heart failure

     

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Display
Trial Studied trt Control trt patientstagsNCTROB Result

aldosterone blockade

eplerenone
EPHESUS, 2003eplerenoneplaceboLow risk of bias suggesting
EMPHASIS-HF, 2010eplerenoneplaceboNCT00232180Low risk of bias suggesting
REMODEL ongoing eplerenoneplaceboNCT00082589 ongoing
Weir ongoing eplerenoneplaceboNCT00132093Exploratory ongoing
spironolactone
Cicoira, 2004spironolactonecontrol -
Cicoira, 2002spironolactonecontrolExploratory -
Ramires, 2000spironolactonecontrolExploratory -
RALES, 1998spironolactoneplaceboRisk of bias suggesting
Agostoni, 2005spironolactoneplaceboExploratory -
Mottram, 2004spironolactoneplaceboExploratory -
Macdonald, 2004spironolactoneplaceboExploratory -
Yee, 2001spironolactoneplacebo -
Tsutamoto, 2001spironolactoneplaceboExploratory -
Farquharson, 2000spironolactoneplaceboExploratory -
MacFadyen, 1997spironolactoneplaceboExploratory -
PIE II ongoing spironolactoneplaceboNCT00123955 ongoing
Han, 1994spironolactone+captoprilcaptoprilExploratory -
Bednarz, 2000aldactonefurosemideExploratory -
Nouvel essai ongoing spironolactonespironolactoneNCT00125437Exploratory ongoing
Mauersberger, 1985spironolactone+furosemidespironolactone+butizideExploratory -

angiotensin-Converting Enzyme Inhibitors

not classified
CASSIS (spirapril), 1995spiraprilplaceboExploratory -
benazepril
McGany, 1991benazeprilcontrolnegative
Colfer, 1992benazeprilplaceboExploratory negative
captopril
Magnani, 1986captoprilplaceboExploratory -
Bussmann, 1987captoprilplaceboExploratory negative
Captopril Digoxin Multicenter Research Group, 1988captoprilplaceboLow risk of bias negative
Barabino, 1991captoprilplaceboExploratory suggesting
Munich MHFT (Kleber), 1992captoprilplaceboLow risk of bias negative
Magnani, 1990captoprilplaceboExploratory -
CMRG, 1983captoprilplaceboExploratory -
Cilazapril-Captopril Multi-centre Group (capt vs pbo), 1995captoprilplaceboExploratory -
SAVE, 1992captoprilplaceboLow risk of bias -
Pfeffer, 1988captoprilplaceboExploratory -
Sogaard, 1994captoprilplaceboExploratory -
Sharpe, 1988captoprilplaceboExploratory -
Mortarino, 1990captoprilplaceboExploratory -
packer, 1986captoprilenalaprilExploratory -
cilazapril
Drexler, 1989cilazaprilplaceboExploratory negative
Dosseger, 1993cilazaprilplaceboExploratory -
Cilazapril-Captopril Multi-centre Group, 1995cilazaprilplaceboExploratory -
Cilazapril-Captopril Multi-centre Group (cila vs capt), 1995cilazaprilcaptoprilExploratory -
enalapril
Rucinska-b (enalapril), 1991enalaprilcontrolnegative
Enalapril CHF investigators, 1987enalaprilcontrolnegative
Rucinska-a (enalapril), 1991enalaprilcontrolnegative
SOLVD treatment, 1991enalaprilplaceboNCT00000516Low risk of bias suggesting
SOLVD prevention, 1992enalaprilplaceboNCT00000516Low risk of bias -
Cleland, 1985enalaprilplaceboExploratory negative
CONSENSUS, 1987enalaprilplaceboLow risk of bias negative
Dickstein, 1991enalaprilplaceboExploratory negative
Sharpe, 1984enalaprilplacebo -
McGrath, 1985enalaprilplacebo -
Chrysant, 1985enalaprilplaceboLow risk of bias -
CASSIS (enalapril), 1995enalaprilplaceboExploratory -
NETWORK (2.5 bid vs 10 bid), 1998enalaprilenalaprilLow risk of bias -
NETWORK (5 bid vs 10 bid), 1998enalaprilenalaprilLow risk of bias -
V-HeFT II, 1991enalaprilhydralazine+ISDNLow risk of bias -
fosinopril
Brown, 1995fosinoprilplaceboExploratory -
FEST (Erhardt), 1996fosinoprilplaceboExploratory -
lisinopril
Zwehl, 1990lisinoprilcontrolnegative
Giles, 1990lisinoprilcontrolnegative
Rucinska-c (lisinopril), 1000lisinoprilcontrolnegative
Gilbert, 1993lisinoprilplacebonegative
International Study Group (Lewis), 1989lisinoprilplaceboExploratory -
ATLAS, 1999lisinoprillisinoprilLow risk of bias -
perindopril
Lechat, 1993perindoprilplacebonegative
PEP CHF, 2006perindoprilplaceboLow risk of bias negative
quinapril
Uprichard-a, 1994controlnegative
Uprichard-b, 1994controlnegative
Uprichard-c, 1994controlnegative
Riegger, 1990placebonegative
Northridge, 1991placeboExploratory negative
Rieger, 1991placeboExploratory negative
Nussberger, 1994placeboExploratory -
Quinapril Heart Failure Trial Investigators, 1993placeboExploratory -
ramipril
Swedberg, 1991ramiprilcontrolnegative
Maass-a, 1991ramiprilplacebonegative
Gordon, 1991ramiprilplaceboExploratory suggesting
Maass-b, 1991ramiprilplaceboExploratory negative
Maass-c, 1991ramiprilplaceboExploratory negative
Lemarie, 1992ramiprilplaceboExploratory negative
Gundersen, 1994ramiprilplaceboExploratory -
AIRE, 1993ramiprilplaceboLow risk of bias -
trandolapril
Hampton, 1998trandolaprilplaceboExploratory -
TRACE, 1995trandolaprilplaceboLow risk of bias -

