Post on 08-Sep-2018
Understanding and Development of Understanding and Development of New Therapies for Heart FailureNew Therapies for Heart Failure
-- Lessons from Recent Clinical Trials Lessons from Recent Clinical Trials --
서울의대서울의대 내과내과
오오 병병 희희
Clinical trialsClinical trials•• EvidenceEvidence--based medicine, clinical practicebased medicine, clinical practice•• Impact uponImpact upon
–– Understanding Understanding pathophysiologypathophysiology–– Changing clinical practice through clarifying risk/benefit of Changing clinical practice through clarifying risk/benefit of
intervention intervention •• ConsCons
–– Cannot address all questionsCannot address all questions–– ““Art of medicineArt of medicine”” not studiednot studied–– Trial patients not like realTrial patients not like real--world patientsworld patients–– Long duration, expensive, Long duration, expensive, ……
100 100 LargeLarge--scale Clinical Trials over 20 yrsscale Clinical Trials over 20 yrs
•• ACE inhibitorsACE inhibitors•• Beta blockersBeta blockers•• AngiotensinAngiotensin receptor blockers (receptor blockers (ARBARB’’ss))•• CCBCCB’’ss, vasodilators, , vasodilators, inotropesinotropes•• AntiAnti--arrhythmic agentsarrhythmic agents•• Device strategies like ICD, RCTDevice strategies like ICD, RCT•• Surgical intervention, Surgical intervention, immunomodulationimmunomodulation, ,
anticoagulation, exerciseanticoagulation, exercise
VHefT - 1VHefT - 1Placebo (273)Prazosin (183)Hz + ISDN (186)
Placebo (273)Prazosin (183)Hz + ISDN (186)
MONTHSMONTHS00 66 1212 1818 2424 3030 3636 4242
0.70.7
0.60.6
PROBABILITYOF
DEATH
PROBABILITYOF
DEATH
0.50.5
0.40.4
0.30.3
0.20.2
0.10.1
00
N Engl J Med 1986;314:1547N Engl J Med 1986;314:1547
PlaceboPlacebo
EnalaprilEnalapril
0.80.8
00
p< 0.001p< 0.001
p< 0.002p< 0.002
N Engl J Med 1987;316:1429N Engl J Med 1987;316:1429
ACEIin Severe Heart Failure
ACEIin Severe Heart Failure
1100CONSENSUS
0.70.7
1212111110109988776655
PROBABILITYOFDEATH
PROBABILITYOFDEATH
0.60.6
0.50.5
0.40.4
0.30.3
0.20.2
0.10.1
MONTHSMONTHS443322
5050
4040
3030
2020
1010
0000 66 1212
p = 0.0036p = 0.0036
%MORTALITY
%MORTALITY
24241818 3030 3636 4242 4848
Enalapriln=1285Enalapriln=1285
Placebon=1284Placebon=1284
SOLVD (Treatment)N Engl J M 1991;325:293SOLVD (Treatment)N Engl J M 1991;325:293
ACEIin Mild to Moderate Heart Failure
ACEIin Mild to Moderate Heart Failure
n = 2589CHF - NYHA II-III- EF < 35
n = 2589CHF - NYHA II-III- EF < 35
MonthsMonths
ACEIIn Asymptomatic LV Dysfunction
ACEIIn Asymptomatic LV Dysfunction
5050
4040
3030
2020
1010
00
MonthsMonths00 66 1212
p = 0.30p = 0.30
24241818 3030 3636 4242 4848
Enalapriln=2111Enalapriln=2111
Placebon=2117Placebon=2117
%MORTALITY
%MORTALITY
n = 4228No CHF symptomsEF < 35
n = 4228No CHF symptomsEF < 35
SOLVD (Prevention)N Engl J Med 1992;327:685SOLVD (Prevention)N Engl J Med 1992;327:685
SAVERadionuclideEF ≤ 40%
All-Cause Mortality
Years
Pro
babi
lity
of E
ven
t
0
0.05
0.1
0.15
0.2
0.25
0.3
0 1 2 3
0.35
0.4
4
ACE-I
Placebo
OR: 0.74 (0.66–0.83)
ACE-I: 702/2995 (23.4%)
Placebo: 866/2971 (29.1%)
AIREClinical and/or radiographic signs of HF
TRACEEchocardiographicEF ≤ 35%
ACE-I 2995 2250 1617 892 223Placebo 2971 2184 1521 853 138
Flather MD, et al. Lancet. 2000;355:1575–1581
β β blockers in CHF blockers in CHF –– AllAll--cause Mortality cause Mortality
CarvedilolCarvedilol(n = 696)(n = 696)
