Transcript Asymptomatic Left Ventricular Dysfunction and Diabetes

Asymptomatic Left Ventricular
Dysfunction and Diabetes:
Prevention and Timely Detection
Disfunzione ventricolare sinistra asintomatica e diabete:
come preveniria e come accorgersene.
Mariell Jessup MD, FAHA, FACC, FESC
Professor of Medicine
University of Pennsylvania
Philadelphia, Pennsylvania
Disclosure: I have no conflicts with respect to this lecture
A Case
• 50 year old woman commercial designer
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No past medical history except well controlled DM
Meds: Multivitamin daily
Non-smoker, social alcohol
No family history of cardiac disease
Travels world-wide, plays tennis, squash and runs
15 miles weekly
• While on business trip – automobile accident –
fracture of right leg – now needs orthopedic
procedure
Pre-Op Clearance – 7/01
• ECG – Left bundle branch block pattern.
– Prior ECG from 1984 – normal
• ECHO: LVEF = 20%, normal wall thickness, mild
mitral regurgitation
• Cath – RA = 8, PA = 32/12 mean 22, PCW = 12,
CI = 2.1 l/min/m2
– Normal coronaries
• Normal labs, including thyroid etc.
• Normal physical exam,
– (BP 130/70, HR 70)
Back to the case
• Medications – First visit 7/01
– Started lisinopril 10 mg daily
• Medications – 4 weeks later
– carvedilol 3.125 mg twice daily
• Medications over next 6 months
– carvedilol titrated to 25 mg twice daily
• Visit 2/4/02 – Feels “great”, leg healed, back to
exercise and traveling
Follow-up ECHO 2/02
• LVEF improved to ~ 30%
• Plan :Continue ACEI and beta blocker
• Follow-up in 6 months
Bad Phone Call – 4/1/02
• She was driving in Florida on business– stopped at
light – witnessed to lose consciousness – falls onto
horn – causes accident as car rolls into intersection
• First responders nearby
• Ventricular fibrillation – cardioverted to sinus
tachycardia with 2 shocks
• Admitted – comatose/intubated for 3 days – recovers
completely over 6 weeks
• ICD implanted/Returned home
What is Stage B?
Left ventricular remodeling has
occurred but the patient never
has experienced signs or
symptoms of heart failure
“pre-clinical” heart failure
ACC/AHA Heart Failure Guidelines - 2005
Stages of CHF — ACC/AHA Guidelines 2005
Ammar et al. Circulation 2007;1151 563
D
Refractory
0.2%
C
11.8%
Prior, current symptoms
B
34%
Structural heart disease
LVH, MI, low LVEF, dilatation, valvular disease
22%
A
High-risk patients
Hypertension, diabetes, coronary disease, family history, cardiotoxic drugs
Who are the Stage B patients?
• Post myocardial infarction
– Patients with an acute MI
– Patients with a history of MI but normal LVEF
• LV remodeling
– Left ventricular hypertrophy
– Low LV ejection fraction
• Asymptomatic valvular heart disease
• Undiagnosed, asymptomatic congenital heart
disease
How many people?
• Up to 4 times the number of symptomatic heart
failure patients (stage C and D combined) may
have asymptomatic left ventricular dysfunction1
• Large public health burden
• Potentially prevent progression to symptomatic
heart failure and death
1Frigerio
M, AJC 2004
Framingham Study: Prevalence
Age Group
40 – 59 years
Men
(n = 1860)
2.1 %
Women
(n= 2397)
0.5 %
60 – 69 years
7.2 %
0.8 %
70 – 79 years
11.3 %
1.0 %
80+ years
14.3 %
1.9 %
Pooled
6.0 %
0.8 %
Wang TJ et al. Circulation. 2003;108:977-982.
Framingham: Summary
• 3% prevalence in general adult population,
similar to overt heart failure
• Increases considerably with age
• Predominantly men
– (confirmed in several studies)
• 50% with history of MI
Wang TJ et al. Circulation. 2003;108:977-982
Other Studies
• 2042 randomly selected men and women >45
years old
– 65% of subjects with low ejection fractions were
asymptomatic1
• 7.7% of elderly have LV dysfunction
– only 48% diagnosed2
• 3 to 5 % of general population has asymptomatic
LV dysfunction3
1Rodeheffer.
J Card Fail 2002; 8:S253-257.
2Morgan. BMJ 1999;318:368-72.
3McDonagh. Heart 2002; 88(Suppl II):ii12-ii14.
