New Concepts for the Management of Chagas Disease

Transcription

1 New Concepts for the Management of Chagas Disease Carlos A. Morillo, MD, FRCPC, FACC, FHRS, FESC Professor Department of Medicine Director Arrhythmia Service - Cardiology Division McMaster University Population Health Research Institute Hamilton, ON, Canada

2 Conflicts of Interest Research Grants: TDR-WHO, CIHR Advisory Boards: Schering Plough Merck I have received Pens, Bags, Memory sticks, tickets to ball games, hockey games, invitations for dinner, drinks and other undisclosed entertainment. Nonetheless I do have my own unbiased opinions!

3 Overview Epidemiology Pathophysiology Role of Trypanocidal therapy Experimental evidence Observational Studies Systematic Reviews The BENEFIT Trial Future Trials Risk Stratification Biomarkers of progression* Conclusions

4 Epidemiology million infected 1980 s 8 11 million infected 2000 s 110 risk? New Cases 700,000 / yr 1980 s 41,200 / yr 2006 Deaths 50,000 / yr 1980 s 12, s Rassi A, et al. Lancet 2010.;375:

5 Patophysiology Carod-Artal FJ & Gascon J. Lancet Neurol 2010;9:

6 Pathogenesis of chronic Chagas cardiomyopathy Neurogenic disturbances Microvascular derangements Autoimmunity epi-phenomenon? Parasite-dependent inflammation * Ancillary * 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:

7 Antimic Agents Chemo 2005;49:

8 Antimic Agents Chemo 2005;49:

9 Elias FE, et al. Am J Trop Med Hyg 2003;68:242-47

10 Basqueira AL, et al. Heart 2003;89:

11 ETIOLOGICAL TREATMENT OF CHAGAS DISEASE % CURE % 60% CURE* % 10 * 0 Acute Phase Negativation of xenodiagnosis Negativation of serological tests Change in the natural course of the disease Recent Chronic Phase Long Standing Chronic Phase

12 ETIOLOGICAL TREATMENT OF CHAGAS DISEASE WITH BENZNIDAZOLE IN THE CHRONIC PHASE Cure - time of negativation of the serological tests* N = 21 Nº of patients * Gradual decrease in titers Years after the etiological treatment Rassi A.

13 Viotti R, et al Am H J 1994;127:151-62

14 Observational Studies V illar JC.

15 Viotti R, et al. Ann Intern Med 2006;144:724-34

16 Villar JC, et al. Cochrane Database Syst Rev. 2002;(1):CD

17 V illar JC.

18 Perez-Molina JA, et al JAC 2009; 64:

19 Perez-Molina JA, et al JAC 2009; 64:

20 Clinical Outcomes: Progression of cardiomyopathy. Perez-Molina JA, et al JAC 2009; 64:

21 Stroke Stroke incidence in Chagas disease 18% - 20% Bambui Study mortality 4.8%/ yr. Afib & BNP increase risk 11 fold* Role of Etiologic treatment? Carod-Artal FJ & Gascon J. Lancet Neurol 2010;9:

22 BENznidazole Evaluation For Interrupting Trypanosomiasis BENEFIT

23 Study Review (1) Primary Objective: To evaluate if benznidazole, administered at a fixed dose of 300 mg x 40 to 80 days (period adjusted according to pt s body weight 12 g (min) 24 g (max) reduces morbidity and mortality in patients with chronic Chagas cardiomyopathy - Minimum dose of 12 g (for 40 kg of weight) - Maximum dose of 24 g (for 80 kg of weight)

24 Study Review (2) Composite Primary Outcome: Death Resuscitated cardiac arrest Sustained VT requiring cardioversion Insertion of pacemaker or ICD Thromboembolic event (stroke, PE or systemic arterial embolism) Heart Transplant New symptomatic HF with at least 2 of following: Signs and symptoms of CHF Chest x-ray confirmation of HF Need for IV therapy (diuretics/inotropes) Hospital admission for HF