PlaceboPlacebo(n = 398)(n = 398)Su
rviv
alSu
rviv
al
DaysDays00 5050 100100 150150 200200 250250 300300 350350 400400
Risk reduction = 65%Risk reduction = 65%P < 0.001P < 0.001
Packer et al (1996)Packer et al (1996)
US US CarvedilolCarvedilol StudyStudy1.01.0
0.90.9
0.80.8
0.70.7
0.60.6
The MERITThe MERIT--HF Study Group (1999)HF Study Group (1999)
Months of followMonths of follow--upupM
orta
lity
%M
orta
lity
%00 33 66 99 1212 1515 1818 2121
PlaceboPlacebo
Metoprolol CR/XLMetoprolol CR/XL
P = 0.0062P = 0.0062Risk reduction = 34%Risk reduction = 34%
MERITMERIT--HFHF1.01.0
0.90.9
0.80.8
0.70.7
0.60.6
CIBISCIBIS--II Investigators (1999)II Investigators (1999)
0 200 400 600 8000 200 400 600 800
BisoprololBisoprolol
PlaceboPlacebo
Time after inclusion (days)Time after inclusion (days)
P < 0.0001P < 0.0001
Surv
ival
Surv
ival
Risk reduction = 34%Risk reduction = 34%
CIBISCIBIS--IIII1.01.0
0.80.8
0.60.6
00
ARBARB’’ss in heart failurein heart failure
•• ELITE, ELITEELITE, ELITE--IIII–– LosartanLosartan vs. vs. captoprilcaptopril in old patientsin old patients–– similar primary end pointsimilar primary end point
•• RESOLVEDRESOLVED–– candesartancandesartan
Spironolactone - RALESn=1,663, NYHA III-IV, EF ≤ 35%, 24months, Spironolactone 25-50 mgProbability of Survival
1.0
6Months
SpironolactoneSpironolactone(n=822)(n=822)
PlaceboPlacebo(n=841)(n=841)
0.9
0.8
0.7
0.6
0.5
0.00 6 12 18 24 30 3
Pitt B, et al. RALES study. N Engl J Med 1999:341:709.
Neurohormonal & cytokine adjustment
Myocardial injury
Cardiac function
Activation of SAS, RAASEndothelin, AVP,Inflammatory cytokines,Oxidative stress
Acute(adaptive)
Chronic(maladaptive)Hypertrophy,Remodeling,Apoptosis
Established guideline from past clinical trialsEstablished guideline from past clinical trials
•• ACE inhibitorsACE inhibitors in all patients with LV systolic in all patients with LV systolic dysfunction who can tolerate themdysfunction who can tolerate them
•• ARBARB’’ss in ACE inhibitor intolerant patients in ACE inhibitor intolerant patients with LV systolic dysfunctionwith LV systolic dysfunction
•• Beta blockersBeta blockers in stable patients with mild to in stable patients with mild to moderate symptoms without significant moderate symptoms without significant congestioncongestion
•• AldosteroneAldosterone antagonistsantagonists in moderate to in moderate to severe HF severe HF
Recent clinical trials impacting HF therapyRecent clinical trials impacting HF therapy
•• Beta blockersBeta blockers•• AngiotensinAngiotensin--aldosteronealdosterone antagonistsantagonists
–– AngiotensinAngiotensin receptor blockersreceptor blockers–– AldosteroneAldosterone antagonistantagonist
•• Other medical therapeuticsOther medical therapeutics–– NEP inhibitorNEP inhibitor–– AnticytokinesAnticytokines–– AntiarrhythmicAntiarrhythmic agentagent–– tt--type type CCBCCB’’ss
•• DeviceDevice–– ICDICD–– RCTRCT
COMET
Effects of Different Effects of Different ββ Blocking Agents Blocking Agents
NENE NENE
NENE
ββ11 ββ22 αα11
BisoprololBisoprololMetoprololMetoprolol
CofactorsCofactors
CarvedilolCarvedilol
Cardiac cell toxicityCardiac cell toxicity
COPERNICUSCOPERNICUSAllAll--cause mortalitycause mortality
PlaceboPlacebo
CarvedilolCarvedilol
100100
9090
% S
urvi
val
% S
urvi
val
8080
7070PP = 0.00013= 0.0001335% risk reduction 35% risk reduction
6060
5050
..
