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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.

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Presentation on theme: "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."— Presentation transcript:

1 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 RDN SYMPLICITY HTN-3 & Global SYMPLICITY Registry (GSR)

2 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

3 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 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. SYMPLICITY HTN-3 Trial Objectives

4 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: 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 m 2 Main renal arteries <4 mm diameter or <20 mm treatable length Key Inclusion/Exclusion Criteria

5 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 Home BP & HTN med confirmation SYMPLICITY HTN-3: Severe Drug-Resistant HTN Office SBP ≥160 mm Hg 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 1 Home BP & HTN med confirmation Home BP & HTN med confirmation Primary endpoint 2 weeks 1 mo 3 mo 6 mo 12-60 mo Patients, BP assessors, and study personnel all blinded to treatment status No changes in medications for 6 M 2 weeks Renal angiogram; Eligible subjects randomized Sham Procedure Renal Denervation Office SBP ≥160 mm Hg 24-h ABPM SBP ≥135 mm Hg Documented med adherence Screening Visit 2 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

6 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.

7 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 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 = (SBP RDN 6 mo – SBP RDN baseline ) – (SBP CTL: 6 mo – SBP CTL 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) Key Efficacy Endpoints

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 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 171 subjects randomly allocated to sham control 350 (96.2%) subjects with 6 month follow-up 169 (98.8%) subjects with 6 month follow-up 1 subject died 1 missed 6-month visit 2 subjects died 1 subject withdrew 11 missed 6-month visit 2:1 Patient Disposition

9 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 Characteristic (Mean ± SD or %) Renal Denervation (N = 364) Sham Procedure (N = 171 ) P Age (years) 57.9 ± 10.456.2 ± 11.2 0.09 Male sex (%)59.164.30.26 Office systolic blood pressure (mm Hg) 180 ± 16180 ± 17 0.77 24-h mean systolic ABPM (mm Hg) 159 ± 13160 ± 15 0.83 BMI (kg/m 2 ) 34.2 ± 6.533.9 ± 6.4 0.56 Race* (%) 0.57 African American24.829.2 White73.069.6 Medical history (%) Renal insufficiency (eGFR<60 mL/min/1.73 m 2 )9.39.90.88 Renal artery stenosis1.42.30.48 Obstructive sleep apnea25.831.60.18 Stroke8.011.10.26 Type 2 diabetes47.040.90.19 Hospitalization for hypertensive crisis22.822.20.91 Hyperlipidemia69.264.90.32 Current smoking9.912.30.45 *Race also includes Asian, Native American, or other

10 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 ) No. of antihypertensive medications 5.1 ± 1.45.2 ± 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 (%)22.528.7 Alpha-adrenergic blocker (%)11.013.5 Beta blocker (%)85.286.0 Calcium channel blocker (%) At maximum tolerated dose 69.8 57.1 73.1 63.7 Centrally acting sympatholytic (%)49.243.9 Diuretics (%) At maximum tolerated dose 99.7 96.4 100 97.7 Direct renin inhibitor 7.1 7.0 Direct-acting vasodilator36.845.0

11 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 Performance Goal = 9.8% P < 0.001 Safety Measures Renal Denervation (N = 364) Sham Procedure (N = 171) Difference (95% CI)P MAE1.4% (5/361)0.6% (1/171)0.8% (-0.9%, 2.5%)0.67 Major Adverse Event (MAE) Rate

12 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 Office Systolic Blood Pressure at 6 Months, 5 mm Superiority Margin -2.39 (-6.89, 2.12), P = 0.255 (Primary analysis with 5 mm Hg superiority margin) N = 353N = 171 Did not meet primary efficacy endpoint RDNControlP value Baseline SBP179.7180.20.765 6 mo SBP165.6168.40.260 Change -14.1 P < 0.001 -11.7 P < 0.001 0.255 1 ∆SBP at 6 mo

