Welcome and Introductions

Welcome and Introductions Serge Lepage MD, FRCPC, CSPQ Full Professor Director, Heart Function Clinic, Department of Cardiology, Université de Sherbrooke Past President, Quebec Heart Failure Society Sherbrooke, QC 2 Faculty 3 Diego Delgado (Chair) MD, MSc, FCCS, FACC Medical Director Inpatient Cardiology Service Site Director, Division of Cardiology, Toronto General Hospital Reuben and Florence Fenwick Family Professorship in Heart Failure Associate Member, Institute of Medical Science, University of Toronto Professor of Medicine, University of Toronto Past President Interamerican Society of Cardiology Toronto, ON Vera Bril BSc, MD, FRCPC Professor of Neurology, University of Toronto Head, Neuromuscular Section, University of Toronto Toronto, ON Margot Davis MD, MSc, FRCPC Clinical Assistant Professor, UBC Cardiology Director, UBC Cardiology-Oncology Program Vancouver, BC Anil Gupta MD, FRCPC Staff Cardiologist, Trillium Health Partners Lecturer, University of Toronto Toronto, ON Serge Lepage MD, FRCPC, CSPQ Full Professor Director, Heart Function Clinic, Department of Cardiology, Université de Sherbrooke Past President, Quebec Heart Failure Society Sherbrooke, QC Disclosures: Dr. Diego Delgado • Consultancy/speaking fees: Pfizer, Akcea, Alnylam • Clinical trial participation: ATTRACT extension (Tafamidis), HELIOS-B (Alnylam), Cardio TTRANSFORM (Ionis-Akcea) ATRIBUTE-CM (AG10) Disclosures: Dr. Vera Bril • Consultancy/speaking fees: Akcea, Alnylam, Ionis • Clinical trial participation: CSL, Takeda, RVT, Momenta, UCB, Alexion, Akcea, Talecris, Octapharma Disclosures: Dr. Margot Davis • Consultancy/speaking fees: Janssen, Novartis, Boehringer-Ingelheim, Takeda, Pfizer, Akcea, Alnylam, Amgen, Ferring • Grant funding: Pfizer, Takeda, Boehringer-Ingelheim, Servier, Akcea Disclosures: Dr. Anil Gupta • Consultancy/speaking fees: Amgen, Astrazeneca, Bayer, Boehringer Ingelheim, BMS/Pfizer Alliance, Novartis, Pfizer, Sanofi, Servier • Clinical trial participation: None Disclosures: Dr. Serge Lepage • Consultancy/speaking fees: Amgen, AstraZeneca, Boehringer Ingelheim, Novartis, Servier • Clinical trial participation: Amgen, Novartis Disclosure of Commercial Support Specific details of relationship: – This program has received financial support from Alnylam in the form of an educational grant – This program has received in-kind support from Canadian Heart Failure Society in the form of logistical support Potential for conflict(s) of interest: – Speakers have received honoraria from Canadian Heart Failure Society – Alnylam is the manufacturer of a product that will be discussed in this program Mitigating Potential Bias Potential biases are acknowledged and are mitigated by presenting data supported by national and international guidelines, and as follows: • Information presented is evidence-based • Material has been developed and reviewed by a Planning Committee Off-label uses of drugs may be discussed and will be identified as such by the speaker Accreditation This event is an accredited Group Learning Activity (Section 1) as defined by the Maintenance of Certification Program of the Royal College of Physicians & Surgeons of Canada and approved by the Canadian Cardiovascular Society. You may claim a maximum of 0.75 hours. Learning Objectives • Distinguish between hereditary and wild-type ATTR amyloidosis in terms of presentation and diagnosis • Establish a care pathway for patients following genetic testing • Assess the treatment options and the benefit of a multidisciplinary team approach to treating hATTR • Understand the importance of tailoring the treatment approach based on the disease phenotype 12 Agenda Topic Facilitator Welcome and Introductions Dr. Serge Lepage Hereditary and Wild-Type ATTR Amyloidosis: Different Diseases, Different Presentations Dr. Diego Delgado Dr. Vera Bril Dr. Anil Gupta Neuropathy in a Systemic Disease Dr. Vera Bril Dr. Anil Gupta Diagnosis of hATTR: The Key to a Hopeful Outcome Dr. Margot Davis Dr. Anil Gupta Treatment Plan and Treatment Goals Dr. Diego Delgado Dr. Vera Bril Treating Patients with hATTR Amyloidosis in the