angiotensin-receptor blockers

not classified
PARAGON-HF ongoing LCZ696ValsartanNCT01920711 ongoing
ADEPT, 2001eprosartan+ACE inhibitorACE inhibitor onlyExploratory -
candesartan
ARCH-J, 2003candesartanplaceboLow risk of bias -
CHARM-Alternative, 2003candesartanplaceboLow risk of bias suggesting
Mitrovic et al., 2003candesartanplaceboExploratory suggesting
SPICE, 2000candesartanplaceboExploratory negative
STRETCH, 1999candesartanplaceboExploratory -
CHARM preserved, 2003candesartanplaceboLow risk of bias -
CHARM-Added, 2003candesartan+ACE inhibitorACE inhibitor onlyLow risk of bias negative
RESOLVD association, 1999candesartan+ACE inhibitorACE inhibitor onlyExploratory negative
RESOLVD (candesartan alone), 1999candesartanenalaprilExploratory negative
irbesartan
I-PRESERVE (McMurray), 2008ibesartanplaceboNCT00095238Low risk of bias negative
Tonkon et al., 2000irbesartan+ACE inhibitorACE inhibitor onlyExploratory -
losartan
NCT00090259 ongoing losartanlosartanNCT00090259 ongoing
HEAAL, 2009losartan 150mglosartan 50mgNCT00090259Low risk of bias suggesting
Losartan Phase III International, 1996losartanplaceboExploratory suggesting
Losartan Phase III U.S., 1995losartanplaceboExploratory negative
Hamroff et al., 1999losartan+ACE inhibitorACE inhibitor onlyExploratory -
ELITE, 1997losartancaptoprilExploratory negative
ELITE II, 2000losartancaptoprilLow risk of bias -
Dickstein et al., 1995losartanenalaprilExploratory -
Lang et al., 1997losartanenalaprilExploratory -
Losartan phase II S, 1996losartanenalaprilExploratory -
losartan phase II US, 1996losartanenalaprilExploratory -
telmisartan
REPLACE, 2001telmisartanenalaprilExploratory -
valsartan
VALIDD, 2007valsartanno valsartanNCT00170924Exploratory negative
Mazayev et al. (vs placebo), 1998valsartanplaceboExploratory -
V-HeFT, 1999valsartan+ACE inhibitorACE inhibitor onlyExploratory negative
Val-HeFT, 2001valsartan+ACE inhibitorACE inhibitor onlyLow risk of bias suggesting
HEAVEN, 2002valsartanenalaprilExploratory -
Mazayev et al. (vs lisinopril, 1998valsartanLisinoprilExploratory -

