1. Clinician Referral Training

2. 10% lower risk of stroke mortality
Even Small Differences in Blood Pressure Are Linked with Risk of Cardiovascular Mortality
Meta-analysis of 61 prospective, observational studies 1 million adults (40–89 years; 70% Europe, 20% North America or Australia, 10% Japan or China) 12.7 million person-years
Associated with
10% lower risk of stroke mortality
7% lower risk of ischemic heart disease mortality
2-mm Hg lower mean office SBP
For ABPM, the gain is even higher. This means that a comparable reduction in ABPM results in an even larger risk reduction than for office BP.
Purpose:
To illustrate the relationship between BP and CV disease mortality.
Key Points:
Data from a meta-analysis of individual data for 1 million adults (40-89 years; 70% Europe, 20% North America or Australia, 10% Japan or China) from 61 prospective observational studies of BP and mortality demonstrated that even a small 2 mm Hg reduction in mean office SBP was associated with a large absolute reduction in the risk of premature death and disabling stroke
In middle age, a 2 mm Hg decrease in mean SBP could lead to approximately a 10% lower risk of death from stroke and a 7% lower risk of death from ischemic heart disease or other vascular cause
Source:
Lewington S, Clarke R, Qizilbash N, et al, and The Prospective Studies Collaboration. 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:
SBP = systolic blood pressure
Lewington S et al. The Lancet. 2002;360:1903–1913. 2

3. Renal Anatomy Allows a Catheter-Based Approach
RENAL DENERVATION Disrupt the renal nerves and reduce overactive SNS
Vessel lumen
Media
Adventitia
Renal nerves
Histological data show that renal nerves are contained in the adventitial layers surrounding the renal artery.

4. SYMPLICITY HTN-1 Long-Term F/U
SYMPLICITY HTN-1 and SYMPLICITY HTN-2 Clinical Trials Showed Significant and Sustained Blood Pressure Reduction
SYMPLICITY HTN-1 Long-Term F/U
Change in office BP through 36 months*
SYMPLICITY HTN-2 RCT
Primary endpoint: 6-month office BP†
RDN (n = 49)
Control (n = 51)
Systolic
Diastolic
Systolic
Diastolic
1 mo
(n = 80)
3 mo
(n = 88)
6 mo
(n = 88)
12 mo
(n = 85)
24 mo
(n = 82)
30 mo
(n = 84)
36 mo
(n = 88)
Difference between RDN and Control highly significant (p<0.0001)
SYMPLICITY HTN 1 showed long term safety and efficacy in a non randomized pilot study. (figure shows cohort available for all follow ups)
SYMPLICITY HTN 2 confirmed these results in a randomized controlled (but not blinded) trial.
Together, these trials set the stage for SYMPLICITY HTN 3.
84% of RDN patients had ≥10 mm Hg reduction in SBP Only 10% of RDN patients had no reduction in SBP
*Krum H et al. The Lancet. 2014;383:622–629.
†SYMPLICITY HTN-2 Investigators. The Lancet. 2010;376:1903–1909

5. SYMPLICITY HTN-3 Results: Primary Safety Endpoint
Performance Goal = 9.8% 10
p<0.001
Major Adverse Event (MAE) Rate (%) 5
1.4
Safety Measures
Renal Denervation (n = 364)
Sham Procedure (n = 171)
Difference
(95% CI)
p-Value
MAE
1.4% (5/361)
0.6% (1/171)
0.8% (-0.9%, 2.5%)
0.67
Bhatt DL et al. N Engl J Med. 2014;370:1393–1401.
Bhatt, ACC 2014.

6. SYMPLICITY HTN-3: Primary Efficacy Endpoint
Office Systolic Blood Pressure at 6 Months, 5-mm Superiority Margin
RDN
Control
p-Value
Baseline SBP
179.7
180.2
0.765
6-Month SBP
165.6
168.4
0.260
Change
-14.1
p<0.001
-11.7
0.255 -8
-16
n = 353
n = 171
∆SBP at 6 Months
-14.1
-11.7
RDN
Control
-2.39 (-6.89, 2.12), p = (Primary analysis with 5-mm Hg superiority margin)
Bhatt DL et al. N Engl J Med. 2014;370:1393–1401.

7. SYMPLICITY HTN3-Like Patients* Change in Blood Pressure (mm Hg)
Change in Office SBP for SYMPLICITY HTN3-Like Patients in Global SYMPLICITY Registry
SYMPLICITY HTN3-Like Patients*
All Patients
N = 784
N = 740
N = 252
N = 234
-10
Change in Blood Pressure (mm Hg)
-11.6 ± 24.7
-13.0 ± 26.3
-20
p<0.001 for all vs. baseline
Error bars = 1.96 SE
The HTN-3 like subgroup consists of patients with baseline office SBP ≥160 mm Hg and mean 24-hr SBP≥135 mm Hg and prescribed ≥3 antihypertensive medication classes. Office systolic blood pressure dropped significantly in both the whole patient cohort and the HTN-3 like sub group at both 6 and 12 months. However, the pressure drops are even greater in the HTN 3 like cohort.
(Error bars are 1.96 x the Standard error of the mean. This is equivalent to the 95% CI range.)
-19.3 ± 22.4
6 Months
-21.5 ± 25.6
12 Months
-30
*Patients with baseline office SBP≥160 mm Hg and mean 24-hr SBP≥135 mm Hg and prescribed ≥3 antihypertensive medication classes.
Mahfoud, ESC 2014.