Community Dr. Diego Delgado Dr. Anil Gupta Dr. Serge Lepage Closing Remarks Dr. Diego Delgado 13 Download the mobile app! Download the app by: 1. Search for and download: CrowdCompass AttendeeHub 2. Find your event: Heart Failure Update Gain access to the: • Congress agenda and session links • Push notifications • Session and symposium evaluation forms • Interactive platform where you can communicate with your fellow attendees! Send in your questions! • Submit your questions for the symposium Q&A by clicking on the Q&A icon on your screen • To direct your question to a specific speaker, please include his/her name at the beginning of your question Hereditary and Wild-Type ATTR Amyloidosis: Different Diseases, Different Presentations Vera Bril Diego Delgado Anil Gupta BSc, MD, FRCPC MD, MSc, FCCS, FACC MD, FRCPC 16 Key Questions • What’s the difference between wtATTR and hATTR? • What are the key red-flag symptoms of hATTR amyloidosis (sensory-motor neuropathy, autonomic neuropathy, and cardiac manifestations)? 17 Dr Diego Delgado, MD, MSc, FCCS, FACC Medical Director Inpatient Cardiology Service Site Director, Division of Cardiology, Toronto General Hospital Reuben and Florence Fenwick Family Professorship in Heart Failure Associate Member, Institute of Medical Science, University of Toronto Professor of Medicine, University of Toronto Past President Interamerican Society of Cardiology Toronto, ON 18 Cardiac Amyloidosis AL, light-chain amyloidosis; ATTR, transthyretin amyloidosis; m, mutated; wt , wild-type. ; h: hereditary Maleszewski JJ. Cardiovascular Pathology 2015;24(6):343-350; Rapezzi C et al. Circulation 2009;120:1203-1212; Maurer MS et al. J Am Coll Cardiol 2016;68(2):161-172. ATTR hATTR ATTRwt Cardiac Amyloidosis AL Clinical Presentations Can J Cardiol. 2020 Mar;36(3):373-383 20 Cardiac Manifestations Can J Cardiol. 2020 Mar;36(3):373-383 21 Can J Cardiol. 2020 Mar;36(3):373-383 Extracardiac Manifestations 22 • Renal • Autonomic • Neurologic peripheral sensorimotor neuropathy (might be predominant feature of hATTR) • Carpal tunnel syndrome • Musculoskeletal • Gastrointestinal • Hematologic • Ocular manifestations Can J Cardiol. 2020 Mar;36(3):373-383 Extracardiac Manifestations 23 Key Clinical Features Can J Cardiol. 2020 Mar;36(3):373-383 24 Dr Vera Bril, BSc, MD, FRCPC Professor of Neurology, University of Toronto Head, Neuromuscular Section, University of Toronto Toronto, ON 25 1. Rapezzi C et al. Nat Rev Cardiol 2010;7:398–408. 2. Coutinho P. In: Glenner GG et al, eds. Amyloid and Amyloidosis. Amsterdam: Excerpta Medica; 1980. Red Flags for TTR-FAP1,2 • Family history • Carpal tunnel syndrome • Cardiac involvement • Small fiber and Autonomic involvement • (2nd to 4th decade onset) hATTR, hereditary amyloid transthyretin 1. Ando Y, et al. Orphanet J Rare Dis 2013;8:31 2. Coelho T, et al. Amyloidosis Foundation, 2008. https://www.researchgate.net/publication/265490881_A_Physician’s_Guide_to_Transthyretin_Amyloidosis_Authored_by Accessed January 3, 2019 • Characterized by symmetrical length-dependent peripheral neuropathy1,2 • Symptoms initially in lower limbs and progress proximally involving areas above the ankles, legs, thighs, arms and anterior trunk • Early clinical findings: • Numbness and pain in feet with impaired temperature and pinprick sensation; muscle strength and tendon reflexes are preserved • Sensory loss progressively increases and light touch and deep sensations become impaired 27 Clinical Presentation: hATTR Amyloidosis with PNP hATTR, hereditary amyloid transthyretin 1. Ando Y, et al. Orphanet J Rare Dis 2013;8:31 2. Coelho T, et al. Amyloidosis Foundation, 2008. https://www.researchgate.net/publication/265490881_A_Physician’s_Guide_to_Transthyretin_Amyloidosis_Authored_by. Accessed January 3, 2019. 3. Coelho T, et al. Amyloidosis Foundation. http://www.amyloidosis.org/wp-content/uploads/2017/05/2017-ATTR-guide.pdf Accessed April 24, 2019. 