anti inflammatory drugs

not classified
ACCLAIM, 2008Celacade™ systemplaceboNCT00111969Low risk of bias negative

antiarrythmic drugs

amiodarone
EPAMSA, 1985amiodaroneno treatmentsuggesting
GESICA, 1994amiodaroneno treatmentsuggesting
Hamer, 1989amiodaroneplacebosuggesting
Nicklas, 1991amiodaroneplacebonegative
STATCHF, 1995amiodaroneplacebonegative
AMIOVIRT, 2003amiodaroneICDnegative
dronedarone
ANDROMEDA, 2008dronedaroneplaceboNCT00543699negative

antithrombotics

not classified
Barzizza (A+D), 1993placebo -
aspirin
WASH (aspirin), 2004aspirinno treatmentnegative
Barzizza (ASA), 1993aspirinplaceboExploratory -
clopidogrel
WATCH (clopidogrel vs aspirin) ongoing clopidogrelaspirin ongoing
enoxaparin
THE-PRINCE (Kleber), 2003enoxaparinUFH -
rivaroxaban
COMMANDER HF ongoing rivaroxabanplaceboNCT01877915 ongoing
warfarin
WASH (warfarin), 2004warfarinno treatmentnegative
HELAS (warfarin vs placebo), 2006warfarinplacebo -
Barzizza (warfarin), 1993warfarinplacebo -
HELAS (warfarin vs aspirin), 2006warfarinaspirin -
WATCH (warfarin vs aspirin), 2009warfarinaspirinNCT00007683suggesting

beta-blockers

bisoprolol
CIBIS, 1994bisoprololplacebosuggesting
CIBIS II, 1999bisoprololplacebosuggesting
CIBIS II (elderly subgroup), 1999Bisoprololplacebosuggesting
bucindolol
BEST, 2001bucindololplaceboNCT00000560suggesting
Pollock, 1990Bucindololplacebo -
Woodley, 1991Bucindololplacebo -
Bristow, 1994Bucindololplacebo -
MERIT-HF (elderly subgroup), 1999Bucindololplacebosuggesting
carvedilol
ANZ-HeFT, 1997carvedilolplacebonegative
COPERNICUS, 2002carvedilolplacebosuggesting
CAPRICORN, 2001carvedilolplacebosuggesting
Metra, 1994carvedilolplacebo -
Olsen, 1995carvedilolplacebo -
Krum, 1995carvedilolplacebo -
Bristow (MOCHA), 1996carvedilolplacebo -
Parker, 1996carvedilolplacebonegative
Colucci, 1996carvedilolplacebo -
Cohn, 1997carvedilolplacebo -
Carvedilol U.S. Trials (elderly subgroup), 1996Carvedilolplacebosuggesting
COPERNICUS (elderly subgroup), 2001Carvedilolplacebosuggesting
CARMEN (carvedilol alone), 2004carvedilolenalaprilnegative
CARMEN (carvedilol+enalapril), 2004 ongoing carvedilol+enalaprilenalapril ongoing
COMET, 2003carvedilolmetoprololsuggesting
metoprolol
MDC (Waagstein), 1993metoprololplacebonegative
MERIT-HF, 1999metoprololplacebosuggesting
Engelmeier, 1985metoprololplacebo -
Fisher, 1994metoprololplacebo -
Eichhorn, 1994metoprololplacebo -
RESOLVD, 2000metoprololplacebo -
BEST (elderly subgroup), 2001Metoprololplacebonegative
nebivolol
Lechat, 1991Nebivololplacebo -
Wisenbaugh, 1993Nebivololplacebonegative
SENIORS, 2005nebivololplacebo -

BNP guided management

not classified
TIME CHF, 2009BNP-guided managementcontrolRisk of bias negative
PRIMABNP-guided managementcontrolRisk of bias negative
PROTECT, 2009BNP-guided managementcontrolNCT00351390 -
STARS-BNP, 2007BNP-guided managementcontrolRisk of bias suggesting
BATTLESCARRED, 2009BNP-guided managementcontrolANZCTR12605000735651Risk of bias negative
STARBRITE, 2007BNP-guided managementcontrolNCT00484770 -
Troughton, 2000BNP-guided managementcontrolRisk of bias suggesting
BASEL ongoing BNP-guided managementcontrolNCT00130611 ongoing
van Kraaij ongoing BNP-guided managementcontrolNCT00149422Risk of bias ongoing
RABBIT ongoing BNP-guided managementcontrolNCT00206856 ongoing

