Chagas Disease in Non-Endemic Countries Carlos A. Morillo, MD, - - PowerPoint PPT Presentation

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

“At night I experienced an attack (for it deserves no less name)

• f the Benchuca, a species of

Reduvius, the great black bug

• f

the Pampas. It is most disgusting to feel soft wingless insects about

• ne

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.”

Overview

Charles Darwin, The Journal of the Voyage of H.M.S. Beagle, Chapter 15, March 25, 1835.

Chagas’ Disease

The Agent Trypanosoma cruzi

(flagellate parasite)

trypomastigote

The vector Triatomine insects

(“kissing bugs”)

• T. infestans

1 cm

• Wild mammals

Reservoirs

• Humans

marsupial rodent armadillo

• Domestic mammals

Zingales et al., 2012

TcI TcII

TcIII TcIV TcV TcVI TcBat Genotype Tc I Tc II

Discrete Typing Units (DTUs)

Rassi A, et al. Lancet 2010.

http://www.who.int/chagas/Global_distribution_Chagas_disease_2006_2010.pdf?ua=1

Malik LH, et al Am J Med 2015;128:1225e7-1251e9.

Chagas in the USA

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

* The pathogenesis of chronic Chagas’ heart disease is inexorably dependent

• n

a low-grade, but incessant systemic infection

Marin-Neto et al – Circulation 2007; 115: 1109 -23 Ancillary

epi-phenomenon ?

 Neurogenic disturbances  Microvascular derangements  Autoimmunity  Parasite-dependent inflammation *

Pathogenesis of chronic Chagas’ cardiomyopathy

* The pathogenesis of chronic Chagas’ heart disease is inexorably dependent

• n

a low-grade, but incessant systemic infection

Marin-Neto et al – Circulation 2007; 115: 1109 -23 Ancillary

epi-phenomenon ?

 Neurogenic disturbances  Microvascular derangements  Autoimmunity  Parasite-dependent inflammation *

25 50 75 100 5 10 15 20 25 30 35

Years after infection

% infected

Circulating trypomastigote Symptoms / cardiac damage

Chagas’ Disease Natural History

• 10% to 30% of the infected patients

will develop visceral damage as late as 20 years after initial infection.

• Heart Disease will respectively occur

in 34%, 40% and 58% , 20, 30 and 40 years after first contact. JC Dias

Chagas disease Manifest form Apparent form Non apparent form Acute phase Chronic phase Indeterminate form

Cardiac Mixed Digestive

Megacolon

Chagas CM

Megaesophagus

Chagas’ Disease: Forms, Phases, and Stages

Chagas’ Heart Disease

Natural History

Chronic Chagas’ Heart Disease

Arrhythmia Indeterminate Form

Ventricular Arrhythmia

Sinus Node Dysfunction

Intra and AV block Sudden Death 55% to 65% Thrombo-Embolism

Pulmonary embolism

Stroke Congestive heart failure

Death 25% to 30% Death 10% to 15%

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

• 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)

Indications:

• Perez-Molina JA, et al JAC 2009; 64:1139-47.

Study Design

Placebo BNZ 300 mg daily Follow-up: 11, 21 days, end of treatment, 6-mos, annually until study end (mean 5.4 yrs)

R

Chronic Chagas Cardiomyopathy Aged 18 to 75 years, ≥2 positive serological tests for T. cruzi, ECG Abnormalities 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)

El Salvador (78) Brazil (1359) Colombia (502) Bolivia (357) Argentina (559) *PCR Core labs: Argentina, Brazil & Colombia **BENEFIT Echo Core lab: Riberao Preto, Brazil LA Coordinating Center: Instituto Dante Pazzanese Sao Paulo, Brazil

CANADA Global Coordinating Center:PHRI

BENEFIT Trial Flow and Adherence

Discontinuation 51 (3.6%) Discontinuation 192 (13.4%)

1431 BNZ

84% took ≥75% of target dose

1423 Placebo

90% took ≥75% of target dose

99.5% Complete Follow- up 1423 analyzed 99.5% Complete Follow- up 1431 analyzed

Lost to follow-up (n=8) Lost to follow-up (n=7)

2854 randomized

Mean FU 5.4 yrs.

