2015 BENEFIT Matteo Casegni.pptx

ScuoladiSpecializzazioneinMala/edell’ApparatoCardiovascolare
Dire8oreProf.MassimoVolpe
FacoltàdiMedicinaePsicologia,UniversitàdiRomaSapienza
AnnoAccademico2014-2015
Dr.Ma8eoCasenghi
Proge8oFormazioneAvanzatainCardiologianelWeb2015
ScuoladiSpecializzazioneinMala/edell’ApparatoCardiovascolare
Dire8ore:Prof.MassimoVolpe
E-mail:[email protected]
Coordinatore:Dr.GiulianoTocci
E-mail:[email protected]
Original Article
Randomized Trial of Benznidazole for Chronic
Chagas’ Cardiomyopathy
Carlos A. Morillo, M.D., Jose Antonio Marin-Neto, M.D., Ph.D., Alvaro Avezum, M.D.,
Ph.D., Sergio Sosa-Estani, M.D., Ph.D., M.P.H., Anis Rassi, Jr., M.D., Ph.D., Fernando
Rosas, M.D., Erick Villena, M.D., Roberto Quiroz, M.D., Rina Bonilla, M.D., Constança
Britto, Ph.D., Felipe Guhl, M.Sc., Elsa Velazquez, Ph.D., Laura Bonilla, M.Sc., Brandi
Meeks, M.Eng., Purnima Rao-Melacini, M.Sc., Janice Pogue, Ph.D., Antonio
Mattos, M.Sc., Janis Lazdins, M.D., Ph.D., Anis Rassi, M.D., Stuart J. Connolly, M.D.,
Salim Yusuf, M.D., Ph.D., for the BENEFIT Investigators
N Engl J Med
Volume 373(14):1295-1306
October 1, 2015
BernC.NEnglJMed2015;373:456-466
Phases of Trypanosoma cruzi Infection
Acute Phase
6-8 weeks
Chronic Phase
Indeterminate
Form
70-80%
Determinate
Form
20-30%
Chagas’ CMP
GI Chagas’
Study Overview
InclusionCriteria:
•  PaZents aged between 18 and 75 years with two posiZve
serological tests for CHAGAS disease and any one or more of the
following:
– 
– 
– 
– 
Abnormalelectrocardiogram
IncreasedcardiothoracicraZo
Complexventriculararrhythmiason24-hECGmonitoring
Evidence of regional wall moZon abnormality or reduced (<50%) global LV
systolicfuncZonorincreasedLVend-diastolicdiameteron2DEcho
ExclusionCriteria:
• 
• 
• 
• 
• 
• 
• 
• 
• 
NewYorkHeartAssociaZonclassIVordecompensatedheartfailure
EvidenceofothereZologyofdilatedcardiomyopathy
Previoustreatmentwithtrypanocidalagents
Inabilitytocomplywithfollow-up
HistoryofseverealcoholabuseorotherdrugaddicZon
KnownchronicrenalfailureorhepaZcinsufficiency
Pregnancyorbreastfeeding
Megaesophaguswithsevereswallowingimpairment
Otherdiseasessignificantlycurtailinglifeexpectancy
Pa3entFlow:
Time0
EnnrolledandRandomized
N=2854
AllocatedtoBenzonidazole(BNZ)
N=1431
AllocatedtoPlacebo
N=1423
300mgfor80days
Mean
FU
5.4
Years
IncludedinprimaryITTanalysis
N=1431
IncludedinprimaryITTanalysis
N=1423
PrimaryOutcome:
•  Firsteventofanyofthecomponentsofthecomposite
outcomeofdeath,resuscitatedcardiacarrest,sustained
ventriculartachycardia,inserZonofapacemakeror
implantablecardioverter–defibrillator,cardiac
transplantaZon,newheartfailure,strokeorother
thromboembolicevent
SecondaryOutcome:
•  ResponsetotreatmentonthebasisofresultsonPCR
assay
BaselineCharacteris3cs
Benzonidazole
N=1431
Placebo
N=1423
MeanAge-yrs
55.4±10.7
55.2±11.2
MaleSex-no.(%)
726(50.7)
682(47.9)
AnyECGabnormaliZes–no(%)
1335(93.3)
1348(94.7)
NYHAclassI–no.(%)
1065(74.4)
1045(73.5)
MeanLVEF-%
54.4±14.8
54.6±14.6
WallMoZonAbnormality–no.(%)
431(38.3)
422(37.6)
DiureZcs–no.(%)
435(30.4)
425(29.9)
ACE-IorARBs–no.(%)
710(49.6)
700(49.2)
Beta-blockers–no.(%)
444(31.0)
431(30.3)
Amiodarone–no.(%)
284(19.8)
267(18.8)
PrimaryCompositeOutcomeduring7YearsofFollow-up
PrimaryOutcomeandItsComponents,Hospitaliza3ons,andDeaths
PrimaryOutcome,AccordingtoSubgroup
ConversiontoNega3veResultsonPCR,AccordingtoSubgroup
Conclusions
•  TrypanocidaltherapywithbenznidazoleinpaZentswith
established Chagas’ cardiomyopathy significantly
reduced serum parasite detecZon, but did not
significantlyreducecardiacclinicalprogression.
Conclusions
WHYTHISTRIALISNEUTRAL?
•  Wrongunderlyingpathogenicconcept?
•  Wrongdrugregimen?
•  WrongpopulaZon?
ScuoladiSpecializzazioneinMala/edell’ApparatoCardiovascolare
Dire8oreProf.MassimoVolpe
FacoltàdiMedicinaePsicologia,UniversitàdiRomaSapienza
AnnoAccademico2014-2015
Dr.Ma8eoCasenghi
GrazieperlaVostraA8enzione!
Proge8oFormazioneAvanzatainCardiologianelWeb2015
ScuoladiSpecializzazioneinMala/edell’ApparatoCardiovascolare
Dire8ore:Prof.MassimoVolpe
E-mail:[email protected]
Coordinatore:Dr.GiulianoTocci
E-mail:[email protected]