25 Secondary Outcomes Development of Echo changes 12 lead ECG alterations Progression of NYHA functional class Need for initiation or change of heart failure therapy Life threatening ventricular arrhythmias and need for pacemaker or ICD

26 BENEFIT Eligibility Inclusion Criteria Serologic evidence of Chagas infection confirmed by two different serologic methods (discussion) Abnormal ECG, in at least two of these: 1 Complete Right Bundle Branch Block 2 Complete Left bundle branch block 3 Left Anterior fascicular block 4 Left Posterior Fascicular Block 5 Ventricular premature beat 6 First degree AV block>220ms in absence of drugs that slow AV conduction 7 Mobitz type I AV block, in absence of drugs that slow AV 8 Sinus bradycardia < 50 bpm or sinus pauses >3.0 s?, with no SN blocking drugs 9 Primary ST-T changes 10 Abnormal Q waves 11 Low voltage of QRS 12 Atrial Fibrillation

27 BENEFIT Eligibility Inclusion Criteria Or Abnormal ECG (Mobitz type II, advanced or 3 rd degree AV block) Or Increased cardiothoracic ratio (>0.50) Or Complex ventricular arrhythmias on 24 hr ambulatory ECG monitoring OR Evidence of regional wall-motion abnormality or reduced (<50%) global left ventricular systolic function (2-D ECHO), RNA, contrast ventriculography) or increased left ventricular end diastolic diameter (>55 mm) on 2-DEcho Patient signs informed consent

28 BENEFIT Pilot 1000 patients chronic Chagas` heart disease Exclude severe disease R 500 patients BENZNIDAZOLE 500 patients PLACEBO mean follow up: 3 years CO- PRIMARY ENDPOINT 1) Negativization of t. cruzi as detected by qualitative & real time PCR 2) Reduction in the mean burden of t. cruzi (parasite load) as detected by the concentration of t. cruzi/ml of blood by PCR in the treated group.

29 BENEFIT Trial 3,000 patients Chronic Chagas` heart disease R Exclude severe disease 1,500 patients BENZNIDAZOLE 1,500 patients PLACEBO mean follow up: 5 years PRIMARY ENDPOINT combination of death, cardiac arrest resuscitation, sustained ventricular tachyarrhythmias, need for pacemaker or defibrillator implant, Heart Tx, thromboembolic phenomena or hospitalization for CHF

30 BENEFIT - Patient Characteristics Data transferred on May 17, 2010 Total Rand N = 2076 % (Data available*) Female (*2018) Age mean (+ SD) (*2015) 54.7 (+ 10.8) Current Smoker (*2017) Reg. Alcohol intake (*2012) Income (*2012) < 10K

31 BENEFIT Social-Economic Status Total Rand N = 2076 (Data available*) % Education (*2012) < 8 years > Employment (*2012) Employed Unemployed House-Wife SS/disability Retired Never worked 6 0.3

32 BENEFIT - Housing Characteristics Total Rand N = 2076(Data available*) % Residence (*2016) Rural Residence Infested House Endemic Region # People living in same residence (mean) 3.78 (+ 2.06) Roof Type (*2016) Tile Concrete Wall Type (*2016) Brick Mud Sticks Other

33 BENEFIT - Patient History Total Rand N = 2076 (Data available*) (*2017) % NYHA I II III Previous Heart Failure Resuscitated Cardiac Arrest Sustained VT Internal Cardiac Defibrillator Atrial Fibrillation Pacemaker Stroke/TIA Syncope

34 BENEFIT - Patient Characteristics Regular Medication Use Total Rand N = 2076(Data available*) (*2017) % Loop diuretics Spironolactone Other diuretics ACE-inhibitors ARBs Digoxin Aspirin Beta-blockers Amiodarone Oral anticoag/antiplatelets Other meds

