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