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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;360:1903-1913. SBP = systolic blood pressure Lewington S et al. The Lancet. 2002;360:1903–1913. 2

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.

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

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.

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 = 0.255 (Primary analysis with 5-mm Hg superiority margin) Bhatt DL et al. N Engl J Med. 2014;370:1393–1401.

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.

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

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

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

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

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

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

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

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