Hospitalization

Acute Heart Failure Syndromes 2011:
End Organ Protection
Heart and Kidney
Mihai Gheorghiade MD, FACC
Professor of Medicine and Surgery
Director of Experimental Therapeutics
Northwestern University, Feinberg School of Medicine
Chicago Illinois USA
Co Director Centre for Drug Development
Duke University
DISCLOSURES
a consultant for and/or received
honoraria from Abbott, Astellas, Bayer,
AstraZeneca, Corthera, Debiopharm, Errekappa
Terapeutici, EKR Therapeutics, GlaxoSmithKline,
Johnson & Johnson,
Medtronic, Merck, Nile, Novartis, Otsuka, PeriCor,
PDL BioPharma, Scios Inc.,
Solvay Pharmaceuticals, and Sigma-Tau.
AHFS
Epidemiology
• Two million admissions per year with the
primary diagnosis of HF(NA and Europe)
• 6,000,000 admissions per year with primary
or secondary diagnosis of HF
• Post discharge event rate (readmissions/
death): 35%* at 60 to 90 days
. at admission
*50% in pts. with BP<120mmHg
Gheorghiade et al Circulation 2005
AHFS: Hospitalizations
• Worsening chronic heart failure
(HF):80% of all admissions*
• Acute de novo heart failure (diagnosed
for the first time) :15%
• Advanced/end-stage/refractory HF:5%
*The majority are managed by a non cardiologist
Gheorghiade et al Circulation 2005
AHFS: General Classification
Clinical
Characteristics of AHFS Patients
Data on approximately 200,000 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%
Adams KF, et al. Am Heart J. 2005;149: 209.
Cleland JGF et al. Eur Heart J. 2003; 24: 442;
Fonarow GC, et al. J Am Coll Cardiol. 2004; 844 – 4A.
Acute versus Chronic Heart Failure
• Is worsening heart failure resulting in
hospitalization (80% of AHFS) a distinct
entity from chronic heart failure?
– Yes
• It requires urgent/emergent therapy
• Acute myocardial &/or renal injury may be present
and contributes to HF progression
– No
• It represents worsening chronic HF
Acute Heart Failure Syndromes vs. Chronic
Heart Failure :
AHFS
Ambulatory HF patients
• Mortality and re
hospitalization as high as
15% and 30%,
respectively, within 60-90
after d/c
• Very abnormal, but
relatively stable lab values
• Event rate has not
changed in the last decade
• Decreased morbidity and
mortality in last two
decades
• Mortality <5% annually in
clinical trials
• Cause of death HF
• Death often sudden
Acute Heart Failure Syndromes vs. Chronic
Heart Failure : Pathophysiology
AHFS
• Cardiac injury is often
present (troponin release)
• Rapid worsening of renal
function
• Very abnormal
hemodynamics
• Very abnormal and
fluctuating neurohormonal
profile
• Rapid changes in
electrolyte profile
(potassium)
Ambulatory HF patients
• Uncommon
• Uncommon
• Uncommon
• Uncommon
• Uncommon
Acute Heart Failure Syndromes vs. Chronic
Heart Failure : Therapies and Clinical Trials
AHFS
Ambulatory HF patients
• Available “lifesaving”
therapies have not been
tested in this setting
(e.g. beta-blockers,
ACEI)
• The majority of clinical
trials conducted to date
have been negative in
terms of efficacy/safety
despite high event rate
• Effective therapies have
been developed over
the last 20 years
• The majority of the
trials conducted show a
significant clinical
benefit on morbidity
and mortality
Admission Systolic BP and Outcomes
in Hospitalized Pts with Heart Failure: An OPTIMIZE-HF Analysis
Characteristic % (SD)
119
Admission SBP mmHg
120-139
140-161
161
Mean Age, y
(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 (%)
Ischemic Etiology
HTN Etiology
Serum Cr>2 (mg/dl)
Mean Wt change (kg)
Edema Admission
33.3 (17.4) 37.8 (17.6) 40.9 (17.1) 44.4 (16.5)
50.7
48.8
44.1
39.2
13.4
18.1
25.4
34.8
20.7
18.0
18.1
21.5
-2.45 (5.00) -2.68 (4.82) -2.60 (4.64) -2.42 (4.62)
63.9
65.1
65.6
63.9
Total mortality in-hospital
Total mortality 60-90d
Readmission
Mean LOS, days
7.2
14.0
30.6
6.5 (6.6)
Gheorghiade M et al. JAMA. 2008;299:2656-66
3.6
8.4
29.9
5.7 (5.3)
2.5
6.0
30.3
5.4 (5.0)
1.7
5.4
27.6
5.1 (4.8)
EVEREST Trials:
Continental Differences
4133 patients admitted with AHFS and reduced
LVEF on standard medical therapy followed 9.9 months
North
America
P-value
South
America
Western
Europe
Eastern
Europe
11.3
(8.9-13.6)
12.1
(9.4-14.8)
6.8
(5.5-8.0)
<0.0001
29.8
(27.2-32.3)
21.3
(18.2-24.3)
26.1
(22.3–29.6)
12.1
(10.5–13.7)
<0.0001
1-year Estimate, %, (95% CI)
Death
30.4
(27.6-33.1)
27.2
(23.3-30.8)
27.1
(23.0-31.1)
20.5
(18.1-22.8)
<0.0001
52.5
(49.4–55.3)
41.6
(37.3–45.6)
47.3
(42.6–51.7)
35.3
(32.4–38.0)
<0.0001
3-month Estimate, %, (95% CI)
Death
11.4
(9.6-13.2)
CV death/HF
hospitalization
CV death/HF
hospitalization
Blair et al,.
Adjudicated Cause of Death after Discharge in 4,133 Pts
Hospitalized with Worsening HF and low EF:
Over-all mortality rate of 26% at 10 months follow-up
O’Connor et al. A H J 2010
Total number of patients by first
Hospitalization type in the Everest trial
All
O’Connor et al. AHJ 2010
Number of pts Percent of
with this type
all patients
as first
N = 4133
hospitalization
2159
52.2
Percent of
all first
hospitalizat
ions
100.0
Non-CV
CV
HF
Arrhythmia
Stroke
MI
Other CV
813
1346
982
100
42
33
189
37.7
62.3
45.5
4.63
1.95
1.53
8.75
Hospitalization
Type
19.7
32.6
23.8
2.42
1.02
.80
4.57
AHFS: Therapeutic Goals
• Improve hemodynamics (PCWP) without causing
myocyte damage (ischemia, necrosis, apoptosis),
arrhythmias, hypotension or renal dysfunction
realizing that the high PCWP may be the result of
specific therapeutic targets (e.g. STEMI, AF,
HTN)
• Improve symptoms and achieve euvolemia.
• Implement life-saving therapies (e.g. ACE
inhibitor, beta blockers, AICD, etc.)
Cardiac and/or Renal
Function
AHFS and Progression of HF
Hypothesis: With each
hospitalization, there is
myocardial and or renal damage
Hospitalization
Hospitalization
Hospitalization
Time
Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A)
Pathophysiology of AHFS
Hemodynamic deterioration
(eg, fluid overload)

