Transcript CHF Trials Update and Surrogate Endpoints

Heart Failure
Liviu Klein MD, MS
http://www.cardiologyfellows.northwestern.edu/cculectures
Outline
• Definition
• Pathophysiology
• Epidemiology (prevalence, incidence, trends)
• Epidemiology (mortality and associated morbidity)
• Risk factors
• Heart failure stages and treatment
• Advanced heart failure and transplant
Heart Failure Definition
• A complex clinical syndrome that can result from any
structural or functional cardiac disorder that impairs the
ability of the ventricle to fill with or eject blood.
• Cardinal manifestations are dyspnea and fatigue (which
may limit exercise tolerance), and fluid retention (which
may lead to pulmonary congestion and peripheral edema).
• Both abnormalities can impair the functional capacity and
quality of life of affected individuals, but they do not
necessarily dominate the clinical picture at the same time.
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
Heart Failure Definition
• Some patients have exercise intolerance but little evidence
of fluid retention, whereas others complain primarily of
edema and report few symptoms of dyspnea or fatigue.
• Because not all patients have volume overload at the time
of initial or subsequent evaluation, the term “heart failure”
is preferred over the older term “congestive heart failure.”
• One line definition: LV EDP > 12 mmHg
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
Outline
• Definition
• Pathophysiology
• Epidemiology (prevalence, incidence, trends)
• Epidemiology (mortality and associated morbidity)
• Risk factors
• Heart failure stages and treatment
• Advanced heart failure and transplant
Heart Failure Pathophysiology
Cardiac injury
Increased load
Reduced systemic perfusion
Activation of RAS, SNS, and cytokines
Altered gene
expression
Growth and
remodeling
Ischemia and
energy depletion
Apoptosis
Necrosis
Cell death
Direct
toxicity
Progression of Heart Failure
Coronary artery disease Cardiomyopathic factors
Atrial Fibrillation
Hypertension
Valvular disease
Left ventricular
injury
Diabetes
Pathologic
Remodeling
Death
Low ejection
fraction
Heart Failure Clinical Stages
NORMAL
Asymptomatic
LV Dysfunction
No symptoms
Normal exercise
Normal LV fxn
No symptoms
Normal exercise
Abnormal LV fxn
Compensated
No symptoms
Exercise
Abnormal LV fxn
Decompensated
Symptoms
Exercise
Abnormal LV fxn
Refractory
Symptoms not
controlled
with treatment
Outline
• Definition
• Pathophysiology
• Epidemiology (prevalence, incidence, trends)
• Epidemiology (mortality and associated morbidity)
• Risk factors
• Heart failure stages and treatment
• Advanced heart failure and transplant
Prevalence of Heart Failure
Source: CDC/NCHS and NHLBI.
Prevalence of Heart Failure
Western Europe
Eastern Europe
Former Soviet Union
North America
Japan
South America
Asia
Absolute Numbers
(millions patients)
Rate
(per thousand)
5.3
1.3
5.6
5.2
2.4
?
?
14
13
19
18
19
?
?
Murray CJL, Lopez AD. Global health statistics: a compendium of incidence, prevalence and mortality estimates
for over 200 conditions. Geneva: World Health Organization; 1996.
Sys/Diastolic Dysfunction Prevalence
Redfield MM et al. JAMA. 2003; 289: 194-202.
Systolic Dysfunction Prevalence
Wang TJ et al. Ann Intern Med. 2003; 138: 907-916.
4%
Temporal Changes in Incidence
Roger VL et al. JAMA. 2004; 292: 344-351.
Outline
• Definition
• Pathophysiology
• Epidemiology (prevalence, incidence, trends)
• Epidemiology (mortality and associated morbidity)
• Risk factors
• Heart failure stages and treatment
• Advanced heart failure and transplant
Cardiovascular Deaths
300,000 death/yr
Survival according to NYHA Class
Placebo
Conventional
therapies (diuretics,
digoxin)
NYHA Class IV
(CONSENSUS)
Mortality (%)
100
90
80
70
60
50
40
30
20
10
0
NYHA Class II–III
(SOLVD Treatment
Trial)
0
6
12
18
24
Months
30
CONSENUS Trial Study Group. N Engl J Med. 1987; 316: 1429-1435.
