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Medtronic RDN
SYMPLICITY HTN-3 &
Global SYMPLICITY Registry (GSR)
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Key Takeaways
•
SYMPLICITY HTN-3 did not reach the primary or powered secondary efficacy
endpoints in this trial. There may be many factors that contributed to the
outcome, which we continue to investigate.
•
SYMPLICITY HTN-3 did meet its safety endpoint, which is consistent with all
other Symplicity trials, including the Global SYMPLICITY Registry.
•
Based upon our detailed analysis of HTN-3, we believe further clinical
investigation is warranted and Medtronic will, in consultation with FDA, pursue a
new IDE trial
•
An unmet need in this uncontrolled hypertension population still exists. Medtronic
will continue to provide access to the Symplicity system in countries where it has
regulatory approval and will continue to support a global hypertension clinical
program
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
SYMPLICITY HTN-3 Trial Objectives
•
SYMPLICITY HTN-3 is the first prospective, multi-center, randomized,
blinded, sham controlled study to evaluate both the safety and
efficacy of percutaneous renal artery denervation in patients with
severe treatment-resistant hypertension.
•
The trial included 535 patients enrolled by 88 participating US
centers.
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Key Inclusion/Exclusion Criteria
Key Inclusion:
•
Stable medication regimen including full tolerated doses of 3+ anti
hypertensive medications of different classes, including a diuretic
•
Office SBP ≥160 mm Hg based on an average of 3 blood pressure
readings measured at both an initial and a confirmatory screening visit
Key Exclusion:
• ABPM 24 hour average SBP <135 mm Hg
• eGFR of <45 mL/min/1.73 m2
• Main renal arteries <4 mm diameter or <20 mm treatable length
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
SYMPLICITY HTN-3: Severe Drug-Resistant HTN
Office SBP ≥160 mm Hg
•
•
•
•
2:1 randomization, blinded and controlled
Sham procedure in control patients that included renal angiogram
535 subjects randomized out of 1441 enrolled (63% screen failure rate)
2-week screening process, including maximum tolerated doses of antihypertensives
2 weeks
1 mo 3 mo
2 weeks
Home BP & HTN med
confirmation
Screening Visit 1
• Office SBP ≥160 mm Hg
• Full doses ≥3 meds
• No med changes in past 2
weeks
• No planned med changes
for 6 mo
Screening Visit 2
• Office SBP ≥160 mm Hg
• 24-h ABPM SBP ≥135
mm Hg
• Documented med
adherence
Home BP &
HTN med
confirmation
6 mo
Sham Procedure
Renal
angiogram;
Eligible subjects
randomized
Primary
endpoint
Renal Denervation
Home BP &
HTN med
confirmation
1 mo 3 mo
2 weeks
6 mo
12-60 mo
• Patients, BP assessors, and study personnel all blinded to
treatment status
• No changes in medications for 6 M
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Key Safety Endpoint
Safety analysis
•
Composite endpoint of death, renal injury, vascular complications,
and embolic tissue injury to 1 month and renal artery stenosis to 6
months. <7% MAE rate required to meet the primary safety endpoint.
Primary safety analysis
•
A performance goal established from renal artery stenting required
the major adverse event rate for safety be <9.8%. This requires the
observed MAE rate to be <7%, given the expected confidence
interval for this endpoint.
