Medtronic : Biennial 2020 Investor & Analyst Meeting - Citations

CRHF CITATIONS

CRHF/CRM IMPLANTABLES: COBALT CROME ICD & CRT-D

• Auricchio A, Schloss EJ, Kurita T, et al. Low inappropriate shock rates in patients with single- and dual/triple- chamber implantable cardioverter-defibrillators using a novel suite of detection algorithms: PainFree SST trial primary results. Heart Rhythm. May 2015;12(5):926-936.
• Volosin KJ, Exner DV, Wathen MS, Sherfesee L, Scinicariello AP, Gillberg JM. Combining shock reduction strategies to enhance ICD therapy: a role for computer modeling. J Cardiovasc Electrophysiol. March 2011;22(3):280-289.
• Birnie D, Lemke B, Aonuma K, et al. Clinical outcomes with synchronized left ventricular pacing: analysis of the adaptive CRT trial. Heart Rhythm. September 2013;10(9):1368-1374.
• Singh JP, Cha YM, Lunati M, et al. Real-world behavior of CRT pacing using the AdaptivCRT algorithm on patient outcomes: Effect on mortality and atrial fibrillation incidence. J Cardiovasc Electrophysiol. April 2020;31(4):825- 833.
• Starling RC, Krum H, Bril S, et al. Impact of a Novel Adaptive Optimization Algorithm on 30-Day Readmissions: Evidence From the Adaptive CRT Trial. JACC Heart Fail. July 2015;3(7):565-572.
• Pürerfellner H, Gillis AM, Holbrook, Hettrick DA. Accuracy of atrial tachyarrhythmia detection in implantable devices with arrhythmia therapies. Pacing Clin Electrophysiol. July 2004;27(7):983-992.

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CRHF CITATIONS

CRHF/CRM IMPLANTABLES: COBALT CROME ICD & CRT-D

• Ziegler PD, et al. Accuracy of Atrial Fibrillation Detection in Implantable Pacemakers. Presented at HRS 2013 (PO02-08); Denver, CO.
• Kauffman ES, Israel CW, Nair GM, et al. Positive predictive value of device-detected atrial high-rate episodes at different rates and durations: an analysis from ASSERT. Heart Rhythm. August 2012;9(8):1241-1246.
• Nowak B, McMeekin J, Knops M, et al. Validation of dual-chamber pacemaker diagnostic data using dual-channel stored electrograms. Pacing Clin Electrophysiol. July 2005;28(7):620-629.
• Birnie D, Hudnall H, Lemke B, et al. Continuous optimization of cardiac resynchronization therapy reduces atrial fibrillation in heart failure patients: Results of the Adaptive Cardiac Resynchronization Therapy Trial. Heart Rhythm. December 2017;14(12):1820-1825.
• Crossley GH, Padeletti L, Zweibel S, Hudnall JH, Zhang Y, Boriani G. Reactive atrial-based antitachycardia pacing therapy reduces atrial tachyarrhythmias. Pacing Clin Electrophysiol. July 2019;42(7):970-979.
• Saxon LA, Hayes DL, Gilliam FR, et al. Long-term outcome after ICD and CRT implantation and influence of remote device follow-up: the ALTITUDE survival study. Circulation. December 7, 2010;122(23):2359-2367.
• Varma N, Piccini JP, Snell J, Fischer A, Dalal N, Mittal S. Relationship between Level of Adherence to Automatic Wireless Remote Monitoring and Survival in Pacemaker and Defibrillator Patients. J Am Coll Cardiol. June 23, 2015;65(24):2601-2610.

2020 Analyst Day | October 14, 2020 1

CRHF CITATIONS

CRHF/CRM IMPLANTABLES: COBALT CROME ICD & CRT-D

• Akar JG, Bao H, Jones PW, et al. Use of Remote Monitoring is Associated with Lower Risk of Adverse Outcomes Among Patients with Implanted Cardiac Defibrillators. Circ Arrhythm Electrophysiol. October 2015;8(5):1173- 1180.
• Cronin EM, Ching EA, Varma N, Martin DO, Wilkoff BL, Lindsay BD. Remote monitoring of cardiovascular devices: a time and activity analysis. Heart Rhythm. December 2012;9(12):1947-1951.
• Varma N. Rationale and design of a prospective study of the efficacy of a remote monitoring system used in implantable cardioverter defibrillator follow-up: the Lumos-T Reduces Routine Office Device Follow-Up Study (TRUST) study. Am Heart J. December 2007;154(6):1029-1034.
• Crossley GH, Boyle A, Vitense H, Chang Y, Mead RH; CONNECT Investigators. The CONNECT (Clinical Evaluation of Remote Notification to Reduce Time to Clinical Decision) trial: the value of wireless remote monitoring with automatic clinician alerts. J Am Coll Cardiol. March 8, 2011;57(10):1181-1189.
• Tarakji KG, Zaidi AM, Zweibel SL, et al. Performance of First in the World Pacemaker to Use Smart Device App for Remote Monitoring. Late-breaking clinical trial presented online at HRS 2020.