The SOLVD Investigators. N Engl J Med. 1991; 325: 293-298.
The SOLVD Investigators. N Engl J Med. 1992; 327: 685-690.
NYHA Class I–II
(SOLVD Prevention
Trial)
36
42
48
Trends in Heart Failure Mortality
Roger VL et al. JAMA. 2004; 292: 344-351.
Mode of Death by NYHA Class
NYHA II
NYHA III
Other 15%
NYHA IV
Other 11%
Other 24%
HF
12%
SD
64%
HF
26%
MERIT-HF Study Group. Lancet. 1999; 353: 2001-2007.
SD
59%
SD
33%
HF
56%
Heart Failure Hospitalizations
Source: CDC/NCHS.
Heart Failure Hospitalizations
Hospitalizations/100,000 Population
250
1 mil hospitalizations/ year
200
65+ years
150
100
45-64 years
50
0
1970
1975
1980
1985
Year
Rosamond W et al. Circulation. 2008; 115: e2-e122.
1990
1995
393.5
254.8
Hypertensive
Disease
Rosamond W et al. Circulation. 2008; 115: e2-e122.
27.9
Total CVD*
59.7
Congestive
Heart Failure
56.8
Stroke
142.1
Coronary
Heart
Disease
450
400
350
300
250
200
150
100
50
0
Heart
Disease
Billions of Dollars
Estimated Direct and Indirect Costs
Heart Failure Direct Costs
Drugs/Medical
Durables
($3 billion) 10%
Physicians/Other
Providers
($2 billion) 7%
Home Health
($3.0 billion) 10%
Total Expenditure (direct costs) = $29 billion
Rosamond W et al. Circulation. 2008; 115: e2-e122.
Hospital/Nursing Home
($21 billion) 73%
Outline
• Definition
• Pathophysiology
• Epidemiology (prevalence, incidence, trends)
• Epidemiology (mortality and associated morbidity)
• Risk factors
• Heart failure stages and treatment
• Advanced heart failure and transplant
Outline
• Definition
• Pathophysiology
• Epidemiology (prevalence, incidence, trends)
• Epidemiology (mortality and associated morbidity)
• Risk factors
• Heart failure stages and treatment
• Advanced heart failure and transplant
New Classification of Heart Failure
Stage
Patient Description
A
High risk for developing heart • Hypertension
• CAD
failure (HF)
B
Asymptomatic HF
C
Symptomatic HF
D
Refractory
end-stage HF
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
•
•
•
•
•
•
•
•
•
Diabetes mellitus
Family history of cardiomyopathy
Previous MI
LV systolic dysfunction
Asymptomatic valvular disease
Known structural heart disease
Shortness of breath and fatigue
Reduced exercise tolerance
Marked symptoms at rest despite maximal
medical therapy (eg, those who are recurrently
hospitalized or cannot be safely discharged from
the hospital without specialized interventions)
Management of Chronic HF
•
•
•
•
•
•
Establish diagnosis (BNP, echo)
Determine etiology
Define syndrome (e.g. systolic vs. diastolic)
Correct precipitating factors (NSAIDS, COX2, etc.)
Evaluate and correct ischemia
Initiate chronic therapy
•
•
•
•
Nonpharmacologic (e.g. exercise, tx. of sleep apnea, etc)
Pharmacologic (ACE - I, b - Blockers, ARB, diuretics, digoxin, etc.)
Electrical
Surgical
• Assess response to therapy
Stage C: Symptomatic HF
Class I
• Level A evidence
– Diuretics in patients with fluid retention
– ACE inhibition, unless contraindicated
– Beta blockade in stable patients, unless contraindicated
– Digitalis, unless contraindicated
• Level B evidence
– Withdrawal of drugs known to adversely affect the clinical status of
patients
All Class I recommendations for Stages A and B
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
Diuretics
•
•
•
•
•
Loop diuretics in pts. with CrCl < 30
Torsemide ↓ hospitalizations compared to furosemide
Have to be given bid to avoid rebound Na reabsorbtion
May use thiazides if CrCl > 30
Use combination (e.g. furosemide + thiazide), iv bolus
or iv drips
• Metolazone in refractory HF or in pts. with renal failure.