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Key Efficacy Endpoints
Efficacy analysis
• Comparison of SBP change from baseline to 6 mo in RDN arm
compared with change from baseline to 6 mo in control arm
– Endpoint = (SBPRDN 6 mo – SBPRDN baseline) – (SBPCTL: 6 mo – SBPCTL baseline)
Primary efficacy (OBP) endpoint assumptions
• Superiority analysis
– Superiority margin of 5 mm Hg, per FDA recommendation
• Assuming a standard deviation of 25 mm Hg for both arms, 10 mm Hg
is the minimum treatment difference required to meet the efficacy
endpoint (95% CI)
Secondary efficacy (ABPM) endpoint assumptions
• Superiority analysis
– Superiority margin of 2 mm Hg, per FDA recommendation
• Assuming a standard deviation of 18 for both arms, 5.5 mm Hg is the
minimum difference required to meet the efficacy endpoint (95% CI)
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Patient Disposition
1441 subjects assessed for eligibility
Excluded:
• 880 not eligible for randomization
• 26 eligible but not randomized because
randomization cap was reached
535 subjects randomized
364 subjects randomly
allocated to renal
denervation
2:1
171 subjects randomly
allocated to sham
control
• 2 subjects died
• 1 subject withdrew
• 11 missed 6-month
visit
350 (96.2%) subjects with
6 month follow-up
• 1 subject died
• 1 missed 6-month visit
169 (98.8%) subjects with
6 month follow-up
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Results: Population Demographics
Renal Denervation
(N = 364)
Sham Procedure
(N = 171 )
P
57.9 ± 10.4
56.2 ± 11.2
0.09
59.1
64.3
0.26
Office systolic blood pressure (mm Hg)
180 ± 16
180 ± 17
0.77
24-h mean systolic ABPM (mm Hg)
159 ± 13
160 ± 15
0.83
BMI (kg/m2)
34.2 ± 6.5
33.9 ± 6.4
0.56
Characteristic
(Mean ± SD or %)
Age (years)
Male sex (%)
Race* (%)
0.57
African American
24.8
29.2
White
73.0
69.6
9.3
9.9
0.88
Renal artery stenosis
1.4
2.3
0.48
Obstructive sleep apnea
25.8
31.6
0.18
Stroke
8.0
11.1
0.26
Type 2 diabetes
47.0
40.9
0.19
Hospitalization for hypertensive crisis
22.8
22.2
0.91
Hyperlipidemia
69.2
64.9
0.32
Current smoking
9.9
12.3
0.45
Medical history (%)
Renal insufficiency (eGFR<60 mL/min/1.73 m2)
*Race also includes Asian, Native American, or other
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Results: Baseline Hypertensive Therapy
Characteristic
mean ± SD or %
Renal Denervation
(N = 364)
Sham Procedure
(N = 171 )
5.1 ± 1.4
5.2 ± 1.4
Angiotensin-converting enzyme inhibitor (%)
At maximum tolerated dose
49.2
45.9
41.5
37.4
Angiotensin receptor blocker (%)
At maximum tolerated dose
50.0
49.5
53.2
51.5
Aldosterone antagonist (%)
22.5
28.7
Alpha-adrenergic blocker (%)
11.0
13.5
Beta blocker (%)
85.2
86.0
Calcium channel blocker (%)
At maximum tolerated dose
69.8
57.1
73.1
63.7
Centrally acting sympatholytic (%)
49.2
43.9
Diuretics (%)
At maximum tolerated dose
99.7
96.4
100
97.7
7.1
7.0
36.8
45.0
No. of antihypertensive medications
Direct renin inhibitor
Direct-acting vasodilator
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
HTN-3 Results: Primary Safety Endpoint
Major Adverse Event
(MAE) Rate
10%
8%
6%
P < 0.001
4%
2%
1.4%
0%
Safety Measures
MAE
Performance Goal = 9.8%
Renal Denervation
(N = 364)
Sham Procedure
(N = 171)
Difference (95% CI)
P
1.4% (5/361)
0.6% (1/171)
0.8% (-0.9%, 2.5%)
0.67
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Primary Efficacy Endpoint
∆SBP at 6 mo
Office Systolic Blood Pressure at 6 Months, 5 mm Superiority Margin
N = 353
RDN
N = 171
Control
P value
Baseline SBP
179.7
180.2
0.765
6 mo SBP
165.6
168.4
0.260
-14.1
-11.7
P < 0.001
P < 0.001
0.2551
Change
-2.39 (-6.89, 2.12), P = 0.255 (Primary analysis with 5 mm Hg superiority margin)
• Did not meet primary efficacy endpoint
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Secondary Efficacy Endpoint
∆ ABPM at 6 mo
Ambulatory Systolic Blood Pressure at 6 Months, 2 mm Superiority Margin
N = 325
RDN
Control
Baseline
SBP
158.55
158.85
0.828
6 mo SBP
151.80
154.05
0.201
Change
-6.75
-4.79
P < 0.001
P < 0.001
0.979
N = 159
P value
-1.96 (-4.97, 1.06), P = 0.979 (ITT analysis with 2 mm Hg superiority margin)
•
Did not meet secondary efficacy endpoint
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
HTN-3 Results: Potential Factors
•
Patient behavior
– Due to being enrolled and closely monitored in a clinical trial, as
well as blinded to treatment, the patients in SYMPLICITY HTN-3
may have improved or modified their lifestyle and drug adherence.