calcium channel blockers

not classified
De Vries, 1996placeboExploratory -
amlodipine
Packer, 1991amlodipinecontrolExploratory -
Smith, 1994amlodipinecontrolExploratory -
Udelson, 1996amlodipinecontrolExploratory -
Binkley, 1996amlodipinecontrolExploratory -
Ghali, 1997amlodipinecontrolExploratory -
PRAISE, 1996amlodipineplaceboLow risk of bias negative
PRAISE II , 2000AmlodipineplaceboLow risk of bias negative
diltiazem
Liao , 1998DiltiazemplaceboExploratory suggesting
DiDi, 1996diltiazemplaceboLow risk of bias negative
felodipine
VHeFT III, 1997felodipineplaceboExploratory negative
Kassis, 1987felodipineplaceboExploratory -
Littler, 1995FelodipineplaceboExploratory negative
Kassis, 1990felodipineplaceboExploratory -
Dunselman, 1990felodipineenalaprilExploratory -
De Vries, 1995felodipineenalaprilExploratory -
isradipine
Van den Toren, 1996isradipineplaceboExploratory -
mibefradil
MACH 1, 2000mibefradilplaceboLow risk of bias suggesting
nicardipine
Gheorghiade, 1991nicardipinecontrolExploratory -
Abrams, 1993nicardipinecontrolExploratory -
nisoldipine
Gaudron, 1996NisoldipineplaceboExploratory -
Rousseau, 1994nisoldipineplaceboExploratory -
Schofer, 1990nisoldipinecaptoprilExploratory -

cell-based therapies

not classified
Revive -
POSEIDON, 2012Mesenchymal stem cellsallogeneic mesenchymal stem cellsNCT01087996 -
ESCAPE ongoing controlNCT00841958 ongoing
BC-14-001-02 ongoing controlNCT02438306 ongoing
Pokushalov (DOUBLON DIB), 2010Bone marrow derived stem cellcontrol -
FOCUS-CCTRN, 2012Bone marrow derived stem cellcontrolNCT00824005 -
CUPID 2b, 2016Bone marrow derived stem cellcontrolNCT01643330 -
TOPCARE-CHD, 2006Bone marrow mononuclear cellscontrol NCT00289822 -
Hendrikx, 2006Bone marrow mononuclear cellscontrol -
Yao, 2008Bone marrow mononuclear cellscontrol -
Ang, 2008Bone marrow mononuclear cellscontrol -
Patel, 2005Bone marrow progenitor cellscontrol -
Manginas, 2007Bone marrow progenitor cellscontrol -
Vrtovec, 2011Bone marrow progenitor cellscontrolNCT00629018 -
Vrtovec, 2013Bone marrow progenitor cellscontrolNCT01350310 -
Perin, 2012Bone marrow progenitor cellscontrol -
SCIPIO, 2011Cardiac stem cellscontrolNCT00474461 -
C CURE, 2013Cardiopoietic stem cellcontrolNCT00810238 -
CADUCEUS, 2012Cardiopoietic stem cellcontrolNCT00893360 -
IMPACT-DCM, 2014ixmyelocel-TcontrolNCT00765518 -
Catheter-DCM, 2014ixmyelocel-TcontrolNCT01020968 -
CAuSMIC, 2005myoblastscontrolnegative
SEISMIC, 2011myoblastscontrolnegative
TAC-HFT, 2014Stem cellscontrolNCT00768066 -
CMMo/MD/2013 ongoing placeboNCT02033278 ongoing
INCL, 2015Bone marrow derived stem cellplaceboNCT00333827 -
ABCD, 2010Bone marrow derived stem cellplacebo -
FOCUS-HF, 2011Bone marrow mononuclear cellsplaceboNCT00203203.negative
CUPID, 2011gene therapyplaceboExploratory -
ixCELL-DCM, 2016ixmyelocel-TplaceboNCT01670981 -
MAGIC, 2001myoblastsplacebonegative
MARVEL, 2011myoblastsplaceboNCT00526253 negative
C41750/3100 ongoing Bone marrow derived stem cellshamNCT02032004 ongoing
REMEDIUM ongoing Repetitive stem cell administrationSingle stem cell administrationNCT02248532 ongoing