Should not be used daily.
• Add spironolactone if Cr < 2.5 and K < 5.
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
ACE - I and Mortality in HF
Mortality
Trial
Drug (mean dose)
ACEI
Placebo
RR (95% CI)
CONSENSUS I
Enalapril (18.4 mg)
39%
54%
0.56 (0.34-0.91)
SOLVD (T)
Enalapril (11.2 mg)
35%
40%
0.82 (0.70-0.97)
SOLVD (P)
Enalapril (12.7 mg)
15%
16%
0.92 (0.79-1.08)
SAVE
Captopril (150 mg)*
20%
25%
0.81 (0.68-0.97)
AIRE
Ramipril (1.25-5 mg)†
17%
23%
0.73 (0.60-0.89)
TRACE
Trandolapril (1-4 mg)†
35%
42%
0.78 (0.67-0.91)
SMILE
Zofenopril (7.5-30 mg)†
5%
6.5%
0.75 (0.40-1.11)
21%
25%
0.84
Chronic HF
Post-MI
Totals
* No mean given; target dose
† No
mean given; dose range
ACE Inhibitors
•
•
•
•
•
•
•
Most pts. tolerate ACE - I.
ACE - I improve symptoms immediately (days).
Pts. should not be “too dry” (no orthostatic ↓ BP).
If ↓ BP, check for orthostatic changes. If none, ACE - I OK.
Low BP and CRF are not CI for ACE - I.
If BUN/ Cr are raising, adjust the diuretic dose.
Low BP, low Na, renal dysfunction: low dose, short acting
ACE - I, titrate to target dose or the highest dose tolerated.
• Low vs. high dose ACE - I: difference in outcomes.
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
Beta - Blockers in HF
Study
All - cause
mortality
All - cause
hospitalizations
CIBIS II 1 (bisoprolol)
2647 pts. NYHA III - IV
 34%
(p < 0.0001)
 20%
(p = 0.0006)
MERIT – HF 2 (metoprolol XL)
3991 pts. NYHA II - IV
 34%
(p = 0.0062)
 8.6%
(p = 0.005)
COPERNICUS 3 (carvedilol)
2289 pts. NYHA IV
35%
(p = 0.0014)
 15%
(p = 0.0029)
1 CIBIS
II Investigators and Committees. Lancet. 1999; 353: 9-17.
2 MERIT - HF Study Group. Lancet. 1999; 353: 2001-2007.
3 Packer M et al. N Engl J Med. 2001; 344: 1651-1658.
Beta-Blockers: Not Created Equal
Study
BEST1 (bucindolol)
2708 pts. NYHA III - IV
SENIORS2 (nebivolol)
2135 pts. NYHA II - III
1 BEST
All - cause
mortality
All - cause
hospitalizations
 10%
(p < 0.1)
 8%
(p = 0.08)
 12%
(p = 0.21)
Investigators. N Engl J Med. 2001; 344: 1659-1667.
2 Flather MD et al.Eur Heart J . 2005; 26: 215-221.
 4%*
(p = 0.47)
*
All-cause mortality/ CV hospitalizations
Beta-Blockers: Not Created Equal ?
COMET: Metoprolol vs. Carvedilol
40
Mortality (%)
Metoprolol IR 50 mg bid
30
Carvedilol 25 mg bid
20
HR 0.83 (0.74 - 0.93)
p = 0.0017
10
0
0
1
2
3
Time (years)
Poole-Wilson PA et al. Lancet. 2003; 362: 7-16.
4
5
Beta - Blockers
• Only bisoprolol, carvedilol and metoprolol succinate.
• Start at low doses, increase every 2 weeks to target dose or the
highest tolerated dose.
• Intermediate vs. high dose: no difference in outcomes.
• Do not start in pts. dependent of inotropic support.