242400 2020161612128844 2828MonthsMonths Packer et al. NEJM 2001Packer et al. NEJM 2001
Recent beta blocker trialsRecent beta blocker trials
•• COMETCOMET, , carvedilolcarvedilol vs. vs. metoprololmetoprolol–– carvedilolcarvedilol is betteris better
•• COPERNICUSCOPERNICUS, , carvedilolcarvedilol in severe (class IIIB & IV) HFin severe (class IIIB & IV) HF–– 35 % mortality reduction35 % mortality reduction
•• CAPRICORNCAPRICORN, , carvedilolcarvedilol in postin post--MI HF(EF<40%)MI HF(EF<40%)–– 23 % reduction in all23 % reduction in all--cause mortality risk reductioncause mortality risk reduction
•• BESTBEST, , bucindololbucindolol–– Only nonOnly non--statistically insignificant reduction in mortality statistically insignificant reduction in mortality
and morbidityand morbidity•• MOXCONMOXCON, , moxonidinemoxonidine, centrally acting beta blocker, centrally acting beta blocker
–– Increased mortalityIncreased mortality
RecentRecentAngiotensinAngiotensin--AldosteroneAldosterone Antagonist TrialsAntagonist Trials
•• AngiotensinAngiotensin receptor blockersreceptor blockers–– OPTIMAAL : OPTIMAAL : losartanlosartan in postin post--MI LV dysfunctionMI LV dysfunction–– ValsartanValsartan : Val: Val--HeFTHeFT, VALIANT, VALIANT–– CandesartanCandesartan : CHARM : CHARM programmeprogramme
•• AldosteroneAldosterone antagonistantagonist–– EplerenoneEplerenone : EPHESUS: EPHESUS
Conventional Conventional TxTx(including ACE inhibitors) + (including ACE inhibitors) + ValsartanValsartan 160mg bid160mg bid
Val-HeFT : Valsartan vs. PlaceboValVal--HeFTHeFT : : ValsartanValsartan vs.vs. PlaceboPlacebon=5,010, NYHA II-IV, EF ≤ 40%, 23months
Add Add Valsartan Valsartan 27.5% 27.5% Hospitalization, Improvement of EF, NYHA class, Hospitalization, Improvement of EF, NYHA class, SxSx and Signsand Signs
100
90
80
70
60
00 3 6 9 12 15 18 2721 24
ValsartanValsartan(n=2,511)(n=2,511)
Placebo Placebo (n=2,499)(n=2,499)
P=0.80
Probability of Survival (%)
Months
Probability of Event-free Survival (%)100
90
80
70
60
00 3 6 9 12 15 18 2721 24
ValsartanValsartan(n=2,511)(n=2,511)
Placebo Placebo (n=2,499)(n=2,499)
P=0.009P=0.009
Months
13.3%Risk Reduction P= 0.009
Cohn JN, et al. N Engl J Med 2001;345:1667.