Study Drug Compliance

Total Pts Randomized n Study Drug Interrupted

(at the end of treatment)

% Pts > 75% compliance % 11 day 21 day 40-80 Argentina 559 16.6

91.6 89.1 87.7

Bolivia 357 2.5

98.8 99.0 97.2

Brazil 1360 12.3

91.6 90.6 88.8

Colombia 502 7.9

92.7 92.0 91.4

El Salvador 78 5.6

98.7 98.7 95.8

OVERALL 2856

11.2 92.8 91.7 90.2

Drug interrupted Drug Restarted

6.3 8.2 11.2 3.3 4.3 3.0

Medical History

Data Received

• n 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

• n 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 Negativization

PCR CONVERSION RATE

• No. of

Patients

Placebo

Interaction P value

0.5 1.0

2.0

4.0 6.08.0

Placebo Benznidazole

Odds Ratio

<0.001

Benznidazole Overall E.O.T. Year 2 >5 Years 918 673 647 33.5 35.3 33.1 66.2 55.4 46.7 Colombia, El Salvador E.O.T. Year 2 >5 Years 317 245 230 45.6 38.5 40.2 43.9 42.6 35.4 Brazil E.O.T. Year 2 >5 Years 213 96 141 24.3 31.1 27.4 86.3 60.8 35.3 Argentina, Bolivia E.O.T. Year 2 >5 Years

388

332 276 28.6 34.1 30.2 73.0 62.9 61.4

(Pts with Events%)

Years of Follow-up Proportion with Events

# at Risk BNZ Pl 1431 1312 1246 1178 936 695 484 323 1423 1316 1233 1155 881 649 459 294

0.0 0.1 0.2 0.3 0.4 1 2 3 4 5 6 7

BNZ Placebo Log-Rank p-value=0.31

Primary Outcome

Primary Outcome Components

Benznidazole (N=1431) (%) Placebo (N=1423) (%) HR 95% CI p Primary composite

• utcome

394 (27.5%) 414 (29.1%) 0.93 0.81-1.07 0.31 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

Primary Outcome: Subgroups

Colombia, El Salvador Brazil Argentina, Bolivia Baseline PCR Positive Baseline PCR Negative Age ≤56 yrs (median) Age >56 yrs (median) Female Male Low Intermediate <40% ≥40% Country Presumed DTU PCR Age Sex Disease Severity Score LV Ejection Fraction 580 1358 916 1148 748 1428 1426 1445 1409 1309 890 389 2465 0.16 0.96 0.56 0.81 0.45 25.6 37.6 18.5 26.9 25.3 25.6 32.7 25.1 33.4 16.2 33.3 63.0 23.9

• No. of

Patients Placebo (Rate %) Interaction P value

24.1 33.2 21.4 24.6 23.7 22.8 32.1 24.1 30.8 16.8 29.9 62.5 21.8

Benznidazole (Rate %)

High 655 0.55 50.0 45.1

Primary Outcome: Subgroups

Colombia, El Salvador Brazil Argentina, Bolivia Baseline PCR Positive Baseline PCR Negative Age ≤56 yrs (median) Age >56 yrs (median) Female Male Low Intermediate <40% ≥40% Country Presumed DTU PCR Age Sex Disease Severity Score LV Ejection Fraction 580 1358 916 1148 748 1428 1426 1445 1409 1309 890 389 2465 0.16 0.96 0.56 0.81 0.45 25.6 37.6 18.5 26.9 25.3 25.6 32.7 25.1 33.4 16.2 33.3 63.0 23.9

• No. of

Patients Placebo (Rate %) Interaction P value

24.1 33.2 21.4 24.6 23.7 22.8 32.1 24.1 30.8 16.8 29.9 62.5 21.8

Benznidazole (Rate %)

