Chagas Disease in Non-Endemic Countries Carlos A. Morillo, MD, FRCPC, FACC, FHRS, FESC Professor Department of Cardiac Sciences Section Chief Cardiology Division, Libin Cardiovascular Institute, University of Calgary Zone Head Cardiology, South Eastern Alberta Alberta Health Services Adjunct Professor of Medicine/Cardiology McMaster University Associate Scientist Arrhythmia & Global Health Population Health Research Institute
Conflicts of Interest Research Grants: Biotronik, Boston Scientific, Medtronic, Merck, PHRI, TDR-WHO, CIHR, COLCIENCIAS, Juan Valdez Café de Colombia Honorarium: Astra Zeneca, Bayer, Biosense Webster, Boston Scientific, Biotronik, Boehringer Ingelheim, Medtronic, St. Jude Medical, Sanofi- Aventis Advisory Boards: Bayer, Biosense Webster, Biotronik, Boehringer Ingelheim, CDC, DNDi, FDA, Medtronic, Schering Plough, Merck, TDR/WHO Steering Committees, PI: BENEFIT Trial, STOP- CHAGAS, CHARITY, CHAGTOP, CHAGBIOMARK.
Overview Epidemiology Pathophysiology Etiologic Treatment CHAGASAZOL E-1224 STOP-CHAGAS BENEFIT Future directions & Conclusions
Overview “At night I experienced an attack (for it deserves no less name) of the Benchuca , a species of Reduvius, the great black bug of the Pampas. It is most disgusting to feel soft wingless insects about one inch long crawling over one´s body. Before sucking they are quite thin, but afterwards they become round and bloated with blood, and in this state they are easily crushed. ” Charles Darwin, The Journal of the Voyage of H.M.S. Beagle , Chapter 15, March 25, 1835.
Chagas’ Disease The Agent Reservoirs The vector 1 cm • Humans • Domestic mammals trypomastigote T. infestans Trypanosoma cruzi Triatomine insects (flagellate parasite) armadillo marsupial rodent (“kissing bugs”) • Wild mammals
Discrete Typing Units (DTUs) TcI TcII TcIII TcIV TcV TcVI TcBat Tc I Tc II Genotype Zingales et al. , 2012
Rassi A, et al. Lancet 2010.
http://www.who.int/chagas/Global_distribution_Chagas_disease_2006_2010.pdf?ua=1
Chagas in the USA Malik LH, et al Am J Med 2015;128:1225e7-1251e9.
Traina MI, et al. Circ Heart Fail 2015;8:938-943.
Traina MI, et al. Circ Heart Fail 2015;8:938-943.
Pathogenesis of chronic Chagas’ cardiomyopathy Neurogenic disturbances Ancillary Microvascular derangements Autoimmunity Parasite-dependent inflammation * epi-phenomenon ? * The pathogenesis of chronic Chagas’ heart disease is inexorably dependent on a low-grade, but incessant systemic infection Marin-Neto et al – Circulation 2007; 115: 1109 -23
Pathogenesis of chronic Chagas’ cardiomyopathy Neurogenic disturbances Ancillary Microvascular derangements Autoimmunity Parasite-dependent inflammation * epi-phenomenon ? * The pathogenesis of chronic Chagas’ heart disease is inexorably dependent on a low-grade, but incessant systemic infection Marin-Neto et al – Circulation 2007; 115: 1109 -23
Chagas’ Disease Natural History 100 • 10% to 30% of the infected patients will develop visceral damage as late Circulating trypomastigote as 20 years after initial infection. 75 Symptoms / cardiac damage • Heart Disease will respectively occur % infected in 34%, 40% and 58% , 20, 30 and 40 years after first contact. 50 JC Dias 25 0 0 5 10 15 20 25 30 35 Years after infection
Chagas’ Disease: Forms, Phases, and Stages Apparent form Acute phase Non apparent form Chagas Indeterminate form disease Chagas Cardiac CM Chronic phase Mixed Manifest form Megaesophagus Digestive Megacolon
Chagas’ Heart Disease Natural History Chronic Chagas’ Heart Disease Thrombo-Embolism Arrhythmia Indeterminate Form Sinus Node Pulmonary Dysfunction embolism Intra and AV Congestive heart failure block Stroke Ventricular Arrhythmia Death 10% to 15% Sudden Death Death 25% to 30% 55% to 65%
Clinical manifestations Prolonged latent phase Angina, SOB, Syncope ECG Abnormalities RBBB, LAFH, Pathologic Q waves (anterior), ST-T wave abnormalities Heart failure Syncope: SND, AV- Block Ventricular arrhythmias VT/VF SCD Rassi A, et al. Lancet 2010.
Clinical manifestations Prolonged latent phase Angina, SOB, Syncope ECG Abnormalities RBBB, LAFH, Pathologic Q waves (anterior), ST-T wave abnormalities Heart failure Syncope: SND, AV- Block Ventricular arrhythmias VT/VF SCD Rassi A, et al. Lancet 2010.
Clinical manifestations Prolonged latent phase Angina, SOB, Syncope ECG Abnormalities RBBB, LAFH, Pathologic Q waves (anterior), ST-T wave abnormalities Heart failure Syncope: SND, AV- Block Ventricular arrhythmias VT/VF SCD Rassi A, et al. Lancet 2010.
