NORRED EXHIBIT 2351 - Page 1
`Medtronic, Inc., Medtronic Vascular, Inc.,
`& Medtronic Corevalve, LLC
`v. Troy R. Norred, MD
`Case IPR2014-00395
`
`

`
`ESC Guidelines
`Page 2 of 62
`
`
`(Belgium), Patrizio Lancellotti (Belgium), Ales Linhart (Czech Republic), Petros Nihoyannopoulos (UK),
`Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Per Anton Sirnes (Norway), Juan Luis Tamargo (Spain),
`Michal Tendera (Poland), Adam Torbicki (Poland), William Wijns (Belgium), and Stephan Windecker (Switzerland).
`
`Document reviewers: Petros Nihoyannopoulos (CPG Review Coordinator) (UK), Michal Tendera (CPG Review
`Coordinator) (Poland), Martin Czerny (Switzerland), john Deanfield (UK), Carlo Di Mario (UK), Mauro Pepi (Italy),
`Maria Jesus Salvador Taboada (Spain), Marc R. van Sambeek (The Netherlands), Charalambos Vlachopoulos (Greece),
`and Jose Luis Zamorano (Spain).
`
`The disclosure forms provided by the experts involved in the development ofthese guidelines are available on the ESC website
`www.escardio.org/guidelines
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`Keywords
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`Guidelines 0 Aortic diseases 0 Aortic aneurysm 0 Acuteaortic syndrome 0 Aortic dissection 0 Intramural
`haematoma 0 Penetratingaortic ulcer 0 Traumaticaorticinjury 0 Abdominalaorticaneurysm I Endovascular
`therapy 0 Vascularsurgery I Congenitalaortic diseases 0 Genetic aortic diseases 0 Thromboembolicaortic
`diseases 0 Aortitis 0 Aortictumours
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`Table of Contents
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`Abbreviations and acronyms
`1. Preamble .
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`2. Introduction .
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`6.2 Pathology and classification .
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`6.3 Acute aortic dissection .
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`6.3.1 Definition and classification .
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`3. The normal and the ageing aorta .
`4. Assessment ofthe aorta .
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`4.1 Clinical examination .
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`4.2 Laboratory testing .
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`4.3 Imaging .
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`4.3.1 Chest X-ray .
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`4.3.2 Ultrasound .
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`4.3.2.1 Transthoracic echocardiography .
`4.3.2.2 Transoesophagealechocardiography .
`4.3.2.3 Abdominal ultrasound .
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`6.3.2 Epidemiology .
`6.3.3 Clinical presentation and complications .
`6.3.3.1 Chest pain .
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`6.3.3.2 Aortic regurgitation .
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`6.3.3.3 Myocardial ischaemia .
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`6.3.3.4 Congestive heart failure .
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`6.3.3.5 Large pleural effusions .
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`6.3.3.6 Pulmonary complications .
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`6.3.3.7 Syncope .
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`6.3.3.8 Neurological symptoms .
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`6.3.3.9 Mesentericischaemia .
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`6.3.3.10. Renal failure .
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`4.3.3 Computed tomography .
`4.3.4 Positron emission tomography/computed
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`4.3.5 Magnetic resonance imaging .
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`4.3.6 Aortography .
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`4.3.7 lntravascular ultrasound .
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`4.4 Assessment ofaonic stiffness
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`5. Treatment options .
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`5.1 Principles of medical therapy .
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`5.2 Endovascular therapy .
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`5.2.1 Thoracic endovascular aortic repair
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`5.2.1.1 Technique .
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`5.2.1.2 Complications .
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`5.2.2 Abdominal endovascular aortic repair .
`5.2.2.1 Technique .
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`5.2.2.2 Complications .
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`5.3 Surgery .
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`5.3.1 Ascending aorta .
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`5.3.2 Aortic arch .
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`6.3.4 Laboratory testing .
`6.3.5 Diagnostic imaging in acute aortic dissection .
`6.3.5.1 Echocardiography .
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`6.3.5.2 Computed tomography .
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`6.3.5.3 Magnetic resonance imaging .
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`6.3.5.4 Aortography .
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`6.3.6 Diagnostic work-up .
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`6.3.7 Treatment .
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`6.3.7.1 Type A aortic dissection .