8. SPYRAL HTN Global Clinical Trial Program
SYMPLICITY HTN-3 Factor Identified
SPYRAL HTN
Obtain off-med data
Standardize meds
No max dose titration
Measure adherence
Medications
Less severe HTN
Fewer prescribed meds
Focus on ABPM
Patients from across globe
Avoid changing patient behavior
Study population
We have learned a great a deal from SYMPLICITY HTN-3 and consulted with a variety of experts and stakeholders, and we believe this new clinical program will help to specifically address the confounding factors encountered in HTN-3, including drug, patient and procedural variability, to ensure we evaluate the full clinical potential of renal denervation therapy.
Symplicity Spyral™ catheter
Main and branch vessel treatment
Experienced proceduralists
Procedural

9. SPYRAL HTN–OFF MED Study
Med titration
every 2 weeks if uncontrolled
Objective: Evaluate safety and blood pressure response after renal denervation in patients with uncontrolled hypertension compared to a sham-controlled population, in the absence of antihypertensive medications.
Follow-up every 2 weeks (through 3 mo)
3 Mo
6 Mo
12 Mo
N<60
2-week
safety check
Renal denervation
1-2-weeks washout
Randomization/
procedure
Patients with HTN
1st screening
3-week
washout
2nd screening
Unblinding
Office SBP
Taken off medications
Baseline ABPM
Office SBP
SBP
>180
Sham procedure
ABPM ≥140 to <170
Office ≥150 to <180
DBP ≥ 90
N<60
Screen
failure
Follow-up every 2 weeks (through 3 mo)
The SPYRAL HTN-OFF MED trial is evaluating renal denervation in the absence of any antihypertensive medications compared to a sham-controlled population. Prior to randomization, patients will undergo an antihypertensive medication washout period of three to four weeks. Patients in both groups will be systematically titrated back into anti-hypertensive medical therapy as appropriate three months following randomization. The off-medication trial will help isolate the effect of renal denervation on blood pressure reduction, and was requested by both the FDA and many clinicians.
3 Mo
6 Mo
12–36 Mo
Drug testing to confirm washout at 2nd screening visit and 3 mo; drug testing at 6 mo and 12 mo
Represents study safety measures

10. OFF MED: Key Inclusion Criteria
1. Individual is willing to discontinue current antihypertensive medications between the 1st screening visit and post-procedure visit at 3 months.
2. Systolic 24-hour mean ABPM after patients’ medication has been discontinued:
≥ 140 mmHg
< 170 mm Hg
3. Office SBP
≥ 150 mmHg
< 180 mm Hg
4. Office DBP
≥ 90 mmHg

11. OFF MED: Key Exclusion Criteria
Ineligible renal artery anatomy
eGFR < 45 mL/min/1.73m2
Type 1 diabetes mellitus or poorly-controlled type 2 diabetes mellitus with HbA1C >8.0%
Secondary causes of hypertension, including primary hyperaldosteronism
Currently taking anti-mineralocorticoid drugs
Prescribed medications for the following conditions that impact blood pressure: coronary artery disease, myocardial infarction, heart failure, unstable angina, cerebrovascular accident or transient ischemic attack, or atrial fibrillation

12. SPYRAL HTN–ON MED Study
Office BP
ABPM
Objective: The objective of this study is to evaluate safety and blood pressure response after renal denervation in patients with uncontrolled hypertension compared to a sham-controlled population, in the presence of the three most commonly prescribed antihypertensive medications: thiazide diuretic, dihydropyridine calcium channel blocker, ACE/ARB.
Office BP
1 Mo
3 Mo
6 Mo
12–36 Mo
N<50
2–4 weeks
Renal denervation + meds
Office SBP >150 and <180 mm Hg on 3 meds for 6 weeks
1st screening
2nd screening
Randomization/
Procedure
Unblinding
Office SBP
Urinalysis
Observed drug intake
Office SBP
ABPM
Sham procedure + meds
N<50
ABPM ≥140 to <170
Office ≥150 and <180
DBP ≥ 90
The SPYRAL HTN-ON MED trial is evaluating renal denervation therapy compared to a sham-controlled population with patients on a standardized treatment regimen of three standard antihypertensive medications, including a thiazide-type diuretic, a dihydropyridine calcium channel blocker, and an ACE-inhibitor/angiotensin receptor blocker (ACE-I/ARB) for at least six weeks prior to randomization and will be expected to maintain that regimen for at least six months. By specifying specific medication classes not a maximum tolerated doses, reducing medication variability will be reduced, the study is more likely to provide a clinically meaningful answer allowing for a more controlled assessment of the impact of renal denervation in the presence of background medications.
1 Mo
3 Mo
6 Mo
12 Mo
Confirmed on meds
Thiazide-type diuretic
Calcium channel blocker
ACE/ARB
Stable meds
Drug testing

13. ON MED: Key Inclusion Criteria
Patient is prescribed three antihypertensive medications at least 50% of the maximum dosage;
thiazide-type diuretic
dihydropyridine calcium channel blocker
ACE-I/ARB
2. Systolic 24-hour mean ABPM following witnessed antihypertensive drug ingestion:
≥ 140 mmHg
< 170 mm Hg
3. Office SBP
≤ 150 mmHg
< 180 mm Hg
4. Office DBP
≥ 90 mmHg

14. ON MED: Key Exclusion Criteria
Ineligible renal artery anatomy
eGFR < 45 mL/min/1.73m2
Type 1 diabetes mellitus or poorly-controlled type 2 diabetes mellitus with HbA1C >8.0%
Secondary causes of hypertension, including primary hyperaldosteronism
Currently taking anti-mineralocorticoid drugs

15. CAUTION: Investigational device
CAUTION: Investigational device. Limited by federal (or United States) law to investigational use. Not for sale in the USA or Japan. Trademarks may be registered and are the property of their respective owners. 07/15