cholesterol lowering intervention

atorvastatin
Wojnicz, 2006atorvastatincontrolheart failurenegative
Yamada, 2007atorvastatincontrolheart failurenegative
Strey, 2005atorvastatinplaceboheart failure -
Sola, 2006atorvastatinplaceboheart failurenegative
cerivastatin
Laufs, 2004cerivastatinplaceboheart failure -
rosuvastatin
CORONA, 2007rosuvastatinplaceboheart failureNCT00206310Low risk of bias negative
Krum, 2007rosuvastatinplaceboheart failureExploratory negative
GISSI-HF rosuvastatine, 2008rosuvastatinplaceboheart failureNCT00336336Low risk of bias negative
simvastatin
Hong, 2005simvastatincontrolheart failureRisk of bias negative
Node, 2003simvastatinplaceboheart failurenegative
Landmesser, 2005simvastatinezetimibeheart failure -

combined inhibition of ACE and neprilysin

not classified
PARADIGM-HF, 2014sacubitril/valsartanenalaprilNCT01035255 -

digitalis glycosides

digoxin
Fleg, 1982digoxinplacebonegative
Lee, 1982digoxinplacebonegative
Taggart, 1983digoxinplacebonegative
Captopril-Digoxin Multicenter Research Group (CDMRG), 1988digoxinplacebosuggesting
German and Austrian Xamoterol Study, 1988digoxinplacebonegative
Guyatt, 1988digoxinplacebonegative
DiBianco, 1989digoxinplacebosuggesting
Pugh, 1989digoxinplacebonegative
Blackwood, 1990digoxinplacebonegative
Radiance, 1993digoxinplacebosuggesting
Proved, 1993digoxinplacebonegative
DIMT, 1993digoxinplacebonegative
Digitalis Investigation Group (DIG), 1997digoxinplaceboNCT00000476suggesting

diuretics

not classified
Burr, 1977diuretic agentsplacebonegative
Mathur, 1984furosemide placeboExploratory -
Sherman, 1986piretanideplaceboExploratory negative
TOPCAT, 2014spironolactoneplaceboNCT00094302 -
De jong, 1994various diureticsplaceboExploratory negative
Myers, 1982various diureticsplaceboExploratory negative
Walma, 1997various diureticsplaceboExploratory suggesting
Richardson, 1987frusemide plus amiloridecaptoprilExploratory negative
Haerer, 1989piretanidedigoxin -
UNLOADUltrafiltrationDiureticsNCT00124137Exploratory -
Myers (copie de 7314), 1982placebo (diuretics withdrawal)various diuretics -
amiloride
Cheitlin, 1991amilorideplaceboExploratory -
eplerenone
EMPHASIS-HF, 2010eplerenoneplaceboNCT00232180Low risk of bias suggesting
EPHESUS, 2003eplerenoneplaceboLow risk of bias suggesting
REMODEL ongoing eplerenoneplaceboNCT00082589 ongoing
Weir ongoing eplerenoneplaceboNCT00132093Exploratory ongoing
furosemide
Boccanelli, 1986furosemidecaptoprilExploratory negative
Cowley, 1986furosemidecaptoprilExploratory -
hydrochlorothiazide
Nordrehaug, 1992hydrochlorothiazidebenazeprilExploratory suggesting
Sievert, 1989hydrochlorothiazide+triamterenedigoxinExploratory -
rolofylline
PROTECT-1rolofyllineplaceboNCT00328692 -
spironolactone
Cicoira, 2004spironolactonecontrol -
Cicoira, 2002spironolactonecontrolExploratory -
Ramires, 2000spironolactonecontrolExploratory -
RALES, 1998spironolactoneplaceboRisk of bias suggesting
Agostoni, 2005spironolactoneplaceboExploratory -
Mottram, 2004spironolactoneplaceboExploratory -
Macdonald, 2004spironolactoneplaceboExploratory -
Yee, 2001spironolactoneplacebo -
Tsutamoto, 2001spironolactoneplaceboExploratory -
Farquharson, 2000spironolactoneplaceboExploratory -
MacFadyen, 1997spironolactoneplaceboExploratory -
Barr, 1995spironolactoneplaceboExploratory -
PIE II ongoing spironolactoneplaceboNCT00123955 ongoing
Han, 1994spironolactone+captoprilcaptoprilExploratory -
Bednarz, 2000aldactonefurosemideExploratory -
Dalhstrom, 1986furosemide + spironolactoneprenalterolExploratory negative
Mauersberger, 1985spironolactone+furosemidespironolactone+butizideExploratory -