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`6.3.7.2 Treatment of Type B aortic dissection .
`6.3.7.2.1 Uncomplicated Type B aortic dissection:
`6.3.7.2.1.1 Medical therapy .
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`6.3.7.2.1.2 Endovasculartherapy .
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`6.3.7.2.2 Complicated Type B aortic dissection:
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`6.3.7.2.2.1 TEVAR .
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`5.3.3 Descending aorta .
`5.3.4 Thoraco-abdominal aorta .
`5.3.5 Abdominal aorta .
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`6. Acute thoracic aortic syndromes .
`6.1 Definition .
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`6.3.7.2.2.2 Surgery .
`6.4 Intramuralhaematoma .
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`6.4.1 Definition .
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`6.4.2 Diagnosis
`6.4.3 Natural history. morphological changes,
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`25
`NORRED EXHIBIT 2351 - Page 2
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`25
`
`

`
`ESC Guidelines
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`Page 3 of 62
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`6.4.4 Indications for surgery and thoracic endovascular
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`6.4.4.1 TypeAintramural haematoma .
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`6.4.4.2 Type Bintramural haematoma .
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`6.5 Penetrating aortic ulcer .
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`6.5.1 Definition .
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`6.5.2 Diagnostic imaging .
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`6.5.3 Management
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`6.6 Aortic pseudoaneurysm .
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`6.7 (Contained) rupture of aortic aneurysm .
`6.7.1 Contained rupture of thoracic aortic aneurysm .
`6.7.1.1 Clinical presentation .
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`6.7.1.3 Treatment
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`6.8 Traumatic aortic injury .
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`6.8.1 Definition. epidemiology and classification .
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`6.8.2 Patient presentation and diagnosis
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`6.8.3 Indications for treatment in traumatic aortic injury .
`6.8.4 Medical therapy in traumatic aortic injury .
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`6.8.5 Surgery in traumatic aortic injury .
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`6.8.6 Endovascular therapyin traumatic aortic injury .
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`6.9 Latrogenic aortic dissection .
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`7. Aortic aneurysms
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`7.1 Thoracic aortic aneurysms .
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`7.1.1 Diagnosis .
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`7.1.2 Anatomy .
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`7.1.4 Natural history .
`7.1.4.1 Aorticgrowth infamilialthoracic aortic aneurysms
`7.1.4.2 Descending aortic growth .
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`7.2 Abdominal aortic aneurysm .
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`7.2.7 (Contained) rupture ofabdominal aortic aneurysm.
`7.2.7.1 Clinicalpresentation .
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`8. Genetic diseases affecting the aorta .
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`8.1 Chromosomal and inherited syndromic thoracic aortic
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`8.2 Aortic diseases associated with bicuspid aortic valve .
`8.2.1 Epidemiology .
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`8.2.1.2 Ascending aorta growth in bicuspid valves .
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`8.2.1.4 Bicuspid aortic valve and coarctation .
`8.2.2 Natural history .
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`8.3 Coarctation of the aorta .
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`8.3.2 Diagnostic work-up .
`8.3.3 Surgicalor catheter interventional treatment
`9. Atherosclerotic lesions of the aorta .
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`9.1 Thromboembolic aortic disease .
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`7.2.4.1 Presentation .
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`7.2.4.2 Diagnostic imaging .
`7.2.4.3 Screening abdominal aortic aneurysm in high—risk
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`7.2.5 Management of small abdominal aortic aneurysms .
`7.2.5.1 Managementofriskfactors .
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`7.2.5.2 Medical therapy .
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`7.2.5.3 Follow-up of small abdominal aortic aneurysm .
`7.2.6 Abdominal aortic aneurysm repair .
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`7.2.6.1 Pre—operative cardiovascular evaluation .
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`7.2.6.3 Open aortic aneurysm repair .
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`7.2.6.4 Endovascular aortic aneurysm repair
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`7.2.6.5 Comparative considerations of abdominal aortic
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`10.1 Definition. types. and diagnosis .
`10.1.1 Giant cell arteritis .
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`10.1.2 Takayasu arteritis
`10.2 Treatment .
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`11.1 Primary malignant tumours of the aorta .
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`9.1.1 Epidemiology .
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`9.1.3 Therapy .
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`9.1.3.2 Lipid—lowering agents .