2020 Analyst Day | October 14, 2020 2

CRHF CITATIONS

CRHF/CRM IMPLANTABLES: LINQ II ICM CITATIONS

• Nölker G, Mayer J, Boldt LH, et al. Performance of an Implantable Cardiac Monitor to Detect Atrial Fibrillation: Results of the DETECT AF Study. J Cardiovasc Electrophysiol. December 2016;27(12):1403-1410.
• Pürerfellner H, Sanders P, Sarkar S, et al. Adapting detection sensitivity based on evidence of irregular sinus arrhythmia to improve atrial fibrillation detection in insertable cardiac monitors. Europace. November 1, 2018;20(FI_3):f321-f328.
• Epstein AE, DiMarco JP, Ellenbogen KA, et al. 2012 ACCF/AHA/HRS focused update incorporated into the ACCF/AHA/HRS 2008 guidelines for device-based therapy of cardiac rhythm abnormalities: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. January 22, 2013;61(3):e6-e75.
• Cronin EM, Ching EA, Varma N, Martin DO, Wilkoff BL, Lindsay BD. Remote monitoring of cardiovascular devices: a time and activity analysis. Heart Rhythm. December 2012;9(12):1947-1951.
• Varma N. Remote monitoring of patients with CIEDs following the updated recommendations - Easing or adding to postimplant responsibilities? Cont Cardiol Educ. December 2016;2(4):198-204.
• Van Heel L, Ousdigian K, Seiler A, Alfaro Vives C, Cheng Y-J. Rogers J. New Algorithms Reduce Clinician Review Burden and Maintain Diagnostic Yield for Repetitive ECGs in Insertable Cardiac Monitors. Circulation. November 11, 2019;140:A11830.

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CRHF CITATIONS

CRHF/CRM IMPLANTABLES: LINQ II ICM CITATIONS

• Passman R, Rogers J, Sarkar S, et al. Development and validation of a dual sensing scheme to improve accuracy of bradycardia and pause detection in an insertable cardiac monitor. Heart Rhythm. 2017;14(7):1016-1023.
• Penela D, Fernández-Armenta J, Aguinaga L, et al. Clinical Recognition of Pure Premature Ventricular Complex- Induced Cardiomyopathy at Presentation. Heart Rhythm. December 2017;14(12):1864-1870.
• Penela D, Van Huls Van Taxis C, Aguinaga L, et al. Neurohormonal, Structural, and Functional Recovery Pattern After Premature Ventricular Complex Ablation Is Independent of Structural Heart Disease Status in Patients With Depressed Left Ventricular Ejection Fraction: A Prospective Multicenter Study. J Am Coll Cardiol. September 24, 2013;62(13):1195-1202.
• Fowles JB, Terry P, Xi M, Hibbard J, Bloom CT, Harvey L. Measuring self-management of patients' and employees' health: further validation of the Patient Activation Measure (PAM) based on its relation to employee characteristics. Patient Educ Couns. October 2009;77(1):116-122.

2020 Analyst Day | October 14, 2020 4

CRHF CITATIONS

CRHF/CRM IMPLANTABLES: MYCARELINK HEARTTM MOBILE APP

• Varma N. Remote monitoring of patients with CIEDs following the updated recommendations - Easing or adding to postimplant responsibilities? Cont. Cardiol Educ. December 2016;2(4):198-204.
• Fowles JB, Terry P, Xi M, Hibbard J, Bloom CT, Harvey L. Measuring self-management of patients' and employees' health: further validation of the Patient Activation Measure (PAM) based on its relation to employee characteristics. Patient Educ Couns. October 2009;77(1):116-12
• Tarakji KG, Zaidi AM, Zweibel SL, et al. Performance of First in the World Pacemaker to Use Smart Device App for Remote Monitoring. Late-breaking clinical trial presented online at HRS 2020.