•
Study population
– The population studied and the requirement for maximum tolerated
medication dosage were different from other SYMPLICITY studies.
•
Procedural experience and variability
– SYMPLICITY HTN-3 included a greater number of trial sites and
proceduralists compared to SYMPLICITY HTN-1 and HTN-2, which
may have led to greater procedural variability.
– Case proctoring was different and not comparable
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Comparison of HTN-2 and HTN-3 Trial Designs
HTN-2
(N = 106)
HTN-3
(N = 535)
Randomized
✓
✓
Patient blinded
✗
✓
F/U assessor blinded
✗
✓
ABPM SBP ≥135 mm Hg required?
✗
✓
Stable 3+ drug regimen with no changes ≥2
weeks prior to enrollment
✓
✓
Omron BP machine with printer
✓
✓
Maximum tolerated doses
✗
✓
2 office visits prior to randomization
✓
✓
✓/✗
✓
✓
✗
New investigators
Homogeneous patient population
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
HTN-3: Challenge of Limiting Medication Changes
in Uncontrolled Hypertension Population
45
• ~40% of patients(n = 211) in the trial
required medication changes
– 69% of first medication changes
were medically necessary
Patients With Medication
Changes (%)
• Protocol mandated maximum doses
and no medication changes
40
38
40
35
30
25
20
15
10
5
0
N = 137
N = 71
RDN
Control
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
CHALLENGES OF SHAM/PLACEBO CONTROLLED RHTN TRIALS
Control Arm Changes from Baseline
OBP
Met EP
DORADO
N=132 BL to 14 wks
EP Not Met
DORADO-AC
N=120 BL to 14 wks
ABPM
Met EP
ASPIRANT
N=56 to 8 weeks .
EP Not Met
RHEOS Pivotal
N=84 0 to 6 mo.
EP Not Met
HTN-3
N=171/159 to 6 mo.
ABPM not
reported
-2
-2
-4
-8.1
-8.6
-4.8
-9
-11.7
-14
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Pre-Specified Subgroup Analysis
RDN Sham
Difference (95% CI) P value
All patients
All patients*
Diabetics
Non-diabetics
Male
Female
African American
350
353
169
181
208
142
85
169
171
68
101
108
61
49
-4.07 (-8.63, 0.49)
-2.39 (-6.89, 2.12)
-4.53 (-11.51, 2.46)
-3.46 (-9.55, 2.62)
-2.30 (-7.63, 3.03)
-6.64 (-14.94, 1.65)
2.25 (-7.27, 11.78)
Non-African American
BMI <30
BMI ≥30
On AA at BL
Not on AA at BL
eGFR <60
eGFR ≥60
Age <65
Age ≥65
264
91
259
76
274
68
282
246
104
120
42
126
47
122
38
131
128
41
-6.63 (-11.81, -1.44) 0.012
-2.77 (-11.47, 5.93) 0.53
-4.36 (-9.76, 1.03) 0.112
-8.05 (-17.63, 1.52) 0.098
-3.24 (-8.42, 1.93) 0.219
0.54 (-8.29, 9.37) 0.904
-5.22 (-10.51, 0.06) 0.053
-5.73 (-11.06, -0.40) 0.035
0.09 (-8.80, 8.99) 0.985
Any med change
132
70
-5.41 (-13.49, 2.67) 0.188
No med change
218
99
-3.44 (-8.83, 1.96)
-20.0
-10.0
RDN Better
0.0
mm Hg
10.0
20.0
Control Better
* ITT population, 5 mm Hg superiority margin test .