• Can start before hospital discharge in pts. not fluid overloaded.
• Do not stop BB in hospitalized pts. who are on chronic BB
therapy (may worsen HF).
• BB will take 3-6 months to improve symptoms.
• Low BP and severe HF are not CI for BB.
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
Time Course of Changes in LV EF
Ejection Fraction
0.40
Standard Therapy
Metoprolol
p < 0.0001
0.35
p = 0.013 for metoprolol vs. standard
therapy
0.30
p < 0.05
0.25
0.20
Baseline
Day 1
1 Mo
3 Mo
Hall SA et al. J Am Coll Cardiol. 1995; 25: 1154-1160.
Baseline
Day 1
1 Mo
3 Mo
Which First: ACE or BB?
Death/Hospitalization
Willenheimer R et al. Circulation.. 2005; 112: 2426-2430.
All-cause mortality
SCD/All-cause Mortality with First
Bisoprolol Compared with Enalapril
End point
HR (95% CI)
p
Monotherapy phase
12 months
End of study
0.50 (0.21-1.16)
0.54 (0.29-1.00)
0.84 (0.51-1.38)
0.107
0.049
0.487
0.72 (0.42-1.24)
0.69 (0.46-1.02)
0.88 (0.63-1.22)
0.24
0.06
0.44
Sudden death
All-cause mortality
Monotherapy phase
12 months
End of study
Willenheimer R. World Congress of Cardiology 2006; September 6, 2006; Barcelona, Spain.
Beta - Blockers
Angiotensin Receptor Blockers
• Combination ARB + ACE - I + Beta - Blockers is safe.
• No mortality benefit when ARB is added to ACE - I.
• ARB are useful in pts. who are ACE intolerant.
• ARB could be added to ACE - I for symptomatic
improvement.
• Triple RAAS blockade (ACE - I, ARB, aldosterone
blockers) should not be used (Hyper K).
CHARM Program
3 component trials comparing candesartan to
placebo in patients with symptomatic HF
CHARMAlternative
CHARMAdded
CHARMPreserved
n=2028
n=2548
n=3025
LVEF < 40%
ACE inhibitor
intolerant
LVEF < 40%
ACE inhibitor
treated
LVEF > 40%
ACE inhibitor
treated/not treated
Primary outcome for each trial: CV death or HF hospitalization
Primary outcome for overall program: All-cause death
Pfeffer MA et al. Lancet. 2003; 362: 759-767.
Effect of Candesartan on Mortality
and HF Hospitalizations
Cardiovascular death/
HF hospitalizations
All-cause mortality
Alternative
Added
Preserved
Overall
0.7
0.8
0.9
Pfeffer MA et al. Lancet. 2003; 362: 759-767.
1.0
1.1
1.2
0.6
0.7
0.8
0.9
1.0
1.1
1.2
Aldosterone Antagonists:
Spironolactone
1.00
0.95
30% Relative risk reduction
0.90
Mortality
0.85
0.80
0.75
Spironolactone
0.70
0.65
0.60
p < 0.001
0.55
Placebo
0.50
0.45
0.00
0
3
6
9
12
15
18
Months
Pitt B et al. N Engl J Med. 1999; 341; 709-715.
21
24
27
30
33
36
Eplerenone post MI: Mortality
22
20
18
16
14
Placebo
Eplerenone
Cumulative 12
Incidence (%)
10
8
RR = 0.85 (95% CI, 0.75–0.96)
P = 0.008
6
4
2
0
0
3
6
9
12 15 18 21 24 27 30 33 36
Months Since Randomization
Pitt B et al. N Engl J Med. 2003; 348: 1309-1315.
Eplerenone and SCD post MI
All Patients
10
9
Cumulative Incidence (%)
Patients with Baseline
Ejection Fraction 30%
16
14
8
12
7
Placebo
Placebo
10
6
5
8
Eplerenone
Eplerenone
4
6
3
1
2
0
0
0
3
6
9
1
2
1
5
1
8
2
1
2
4
2
7
3
0
RR = 0.67 (95% CI, 0.50–0.91)
P = 0.009
4
RR = 0.79 (95% CI, 0.64–0.97)
P = 0.03
2
3
3
3
6
0
3
6
9
12
Months Since Randomization
Pitt B et al. N Engl J Med. 2003; 348: 1309-1315.