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`9.3 Atherosclerotic aortic occlusion .
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`9.4 Calcified aorta .
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`12. Long—term follow-up ofaortic diseases .
`12.1 Chronic aortic dissection .
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`12.1.1 Definition and classification .
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`12.1.2 Presentation .
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`12.1.3 Diagnosis
`12.1.4 Treatment .
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`12.2 Follow—up after thoracic aortic intervention .
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`12.2.1 Clinical follow-up .
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`12.2.2 Imaging after thoracic endovascular aortic repair
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`12.3 Follow—up of patients after intervention for abdominal
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`12.3.1 Follow—up after endovascular aortic repair
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`14. Appendix .
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`Abbreviations and acronyms
`
`three-dimensional
`
`abdominal aortic aneurysm
`acute aortic syndrome
`American College of Cardiology
`angiotensin-converting enzyme
`Aortic dissection
`
`Aneurysm Detection and Management
`American Heart Association
`
`Amsterdam Acute Aneurysm
`aorta
`
`aneurysms-osteoarthritis syndrome
`Aortic Arch Related Cerebral Hazard
`
`arterial tortuosity syndrome
`bicuspid aortic valve
`body surface area
`confidence interval
`coarctation of the aorta
`Committee for Practice Guidelines
`
`cerebrospinal fluid
`computed tomography
`Dutch Randomized Aneurysm Management
`Doppler ultrasound
`electron beam computed tomography
`electrocardiogram
`Ehlers-Danlos syndrome
`Ehlers-Danlos syndrome type IV
`European Society of Cardiology
`European Society of Hypertension
`endovascular aortic repair
`IBF-fluorodeoxyglucose
`false lumen
`
`DREAM
`
`giant cell arteritis
`GERAADA German Registry for Acute Aortic Dissection Type A
`iatrogenic aortic dissection
`
`ESC Guidelines
`
`IMH
`
`intramural haematoma
`
`INSTEAD
`
`Investigation of Stent Grafts in Patients with type B
`Aortic Dissection
`
`IRAD
`IVUS
`
`LCC
`LDS
`MASS
`MESA
`MPR
`MRA
`MRI
`MSCT
`NA
`NCC
`ns—TAAD
`
`OR
`
`International Registry of Aortic Dissection
`intravascular ultrasound
`
`left coronary cusp
`Loeys-Dietz syndrome
`Multicentre Aneurysm Screening Study
`Multi—Ethnic Study of Atherosclerosis
`multiplanar reconstruction
`magnetic resonance angiography
`magnetic resonance imaging
`multislice computed tomography
`not applicable
`non-coronary cusp
`non-syndromic thoracic aortic aneurysms and
`dissection
`odds ratio
`
`Open Versus Endovascular Repair
`OVER
`Oxford Vascular study
`OxVasc
`PARTNER Placement of AoRtic TraNscathetER Valves
`
`PAU
`PICSS
`
`PET
`RCCA
`RCC
`RCT
`RR
`
`SIRS
`SMC
`
`TAA
`TAAD
`TAI
`TEVAR
`TGF
`TI
`TL
`
`TOE
`TS
`'|TE
`UKSAT
`ULP
`WARSS
`
`penetrating aortic ulcer
`Patent Foramen Ovale in Cryptogenic Stroke
`study
`positron emission tomography
`right common carotid artery
`right coronary cusp
`randomized. clinical trial
`relative risk
`
`systemic inflammatory response
`smooth muscle cell
`
`thoracic aortic aneurysm
`thoracic aortic aneurysms and dissection
`traumatic aortic injury
`thoracic endovascular aortic repair
`transforming growth factor
`separate thyroid artery (A. thyroidea)
`true lumen
`
`transoesophageal echocardiography
`Turner Syndrome
`transthoracic echocardiography
`UK Small Aneurysm Trial
`ulcer-like projection
`Warfarin—Aspirin Recurrent Stroke Study
`
`
`
`yroa‘gzraqura/loNuoxsanfiAqum);papeorumog
`
`1. Preamble
`
`Guidelines summarize and evaluate all available evidence at the time
`
`ofthe writing process. on a particular issue with the aim of assisting
`health professionals in selecting the best management strategies for
`an individual patient. with a given condition. taking into account the
`impact on outcome. as well as the risk-benefit-ratio ofparticular diag-
`nostic or therapeutic means. Guidelines and recommendations
`should help the health professionals to make decisions in their daily
`NORRED EXHIBIT 2351 - Page 4
`practice. However, the final decisions concerning an individual
`patient must be made by the responsible health professional(s) in
`consultation with the patient and caregiver as appropriate.
