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Heart Failure the present and the future!
Sam Haddad ,MD,FRCPCProfessor of Medicine, University of Ottawa
Ottawa Heart Institute
Heart Failure
• Heart failure is common, yet it is difficult to treat. It presents in many different circumstances in which therapy needs to be individualized.
• About 500.000 Canadian with Heart Failure “5 million Americans”
• HF remains one of the most common reasons for hospital admission, as well as one of the most costly cardiovascular disorders.
• Canada’s average annual in-hospital mortality rate is:– 9.5 deaths/100 hospitalized patients >65 years of age– 12.5 deaths/100 hospitalized patients >75 years of age
• HF patients have a poor prognosis, with an average 1-year mortality rate of 33%
Causes of Left Ventricular Dysfunction
Metabolic
Drugs
Heavy metals
Infections
Connectivetissue diseases Neurologic
diseases
Inheriteddiseases
Otherdiseases
Pressure overload
Volume overload
Restrictivedisease
Primarycardiomyopathy
Coronary artery disease
Stage AHigh Risk for developing
Heart failure
Stage BAsymptomatic LV dysfunction
Stage CPast or current
Symptoms of HF
Stage DEnd-stage HF
Stages of HF: ACC/AHA
Class Isymptoms at activity levels thatwould limit normal individuals
Class IIsymptoms of HF with
ordinary exertionClass III
symptoms of HF with lessthan ordinary exertion
Class IVSymptoms of HF at rest
NYHA Functional Class
DiastolicDysfunction
SystolicDysfunction
HeartFailure
SyndromeDeath
LVH
MI
ObesityDiabetes
HypertensionAbn. Sleep
HypertensionSmoking
LipidsDiabetes
LV Remodels
Time Decades Time Months
A B C D
Evidence-Based Approach to Left Ventricular Dysfunction
ModerateCHF
SevereCHF
MildCHF
ALVD
ALVD=asymptomatic left ventricular dysfunction.
Pre-Heart
Failure
X X X X
Monitor Therapy / Disease Modification
Evidence-Based Approach to Left Ventricular Dysfunction
ModerateCHF
SevereCHF
MildCHF
ALVD
ALVD=asymptomatic left ventricular dysfunction.
Pre-Heart
Failure
Choose Therapy / Monitor Disease Regression
Heart Failure
The Present
Treatment of Heart Failure
Eplerenone in Patients with Systolic Heart Failure and Mild
Symptoms
EMPHASIS-HF
Inclusion Criteria• Inclusion
– > 55 years of age– NYHA functional class II– Ejection fraction < 30% (or, if between 31% and 35%, QRS >130 msec)– Treated with the recommended or maximally tolerated dose of ACE
inhibitor (or an ARB or both) and a beta-blocker (unless contraindicated).– Within 6 months of hospitalization for a cardiovascular reason [or, if no
such hospitalization, BNP > 250 pg/ml or NT-pro-BNP >500 pg/ml (males) or 750 pg/ml (females) ]
• Exclusion– Serum potassium > 5.0 mmol/L– eGFR < 30 ml/min/1.73 m2
– Need for a potassium-sparing diuretic– Any other significant comorbid condition
Disposition of Patients
1373 Randomizedto placebo
2737 Randomized
1364 Randomizedto eplerenone 25-50 mg/d
4 did not start study drug17 lost to follow up
4 did not start study drug15 lost to follow up
EMPHASIS-HF Investigators (29 countries, 278 sites)
Median follow-up time 21 months, 4783 patient-years of follow-up
Prepared by Pfizer in response to an unsolicited request – Not for further distribution
Primary Endpoint Cardiovascular Death or Hospitalization for HF
*Unadjusted HR 0.66; 0.56, 0.78; p<0.0001
0
10
20
30
40
50
0 1 2 3
Prim
ary
Endp
oint
: Cu
mul
ativ
e K-
M R
ate
(%)
Years from Randomization
Eplerenone
HR [95% CI] = 0.63 [0.54, 0.74] P < 0.0001
Placebo
No. at RiskPlacebo 1373 848 512 199 Eplerenone 1364 925 562 232
356 (25.9)
249 (18.3)
Prepared by Pfizer in response to an unsolicited request – Not for further distribution
Mortality From Any Cause
*Unadjusted HR, 0.78; 0.64, 0.95; p=0.01
0
10
20
30
40
0 1 2 3
Years from Randomization
All-
Cau
se M
orta
lity:
C
umul
ativ
e K
-M R
ate
(%)
Eplerenone