2020 Analyst Day | October 14, 2020 5

CITATIONS

TAVR - EVOLUTTM PRO, PRO+ TRANSCATHETER AORTIC VALVE REPLACEMENT SYSTEM

1. Gleason TG, Reardon MJ, Popma JJ, et al. 5-year Outcomes from the Randomized CoreValve US Pivotal HighRisk Trial: Final Results, J AM Coll Cardiol. September 2015;72(13 Supp.).
2. Popma, JJ, et al. Leaflet Thickening or Immobility in Transcatheter or Surgical Aortic Valves: Results from The Evolut Low Risk LTI Sub-Study. Presented at ACC/WCC 2020 Virtual; March 28, 2020.
3. Popma JJ, Deeb GM, Yakubov SJ, et al. Transcatheter Aortic-Valve Replacement with a Self-Expanding Valve in Low-Risk Patients. N Engl J Med. May 2, 2019;380(18):1706-1715.
4. Testa L, Fiorina C, Giannini C, et al. Valve performance and echocardiographic data throughout 8 years follow up after TAVR. Presented at EuroPCR 2019; Paris, France.
5. Ring ME, Jin R, Parrish R, et al. Comparison of Echocardiographic Outcomes Following Trans Catheter Aortic Valve Replacement with Edwards S3 23 mm versus Medtronic Evolut 26 mm Valves. Poster presented at ACC 2020 Virtual.
6. Rashid HN, Gooley RP, Nerlekar N, et al. Bioprosthetic aortic valve leaflet thrombosis detected by multidetector computed tomography is associated with adverse cerebrovascular events: a meta-analysis of observational studies. EuroIntervention. February 2, 2018;13(15):e1748-e1755.
7. Dvir D, Webb JG, Bleiziffer S, et al. Transcatheter aortic valve implantation in failed bioprosthetic surgical valves. JAMA. 2014;312:162-170.
8. Ramlawi B, et al. Primary Results From the Evolut Low Risk Bicuspid Study. Presented at ACC; March 29, 2020.
9. Mangieri A, Tchetche D, Kim WK, et al. Balloon vs Self-Expandable valve for the treatment of bicuspid Aortic valve stenosis: insights from the BEAT international collaborative registry. J AM Coll Cardiol. September 2018;72(13 Suppl_B):B168.
10. Data from STS/ACC TVT Registry. Data on file.
11. IFU, Study Enrollment Criteria

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CITATIONS

PELVIC HEALTH- INTERSTIMTM SYSTEMS

1. In the U.S. alone, 37.5 million people are living with overactive bladder.
2. • Stewart WF, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003 May;20(6):327-336.
   • United Nations, Department of Economic and Social Affairs, Population Division (2011). World Population Prospects: The 2010 Revision, CD-ROM Edition.
3. Of those, 4.5 million are indicated for a third line therapy and only 5% pursue treatment.
4. • Medtronic data on file. (See attached slide: "OAB severely under-treated")
5. We have taken advances in battery technology and microelectronics to develop a rechargeable system that is smaller, faster, and better than the Axonics' system.
6. • Add fair balance statement: The most common adverse events experienced during clinical studies include pain at implant sites, new pain, lead migration, infection, technical or device problems, adverse change in bowel or voiding function, and undesirable stimulation or sensations. Any of these may require additional surgery or cause return of symptoms
7. It's faster because our battery has the fastest recharge speed - from zero to 100% in less than an hour.*
8. • *Based on appropriate recharger placement
9. It's better because our battery has zero fade*
10. • *Under standard patient therapy settings

    6. And, let's not forget ... we have a new basic evaluation lead. It's designed to move less than the trial lead by Axonics, providing patients with a BETTER chance to move on to an implant.

    • Add fair balance statement: Complications can occur with the evaluation, including tissue damage, infection, and technical problems with the device. Patients should be instructed on operating the programmer and given precautions related to the evaluation.
    • For the Medtronic vs Axonics lead video, the reference is: Medtronic data on file.

2020 Analyst Day | October 14, 2020

OVERACTIVE BLADDER IS SEVERELY UNDER-TREATED

37.5M

Total US OAB

Population

US data for illustration - drop-out rates are similar globally

More than 40% of adults with OAB don't ask for help7

	Women experience OAB symptoms for 6.5 years	7
	before being diagnosed.
	Fewer than 10% of urologists specialize in OAB.	8

OAB population is

significantly under-treated

with high fallout from

continuum

1. "Population based survey of UI, OAB, and other lower urinary tract symptoms in 5 countries", Irwin, et al., Eur Urol. 2006;50(6):1306-14.
2. "The Prevalence of Lower Urinary Tract Symptoms (LUTS)
   and Overactive Bladder (OAB) by Racial/Ethnic Group
   and Age: Results From OAB-POLL", Coyne, et al., Neurology and Urodynamics 32:230-237 (2013)

3. Stewart WF, et al. Prevalence and burden of overactive bladder in the United States. World J Urol. 2003 May;20(6):327-336.