15
18
21
24
27
30
33 36
Sudden Death Post MI in VALIANT
Solomon SD et al. N Engl J Med. 2005; 352: 2581-2588.
Eplerenone and SCD Post MI
Pitt B et al. J Am Coll Cardiol. 2005; 46: 425-430.
Risk of Death and Serum Digoxin
Hazard Ratio
(Dig versus Placebo)
1.5
1.4
Women
All
Men
1.3
1.2
1.1
1.04
1.0
0.9
0.8
0.7
0.6
0.5
Undetectabl
< 0.5
e
0.5
0.8
1.0
1.2
1.4
1.6
1.8
Serum Digoxin Concentration (ng/ml)
Adams KF et al. J Am Coll Cardiol. 2005; 46: 505-510.
2.0
Digoxin: Mortality/ Hospitalizations
Total mortality/
hospitalization
HF mortality/
hospitalizations
All pts. EF< 45%
0.94 (0.88 - 1.00)
0.69 (0.63 - 0.76)
EF < 25%
0.84 (0.76 - 0.93)
0.84 (0.76 - 0.93)
EF 25 - 45%
0.99 (0.91 - 1.07)
0.74 (0.66 - 0.84)
EF > 45%
1.04 (0.88 - 1.23)
0.72 (0.53 - 0.99)
NYHA I/ II
0.96 (0.89 - 1.04)
0.70 (0.62 - 0.80)
NYHA III/ IV
0.88 (0.80 - 0.97)
0.65 (0.57 - 0.75)
CTR ≤ 55%
CTR > 55%
0.98 (0.91 - 1.06)
0.85 (0.77 - 0.94)
0.71 (0.63 - 0.81)
0.65 (0.57 - 0.75)
DIG Investigators. N Engl J Med. 1997; 336: 525-532.
* At 24 months
ISDN – Hy in African Americans
Taylor AL et al. N Engl J Med. 2004; 351: 2049-2057.
Hy – ISDN and NO Genotype
NOS3 exon 7
genotype
GRACE
whites
GRACE
blacks
A-HeFT
Asp-Asp (%)
14
2
1
Asp-Glu (%)
45
31
20
Glu-Glu (%)
41
67
79
McNamara DM et al. Heart Failure Society of America 2005 Annual Scientific Meeting; September 18-21, 2005;
Boca Raton, FL.
Primary End-point in A-HeFT
Parameter
Placebo
ISDNhydralazine
p
Glu-Glu
-0.22
0.18
0.051
Heterozygous or Asp-Asp
0.29
0.38
0.82
Glu-Glu
-0.08
0.43
0.046
Heterozygous or Asp-Asp
0.58
0.61
0.93
Genotype subset (treatment impact
on composite score)
Genotype subset (treatment impact
on composite's QOL component)
McNamara DM et al. Heart Failure Society of America 2005 Annual Scientific Meeting; September 18-21, 2005;
Boca Raton, FL.
ICD for Primary Prevention
• Patients with heart failure due to severe LV
systolic dysfunction (EF < 30%) with class II
and III symptoms, with survival > 12 months.
• At least 40 days post MI, > 3 months for NICM.
SCD-HeFT Trial: Survival
.4
Mortality
.3
HR
97.5% Cl
P
Amiodarone vs
Placebo
1.06
0.86-1.30
0.53
ICD vs Placebo
0.77
0.62-0.96
.007
†22%
.2
†17%
Amiodarone
.1
0
ICD Therapy
Placebo
0
6
12
18
24
30
36
Months of Follow-Up
Bardy GH et al. N Engl J Med. 2005; 352: 225-231.
42
48
54
60
CRT: Who Should Get It?
• Patients with heart failure due to severe
LV systolic dysfunction (EF < 35%) with
class III and IV symptoms, in spite of
adequate and maximum medical therapy.
