4 weeks ReCor RADIANCE-HTN TRIO 4 weeks CO-19 Medication Use in Trials Can Bias in Favor of Sham Arm

RADIANCE-HTN SOLO1 Antihypertensive medication use RDN Sham by patient report N=74 N=72 p-value At 2 months 6.8% 18.1% 0.04

SPYRAL HTN-OFF MED2 Hypertensive medication RDN Sham by drug testing N=38 N=42 p-value At baseline 7.9% 11.9% 0.72 At 3 months 5.7% 7.3% 1.00

1. Azizi M, et al. Lancet. 2018;391.2335-2345; 2. Medtronic data on file Diversity of Medical Devices Under Investigation: CO-20 All Devices Need to Be Evaluated with High Rigor

Baroreceptor Amplification Carotid Body Modulation

Baroreceptor Stimulator Renal Denervation via Urethral Access

Median Nerve Stimulator

Renal Denervation

AV Fistula CO-21 11 Sham-Controlled Trials in Renal Denervation

TRIAL N Method Sponsor SPYRAL PIVOTAL 353 Radiofrequency Medtronic SPYRAL HTN-ON MED 260 Radiofrequency Medtronic TARGET BP I 100 Ethanol injection Ablative Solutions TARGET BP OFF-MED 400 Ethanol injection Ablative Solutions RADIANCE HTN-TRIO 146 Ultrasound ReCor / Otsuka REQUIRE 140 Ultrasound Otsuka RADIANCE II 225 Ultrasound ReCor / Otsuka IBERIS HTN 216 Radiofrequency Angiocare SMART 212 Radiofrequency Terumo SYNAPTIC 264 Radiofrequency Synaptic Golden Leaf 110 Radiofrequency Golden Leaf

Source: clinicaltrials.gov Source: clinicaltrials.gov CO-22 Key Topics in Renal Denervation Clinical Study Design

OFF MED ON MED Post-Market • Minimizes confounding • Supporting information • Collects larger amount effect of adherence in clinically relevant of data • Design of great interest population • Assesses durability in to patients and • Treats patients who are practice settings clinicians prescribed anti- • Allows subgroup • Faster enrollment hypertension meds and analysis and predictive compared to On Med are interested in modeling studies signals additional treatment options • More robust safety patient interest assessment CO-24 Key Topics in Renal Denervation Clinical Study Design

• Study design • Controlling bias and medication use • Evolution of study population • Evaluating effect in absence of medications • Measuring efficacy • What reduction in blood pressure is meaningful to patients? • Beyond feasibility and pivotal studies • Questions for future investigation CO-25 Reduction in Office Systolic BP Are Associated With Clinical Reductions Across RCTs Meta-analysis1: 123 HTN trials, N=613,815 RR (95% CI) ← Favors Intervention Favors Control → Major CV events 0.80 (0.77, 0.83)

Coronary heart disease 0.83 (0.78, 0.88)

Stroke 0.73 (0.68, 0.77)

Heart failure 0.72 (0.67, 0.78)

Renal failure 0.95 (0.84, 1.07)

All-cause mortality 0.87 (0.84, 0.91)

0.5 0.7 0.9 1.1 1.3 1.5 Relative Risk Per 10 mm Hg Reduction in Systolic Blood Pressure 1. Ettehad, et al. Lancet. 2016 Mar 5;387(10022):957-967. CO-26 Continuous Effect of Ambulatory Systolic Blood Pressure on Cardiovascular Risk

• In randomized trials, relative risk reduction with antihypertensive therapy is independent of baseline blood pressure1 • Absolute risk reduction is greater with higher baseline systolic blood pressure1 • In observational studies a ~5 mmHg reduction in ambulatory systolic blood pressure is associated with ~ 15-20% reduction in CV events2

1. Ettehad, et al. Lancet. 2016 Mar 5;387(10022):957-967. 2. Staessen J, et al. JAMA. 1999;282539-546; Sega R, et al. Circulation. 2005;111:1777-1783; Dolan E, et al. Hypertension. 2005;46:156-161. CO-27 24-Hour Ambulatory SBP More Strongly Associated with All-Cause Mortality

Multi-center Registry1 : N=63,910 HR (95% CI) 24-hour ambulatory systolic 1.58 (1.56, 1.60) blood pressure