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
0.080
0.255
0.203
0.264
0.396
0.116
0.641
0.211
Interaction
P value
0.821
0.365
0.089
0.766
0.364
0.309
0.273
0.677
Demographics and Control Group Impact
(N = 50)
(N = 121)
183.9 ± 19.8
178.6 ± 10.7
Age
52.4 ± 10.7
57.8 ± 11.1
Male
54.0%
68.6%
Smoking
30.0%
47.1%
Type 2 diabetes
34.0%
43.8%
Hypercholesterolemia
56.0%
68.6%
History of sleep apnea
26.0%
33.9%
No. of antihypertensive
medications
5.5 ± 1.6
5.1 ± 1.3
56.0%
40.5%
OBP at baseline
Vasodilator usage at baseline
Vasodilators are dosed up to
4x daily, making compliance
a challenge
RDN
AA
N = 85
N-AA
N = 264
mm Hg
Non–African
American
Control
-15.2
-15.5
Control
AA
N = 49
mm Hg
African
American
Control
N-AA
N = 120
-8.6
-17.8
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
ALDOSTERONE ANTAGONISTS SUB GROUP
Aldosterone Antagonist Subgroup Efficacy
AA at
Baseline
0
N=76
N=47
AA at
Baseline
No AA at
Baseline
N=274
N=122
0
N=73
N=46
-5.4
mm Hg
-10.3
-13.8
-13.5
mm Hg
-10
N=252
N=113
-4.5
-5.5
P = 0.574
-10
-11.1
P = 0.219
-20
No AA at
Baseline
P = 0.127
RDN
Control
-21.9
P = 0.098
-30
Office BP
-20
Ambulatory BP
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
HTN-3: Procedural Experience
HTN-1
HTN-3
No. of operators
20
112
No. of procedures per operator
6.0
3.3
No. of procedures per site
8.6
4.7
a) 5X more operators vs HTN-1
b) Greater heterogeneity of operator
experience vs. HTN-1 and HTN-2
c) Case proctoring was different and not
comparable
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
HTN-3: Continuing Areas of Investigation
Heterogeneity of US
Operator Experience
Patient
Demographics
Medication
Changes or
Adherence
Catheter Design
?
Hawthorne Effect
Trial Conduct
Placebo Effect
Regression to Mean
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Global Symplicity Registry (GSR)
Consecutive patients treated
in real-world population
5000 patients
GREAT Registry
N = 1000
Korea Registry*
N = 102
South Africa
Registry*
N = 400
Rest of GSR
N ≈ 3500
Canada and
Mexico*
231 international sites in 37 countries
Min. 10% randomly assigned to 100% monitoring
Follow-up schedule
3M
6M
1Y
2Y
3Y
* Limited to resistant hypertension only
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
4Y
5Y
GSR Patient Disposition
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
GSR Baseline Patient Characteristics
All Patients
(N = 1000)
SBP ≥160 mm Hg and Ambulatory
SBP ≥135* mm Hg
(N = 327)
61.2%
63.9%
Age (years)
60.7 ± 12.0
61.0 ± 10.9
BMI (kg/m2)
30.5 ± 5.5
30.9 ± 5.5
Current smoking
10.0%
11.0%
History of cardiac disease
50.5%
52.9%
Renal impairment
(eGFR <60 mL/min/1.73 m2)
23.4%
27.9%
Sleep apnea (AHI≥5)
4.2%
5.9%
Diabetes, type 1
3.2%
2.5%
Diabetes, type 2
38.5%
42.6%
1 comorbidity
39.7%
36.7%
2 comorbidities
35.5%
34.6%
3+ comorbidities
24.6%
Gender (% male)
28.4%
* With ≥3 antihypertensive medication classes
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
GSR Antihypertensive Medication Use
All Patients
(N = 1000)
SBP ≥160 mm Hg and Ambulatory
SBP ≥135 mm Hg*
(N = 327)
4.5 ± 1.3
4.7 ± 1.2
Beta-blockers
78.9%
81.0%
ACE inhibitors
33.8%
38.5%
Angiotensin receptor blockers
67.3%
67.9%
Calcium channel blockers
76.3%
78.9%
Diuretics
78.2%
79.8%
Aldosterone antagonists
21.1%
19.3%
18.6%
15.9%
Alpha-adrenergic blockers
35.2%
40.1%
Direct-acting vasodilators
15.1%
19.0%
Centrally acting sympatholytics
33.2%
37.6%
7.4%
7.7%
Antihypertensive medication class
Spironolactone
Direct renin inhibitor
*With ≥3 antihypertensive medication classes.