35 BENEFIT - Patient Characteristics Ecocardiographic Results Total Rand N = 2076 (Data available*) Mean SD LV Ejection Fraction (*2012) LV Percent Shortening (*2012) LV End Diastolic Diameter (*2012) LV Thrombus (*1679)

36 BENEFIT ECG Results Total Rand N = 2076(Data available*) (*1894) % 1 st degree AV Block nd degree Mob I AV Block Mob II AV Block rd degree AV Block RBBB complete incomplete (*1892) LBBB - complete incomplete (*1792) Left anterior fascicular block Q-Waves Left posterior fascicular block

37 BENEFIT ECG Results (II) Total Rand N = 2076 (Data available*) (*1894) % Sinus bradycardia (< 50 bpm) Low voltage ST-T segment changes Ventricular extra-systole (PVC) Atrial fibrillation/flutter Pacemaker

38 BENEFIT - Patient Characteristics Clinical & Anthropometric Results Total Rand N = 2076 (Data available*) Mean SD Heart Rate (*2018) Systolic BP (*2018) Diastolic BP (*2018) Weight (kg) (*2042) Height (cm) (*2018) BMI (kg/m 2 ) (*2003)

39 Drug Compliance % of pts Given Meds > 75 % Drug Interrupted Drug Restarted 11 day visit day visit day visit Cummulative Brazil (n= 1000) 11 day visit day visit day visit Cummulative

40 BENEFIT: Study Organization Coordination PHRI POPULATION HEALTH RESEARCH INSTITUTE McMaster University Hamilton, Canada Instituto Dante Pazzanese Sao Paulo, Brazil Co-Principal Investigators Carlos Morillo (Canada) JA Marin-Neto (Brazil) Steering Committee Chairs Salim Yusuf Carlos A. Morillo JA Marin Neto Members Álvaro Avezum Jr. Stuart Connolly Susan Chrolavicius Fernando Rosas Sergio Sosa-Estani Erick Villena Rina Bonilla National Coordinators JA Marin-Neto. (Brazil) Sergio Sosa-Estani (Argentina) Erick Villena (Bolivia) Fernando Rosas (Colombia) Rina Bonilla (El Salvador) Independent Data Safety Monitoring Board (DSMB) 45 clinical centers in 5 countries

41 Future Trials Etiologic Treatment Posaconazole 2 Phase II trials Ravuconazole 1 Phase II trial Management of HF Beta-blockers CHARITY Trial ICD CRT Trials? Stem Cells 2 Trials

42 CHARITY Chagas Cardiomyopathy Bisoprolol Intervention Study A Double-blind Randomized Placebo Controlled trial of Bisoprolol in Chagas Cardiomiopathy 7 centers in Colombia (n=500) NYHF classes II,III,IV LV EF < 45% Optiazed dosis of IECAs or de ARA II Age: 18 to 70y No c.i. to BB R N=250 BISOPROLOL FU: 2,5 anos PLACEBO N=250 Primary end-point Combination of: Cardiovascular death Aborted sudden death Sustained VT PM implantation Thromboembolic event Hospitalization for HF Morillo CA et al. Trials 2006;9:7-21.

43 424 non selected patients with Chagas heart disease ( ECG and/or ECHO findings) Clinical evaluation and noninvasive tests (ECG, Chest X-Ray, Holter, HRV, ETT, and Echocardiography) Mean follow-up of 7.9±3.2 years (3% lost) Rassi A, et al. NEJM 2006; 355:

44 Rassi A, et al. NEJM 2006; 355:

45 Rassi A, et al. NEJM 2006; 355:

46 Conclusions Chagas disease continues to be a burden and has globalized. Trypanocidal therapy during the chronic stage of the disease may be beneficial, the BENEFIT trial will answer this question. Newer more effective and safer trypanocidal agents are currently being tested. Risk stratification of SCD and identification of infected subjects that will progress to cardiomyopathy remains a challenge and should be the focus of future research After 101 years of solitude it is time for action against Chagas disease!