Clinic systolic blood pressure 1.02 (1.00, 1.04)

0.8 1 1.2 1.4 1.6 1.8 Hazard Ratio for All-Cause Mortality per SD of Blood Pressure

1. Banegas JR, et al. N Engl J Med 2018;378:1509-20. CO-28 Summary of Renal Denervation Clinical Study Design

• Study design • Randomization, sham control, careful attention to medication adherence, and careful ABP ascertainment are necessary to evaluate efficacy • Evolution of study population • OFF med study design is best way to determine efficacy and identifies important patient unmet need • Measuring efficacy • 24-hour ASBP reductions are associated with prevention of cerebrovascular and CV events, and mortality CO-29 Questions for Investigation Beyond Pivotal Studies

• Long term safety and durability • Impact of eliminating factor of medication adherence • Deeper understanding of patient preferences CO-30

Safety and Imaging

Raymond Townsend, MD Professor of Medicine Director, Hypertension Program Perelman School of Medicine, The University of Pennsylvania CO-31 Important Safety Events to Consider When Evaluating Renal Denervation

 All-cause mortality  Stroke / myocardial infarction  Procedural events, e.g. major bleeding, vascular complications  Changes in kidney function  Renal artery changes as a result of procedure, e.g. Stenosis  Hospitalization due to hypertension crisis CO-32

Strong Safety Profile in Renal Denervation

SPYRAL HTN-OFF MED1 SPYRAL HTN-ON MED2 3M post-procedure 3M and 6M post-procedure RDN Sham RDN Sham Major Adverse Events (%) N=38 N=42 N=38 N=42 Death 0 0 0 0 New myocardial infarction 0 0 0 0 Major bleeding (TIMI3) 0 0 0 0 New onset end stage renal disease 0 0 0 0 Serum creatinine elevation >50% 0 0 0 0 Significant embolic event resulting in end-organ damage 0 0 0 0 Vascular complications 0 0 0 0 Hospitalization for hypertensive crisis/emergency 0 0 0 0 New stroke 0 0 0 0

1. Townsend R, et al. Lancet. 2017;390:2160-2170; 2. Kandzari D, et al. Lancet. 2018;391:2346-2355 3. TIMI definition: intracranial hemorrhage, ≥5g/dl decrease in hemoglobin concentration, a ≥15% absolute decrease in hematocrit, or death due to bleeding within 7 days of procedure. CO-33 No Difference in Renal Function Difference in Renal Function up to 6 Months

SPYRAL HTN-OFF MED1 SPYRAL HTN-ON MED2 RDN Sham RDN Sham 125 125

100 100

75 eGFR ± SD 75 (mL/min/1.73 m2) 50 50

25 25

0 0 Baseline 1M 3M 6M Baseline 1M 3M 6M n = 38 42 37 41 36 39 35 37 38 42 38 42 36 40 38 40

1. Townsend R, et al. Lancet. 2017;390:2160-2170; 2. Kandzari D, et al. Lancet. 2018;391:2346-2355 CO-34

No New Events of Stenosis (> 70%) Detected

Duplex Ultrasound is Preferred Imaging Modality

 Different methods to address stenosis: repeat angiography, CTA, MRA, and DUS  Repeat angiography not utilized due to patient burden and risk of additional interventional procedure

Computer tomography angiography (CTA) / Magnetic resonance angiography (MRA)  Readily available  Commonly used but not routine in evaluating renal artery branch vessels  Safety concerns due to ionizing radiation and/or use of dye

Duplex ultrasound (DUS)  Long history of use with well-described evaluation of renal artery branch vessels  No safety concerns due to radiation or dye exposure Medtronic36 Confidential CO-36

Renal Artery Imaging Protocol

Ultrasonographers trained and given feedback by core lab – 90% of patients had diagnostic 1st or 2nd DUS

DUS Non-diagnostic

Repeat DUS Diagnostic Evidence of or CTA/MRA No evidence potential of potential stenosis stenosis Non-diagnostic or evidence of Diagnostic potential stenosis

Angiogram Complete Complete Angiogram CO-37 Imaging Timing in Ongoing Medtronic Clinical Trials for Renal Denervation

 6-month imaging is appropriate for renal stenosis . Early assessment with DUS identifies potential safety issue