4. Ando Y, et al. Muscle Nerve 1992;15:507-12. Clinical Presentation: hATTR Amyloidosis with PN • Eventually until walking, balance, and gait are compromised, fine hand movements become difficult, and autonomic dysfunction manifests1,2 • Symptoms of autonomic dysfunction:3,4 • Autonomic dysfunction can occur early in the disease4 • Weight loss and muscle wasting are common 28 • Alternating diarrhea and constipation • Vomiting • Anhidrosis • Erectile dysfunction • Nausea • Urinary retention and incontinence • Delayed gastric emptying Neuropathy in a Systemic Disease 29 Vera Bril, BSc, MD, FRCPC Professor of Neurology, University of Toronto Head, Neuromuscular Section, University of Toronto Toronto, ON Anil Gupta, MD, FRCPC Staff Cardiologist, Trillium Health Partners Lecturer, University of Toronto Toronto, ON Small Fiber Polyneuropathy • Distal symmetrical polyneuropathy (PNP) • Burning pain in the feet • Worse at night • Less noticeable during the day • Difficult to control • Associated with fear, anxiety, depression • Reduced quality of life • Refractory to many treatments • Loss of pinprick, temperature on examination • Normal reflexes strength, vibration and proprioception hATTR Predominant Neurologic Presentation Predominant Cardiac Presentation Mixed Presentation V30M early onset C10R R34T G47A F64L L58H E89Q I107V S23N T60A I68L F33L S50R S77Y A36P T49A V30M Late onset W41L H88R L111M V122I hATTR, hereditary amyloid transthyretin; TTR, transthyretin 1. Rowczenio D, et al. Hum Mutat 2014;35:E2403-E2412 2. Ando Y, et al. Orphanet J Rare Dis 2013;8:31; 3. Coelho T, et al. Curr Med Res Opin 2013;29:63-76. 4. Gertz MA, et al. J Am Coll Cardiol 2015;66:2451-66. Figure sources: Benson MD. Am J Pathol 1996;148: 351–54. Rapezzi C, et al. Eur Heart J 2013;34:520-28. Connors LH, et al. Amyloid 2003;10:160-84. hATTR Amyloidosis: Broad Spectrum of Presentation with Different TTR Mutations • Hereditary amyloidosis is caused by many gene variants, but TTR mutations account for the majority1 • Transmitted in an autosomal dominant manner with variable penetrance2,3 • More than 120 TTR mutations have been discovered1 • Although some genotypes are associated predominantly with polyneuropathy or cardiomyopathy, most patients with hATTR have mixed clinical phenotypes3,4 When to Suspect hATTR Amyloidosis – RED FLAGS Look for evidence of multisystem involvement, which may include: Progressive, symmetric sensorimotor neuropathy Bilateral carpal tunnel syndrome* Early autonomic dysfunction (e.g., erectile dysfunction or postural hypotension) GI complaints (e.g., chronic diarrhea, constipation or diarrhea, constipation) Unexplained weight loss Cardiac signs & symptoms (e.g., cardiac hypertrophy, arrhythmias, ventricular blocks, or cardiomyopathy) Positive family history Vitreous opacities Renal abnormalities (e.g., albuminuria or mild azotemia) 32 Additional alert signs: Rapid disease progression Failure of response to prior therapies *Consider particularly in men without predisposing occupation Key Questions •When should the cardiologist refer the patient to a neurologist? •How can both work together to improve outcomes for the mixed phenotype patient? 33 Diagnosis of hATTR: The Key to a Hopeful Outcome 34 Margot Davis, MD, MSc, FRCPC Clinical Assistant Professor, UBC Cardiology Director, UBC Cardiology-Oncology Program Vancouver, BC Anil Gupta, MD, FRCPC Staff Cardiologist, Trillium Health Partners Lecturer, University of Toronto Toronto, ON Margot Davis, MD, MSc, FRCPC Clinical Assistant Professor, UBC Cardiology Director, UBC Cardiology-Oncology Program Vancouver, BC 35 Cardiac Manifestations Index of Suspicion – Key Features Pre-contrast T1 Post-contrast T1 ECV LGE • Increased LV and RV wall thickness • Preserved ventricular size, biatrial enlargement • Diastolic dysfunction • Increased valvular and interatrial septum thickness • Small pericardial effusion • Reduced LV GLS, preserved apical strain (basal-apical strain gradient) • Diffuse transmural or subendocardial pattern LGE • Left atrial LGE • Elevated native (non- contrast) T1 mapping time • Extracellular volume expansion (post- contrast T1 mapping) • Low voltage (especially limb leads) • Pseudo-infarct pattern • Atrial fibrillation • Conduction system disease • Ventricular ectopy • Increased myocardial radiotracer uptake equal to or greater than bone (≥Grade 2), or in quantitative comparison with the contralateral lung (HCL ratio ≥1.5) ECG Echo CMRI Tc-99m-PYP Courtesy Dr. James White, Dr. Denise Chan, University of Calgary Can J Cardiol. 