Val-HeFT : Valsartan vs. PlaceboValVal--HeFTHeFT : : ValsartanValsartan vs. Placebovs. Placebon=5,010, NYHA II-IV, EF ≤ 40%, 23months
Combined End Point (Death from Any Cause, Cardiac Arrest with Resuscitation, Hospitalization for Worsening HF, IV Inotropes or Vasodilators)
Valsartan better Placebo better1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.90.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9
RR, 95% CIACEi +, β-blocker -ACEiACEi +, +, ββ--blocker +blocker +ACEi -, β-blocker -ACEi -, β-blocker +
ACEi +, β-blocker -ACEiACEi +, +, ββ--blocker +blocker +ACEi -, β-blocker -ACEi -, β-blocker +
30341610226140
30341610226140
Death
Combined End Point
Cohn JN, et al. N Engl J Med 2001;345:1667.
CV Death, MI, or HF by TreatmentCV Death, MI, or HF by TreatmentCaptoprilCaptopril
Months
Valsartan vs. Captopril: HR = 0.96; P = 0.198
Valsartan + Captopril vs. Captopril: HR = 0.97; P = 0.369
0
0.1
0.2
Pro
babi
lity
of E
ven
t
ValsartanValsartan
ValsartanValsartan + + CaptoprilCaptopril
VALIANTVALIANT
0.4
0.3
0 6 12 18 24 30 36
Pfeffer, McMurray, Velazquez, et al. N Engl J Med 2003;349
Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity
CHARM Programme3 component trials comparing candesartan to
placebo in patients with symptomatic heart failure
CHARMAlternative
CHARM Added
CHARMPreserved
n=2028LVEF ≤40%
ACE inhibitor intolerant
n=2548LVEF ≤40%
ACE inhibitor treated
n=3025LVEF >40%
ACE inhibitor treated/not treated
Primary outcome for Overall Programme: All-cause deathPrimary outcome for each trial: CV death or CHF hospitalisation
Pfeffer et al, Lancet 2003
CHARM-AlternativePrimary outcome, CV death or CHF hospitalisation
50%
Placebo
Candesartan
HR 0.77 (95% CI 0.67-0.89), p=0.0004Adjusted HR 0.70, p<0.0001
406 (40%)
334 (33%)40
30
20
10
00 1 2 3 yearsNumber at risk
Candesartan 1013 929 831 434 122Placebo 1015 887 798 427 126
3.5
Granger et al, Lancet 2003
50
Placebo
Candesartan
%
HR 0.85 (95% CI 0.75-0.96), p=0.011Adjusted HR 0.85, p=0.010
483 (37.9%)538 (42.3%)
CHARM-AddedPrimary outcome, CV death or CHF hospitalisation
40
30
20
10
00 1 2 3 yearsNumber at risk
Candesartan 1276 1176 1063 948 457Placebo 1272 1136 1013 906 422
3.5
McMurray et al, Lancet 2003
CHARM-PreservedPrimary outcome, CV death or CHF hospitalisation
Number at riskCandesartan 1514 1458 1377 833 182Placebo 1509 1441 1359 824 195
Yusuf et al, Lancet 2003
0 1 2 3 years3.5
Placebo
Candesartan
HR 0.89 (95% CI 0.77-1.03), p=0.118Adjusted HR 0.86, p=0.051
366 (24.3%)333 (22.0%)
30%
25
20
15
10
5
0
ARBARB’’ss in Heart Failurein Heart Failureesp. esp. valsartanvalsartan & & candesartancandesartan
•• Alternative in patients who are intolerant Alternative in patients who are intolerant to ACE inhibitorsto ACE inhibitors
•• Added to standard therapyAdded to standard therapy
•• Avoid using with both ACE inhibitor and Avoid using with both ACE inhibitor and beta blockers, esp. beta blockers, esp. valsartanvalsartan
EPHESUSEpelerenone
Post-acute myocardial infarction Heart failure Efficacy and
SUrvival Study
All cause mortality
Cardiovascular mortality and hospitalization
Sudden cardiac death
EplerenoneEplerenone can be addedcan be addedto standard therapyto standard therapyin postin post--MI patientsMI patients