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Safety in HTN-3 and GSR
HTN-3
RDN Arm
(N = 364)
GSR
All Patients
(N = 1000)
GSR
Office SBP ≥160 mm Hg
and ABPM ≥ 135* mm Hg
(N=327)
1.4%
0.8%
1.3%
Death
0.6%
0.4%
0.3%
New-onset end-stage renal disease
0.0%
0.2%
0.3%
Significant embolic event resulting in
end-organ damage
0.3%
0.0%
0.0%
Renal artery re-intervention
0.0%
0.2%
0.0%
Vascular complication
0.3%
0.4%
0.7%
Hypertensive crisis/emergency
2.6%
1.0%
1.7%
New renal artery stenosis >70%
0.3%
0.0%
0.0%
MAE
At 6 months
*With ≥3 antihypertensive medication classes.
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future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Change in Office SBP at 6 Months for GSR and
SYMPLICITY HTN-3 Patients
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future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Change in Office SBP at 6 Months for GSR and
Non–African American Patients in SYMPLICITY
HTN-3
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future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Change in Ambulatory SBP for GSR and SYMPLICITY
HTN-3 Patients
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Distribution of SBP in Patients With Office SBP≥160
mm Hg and Ambulatory SBP ≥135 mm Hg* at
Baseline
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future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
GSR LBCT Conclusions
• Excellent procedural and clinical safety profile in the largest data
set of real-world RDN patients to date.
• Significant reductions in both office and ambulatory BP from
baseline.
– Differences from SYMPLICITY HTN-3 include randomization,
blinding, sham control, BP inclusion criteria, antihypertensive-drug
treatment intensity, and an African American cohort in HTN-3.
– Despite the limitations of comparing a registry with a randomized,
blinded, controlled study, the reduction in blood pressure is
numerically larger in the GSR at 6 months after treatment.
– Due to the nature of registry studies, it is difficult to account for the
magnitude of a possible placebo effect in GSR.
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Medtronic Next Steps
•
Medtronic will continue to provide access to the Symplicity™ system in
countries where it has regulatory approval and will continue to support a
global hypertension clinical program.
•
Medtronic will continue to enroll in the Global SYMPLICITY Registry.
•
Our detailed analyses of HTN-3 suggest that further investigation is
warranted; Medtronic is in discussions with the FDA to determine the
path forward for the next US IDE trial.
•
In light of the results of the SYMPLICITY HTN-3 trial, Medtronic will
discontinue the already suspended SYMPLICITY HTN-4 trial
•
Medtronic will consult with local regulatory bodies to determine the future
of the HTN-Japan and HTN-India clinical studies.
•
Medtronic will continue to pursue its studies in other disease states,
including AF, CKD, HF, etc.
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Key Takeaways
•
SYMPLICITY HTN-3 did not reach the primary or powered secondary efficacy
endpoints in this trial. There may be many factors that contributed to the
outcome, which we continue to investigate.
•
SYMPLICITY HTN-3 did meet its safety endpoint, which is consistent with all
other Symplicity trials, including the Global SYMPLICITY Registry.
•
Based upon our detailed analysis of HTN-3, we believe further clinical
investigation is warranted and Medtronic will, in consultation with FDA, pursue a
new IDE trial
•
An unmet need in this uncontrolled hypertension population still exists. Medtronic
will continue to provide access to the Symplicity system in countries where it has
regulatory approval and will continue to support a global hypertension clinical
program
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
www.medtronic.com
www.medtronicRDN.com
United States
Medtronic USA, Inc.