HR [95% CI] = 0.76 [0.62, 0.93] P = 0.0081
Placebo
No. at RiskPlacebo 1373 947 587 242 Eplerenone 1364 972 625 269
213 (15.5)
171 (12.5)
Prepared by Pfizer in response to an unsolicited request – Not for further distribution
Hospitalization From Any Cause
*Unadjusted HR, 0.78; 0.69, 0.89; p <0.0001
0
10
20
30
40
50
60
70
0 1 2 3
All-C
ause
Hos
pita
lizat
ion:
Cu
mul
ativ
e K-
M R
ate
(%)
Years from Randomization
Eplerenone
HR [95% CI] = 0.77[0.67, 0.88] P < 0.0001
Placebo
No. at RiskPlacebo 1373 742 403 146 Eplerenone 1364 795 451 179
491(35.8)
408 (29.9)
Prepared by Pfizer in response to an unsolicited request – Not for further distribution
Heart Failure Hospitalization
0
10
20
30
40
0 1 2 3
Hea
rt F
ailu
re H
ospi
taliz
atio
n:
Cum
ulat
ive
K-M
Rat
e (%
)
Years from Randomization
Eplerenone
HR [95% CI] = 0.58 [0.47, 0.70] P < 0.0001
Placebo
No. at RiskPlacebo 1373 848 512 199 Eplerenone 1364 925 562 232
*Unadjusted HR, 0.61; 0.50, 0.75; p <0.0001
253 (18.4)
164 (12.0)
Prepared by Pfizer in response to an unsolicited request – Not for further distribution
Conclusions
• The addition of eplerenone to recommended treatment resulted in a
– 37% reduction in the rate of the composite outcome of death from cardiovascular causes or hospitalization for heart failure.
– 24% reduction in the rate of death from any cause– 23% reduction in the rate of hospitalization from any cause– 42% reduction in the rate of hospitalization for heart failure
• The effect of eplerenone on the primary outcome was consistent across all prespecified subgroups.
• NNT – To prevent one patient experiencing the primary endpoint, per year of follow
up, is 19– To postpone one death, per year of follow up, is 51
Heart Rate
Background
• Elevated heart rate is associated with poor outcome in a number of cardiovascular conditions including heart failure
• Heart rate remains elevated in many heart failure patients despite treatment with beta-blockers
Systolic Heart failure treatment withthe If inhibitor ivabradine Trial
SHIFT Primary Objective
To evaluate whether the If inhibitor ivabradineimproves cardiovascular outcomes in patients with:
1. Moderate to severe chronic heart failure2. Left ventricular ejection fraction ≤35%3. Heart rate ≥70 bpm in sinus rhythm4. Best recommended therapy
• ≥18 years
• Class II to IV NYHA heart failure
• Ischaemic/non-ischaemic aetiology
• LV systolic dysfunction (EF ≤35%)
• Heart rate ≥70 bpm
• Sinus rhythm
• Documented hospitalization for worsening heart failure ≤ 12 months
Inclusion Criteria
Swedberg K et al. Eur J Heart Fail 2010;12:75-81
Study Design
HR and tolerabilityIvabradine 5 mg bid
Matching placebo, bid
Every 4 monthsD0 D14 D28 M4
Ivabradine 7.5/5/2.5 mg bid according to
3.5 years
Screening7 to 30 days
Swedberg K et al. Eur J Heart Fail 2010;12:75-81
Chronic Heart Failure Background Treatment
89 9184
61
22
3
90 9183
59
22
40
10
20
30
40
50
60
70
80
90
100
Beta-blockers ACEIs and/orARBs
Diuretics Aldosterone antagonists
Digitalis ICD/CRT
Patients (%)IvabradinePlacebo
Swedberg K et al. Lancet 2010;376(9744):875-85
0
10
20
30
40
50
60
70
80
90
100
BB at randomization
At least 50% target daily dose
Target daily dose
89
56
26
IvabradinePlacebo89
56
26
Patients (%)
Background Beta-blocker Treatment
Swedberg K et al. Lancet 2010;376(9744):875-85
Mean Heart Rate Reduction
(70% of patients on ivabradine 7.5 mg bid)
0 2 weeks 1 4 8 12 16 20 24 28 32Months
90
80
70
60
50
67
7575
80
64
Heart rate (bpm)
Placebo
Ivabradine
Swedberg K et al. Lancet 2010;376(9744):875-85
0 6 12 18 24 30
30
20
10
0
Hospitalization for HF
26%Placebo
Ivabradine
HR = 0.74 (0.66–0.83)P < 0.0001
Months
Cumulative frequency (%)
Swedberg K et al. Lancet 2010;376(9744):875-85
Death from Heart Failure
26%
0 6 12 18 24 30
10
5
0
HR = 0.74 (0.58–0.94) P = 0.014
Placebo
