Download Clinical Concept of Heart Failure

Clinical Concept of Heart Failure
Mihai Gheorghiade MD, FACC
Professor of Medicine and Surgery
Director of Experimental Therapeutics
Center for Cardiovascular Innovation
Northwestern University Feinberg School of Medicine
FDA’s View -Treat the Disease instead
of the Condition
“Heart Failure is not a disease and we should no
longer approve drugs for a heterogeneous broad
population, but for a well defined sub-population
where we can demonstrate a marked benefit”
Dr. Stephen Grant
Deputy Director, Division of Cardiovascular
Renal Products, CDER
ACC/AHA 2009 Guideline:
Classification of HF
Stage
Patient Description
A
High risk for(60mil.) ••
•
developing HF
HTN
CAD
Diabetes mellitus
B
C
D
MI
Asymptomatic HF •• Previous
LV systolic dysfunction
• Asymptomatic valvular disease
10 mil.
• Known structural heart disease
Symptomatic HF
• Shortness of breath and fatigue
• Reduced exercise tolerance
5 mil.
• Marked symptoms at rest despite
Refractory
maximal medical therapy (eg, those who are
end-stage HF(200000) recurrently hospitalized or cannot be safely
discharged from the hospital without specialized
interventions)
Hunt SA et al. J Am Coll Cardiol. 2009.
Congestive Heart Failure
• Congestive heart failure (CHF) is a lifethreatening condition in which the heart
isn't able to pump enough blood to the rest
of the body. The failing heart continues to
work, but not as efficiently as it should.
Many conditions that lead to congestive
heart failure can't be reversed, but heart
failure can often be treated with
medications and lifestyle changes.
Case Study
•
•
•
•
51 year-old Elecrophysiologist
Functional Class III for 6 months
BP 90/60 mmHg; PCWP 30 mmHg; LVEF 10%
Angiogram: no significant coronary disease; MRI: no
hyper-enhancement (no scar tissue)
• Receiving: furosemide, digoxin, enalapril
• Started on carvedilol 3.125 mg BID that was titrated to
25 mg BID in addition to micro and macronutrients
• 6 months later:
– EF 60%
– Functional Class I
Bruce
Bruce H
H AJC
AJC 2005
2005
Improve HF
Viable but Dysfunctional Myocardium:
Possibility for Recovery
Etiologic Factors
Ischemia/Hibernation
Neurohormones (e.g. NE)
Myocyte
Cytokines (e.g. TNF a)
Hemodynamics
Metabolic
Gheorghiade M. JACC 2009
Metabolism Needs
The human heart weighs between 200-425 g
This relatively small mass uses more energy, in the form of
adenosine triphosphate (ATP), than any other organ
It pumps 5 liters of blood per minute, 7200 liters per day, and
over 2.6 million liters per year
Over 6 kilograms of ATP is hydrolyzed by the heart daily
undergo constant turnover and rebuilding.
Every 30 days, an entire heart itself is reconstructed with
brand new protein components
Soukoulis et al JACC 2010
Chronic Heart Failure
HOSPITALIZED
• >3 million admissions in
US
• Cardiac injury (+troponin)
• Rapid changes in lab
values
• Mortality and re
hospitalization as high as
15% and 30%,
respectively, within 60-90
after d/c
• Event rate has not
changed in the last decade
OUTPATIENTS
• Prevalence of 6 million
(Stage C and D AHA/ACC)
• Very abnormal, but
relatively stable lab values
• Mortality <5% annually in
clinical trials
• Decreased morbidity and
mortality in last two
decades
• Death often sudden
Hospitalizations for HF
• Worsening chronic heart failure (HF):80% of
all admissions*
*The
majority managed by non cardiologist
• Acute de novo heart failure (diagnosed for
the first time) :15%
• Advanced/end-stage/refractory HF:5%
Gheorghiade et al Circulation 2005
Heart Failure Hospitalizations
EVEREST - HHF
TRILOGY - ACS
Both registries and clinical trials highlight the unmet
need in new therapies for patients hospitalized for heart failure.
Clinical
Characteristics of HHF Patients
Data on 200,000 US patients
Median age (years)
75
Hx of Atrial
Fibrillation
30%
Women
>50%
Renal abnormalities
30%
Hx of CAD
60%
SBP >140 mm Hg
50%
Hx of Hypertension
70%
SBP 90-140 mm Hg
45%
Hx of Diabetes
40%
SBP <90 mm Hg
5%
Gheorghiade et al JACC 2013;61:391-403.