`
`

`
`ESC Guidelines
`Page 5 of 62
`
`A great number of Guidelines have been issued in recent years by
`the European Society of Cardiology (ESC) as well as by other soci-
`eties and organisations. Because of the impact on clinical practice.
`quality criteria for the development of guidelines have been estab-
`lished in order to make all decisions transparent to the user. The
`recommendations for formulating and issuing ESC Guidelines can
`be found on the ESC website (http://www.escardio.org/guidelines-
`surveys/esc-guidelines/about/Pages/rules-writing.aspx). ESC Guide-
`lines represent the official position of the ESC on a given topic and
`are regularly updated.
`Members ofthis Task Force were selected by the ESC to rep resent
`professionals involved with the medical care of patients with this
`pathology. Selected experts in the field undertook a comprehensive
`review ofthe published evidence for management (including diagno-
`sis, treatment. prevention and rehabilitation) of a given condition
`according to ESC Committee for Practice Guidelines (CPG) policy.
`A critical evaluation of diagnostic and therapeutic procedures was
`performed including assessment of the risk-benefit-ratio. Estimates
`of expected health outcomes for larger populations were included.
`where data exist. The level of evidence and the strength of recom-
`mendation of particular management options were weighed and
`graded according to predefined scales, as outlined in Tables 1 and 2.
`The experts of the writing and reviewing panels filled in declara-
`tions of interest forms which might be perceived as real or potential
`sources of conflicts of interest. These forms were compiled into one
`file and can be found on the ESC website (http://www.escardio.ory
`guidelines). Any changes in declarations of interest that arise during
`the writing period must be notified to the ESC and updated. The
`Task Force received its entire financial support from the ESC
`without any involvement from healthcare industry.
`The ESC CPG supervises and coordinates the preparation of new
`Guidelines produced by Task Forces. expert groups or consensus
`panels. The Committee is also responsible for the endorsement
`process of these Guidelines. The ESC Guidelines undergo extensive
`
`review by the CPG and external experts. After appropriate revisions
`it is approved by all the experts involved in the Task Force. The fina-
`lized document is approved by the CPG for publication in the Euro-
`pean Heartjournal. It was developed after careful consideration of
`the scientific and medical knowledge and the evidence available at
`the time of their dating.
`The task of developing ESC Guidelines covers not only the
`integration ofthe most recent research. but also the creation of edu-
`cational tools and implementation programmes for the recommen-
`dations. To implement the guidelines. condensed pocket guidelines
`versions.
`summary slides. booklets with essential messages.
`summary cards for non-specialists, electronic version for digital
`applications (smartphones etc) are produced. These versions are
`abridged and, thus. if needed. one should always refer to the full
`text version which is freely available on the ESC website. The Na-
`tional Societies of the ESC are encouraged to endorse. translate
`and implement the ESC Guidelines. Implementation programmes
`are needed because it has been shown that the outcome of
`
`disease may be favourably influenced by the thorough application
`of clinical recommendations.
`
`Surveys and registries are needed to verify that real-life daily
`practice is in keeping with what is recommended in the guidelines.
`thus completing the loop between clinical research, writing of
`guidelines. disseminating them and implementing them into clinical
`practice.
`Health professionals are encouraged to take the ESC Guidelines
`fully into account when exercising their clinical judgment 3 well as
`in the determination and the implementation of preventive. diagnos-
`tic or therapeutic medical strategies. However. the ESC Guidelines
`do not override in any way whatsoever the individual responsibility
`of health professionals to make appropriate and accurate decisions
`in consideration ofeach patient's health condition and in consultation
`with that patient and the patient's caregiver where appropriate and/
`or necessary. It is also the health professional's responsibility to verify
`
`
`
`
`
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`
`Table I Classes of recommendations
`
`Definition
`
`Suggested wording to use
`
`
`
`Classes of
`recommendations
`(
`I ,.
`
`1
`
`V
`
`‘
`
`.