 12-month additional imaging also included . Modalities: CTA/MRA . Collected in minimum of 150 patients to assess for stenosis CO-38

Medtronic to Use Performance Goal for PMA

 Direct comparison between arms not ideal for sham-controlled trials . Would only provide insight into incremental safety endpoints for renal denervation on top of that from obtaining vascular access . Markedly increases sample size for safety cohort due to low expected event rates . Limited usefulness in clinical decision making  Use of a performance goal . Most relevant for clinical assessment of safety . Utilizing a performance goal for renal intervention would be more informative CO-39

Components of Primary Safety Endpoint

 Safety endpoint assessment at 30 days is standard timeframe for peri- procedural risks for an interventional device trial . All-cause mortality . End-stage renal disease (ESRD) . Significant embolic event resulting in end-organ damage . Renal artery perforation requiring intervention . Vascular complications . Hospitalization for hypertensive crisis . New renal artery stenosis > 70%, confirmed by angiography (assessed at 6 months) CO-40

Important Secondary Safety Endpoints

 All components of primary safety endpoint are assessed to 3 years  Comparison between groups at each time point . Increase in serum creatinine >50% from baseline . New myocardial infarction . New stroke © 2018 Medtronic. All rights reserved. Medtronic, Medtronic logo and Further, Together are trademarks of Medtronic CO-41

> 4,000 Patients Will be Followed to Three Years

Status Study Design Status of 3-Year Follow-up N SPYRAL HTN-OFF MED Pilot RCT w/sham Ongoing 80 Follow-up Ongoing SPYRAL HTN-ON MED Pilot RCT w/sham Ongoing 80 SPYRAL HTN-OFF MED Pivotal RCT w/sham Ongoing ~353 Activity Enrolling SPYRAL HTN-ON MED RCT RCT w/sham Ongoing ~260 Continuously Enrolling Global SYMPLICITY Registry Prospective registry 1,000 at 3 years 3,000 Symplicity HTN-1 Non-randomized Completed 153 Symplicity HTN-2 RCT Completed 106 Legacy Studies Symplicity HTN-3 RCT w/sham Completed 535 Symplicity Japan RCT Completed 41 SPYRAL First-in-Man Non-randomized Completed 50 CO-42

Summary and Conclusions

 Duplex ultrasound is an appropriate, non-invasive imaging modality  Low frequency of AEs in pilot trials render non-inferiority comparisons impractical . Performance goal are preferable  Safety profile is strong and well-characterized in renal denervation program CO-43

Path Forward

David E Kandzari, MD Director, Interventional Cardiology, Piedmont Heart Institute Chief Scientific Officer, Piedmont Healthcare Atlanta, GA CO-44 RDN Lowered Blood Pressure in 2 Sham- Controlled Pilot Trials With and Without Meds

SPYRAL HTN-OFF MED1 SPYRAL HTN-ON MED2 (change from baseline to 3 months) (change from baseline to 6 months)

* Between group difference 1. Townsend R, et al. Lancet. 2017;390:2160-2170; 2. Kandzari D, et al. Lancet. 2018;391:2346-2355 CO45 -45 Evolution of Trial Design and Methods: SPYRAL HTN vs. HTN-3

Medications Patients/Endpoints Procedure

. Resistant hypertension . Mono-electrode, sequential . 5.1 prescribed anti-HTN patients (OSBP 180±16) ablation system SYMPLICITY drugs at randomization . Mostly inexperienced . No diastolic cutoff . No drug testing operators HTN-3 . Office SBP endpoint . Main artery RDN only

. . No anti HTN meds (OFF) and . Moderate hypertension Four-electrode, simultaneous ablation system with anti-HTN meds but not patients SPYRAL HTN . Highly experienced operators maximum tolerated (ON) . Excluding ISH patients with proctoring Program . Drug testing . 24 hr ABPM endpoint . Main + branches RDN CO-46 Variable and Dynamic Adherence in SPYRAL HTN-ON MED Pilot Trial

 Qualitative assessment using Tandem HPLC and mass spectroscopy

Missing Incomplete or Non-adherent Adherent 100%

80% n=38 55.0% n=37 62.5% N=44 62.5% 60% N=50 N=50 Patients 40%

20% n=24 42.5% n=22 37.5% N=34 36.3% N=30 N=29 n=1 0% Baseline 3 Months 6 Months

Medication adherence: detectable levels of all prescribed antihypertensive medications at each follow-up visit and includes cases in which an extra antihypertensive medication was also detected. Kandzari D, et al. Lancet. 2018;391:2346-2355. CO-47 Common Rates of Non-Adherence in Other Antihypertension Trials