Admission Systolic BP and Outcomes in Hospitalized
Patients With HF: An OPTIMIZE-HF Analysis
Characteristic % (SD)
Mean Age, y
≤119
Admission SBP mmHg
120-139
140-161
≥161
(n=12,252) (n=12,096) (n=12,099) (n=12,120)
72.9 (14.0) 74.0 (13.5) 73.8 (13.6) 72.1 (14.6)
Mean EF (%)
33.3 (17.4) 37.8 (17.6) 40.9 (17.1) 44.4 (16.5)
Ischemic Etiology
50.7
48.8
44.1
39.2
HTN Etiology
13.4
18.1
25.4
34.8
Serum Cr>2 (mg/dl)
20.7
18.0
18.1
21.5
Mean Wt change (kg)
-2.45 (5.00) -2.68 (4.82)-2.60 (4.64)-2.42 (4.62)
Edema Admission
63.9
65.1
65.6
63.9
Total mortality in-hospital
7.2
3.6
2.5
1.7
Total mortality 60-90d
14.0
8.4
6.0
5.4
Readmission
30.6
29.9
30.3
27.6
Mean LOS, days
6.5 (6.6)
5.7 (5.3)
5.4 (5.0)
5.1 (4.8)
Gheorghiade M et al. JAMA. 2008;299:2656-66
Hibernating Myocardium
In an experimental study of short-term hibernation, dobutamine infusion resulted in
myocardial infarction (right) when subendocardial blood flow was further reduced from
0.17 mL/min per gram (right). With and Without indicate with and without infarction.
Reproduced with kind permission of Professor Gerd Heusch, Essen, Germany.
Hospitalization for Heart
Failure(HHF)
• Improving post-discharge
mortality and prevention of
readmissions are the most
important goals for HHF patients.
Treat Beyond Clinical Congestion.
The main reason for admission and readmission among
patients
Although this goal is often accomplished, some patients may
be discharged with high left ventricular filling pressures as
illustrated by high circulating natriuretic peptide levels,
orthopnea, and poor exercise capacity.
A more aggressive strategy to treat “subclinical”
congestion may potentially improve outcomes.
Gheorghiade and Braunwald JAMA 2012
Adopt a Mechanistic Approach to Cardiac Abnormalities.
Heart failure is not a disease, but a manifestation of different
cardiac abnormalities.
Accordingly, an in-depth systematic assessment should be
conducted of cardiac abnormalities (eg, valvular disease,
cardiac dyssynchrony,ischemia).
Gheorghiade and Braunwald JAMA 2011
Pang,Komajda,Gheorghiade EHJ 2010
Treat Noncardiac Comorbidities.
The increasing rates of important non cardiac comorbidities,
including hypertension and renal dysfunction, over
the last decade, highlight the importance of targeting these
conditions in the overall management of HF.
In addition, diabetes, chronic obstructive pulmonary disease,
and sleep apnea may also contribute to this high event rate after
hospitalization.
Gheorghiade and Braunwald JAMA 2011
Augment Use of Underused Agents Known to Decrease
Hospitalizations.
The use of digoxin is on a steep decline and
mineralocorticoid antagonists are underused in patients with
HF in the United States.
DIG trial showed that use of digoxin reduced overall
hospitalization rate by almost 30%,
EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization
and Survival Study in Heart Failure) trial revealed
that compared with placebo, use of eplerenone reduced
all-cause hospitalization by almost 25%.
Gheorghiade and Braunwald JAMA 2011
Results by high-risk patients subgroups: HF
Hospitalization or HF mortality in DIG Trial
% (events/total)
NYHA class III or IV
LVEF <25%
CTR >55%
High risk (either of the
above)
Placebo
Digoxin
40%
(445/1105)
39%
(444/1129)
40%
(465/1170)
36%
(783/2167)
29%
(329/1118)
27%
(304/1127)
29%
(336/1175)
26%
(566/2191)
Absolute
risk
difference
– 11%
– 12%
– 11%
– 10%
Hazard
ratio
(95% CI)
0.65
(0.57–0.75)
0.61
(0.53–0.71)
0.65
(0.57–0.75)
0.66
(0.59–0.73)
P
value
<0.001
<0.001
<0.001
<0.001
Gheorghiade et al, LBCT ESC HF Belgrade 2012
Translating the Basic Knowledge of Mitochondrial
Functions to Metabolic Therapy
Mitochondrial dysfunction is at the
basis of a constellation of metabolic
abnormalities that significantly
contribute to Chronic conditions and diseases.
Summary
Myocardium as a main target for therapy
Hospitalized Heart Failure (HHF)
Practical consideration to improve HHF
outcomes