`
`H
`
`‘
`
`_
`
`V
`
`g
`
`_.
`
`NORRED EXHIBIT 2351 - Page 5
`
`
`

`
`ESC Guidelines
`Page 6 of 62
`
`
`Table 2 Levels of evidence
`
`disorders, congenital abnormalities. aortic aneurysms, and AD are
`discussed in more detail.
`
`in the following section. the normal- and the ageing aorta are
`described. Assessment of the aorta includes clinical examination
`
`and laboratory testing. but is based mainly on imaging techniques
`using ultrasound. computed tomography (CT). and MRI. Endovascu-
`lar therapies are playing an increasingly important role in the treat-
`ment of aortic diseases. while surgery remains necessary in many
`situations. In addition to acute coronary syndromes, a prompt differ-
`ential diagnosis between acute coronary syndrome and AAS is diffi-
`cult—but very important. because treatment of these emergency
`situations is very different. Thoracic- and abdominal aortic aneurysms
`(TAA and AAA. respectively) are often incidental findings. but
`screening programmes for AAA in primary care are progressively
`being implemented in Europe. As survival rates after an acute
`aortic event improve steadily. a specific section is dedicated for
`chronic AD and follow-up of patients after the acute phase of AAS.
`Special emphasis is put on genetic and congenital aortic diseases.
`because preventive measures play an important role in avoiding sub-
`sequent complications. Aortic diseases of elderly patients often
`present as thromboembolic diseases or atherosclerotic stenosis.
`The calcified aorta can be a major problem for surgical or interven-
`tional measures. The calcified ‘coral reef’ aorta has to be considered
`
`as an important differential diagnosis. Aortitis and aortic tumours are
`also discussed.
`
`importantly. this document highlights the value of a holistic ap-
`proach, viewing the aorta as a ‘whole organ’; indeed, in many cases
`(e.g. genetic disorders) tandem lesions ofthe aorta may exist, as illu-
`strated by the increased probability of TAA in the case of AAA.
`making an arbitrary distinction between the two regions—with
`TAAs managed in the past by ‘cardiovascular surgeons’ and AAAs
`by ‘vascular surgeons'—although this diiierentiation may exist in
`academic terms.
`These Guidelines are the result ofa close collaboration between
`
`
`
`
`
`9103'93JQQLIJBAONuoisanfiriqum)papeojumoo
`
`physicians from many different areas of expertise: cardiology, radi-
`ology. cardiac and vascular surgery. and genetics. We have worked
`together with the aim of providing the medical community with a
`guide for rapid diagnosis and decision-making in aortic diseases. In
`the future. treatment of such patients should at best be concentrated
`in ‘aorta clinics‘. with the involvement ofa multidisciplinary team, to
`ensure that optimal clinical decisions are madefor each individual. es-
`pecially during the chronic phases of the disease. indeed. for most
`aortic surgeries. a hospital volume—outcome relationship can be
`demonstrated. Regarding the thoracic aorta. in a prospective cardio-
`thoracic surgery-specific clinical database including over 13 000
`patients undergoing elective aortic root and aortic valve-ascending
`aortic procedures. an increasing institutional case volume was asso-
`ciated with lower unadjusted and risk-adjusted mortality.” The op-
`erative mortality was 58% less when undergoing surgery in the
`highest-. rather than in the lowest-volume centre. When volume
`was assessed as a continuous variable, the relationship was non-
`linear. with a significant negative association between risk-adjusted
`mortality and procedural volume observed in the lower volume
`range (procedural volumes <30—40 cases/year)” A hospital
`NORRED EXHIBIT 2351 - Page 6
`volume—outcome relationship analysis for acute Type A AD repair
`in the United States also showed a significant inverse correlation
`between hospital procedural volume and mortality (34% in low-
`
`Data derived from multiple randomized
`clinical trials or meta-analyses.
`Data derived from a single randomized
`clinical trial or large non-randomized
`
`Level of
`evidence A
`
`Level of
`
`evidence B
`
`the rules and regulations applicable to drugs and devices atthe time of
`prescription.