70 Partial Non-adherence  30 to 50% non-adherence rate Total Non-adherence is consistent between clinical 60

trials and medical practice 50 44%  Poor and dynamic adherence 40

introduces variability to trial 30 endpoints 20 17% . Not easily controlled, 10 even with rigorous trial 0 design Ceral Jung Strauch Tomaszewski Brinker Ewen Patel Hamdidouche Schmieder (2011) (2013) (2013) (2014) (2014) (2014) (2014) (2015) (2016)

Berra E, et al. Hypertension. 2016;68:297-306 CO-48 RDN Blood Pressure Lowering Effects are Independent of Drug Adherence and Drug Pharmacokinetics

RDN Sham Control

SPYRAL HTN-ON MED Pilot Study. Dashed line represents the 24-hr mean at baseline (blue) and 6 months (red). Graphs based on actual clock times. Similar results were observed when 24-hour BP patterns were normalized to patient reported time of waking. Kandzari D, et al. Lancet. 2018;391:2346-2355. CO-49 Patient Preference is a Key Consideration for Hypertension Therapy

 Many patients struggle to All Patients adhere to lifelong Statement N=1011 polypharmacy therapy plans I would rather take an additional 71.8 % tablet for the high blood pressure.  Recent study from Germany indicated high level of interest (28.2%) in non-drug therapies I would opt for a single medical 1 in hypertensive patients procedure using a catheter 28.2 % (ablation treatment) and not to have to take even more drugs.

1. Schmieder R, ESC 2018 CO-50

Capturing Patient Preferences

Patient Preference Information (PPI)  Goal of Patient Preference Study . To assess patients’ perspectives relating to an interventional procedure as an adjunctive option to current standard of care  Protocol to be reviewed by FDA  Estimates treatment-related risks patients are willing to accept in exchange for specific benefits  Component of PMA submission Patient-reported outcomes (PRO)  Difficult to assess in hypertension (asymptomatic disease) CO-51

Demonstrating Durability with Renal Denervation

 Ideal assessment of durability would be comparison of renal denervation and sham-controlled arms . Variable medication adherence confounds comparison . Safety prevents extended time off medications (> 4 months) . Patient crossover (at 6 months) on/after primary endpoint assessment . Late phase washout challenging due to patient/provider behavior, variability in medications, and maintaining blind beyond primary endpoint  Durability will be demonstrated by long-term evaluation of patients receiving renal denervation CO-52 Durability in Patients Treated with Renal Denervation

HTN-11 HTN-32 Global SYMPLICITY Registry3 6M 1Y 2Y 3Y 6M 1Y 2Y 3Y 6M 1Y 2Y 3Y 0 0 0

-5 -5 -3 -10 -10 -6 -15 -15 Change in SBP -20 -20 -9 (mmHg) -25 -25 -12 -30 -30 -15 -35 -35

-40 -40 -18 n = 88 85 82 88 350 320 266 219 1937 1841 1386 1093

1. Krum H, et al. Lancet 2014;383:622-9; 2. Medtronic data on file ; 3. Mahfoud F et al. EuroPCR 2018 CO-53

Medtronic Trials In Renal Denervation

GLOBAL SYMPLICITY REGISTRY currently N≈2,600 patients, ~350 SPYRAL Single-arm registry evaluating safety and efficacy in real-world patients Additional post-approval studies (TBD) CO-54 How Renal Denervation Should be Reflected in Indications for Use

 Renal denervation could be considered for the reduction of blood pressure in patients with hypertension alone or in combination with other blood pressure-lowering therapy  Shared decision between patients and physicians CO-55

Summary

 Many patients fail to meet blood pressure goals, despite availability of effective drugs . Adherence is a significant and complex issue  Renal denervation lowers blood pressure alone or in combination with drugs . Reductions are clinically meaningful . 24-hour effect, independent of adherence and pharmacokinetics  SPYRAL HTN clinical trial program is comprehensive and rigorous . Pilot studies informed design of prospectively powered trials . Support an indication in presence or absence of medications