3576 Unocal Place
Santa Rosa, CA 95403
USA
Tel: 707.525.0111
LifeLine Customer Support
Tel: 877.526.7890
Tel: 763.526.7890
Europe
Medtronic Intl. Trading SARL
Route du Molliau 31
Case Postale
CH-1131 Tolochenaz
Switzerland
Tel: 41.21.802.7000
Fax: 41.21.802.7900
Canada
Medtronic of Canada Ltd.
99 Hereford Street
Brampton, Ontario L6Y0R3
Canada
Tel: 905.460.3800
Fax: 905.460.3998
Toll-free: 800.268.5346
Asia Pacific
Medtronic Intl. Ltd.
49 Changi South Avenue 2
Nasco Tech Center
Singapore 486056
Singapore
Tel: 65.6436.5000
Fax: 65.6776.6335
Latin America
Medtronic USA, Inc.
Doral Corporate Center II
3750 NW 87th Avenue, Suite 700
Miami, FL 33178
USA
Tel: 305.500.9328
Fax: 786.709.4244
Product Services
Tel: 888.283.7868
Fax: 800.838.3103
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Appendix
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Results: Blinding Efficacy
Time
Blinding Index*
95% CI
Discharge
0.68
(0.64, 0.72)
6 Months
0.77
(0.74, 0.81)
*The lower boundaries of the confidence intervals of the blinding index are both >0.5, indicating
sufficient evidence for blinding.
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Sample Size Assumptions
• SYMPLICITY HTN-3 sample size was driven by the safety endpoint, a
composite of Major Adverse Events (MAE).
• Safety endpoint compared to an Objective Performance Criterion
(OPC) of 9.8%, derived from historical data.
–
316 RDN therapy group subjects were required to provide 80% power, using a
one-sided significance level of 0.05.
• Given 2:1 randomization, 158 control group subjects were required.
• Accounting for expected patient attrition, sample size was increased to
a minimum of 530 randomized total patients
MAE was defined as all-cause mortality, ESRD, embolic event resulting in end-organ damage, renal artery or
other vascular complication, hypertensive crisis through 30 days, including new renal artery stenosis within 6
months.
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
HTN-3: Different Control Response in African
American Population
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
SYMPLICITY HTN-1: Significant, Sustained BP
Reduction to 3 Years
6 Months
(N = 144)
1 Year
(N = 132)
2 Years
(N = 105)
3 Years
(N = 88)
Systolic
Diastolic
P < 0.01 for  from baseline for all time points.
Data is reported only on the patients available at each time point.
Expanded results presented at the European Society of Cardiology Annual Meeting, 2013.
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
SYMPLICITY HTN-2: BP Reductions Sustained
to 3 Years
Sustained Reductions in the Pooled (RDN and Crossover) Group*
12 Months
N = 80
18 Months
N = 74
24 Months
N = 69
30 Months
N = 69
36 Months
N = 40
∆ From Baseline to
36 Months (mm Hg)
6 Months
N = 84
Systolic
Diastolic
P <0.01 at all time points
*Crossover patients only had 30 months post-procedure data.
Whitbourn, TCT 2013
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14
Multiple Unblinded Trials Show RDN Lowers Blood
Pressure
Medtronic
EnligHTN/St Jude
Vessix/Boston Sci.
Maya/Covidien
Recor
Published Sources:
1. Lancet 2009
2. Lancet 2010
3. TCT 2013
4. Journal of Human Hypertension 2013
5. Circulation 2013
6. Clin Res Cardiol 2013
7. J Am Soc Nephrol 2012
8. Eur Heart J 2013
9. TCT 2013
10. Eurointervention 2013
11. EuroIntervention 2013
Trademarks may be registered and are the property of their respective owners. A reminder that this is a discussion of SYMPLICITY trial results and their implications for the
future of RDN. Today’s discussion may regard information or indications not evaluated by regulatory authorities in your geography. Always refer to the Instructions for Use
prior to using the Symplicity renal denervation system. Investigational use only in the USA © 2014 Medtronic, Inc. All rights reserved.UC2014006134IE 3/14