High 655 0.55 50.0 45.1

BENEFIT RISK SCORE Primary Outcome

Parameter Label HR (95% CI) p-value Age age 1.01(1.01-1.02) 0.0005 NYHA NYHA Class III 1.77(1.25-2.5) 0.001 CardTxr increased Cardiothor 1.63(1.37-1.94) <0.0001 Male Males 1.24(1.06-1.46) 0.008 RegWallMot Regional Wall motion 1.57(1.33-1.85) <0.0001 ComVA ComVA 1.38(1.13-1.68) 0.002 HSyncope Hx Syncope 1.55(1.22-1.96) 0.0003 RSST ST-T Segment Changes 1.24(1.05-1.47) 0.01 AF/Aflt Atrial Fibrillation/Aflt 1.52(1.2-1.94) 0.0006 LVEF <40 LVEF<40% 2.63(2.2-3.14) <0.0001

BENEFIT RISK SCORE Primary Outcome

Parameter Label HR (95% CI) p-value Age age 1.01(1.01-1.02) 0.0005 NYHA NYHA Class III 1.77(1.25-2.5) 0.001 CardTxr increased Cardiothor 1.63(1.37-1.94) <0.0001 Male Males 1.24(1.06-1.46) 0.008 RegWallMot Regional Wall motion 1.57(1.33-1.85) <0.0001 ComVA ComVA 1.38(1.13-1.68) 0.002 HSyncope Hx Syncope 1.55(1.22-1.96) 0.0003 RSST ST-T Segment Changes 1.24(1.05-1.47) 0.01 AF/Aflt Atrial Fibrillation/Aflt 1.52(1.2-1.94) 0.0006 LVEF <40 LVEF<40% 2.63(2.2-3.14) <0.0001

Towards the establishment of a consensus Real-Time qPCR to monitor Trypanosoma cruzi parasitemia in chronic chagasic cardiomyopathy patients: A BENEFIT Trial Substudy

Otacilio C. Moreira, Juan David Ramírez, Elsa Velázquez, Myllena Melo, Carolina L. Ferreira, Felipe Guhl, Sergio Sosa-Estani, Jose Antonio Marin-Neto, Carlos A. Morillo, and Constança Britto

CHARITY

Chagas´Cardiomyopathy Bisoprolol Intervention Study

A Double-blind Randomized Placebo Controlled trial of Bisoprolol in Chagas Cardiomiopathy

Morillo C. Principal investigator, FUNDED COLCIENCIAS

• NYHF classes II,III,IV
• LV EF < 45%
• Optiazed dosis of IECAs
• r de ARA II
• Age: 18 to 70y
• No c.i. to BB

R

PLACEBO BISOPROLOL

Primary end-point

Combination of:

• Cardiovascular death
• Aborted sudden

death

• Sustained VT
• PM implantation
• Thromboembolic

event

• Hospitalization for

HF FU: 2,5 anos

7 centers in Colombia (n=500)

N=250 N=250

ICD (n=400)

TOTAL MORTALITY

(mean FU = 3 years)

Best medical therapy

AMIODARONE (n=400)

1) Documented VF 2) Out-of-hospital cardiac arrest requiring defibrillation or cardioversion 3) Documented sustained VT causing syncope 4) Documented sustained VT at a rate > 120 beats/min causing hypotension (systolic blood pressure < 80 mmHg), angina or presyncope (EF < 40%) 5) Syncope of unknown etiology with subsequent documentation of sustained (> 30s) monomorphic VT induced by programmed ventricular stimulation (EF < 40%)

CHAGASIC -

Multicenter, randomized Trial

Sponsor SOBRAC

Carmo A, Ribeiro A, Agudelo JF, Morillo CA.

PLoS One. 2014 Mar 7;9(3):e91154. doi: 10.1371/journal.pone.0091154. eCollection 2014.

• Bern C, et al. JAMA 2007;298:2171-81.

Summary and Conclusions

• Chagas Disease is in North America, and under diagnosed.
• Screening and diagnostic awareness are important as patients

in the early stages may benefit from trypanocidal treatment.

• Trypanocidal treatment in patients with mild-moderate Chagas

CM reduces parasite load but is not parallelled with a significant reduction in clinical progression.

• The BENEFIT risk score also failed to identify whether

patients at lower risk derive larger benefits from treatment.

• Further analysis of parasite load and genotype is ongoing and

may shed some light on parasite pathogenecity and susceptibility to BNZ.

• Newer agents are needed.
• Biomarkers to determine risk of progression are under

development.