Exercise Therapy

not classified
HEARTS ongoing Resistance and Aerobic Trainingcontrol ongoing
HF-ACTION, 2008structured exercise trainingcontrolNCT00047437Risk of bias negative
Patwala, 2009structured exercise trainingcontrolExploratory -
Exercise Therapy
Belardinelli et al, 1999Exercise trainingcontrol -
Dubach et al, 1997Exercise trainingcontrol -
Giannuzzi et al, 1997Exercise trainingcontrol -
Hambrecht et al, 1995Exercise trainingcontrol -
Kiilavuori et al, 2000Exercise trainingcontrol -
McKelvie et al, 2002Exercise trainingcontrol -
Zanelli et al, 1997Exercise trainingcontrol -
Wielenga et al, 1999Exercise trainingcontrol -
Willenheimer et al, 1998Exercise trainingcontrol -
ExTraMATCH, 2004Exercise trainingcontrol -

HR-slowing agents

ivabradine
SHIFT, 2010ivabradineplaceboISRCTN70429960Low risk of bias suggesting
BEAUTIFUL, 2008ivabradine 15mgplaceboNCT00143507Low risk of bias negative

increasing hemoglobin concentration

not classified
Palazzuoli, 2006beta-erythropoietinplaceboExploratory negative
FAIR-HF (Anker), 2009ferric carboxymaltoseplaceboLow risk of bias -
taspoglutide
STAMINA-HeFT (Ghali), 2008darbepoetin alfaplaceboNCT00049985Exploratory negative
van Veldhuisen, 2007darbepoetin alfaplaceboNCT00086086Exploratory negative
Ponikowski, 2007darbepoetin alfaplaceboNCT00117234Exploratory negative
Parissis, 2008darbepoetin alfaplaceboExploratory negative
Parissis, 2009darbepoetin alfaplaceboExploratory -
Kourea, 2008darbepoetin alfaplaceboExploratory negative

inhibition of the renin-angiotensin system (ACEI or ARB)

candesartan
CHARM preserved, 2003candesartanplaceboLow risk of bias -
irbesartan
I-PRESERVE (McMurray), 2008ibesartanplaceboNCT00095238Low risk of bias negative
perindopril
PEP CHF, 2006perindoprilplaceboLow risk of bias negative

mineralocorticoid receptor antagonists

not classified
TOPCAT, 2014spironolactoneplaceboNCT00094302 -

percutaneous left ventricular assist devices

not classified
REMATCH, 2001pulsatile-flowmedical treatment -
HeartMate II, 2009continuous-flow HeartMate IIpulsatile-flow HeartMate XVENCT00121485Risk of bias -

phosphodiesterase III inhibitors

not classified
IRG, 1991Imazodanplacebonegative
Dies, 1989Indolidanplacebonegative
Bergler-Klein, 1992Pimobendanplacebonegative
EPOCH, 2002Pimobendanplacebonegative
PICO, 1996Pimobendanplacebonegative
PMRG, 1992Pimobendanplacebonegative
amrinone
AMTG, 1985Amrinoneplacebonegative
Enoximone
WESG, 1991Enoximoneplacebonegative
EMTG, 1990Enoximoneplacebonegative
ESG, 2000Enoximoneplacebonegative
Lardoux, 1987Enoximoneplacebonegative
ESSENTIAL (I and II), 2009enoximoneplaceboNCT00051285Low risk of bias negative
Cowley, 1994Enoximoneplacebonegative
EMOTE, 2007enoximoneplacebo -
EMPOWER ongoing enoximoneplacebo (on top metoprolol)NCT00077948 ongoing
Flosequinan
Cowley, 1993Flosequinanplacebonegative
FACET, 1993Flosequinanplacebonegative
REFLECT, 1993Flosequinanplacebonegative
REFLECT II, 1991Flosequinanplacebonegative
ibopamine
PRIME II, 1997ibopamineplacebonegative
Milrinone
PROMISE, 1991Milrinoneplacebonegative