22M

Non-Responders to

1st Line Therapy

4. "Real-world patterns of care for the overactive bladder syndrome in the U.S. ", Goldman et al., Urology 2016;87:64-9.

5. Long-term patterns of use and treatment failure with anticholinergic agents for OAB", Chancellor, et al., Clinical Gherapeutics. 2013;35(11)

17.5M

Non-Adherent to

2nd Line

Medications

6. "Persistence and adherence in the treatment of overactive

bladder syndrome with anticholinergic therapy: a systematic review of the literature", Sexton, et al, Int'l J Clin Pract, May 2011, 65, 5, 567-585

4.5M

Indicated for 3rd Line

~225k

currently treated

in 3rd line

• Medications have harsh side effects and limited efficacy
• Patients reluctant to move to third line therapies (invasiveness, side-effects& inconvenience)
• Most urologists unwilling to offer third line therapies (difficult to integrate in practice)

1. Leede Research. "Views on OAB: A Study for the National Association of Continence" Dec 16, 2015
2. AUA Member Census 2018 https://www.auanet.org/research/research-resources/aua-census/census-results

CITATIONS

NEUROMODULATION

• NEUROMODULATION - DTM Segment
• Market Size data: "100M Americans suffer from chronic pain, >$500B Annual Cost"
• • 1 Institute of Medicine. Relieving pain in America: a blueprint for transforming prevention, care, education, and research. Washington
    DC, United States: The National Academies Press; 2011
• Market Size data: "Chronic pain is costlier than diabetes, heart disease and cancer"
• • 2 Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain. 2012;13(8):715-724
• DTM 3 month data publication:
• • Fishman M, Cordner H, Justiz R et al. Randomized Controlled Clinical Trial to Study the Effects of DTM-SCS in Treating Intractable Chronic Low Back Pain: 3 Month Results. Presentation at NANS 2020, Las Vegas, Nevada

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CITATIONS

RENAL DENERVATION - SYMPLICITY SPYRALTM MULTI-ELECTRODE RENAL DENERVATION

1. World Health Organization. Hypertension fact sheet. 13 September 2019. https://www.who.int/news-room/fact-sheets/detail/hypertension Accessed January 24, 2020.
2. Kearney PM, Whelton M, Reynolds K, et al. Global burden of hypertension: analysis of worldwide data. Lancet. 2005:365:217-223.
3. Schmieder R, Hogerl K, Jung S, et al. Patient preference for therapies in hypertension: a cross-sectional survey of German patients.
4. Schmieder R, Kandzari D, Wang T, et. al. Differences in patient and physician perspectives on pharmaceutical therapy and renal denervation for the management of hypertension
5. Medtronic Renal Denervation Research Synthesis. June 2019.
6. Kandzari DE, Böhm M, Mahfoud F, et al. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomized trial. Lancet. 2018 Jun 9;391(10137):2346-2355.
7. Böhm M, Kario K, Kandzari DE, et al. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet 2020; Published online March 29, 2020. DOI: 10.1016/S0140-6736(20)30554-7.
8. Kandzari DE. Renal Denervation in the Presence of Antihypertensive Medications: Six-month Results from the Randomised, Blinded, Sham-controlled SPYRAL HTN-ON MED Trial. Presented at EuroPCR 2018.
9. Mahfoud F, Mancia G, Schmieder R, et. al. Renal Denervation in high-risk patients with hypertension. Journal of the American College of Cardiology. 2020; 75(23): 2879 - 2888.
10. Whitbourn B, Harding SA, Walton A. Symplicity multi electrode radiofrequency renal denervation feasibility study. Eurointervention. 2015;11:104-9.
11. Townsend RR, Mahfoud F, Kandzari DE, et al. Catheter-based renal denervation in patients with uncontrolled hypertension in the absence of antihypertensive medications (SPYRAL HTN-OFF MED): a randomised, sham-controlled,proof-of-concept trial. Lancet. 2017;390:2160-2170.