13 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 Ambulatory Systolic Blood Pressure at 6 Months, 2 mm Superiority Margin -1.96 (-4.97, 1.06), P = 0.979 (ITT analysis with 2 mm Hg superiority margin) N = 325N = 159 Did not meet secondary efficacy endpoint ∆ ABPM at 6 mo RDNControlP value Baseline SBP 158.55158.850.828 6 mo SBP151.80154.050.201 Change -6.75 P < 0.001 -4.79 P < 0.001 0.979

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 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

15 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 ✓✗

16 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 Protocol mandated maximum doses and no medication changes ~40% of patients(n = 211) in the trial required medication changes –69% of first medication changes were medically necessary N = 137 N = 71 Patients With Medication Changes (%)

17 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 N=132 BL to 14 wksN=120 BL to 14 wksN=84 0 to 6 mo.N=171/159 to 6 mo.N=56 to 8 weeks. Met EP EP Not Met Met EP EP Not Met EP Not Met Control Arm Changes from Baseline CHALLENGES OF SHAM/PLACEBO CONTROLLED RHTN TRIALS

18 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 RDNSham Difference (95% CI)P value Interaction P value All patients350169-4.07 (-8.63, 0.49)0.080 All patients*353171-2.39 (-6.89, 2.12)0.255 Diabetics16968-4.53 (-11.51, 2.46)0.2030.821 Non-diabetics181101-3.46 (-9.55, 2.62)0.264 Male208108-2.30 (-7.63, 3.03)0.3960.365 Female14261-6.64 (-14.94, 1.65)0.116 African American85492.25 (-7.27, 11.78)0.6410.089 Non-African American264120-6.63 (-11.81, -1.44)0.012 BMI <309142-2.77 (-11.47, 5.93)0.530.766 BMI ≥30259126-4.36 (-9.76, 1.03)0.112 On AA at BL7647-8.05 (-17.63, 1.52)0.0980.364 Not on AA at BL274122-3.24 (-8.42, 1.93)0.219 eGFR <6068380.54 (-8.29, 9.37)0.9040.309 eGFR ≥60282131-5.22 (-10.51, 0.06)0.053 Age <65246128-5.73 (-11.06, -0.40)0.0350.273 Age ≥65104410.09 (-8.80, 8.99)0.985 Any med change13270-5.41 (-13.49, 2.67)0.1880.677 No med change21899-3.44 (-8.83, 1.96)0.211 * ITT population, 5 mm Hg superiority margin test. RDN Better Control Better mm Hg

19 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 Demographics and Control Group Impact RDN Control AA N = 85 N-AA N = 264 AA N = 49 N-AA N = 120 Vasodilators are dosed up to 4x daily, making compliance a challenge mm Hg African American Control (N = 50) Non–African American Control (N = 121) OBP at baseline 183.9 ± 19.8178.6 ± 10.7 Age 52.4 ± 10.757.8 ± 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 ± 1.65.1 ± 1.3 Vasodilator usage at baseline 56.0%40.5% mm Hg

20 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 Antagonist Subgroup Efficacy mm Hg AA at Baseline ALDOSTERONE ANTAGONISTS SUB GROUP No AA at Baseline P = 0.219 P = 0.098 Office BP mm Hg AA at Baseline No AA at Baseline P = 0.574 P = 0.127 Ambulatory BP RDN Control N=76 N=47 N=73 N=46 N=274 N=122 N=252N=113

21 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 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 HTN-1HTN-3 No. of operators 20112 No. of procedures per operator 6.03.3 No. of procedures per site 8.64.7

22 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 Hawthorne EffectPlacebo Effect Patient Demographics Heterogeneity of US Operator Experience Trial Conduct ? Medication Changes or Adherence Catheter Design ? Regression to Mean

23 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 6M3Y2Y1Y Follow-up schedule 3M 4Y 5Y * Limited to resistant hypertension only 231 international sites in 37 countries Min. 10% randomly assigned to 100% monitoring 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 Canada and Mexico* Rest of GSR N ≈ 3500