• QRS duration of 120 ms.
• Responders?
CARE-HF: All-cause Mortality or
Unplanned CVD Hospitalizations
Event-free Survival
1.00
HR 0.63 (95% CI 0.51 to 0.77)
0.75
CRT
0.50
P < .0001
Medical
Therapy
0.25
0.00
0
500
Cleland JGF et al. N Engl J Med. 2005; 352: 1539-1549.
1000
1500 Days
CARE-HF: All-Cause Mortality
Event-free Survival
1.00
HR 0.64 (95% CI 0.48 to 0.85)
0.75
CRT
P = .0019
0.50
Medical
Therapy
0.25
0.00
0
500
Cleland JGF et al. N Engl J Med. 2005; 352: 1539-1549.
1000
1500 Days
Recommendation for Diastolic HF
• Control of systolic and diastolic BP.
• Control ventricular rate in pts. with A Fib.
• Diuretics to control pulmonary and peripheral edema.
• Anticoagulation in pts. with A Fib.
• Coronary revascularization in pts. with CAD and ischemia.
• Restoration of sinus rhythm in pts. with A Fib.
• Addition of Beta - Blockers, ACE - I, ARB, or CCB to control HTN.
• ACE –Inhibitors, ARBs, digoxin to minimize HF symptoms.
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
Perindopril for Diastolic HF
Cleland JGF et al. Eur Heart J. 2006; 27: 2338-2346.
Digoxin for Diastolic HF?
Ahmed A et al. Circulation. 2006; 114: 397-404.
Candesartan For Diastolic HF
Cardiovascular death/
HF hospitalizations
All-cause mortality
Alternative
Added
Preserved
Overall
0.7
0.8
0.9
1.0
Pfeffer MA et al. Lancet. 2003; 362: 759-767.
1.1
1.2
0.6
0.7
0.8
0.9
1.0
1.1
1.2
Stage D: End-stage HF
Class I
• Level A evidence
– Refer patient to specialist in HF management
• Level B evidence
– Closely watch for and control fluid retention
– Refer eligible patients for cardiac transplantation, LVAD
All Class I recommendations for Stages A- C
Hunt SA et al. J Am Coll Cardiol. 2005; 46: e1-e86.
LVADs as Destination Therapy
Lietz K et al. Circulation. 2007; 116: 497-505.
Heart Transplants Reported by Year
Taylor DO et al. J Heart Lung Transplant 2006; 25: 869-879.
Adult Heart Transplant Survival
100
Survival (%)
80
60
1982-1988 (N=9,071)
1989-1993 (N=17,685)
1994-1998 (N=18,758)
1999-6/2004 (N=16,227)
40
20
Average: 1982-1988: 8.2 years; 1989-1993: 9.7 years; 1994-1998: 10.2 years
0
0
1
2
3
4
5
6
Years
Taylor DO et al. J Heart Lung Transplant 2006; 25: 869-879.
7
8
9
10
11
12
CONCLUSIONS: Chronic HF
• STAGE A (HTN, CAD or DM):
– Routine: ACE-I/ARB; selected pts. BB, statin, antiplatelets
• STAGE B (Asymptomatic structural heart disease):
– Routine: ACE-I/ARB, BB; selected pts. statin, antiplatelets
• STAGE C (Symptomatic HF and low EF):
– Routine: ACE-I/ARB, BB, Aldo blockers, diuretics, digoxin
– Selected pts. CRT, ICD, Hy-ISDN
• STAGE C (Symptomatic HF and preserved EF):
– Consider ACE-I/ARB, digoxin ?, BB, CCB, Aldo blockers.
• STAGE D (End-stage HF):
– Referral to HF program for LVAD, OHT.
Paradigm for Management of HF
Treat Congestion:
Diuretics
Slow Disease Progression:
ACE – I /ARB
Sudden Death:
BB
BB
Aldo bloc.
Aldo bloc.
ICD
Treat Residual Symptoms:
Digoxin
ARB
Cardiac Resynchronization
Therapy (CRT)
Advanced Disease:
LVAD
OHT
Heart Failure
The future is here….