2020 Mar;36(3):322-332 CCS/CHFS Joint Position Statement Key Question •How would a community cardiologist go about having a patient undergo all of these tests when the physician doesn’t have the resources of an academic centre? 40 Availability of Diagnostic Testing Serum/urine protein studies: widely available, may need to argue for IFE PYP scans: increasingly available (>10 hospitals in BC), but may need QA Endomyocardial biopsy: all transplant centres, most centres with cath labs IHC: not widely available, depends on local expertise/experience Mass spectrometry: not widely available, send out to Mayo or Toronto Genetic testing: Publicly funded availability varies by province, industry partners provide testing kits (US-based) Treatment Plan and Treatment Goals 42 Vera Bril, BSc, MD, FRCPC Professor of Neurology, University of Toronto Head, Neuromuscular Section, University of Toronto Toronto, ON Diego Delgado, MD, MSc, FCCS, FACC Medical Director Inpatient Cardiology Service Site Director, Division of Cardiology, Toronto General Hospital Reuben and Florence Fenwick Family Professorship in Heart Failure Associate Member, Institute of Medical Science, University of Toronto Professor of Medicine, University of Toronto Past President Interamerican Society of Cardiology Toronto, ON Dr Diego Delgado, MD, MSc, FCCS, FACC Medical Director Inpatient Cardiology Service Site Director, Division of Cardiology, Toronto General Hospital Reuben and Florence Fenwick Family Professorship in Heart Failure Associate Member, Institute of Medical Science, University of Toronto Professor of Medicine, University of Toronto Past President Interamerican Society of Cardiology Toronto, ON 43 44 Disease-Modifying Therapy Can J Cardiol. 2020 Mar;36(3):373-383 45 Disease-Modifying Therapy: CCS/CHFS Recommendations Can J Cardiol. 2020 Mar;36(3):373-383 46 • ATTR Cardiac Amyloidosis and NYHA I-III: Tafamidis • hATTR with ambulatory polyneuropathy: Patisiran or Inotersen 47 Vera Bril, BSc, MD, FRCPC Professor of Neurology, University of Toronto Head, Neuromuscular Section, University of Toronto Toronto, ON UHN Experience • Patients started on gene silencers just over 1 year ago • Variable results: stable, better, worse • Manage expectations to encourage continued therapy • Patients do not always separate progression of disease from side-effects of medication 48 Treating Patients with hATTR Amyloidosis in the Community Diego Delgado Anil Gupta Serge Lepage MD, MSc, FCCS, FACC MD, FRCPC MD, FRCPC, CSPQ 49 Key Questions •How can a community cardiologist take all the learnings from this program and apply them into his or her practice? •How can he/she start diagnosing, testing, and treating patients with hATTR amyloidosis in practice today? 50 Dr Diego Delgado, MD, MSc, FCCS, FACC Medical Director Inpatient Cardiology Service Site Director, Division of Cardiology, Toronto General Hospital Reuben and Florence Fenwick Family Professorship in Heart Failure Associate Member, Institute of Medical Science, University of Toronto Professor of Medicine, University of Toronto Past President Interamerican Society of Cardiology Toronto, ON 51 Collaboration and Interdisciplinary Management Can J Cardiol. 2020 Mar;36(3):373-383 52 Key Learnings • Cardiac amyloidosis is a potentially fatal disease in which early recognition and diagnosis are crucial • TTR RNA silencing agents are indicated for hATTR patients with polyneuropathy and mixed phenotype • Comprehensive interdisciplinary management is recommended 53 Q&A 54 Evaluations and Certificates • Here’s how to access evaluations: • Congress APP: “Evaluation Forms” icon • You’ll also get a notification and email each day with evaluation links • Information regarding certificates to be emailed next week Next Up…A Break • Join your workshop at 6:10 PM ET by accessing the link received or check your calendar • Not yet signed up? 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