Recent clinical trialsRecent clinical trials–– other medical therapeutics other medical therapeutics --
•• NEP inhibitorNEP inhibitor–– omapatrilat(OVERTUREomapatrilat(OVERTURE))
•• AnticytokinesAnticytokines–– EndothelinEndothelin antagonists : antagonists : bosentanbosentan, , enrasentanenrasentan–– TNFTNF--alpha antagonist : alpha antagonist : etanerceptetanercept, , infliximabinfliximab
•• AntiarrhythmicAntiarrhythmic agentagent–– DofetilideDofetilide
•• Calcium channel blockersCalcium channel blockers–– MibefradilMibefradil –– increased mortality by 11%increased mortality by 11%
TNF in heart failureTNF in heart failure
Recent clinical trials using deviceRecent clinical trials using device
•• ICDICD–– MADITMADIT--II, SCDII, SCD--HeFTHeFT
•• RCT(ResynchronizationRCT(Resynchronization therapy) or therapy) or bibi--ventricular pacingventricular pacing–– MIRACLE, COMPANIONMIRACLE, COMPANION
CRTCardiac Resynchronization Therapy
COMPANIONCOMPANION
•• Pharmacological therapy plusPharmacological therapy plus–– CRTCRT mortalitymortality 23.7 %23.7 %–– CRT + ICDCRT + ICD mortalitymortality 43.4 %43.4 %
CRT : Cardiac Resynchronization TherapyCRT : Cardiac Resynchronization TherapyICD :ICD : Implantable cardioverterImplantable cardioverter defibrillatordefibrillator
Treatment of Heart FailureTreatment of Heart FailureTreatment of Heart Failure
Stage BStage B
Stage CStage C
Stage DStage D
InotropesSpecialized therapyTransplantationMechanical assist
InotropesSpecialized therapyTransplantationMechanical assist
Secondary preventionModification of physical activitySecondary preventionModification of physical activity
ACEIBeta blockersICD in proper Pt
ACEIBeta blockersICD in proper Pt ACEI, BB
Diuretics, DigoxinARB’s, aldosteoneAntagonistConsider ICD+CRT
ACEI, BBDiuretics, DigoxinARB’s, aldosteoneAntagonistConsider ICD+CRT
Stage AStage A
Risk controlRisk control
Lessons from Recent HF Clinical TrialsLessons from Recent HF Clinical Trials•• Mortality and morbidity of HF is still high.Mortality and morbidity of HF is still high.
•• Beta blockersBeta blockers–– CarvedilolCarvedilol seems better than seems better than metoprololmetoprolol–– Added benefit with Added benefit with carvedilolcarvedilol even in posteven in post--MI and severe HFMI and severe HF
•• ARBARB’’ss is valuable as an alternative to ACEI intolerant is valuable as an alternative to ACEI intolerant patients or can be added to standard therapy.patients or can be added to standard therapy.
•• CRT(biCRT(bi--ventricular pacing) coupled with ICD is superior ventricular pacing) coupled with ICD is superior to medical therapy alone in selected HF population.to medical therapy alone in selected HF population.
•• More aggressive blockade of More aggressive blockade of neurohormonalneurohormonal or cytokine or cytokine activation is not necessarily beneficial.activation is not necessarily beneficial.
Saturation of Benefit with Incremental Saturation of Benefit with Incremental NeurohormonalNeurohormonalBlockade in Chronic Heart FailureBlockade in Chronic Heart Failure
VAL-HeFTCHARM
Aldosterone antagonists
Potential Therapeutic Target Beyond Potential Therapeutic Target Beyond NeurohormonalNeurohormonalActivationActivation
ICD
CRT