Clinical manifestations Prolonged latent phase Angina, SOB, Syncope ECG Abnormalities RBBB, LAFH, Pathologic Q waves (anterior), ST-T wave abnormalities Heart failure Syncope: SND, AV- Block Ventricular arrhythmias VT/VF SCD Rassi A, et al. Lancet 2010.
Rassi A, et al. Lancet 2010.
Chagas` Disease Etiological Treatment ANTIPARASITIC DRUGS: Nifurtimox and Benznidazole Indications: Acute Chagas Disease Recently acquired infection Reactivation of the infection following treatment by immunosuppressive drugs Organ transplantation procedures Indeterminate form and mild chronic cardiac form (investigational)
• Perez-Molina JA, et al JAC 2009; 64:1139-47.
Study Design Chronic Chagas Cardiomyopathy Aged 18 to 75 years, ≥2 positive serological tests for T. cruzi , ECG Abnormalities R BNZ 300 mg daily Placebo Follow-up: 11, 21 days, end of treatment, 6-mos, annually until study end (mean 5.4 yrs) Primary Outcome: Composite: death, resuscitated cardiac arrest, sustained VT, pacemaker/ICD, cardiac transplant, new or hospitalized HF, stroke/TIA and systemic or pulmonary embolism
BENEFIT: 49 sites, 5 countries 2854 patients randomized (2004 to 2011) CANADA Global Coordinating Center: PHRI *PCR Core labs: El Salvador (78) Argentina, Brazil & Colombia Brazil (1359) **BENEFIT Echo Core lab: Colombia (502) Riberao Preto, Brazil Bolivia (357) Argentina (559) LA Coordinating Center: Instituto Dante Pazzanese Sao Paulo, Brazil
BENEFIT Trial Flow and Adherence 2854 randomized 1423 Placebo 1431 BNZ 84% took ≥75% of target dose 90% took ≥75% of target dose Discontinuation 192 Discontinuation 51 (3.6%) (13.4%) Mean FU 5.4 yrs. Lost to follow-up (n=8) Lost to follow-up (n=7) 99.5% Complete Follow- 99.5% Complete Follow- up up 1423 analyzed 1431 analyzed
Study Drug Compliance Study Drug Total Pts Pts > 75% compliance Interrupted Randomized % (at the end of treatment) n 11 day 21 day 40-80 % 91.6 89.1 87.7 Argentina 559 16.6 98.8 99.0 97.2 Bolivia 357 2.5 91.6 90.6 88.8 Brazil 1360 12.3 92.7 92.0 91.4 Colombia 502 7.9 98.7 98.7 95.8 El Salvador 78 5.6 11.2 92.8 91.7 90.2 OVERALL 2856 6.3 8.2 11.2 Drug interrupted Drug Restarted 3.3 4.3 3.0
Medical History Data Received on 2854 pts % NYHA Class I 74.6 II 22.8 III 2.6 Previous Heart Failure 9.5 Resuscitated Cardiac Arrest 1.3 Sustained VT 2.8 Internal Cardiac Defibrillator 2.5 Atrial Fibrillation 7.0 Pacemaker 14.2 Stroke/TIA 4.4 Syncope 8.5
Regular Concomitant Medications Data Received on 2854 pts % Any Diuretic 35.4 Loop diuretics 19.5 Spironolactone 16.8 Other diuretics 11.8 ACE-inhibitors 40.8 ARBs 9.2 Digoxin 10.9 Aspirin 29.9 Beta-blockers 30.8 Amiodarone 19.3 Oral anticoag/antiplatelets 7.6/2.2 Other meds 29.7
PCR CONVERSION RATE PCR Negativization No. of Placebo Benznidazole Interaction Patients P value (Pts with Events%) Overall E.O.T. 918 33.5 66.2 Year 2 673 35.3 55.4 >5 Years 647 33.1 46.7 Brazil E.O.T. 213 24.3 86.3 < 0.001 Year 2 96 31.1 60.8 >5 Years 141 27.4 35.3 Argentina, Bolivia E.O.T. 28.6 73.0 388 Year 2 332 34.1 62.9 >5 Years 276 30.2 61.4 Colombia, El Salvador E.O.T. 317 45.6 43.9 Year 2 245 38.5 42.6 >5 Years 230 40.2 35.4 0.5 1.0 2.0 4.0 6.08.0 Benznidazole Placebo Odds Ratio
Primary Outcome 0.4 0.3 Log-Rank p-value=0.31 BNZ Proportion with Events Placebo 0.2 0.1 0.0 0 1 2 3 4 5 6 7 Years of Follow-up # at Risk BNZ 1431 1312 1246 1178 936 695 484 323 1423 Pl 1316 1233 1155 881 649 459 294
Primary Outcome Components Benznidazole Placebo (N=1431) (N=1423) HR 95% CI p (%) (%) Primary composite 394 (27.5%) 414 (29.1%) 0.93 0.81-1.07 0.31 outcome Death 246 (17.2%) 257 (18.1%) 0.95 0.79-1.13 RCArrest 10 (0.7%) 17 (1.2%) 0.58 0.27-1.28 Sustained VT 33 (2.3%) 41 (2.9%) 0.80 0.50-1.26 Pacemaker/ICD 109 (7.6%) 125 (8.8%) 0.86 0.66-1.11 New/Worsening HF 109 (7.6%) 122 (8.6%) 0.88 0.68-1.15 Cardiac Transplant 3 (0.2%) 9 (0.6%) 0.33 0.09-1.22 Stroke/TIA, SE or PE 54 (3.8%) 61 (4.3%) 0.88 0.61-1.27
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