Myocardial injury (Tn release)

Progression of heart failure
Gheorghiade et al. Am Heart J. 2003;145:S3-S17.
AHFS
AHFS
Myocardial Injury in AHFS:
“The Perfect Storm”
• Substrate
– Obstructive CAD with ischemic/hibernating
myocardium
– Viable but dysfunctional myocardium in non-CAD
• Aggravating Factors (Decreased coronary
perfusion)
– High LV diastolic pressure (subendocardial ischemia)
– Low blood pressure often as a result of Rx
– Further and excessive activation of neurohormones
(e.g. catecholamines) that may cause further damage
of viable but dysfunctional myocardium
Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A)
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.
Survival
OPTIME-CHF: Etiology and Mortality
;
Felker GM et al. J Am Coll Cardiol. 2003
The cardio-renal syndrome in AHFS
„Vasomotor“ Nephropathy
Chronic renal disease
•Diabetes
•Decreased cardiac output
and/or systemic vasodilation
•Hypertension
•High renal venous pressure
•Arteriosklerosis
•Neurohormonal activation
•High dose loop diuretic
therapy
Cardio-renal Syndrome
Gheorghiade et al JACC 2009
Worsening renal function
during hospitalization, in spite
of clinical improvement in
response to loop diuretics and
adequate volume
EVEREST: 4133 patients admitted with AHFS and reduced
LVEF on standard medical therapy followed 9.9 months.
Mortality
CV Mortality/HF Hospitalization
BUN
Cr
31
Post Discharge “Vulnerable” Phase
• In the EVEREST Trial Pts with early events
had significantly more HF signs and
symptoms, worse renal function, and more
electrolyte, liver, and neurohormonal
abnormalities early after discharge,
compared to the group without events.
Gheorghiade et al. in press Heart Failure Reviews
37
Mortality : Everest
38
AHFS
• With each hospitalization, there may be
myocardial and/or renal damage
• The contribution of myocardial and renal injury
during AHFS remains to be studied:
- Why does it happen?
- How does it happen?
- How much injury?
- In Whom?
- When does it happen? Before, early, during or
after hospitalization
AHFS :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
Viable but Dysfunctional Myocardium:
Possibility for Recovery
Etiologic factors:
Neurohormones
(e.g. NE)
Ischemia/ Hibernation
Myocyte
Cytokines (e.g. TNF a)
Gheorghiade M. JACC 2009
Metabolic
? Hemodynamics
New potentially cardio and or
renal protective agents AHFS
• Vasopressin non selective
Antagonists
• Adenosine partial Agonists
• SERCA Modulators
• Cycle GMP Activators/Stimulators
• Micro and Micronutrients
• New Mineralocorticoid Antagonists
Cardiac and/or Renal
Function
AHFS and Progression of HF
Hypothesis: With each
hospitalization, there is
myocardial and or renal damage
Hospitalization
Hospitalization
Hospitalization
Time
Gheorghiade M et al. Am J Cardiol. 2005; 96 (6A)

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