`
`2. Introduction
`
`In addition to coronary and peripheral artery diseases. aortic diseases
`contribute to the wide spectrum of arterial diseases: aortic aneur-
`ysms. acute aortic syndromes (AAS)
`including aortic dissection
`intramural haematoma (IMH), penetrating atherosclerotic
`ulcer (PAU) and traumatic aortic injury (TAI), pseudoaneurysm.
`aortic rupture. atherosclerotic and inflammatory affections. as well
`as genetic diseases (e.g. Marfan syndrome) and congenital abnormal-
`ities including the coarctation of the aorta (CoA).
`Similarly to other arterial diseases. aortic diseases may be diag-
`nosed after a long period of subclinical development or they may
`have an acute presentation. Acute aortic syndrome is often the
`first sign of the disease. which needs rapid diagnosis and decision-
`making to reduce the extremely poor prognosis.
`'
`Recently, the Global Burden Disease 2010 project demonstrated
`the overall global death rate from aortic aneurysms and
`AD increased from 2.49 per 100 000 to 2.78 per 100 000
`inhabitants between 1990 and 2010. with higher rates for men.”
`On the other hand the prevalence and incidence of abdominal aortic
`aneurysms have declined over the last two decades. The burden
`increases with age. and men are more often affected than women.2
`The ESC's Task Force on Aortic Dissection. published in 2001 . was
`one ofthe first documents in theworld relating to disease ofthe aorta
`and was endorsed by the American College of Cardiology (ACC).3
`Since that time, the diagnostic methods for imaging the aorta have
`improved significantly. particularly by the development of multi-slice
`computed tomography (MSCT) and magnetic resonance imaging
`technologies. Data on new endovascular and surgical
`approaches have increased substantially during the past 10 years.
`Data from multiple registries have been published. such as the Inter-
`national Registry of Aortic Dissection (lRAD)4 and the German
`Registry for Acute Aortic Dissection Type A (GERAADA).5 consen-
`sus documents.“ (including a recent guideline for the diagnosis and
`management of patients with thoracic aortic disease authored by
`multiple American societies).8 as well as nationwide and regional
`population—based studies and position papers.9’“ The ESC there-
`fore decided to publish updated guidelines on the diagnosis and treat-
`ment of aortic diseases related to the thoracic and abdominal aorta.
`
`Emphasis is made on rapid and efficacious diagnostic strategies and
`therapeutic management, including the medical, endovascular. and
`
`

`
`
`
`
`
`no;'§3JSq|1J9I\ONuoisanfiAquioupapeoiumoq
`
`ESC Guidelines
`
`Page 7 of 62
`
`patients undergoing urgent or emergent repair of acute Type A
`AD.” A similar
`relationship has been reported for
`the
`thoraco-abdominal aortic aneurysm repair, demonstrating a near
`doubling ofin-hospital mortality at low- (median volume 1 proced-
`ure/year)
`in comparison with high-volume hospitals (median
`volume 12 procedures/year; 27 vs. 15% mortality; P < 0.001)”
`and intact and ruptured open descending thoracic aneurysm
`repair.“ Likewise,
`several
`reports have demonstrated the
`volume—outcome relationshipforAAA interventions. in an analysis
`ofthe outcomes afterAAA open repair in 131 German hospitals.“
`an independent relationship between annual volume and mortality
`has been reported. In a nationwide analysis ofoutcomes in UK hos-
`pitals. elective AAA surgical repair performed in high-volume
`centres was significantly associated with volume-related improve-
`ments in mortality and hospital
`stay. while no relationship
`between volume and outcome was reported for ruptured AAA
`repairs.l7The results for endovasculartherapy are more contradic-
`tory. While no volume—outcome relationship has been found for
`thoracic endovascular aortic repair (TEVAR),13 one report from
`the UK suggests such a relationship for endovascular aortic repair
`(EVAR).l9 Overall.
`these data support the need to establish
`centres of excellence.
`so-called ‘aortic teams‘.
`throughout
`Europe; however. in emergency cases (e.g. Type A AD or ruptured
`AAA) the transfer of a patient should be avoided,
`if sufficient
`medical and surgical facilities and expertise are available locally.
`Finally. this document lists major gaps of evidence in many situa-
`tions in order to delineate key directions for further research.
`
`3. The normal and the ageing aorta
`The aorta is the ultimate conduit, carrying, in an average lifetime.
`almost 200 million litres of blood to the body. It is divided by the d