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CAS CITATIONS

CAS: ARCTIC FRONT™ FAMILY OF CARDIAC CRYOABLATION CATHETERS

• Fürnkranz A, Bologna F, Bordignon S, et al. Procedural characteristics of pulmonary vein isolation using the novel third-generation cryoballoon. Europace. December 2016;18(12):1795-1800.
• Mugnai G, de Asmundis C, Hünük B, et al. Improved visualisation of real-time recordings during third generation cryoballoon ablation: A comparison between the novel short-tip and the second generation device. J Interv Card Electrophysiol. September 2016;46(3):307-314.
• Heeger CH, Wissner E, Mathew S, et al. Short tip-big difference? First-in-man experience and procedural efficacy of pulmonary vein isolation using the third-generation cryoballoon. Clin Res Cardiol. June 2016;105(6):482-488.
• Pott A, Petscher K, Messemer M, Rottbauer W, Dahme T. Increased rate of observed real-time pulmonary vein isolation with third-generationshort-tip cryoballoon. J Interv Card Electrophysiol. December 2016;47(3):333- 339.
• Aryana A, Kowalski M, O'Neill PG, et al. Catheter ablation using the third-generation cryoballoon provides an enhanced ability to assess time to pulmonary vein isolation facilitating the ablation strategy: Short- and long- term results of a multicenter study. Heart Rhythm. December 2016;13(12):2306-2313.

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CAS CITATIONS

CAS: ARCTIC FRONT™ FAMILY OF CARDIAC CRYOABLATION CATHETERS

• Sciarra L, Iacopino S, Palama Z, et al. Impact of the third generation cryoballoon on atrial fibrillation ablation: An useful tool? Indian Pacing Electrophysiol J. July-August2018;18(4):127-132.
• Aryana A, Kenigsberg DN, Kowalski M, et al. Verification of a novel atrial fibrillation cryoablation dosing algorithm guided by time-to-pulmonary vein isolation: Results from the Cryo-DOSING Study. Heart Rhythm. 2017;14(9):1319-1325.
• Chun KR, Stich M, Fürnkranz A, et al. Individualized cryoballoon energy pulmonary vein isolation guided by real- time pulmonary vein recordings, the randomized ICE-T trial. Heart Rhythm. April 2017;14(4):495-500.
• Su WW, et al. Cryoballoon Ablation of Pulmonary Veins for Persistent Atrial Fibrillation: Results From the Multicenter STOP Persistent AF Trial. Heart Rhythm. Published online June 23, 2020.

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CRHF CITATIONS

MICRA/EV-ICD: MICRA AV & VR TPS PORTFOLIO

• El-ChamiMF, Al-Samadi F, Clementy N, et al. Updated performance of the Micra transcatheter pacemaker in the real-world setting: A comparison to the investigational study and a transvenous historical control. Heart Rhythm. December 2018;15(12):1800-1807.
• Reynolds D, Duray GZ, Omar R, et al. A Leadless Intracardiac Transcatheter Pacing System. N Engl J Med. February 11, 2016;374(6):533-541.
• Piccini JP, et al. Comparison of outcomes among patients implanted with a tined leadless versus transvenous single-chamber ventricular pacemaker in the novel Micra Coverage with Evidence Development Study. Heart Rhythm. Published online May 8, 2020.
• Steinwender C, Khelae SK, Garweg C, et al. Atrioventricular synchronous pacing using a leadless ventricular pacemaker: Results from the MARVEL 2 study. JACC Clin Electrophysiol. January 2020;6(1):94-106.
• Ritter P, Duray GZ, Zhang S, et al. The rationale and design of the Micra Transcatheter Pacing Study: safety and efficacy of a novel miniaturized pacemaker.Europace. May 2015;17(5):807-813.
• Udo EO, Zuithoff NP, van Hemel NM et al. Incidence and predictors of short- and long-term complications in pacemaker therapy: the FOLLOWPACE study. Heart Rhythm. May 2012;9(5):728-735.

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CRHF CITATIONS

MICRA/EV-ICD: MICRA AV & VR TPS PORTFOLIO

• Duray GZ, Ritter P, El-Chami M, et al. Long-term performance of a transcatheter pacing system: 12-Month results from the Micra Transcatheter Pacing Study. Heart Rhythm. May 2017;14(5):702-709.
• Ritter P, et al. Long-Term Performance of a Transcatheter Pacing System: 12-month results from the Micra Global Clinical Trial. LBCT presentation at ESC 2016; Rome, Italy.
• Eggen MD, Grubac V, Bonner MD. Design and Evaluation of a Novel Fixation Mechanism for a Transcatheter Pacemaker. IEEE Trans Biomed Eng. September 2015;62(9):2316-2323.
• Bonner M, Eggen M, Haddad T, Sheldon T, Williams E. Early Performance and Safety of the Micra Transcatheter Pacemaker in Pigs. Pacing Clin Electrophysiol. November 2015;38(11):1248-1259.
• Kiani S, Merchant FM, El-Chami MF. Extraction of a 4-year-old leadless pacemaker with a tine-based fixation. Heart Rhythm Case Rep. August 2019;5(8):424-425.

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