24 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 Patient Disposition

25 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 All Patients (N = 1000) SBP ≥160 mm Hg and Ambulatory SBP ≥135* mm Hg (N = 327) Gender (% male)61.2%63.9% Age (years)60.7 ± 12.061.0 ± 10.9 BMI (kg/m 2 )30.5 ± 5.530.9 ± 5.5 Current smoking10.0%11.0% History of cardiac disease50.5%52.9% Renal impairment (eGFR <60 mL/min/1.73 m 2 ) 23.4%27.9% Sleep apnea (AHI≥5) 4.2%5.9% Diabetes, type 13.2% 2.5% Diabetes, type 238.5% 42.6% 1 comorbidity39.7%36.7% 2 comorbidities35.5%34.6% 3+ comorbidities24.6%28.4% * With ≥3 antihypertensive medication classes GSR Baseline Patient Characteristics

26 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 All Patients (N = 1000) SBP ≥160 mm Hg and Ambulatory SBP ≥135 mm Hg* (N = 327) Antihypertensive medication class4.5 ± 1.34.7 ± 1.2 Beta-blockers78.9%81.0% ACE inhibitors33.8%38.5% Angiotensin receptor blockers67.3%67.9% Calcium channel blockers76.3%78.9% Diuretics78.2%79.8% Aldosterone antagonists21.1%19.3% Spironolactone18.6%15.9% Alpha-adrenergic blockers35.2%40.1% Direct-acting vasodilators15.1%19.0% Centrally acting sympatholytics33.2%37.6% Direct renin inhibitor 7.4% 7.7% GSR Antihypertensive Medication Use *With ≥3 antihypertensive medication classes.

27 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 RDN Arm (N = 364) GSR All Patients (N = 1000) GSR Office SBP ≥160 mm Hg and ABPM ≥ 135* mm Hg (N=327) MAE1.4%0.8%1.3% At 6 months Death0.6%0.4%0.3% New-onset end-stage renal disease0.0%0.2%0.3% Significant embolic event resulting in end-organ damage 0.3%0.0% Renal artery re-intervention0.0%0.2%0.0% Vascular complication0.3%0.4%0.7% Hypertensive crisis/emergency2.6%1.0%1.7% New renal artery stenosis >70%0.3%0.0% Safety in HTN-3 and GSR *With ≥3 antihypertensive medication classes.

28 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 Change in Office SBP at 6 Months for GSR and SYMPLICITY HTN-3 Patients

29 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 Change in Office SBP at 6 Months for GSR and Non–African American Patients in SYMPLICITY HTN-3

30 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 Change in Ambulatory SBP for GSR and SYMPLICITY HTN-3 Patients

31 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

32 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 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. GSR LBCT Conclusions

33 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.

34 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

35 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 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 Asia Pacific Medtronic Intl. Ltd. 49 Changi South Avenue 2 Nasco Tech Center Singapore 486056 Singapore Tel: 65.6436.5000 Fax: 65.6776.6335 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 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 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 Product Services Tel: 888.283.7868 Fax: 800.838.3103

36 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

37 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 TimeBlinding Index* 95% CI Discharge0.68(0.64, 0.72) 6 Months0.77(0.74, 0.81) *The lower boundaries of the confidence intervals of the blinding index are both >0.5, indicating sufficient evidence for blinding.

38 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.

39 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

40 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 Expanded results presented at the European Society of Cardiology Annual Meeting, 2013. P < 0.01 for  from baseline for all time points. Data is reported only on the patients available at each time point. 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

41 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* P <0.01 at all time points ∆ From Baseline to 36 Months (mm Hg) 30 Months N = 69 24 Months N = 69 6 Months N = 84 12 Months N = 80 18 Months N = 74 36 Months N = 40 *Crossover patients only had 30 months post-procedure data. Whitbourn, TCT 2013 Systolic Diastolic

42 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 N=153 N=102 N=313 N=109 N=346 N=63 N=15 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 N=46 N=146 N=47 N=15 Medtronic EnligHTN/St Jude Vessix/Boston Sci. Maya/Covidien Recor


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