Ivabradine
Months
Cumulative frequency (%)
Swedberg K et al. Lancet 2010;376(9744):875-85
• Ivabradine significantly reduces major risks associated with heart failure:
–18% reduction in CV death or hospital admission for worsening HF
–26% reduction in death from heart failure
–26% reduction in hospital admission for worsening heart failure
• Benefits are apparent early, are consistent in predefined subgroups, and have been demonstrated on top of recommended therapy
• Treatment is well tolerated
Conclusion
Swedberg K et al. Lancet 2010;376(9744):875-85
Neprilysin
• a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin.
• Inhibition of neprilysin increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling.
The Rise and Fall of Omapatrilat
inhibits both neutral endopeptidase (NEP) and angiotensin converting enzyme.
Overture: Hear FailureOctave: Hypertension
The rates of angioedema were much higher in blacks, 5.54% forOmapatrilat and 1.62% for enalapril.
Background
To compare the angiotensin receptor–neprilysin inhibitor LCZ696 with enalaprilin patients who had heart failure with a reduced ejection fraction.
In previous studies, enalapril improved survival in such patients.
Methods
In this double-blind trial, 8442 patients with class II, III, orIV heart failure and an ejection fraction of 40% or less randomly assigned to receive either LCZ696 (at a dose of 200 mg twice daily)or enalapril (at a dose of 10 mg twice daily), in addition torecommended therapy.
The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designedto detect a difference in the rates of death from cardiovascular causes.
Screening
Primary and Secondary Outcomes
In heart failure with reduced ejection fraction, when compared with recommended doses of enalapril:LCZ696 was more effective than enalapril in . . .• Reducing the risk of CV death and HF hospitalization• Reducing the risk of CV death by incremental 20%• Reducing the risk of HF hospitalization by incremental 21%• Reducing all-cause mortality by incremental 16%• Incrementally improving symptoms and physical limitationsLCZ696 was better tolerated than enalapril . . .• Less likely to cause cough, hyperkalemia or renal impairment• Less likely to be discontinued due to an adverse event• More hypotension, but no increase in discontinuations• Not more likely to cause serious angioedema
PARADIGM-HF: Summary of Findings
10%
Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current Inhibitors of the
Renin-Angiotensin System
20%
30%
40%
ACEinhibitor
Angiotensinreceptorblocker
0%
% D
ecre
ase
in M
orta
lity
18%
20%
Effect of ARB vs placebo derived from CHARM-Alternative trialEffect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial
Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial
Angiotensinneprilysininhibition
15%
Heart Failure
The Future!
Heart Failure, The Future!
• Devices and Transplantation• Stem cell treatment• Genetic, Personal medicine• Prevention
Devices in HF Care
HMII vs REMATCH
Proposed LVAD Candidate “Triggers”
• Cardiogenic shock “temp device”• Refractory Ventricular Arrhythmia • Need for inotrope more than 24 hrs!• Refractory heart failure symptoms• Multiple admissions• Others
Future directions
• By 2050 there would be >1 million new cases per year in the United States.
• While the war to reduce the toll of CVD, broadly considered, must continue, the battle to control HF has now moved to the center stage of this war.
• This battle will be long and difficult, and because the “enemy has many faces” it will have to be fought simultaneously on multiple fronts and with many different weapons.
Braunwald, JACC, HF 2013
Prevention
• Childhood or adolescence• Target high risk group “Genomic profiles”• High risk per Markers “ex NT-proBNP and
cardiac-specific hs Tn• Multi-markers panel