Framingham Study:
Heart Failure Morbidity
EF > 50%
EF 40 to 50%
EF < 40%
Wang TJ et al. Circulation. 2003;108:977-982.
Framingham Study - Mortality
1.0
Survival
0.8
No ALVD (EF >50%) and no
HF history
0.6
0.4
Mild ALVD (EF 40% to 50%)
P<.0001
0.2
Moderate-to-severe ALVD (EF <40%)
Systolic HF (EF 50%)
0.0
0
2
4
6
Years
Wang TJ et al. Circulation. 2003;108:977-982.
8
10
12
Screening for Stage B
1. Has the effectiveness of the program been
demonstrated in a randomized trial?
2. Are efficacious treatments available?
3. Does the burden of suffering warrant screening?
4. Is there a good screening test?
5. Does the program reach those who could benefit?
6. Can the health system cope with the program?
7. Do persons with positive screenings comply
with advice and interventions?
FHS: Framingham Heart Study
ABC: the Health ABC study
CHS: Cardiovascular Health study
The Treatment
• Limited evidence in this population
• Extrapolate from the vast symptomatic heart
failure literature…..
• Goals
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Prevent progression to symptomatic disease
Prevent death
Maintain an excellent quality of life
“Do no harm”
The argument for ACE inhibitors
• They work for symptomatic HF: Stage C
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Reduce morbidity
Reduce mortality
Improve quality of life
Promote “positive” remodeling of the ventricle
• The data for “asymptomatic” HF: Stage B
– SOLVD-Prevention
– SAVE
– TRACE
SOLVD-Prevention
4228 asymptomatic pts with LVEF < 35%
(mean EF 28%)
>30% s/p MI greater than 3 months
Randomized to enalapril vs placebo
Mean follow-up 37 months
Results:
No difference in mortality in enalapril group (8% “trend”)
Significant decrease in new onset HF, hospitalizations in
enalapril group
SOLVD investigators. NEJM 1992;327:685-691
SOLVD-Prevention
All-Cause Mortality
*P=0.30 enalapril vs placebo
50
Placebo (n=2117)
40
Mortality
(%)
*
30
Enalapril (n=2111)
20
10
0
0
6
12
18
24
Months
SOLVD Investigators. N Engl J Med 1992;327:685
30
36
42
48
SOLVD Long Term Follow-up
• 12 year follow-up of
SOLVD-Prevention
Cardiac Mortality
Prevention Trial
– 14% reduction in
mortality
0
2
4
6
8
Years
Jong et al. Lancet 2003;361:1843
10
12
The SAVE Trial
• 2231 patients 3 days s/p MI without heart failure
and EF < 40%
• Randomized to captopril or placebo and
followed for an average of 3.5 years
• Re-assessment of EF: fell > 9% in placebo
• Captopril – 19% reduction in all cause mortality
and 22% reduction in heart failure
hospitalization
Pfeffer MA, et. al., NEJM 1992;327:669-677.
SAVE Remodeling
Number of patients that developed LV dilatation in the SAVE
study of captopril versus placebo after acute MI
80 70 60 50 40 30 20 10 -
Placebo
Captopril
1 year
2 year
Time Post-MI
Sutton, et al. Circulation 1997;96:3294-9
Sutton M, et. al., Circulation
1997, 96:3294-9
TRACE
• 1749 patients with MI and EF < 35%
– 41% had no heart failure
– Followed for 50 months
• In the asymptomatic group: 30% reduction in
mortality in trandolapril
Kober L, NEJM 1995;333:1670-76.
The argument for beta-blockers
• Alter the natural history of cardiovascular disease by
influencing neurohormonal pathways
• Like ACE inhibitors, beta-blockers have been shown to
improve survival, improve remodeling and decrease
hospitalizations in patients with symptomatic systolic
heart failure
• Most effective when initiated early in disease state but
may also impact survival in patients with advanced
disease
• Underutilized in most disease states
– Fear of side-effects (especially in asymptomatic pts)
– Lack of understanding of pathophysiology of disease
SOLVD - Prevention
• Plasma norepinepherine levels were
strongly associated with progression to
symptomatic heart failure
• This supports the concept that even in the
absence of symptoms the adrenergic system
is activated and can lead to negative
remodeling
Beta blocker and mortality
in SAVE
The best survival occurred with a
combination of beta-blockers and
ß BLOCKER
ACE inhibitors
n=2231
YES
No
Yes
13.3%
24.3%
No
19.5%
27.7%
ACEI
SAVE
Circulation 1995;92:3132
CAPRICORN
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Acute myocardial infarction within 21 days
Received all “adjuvent” therapies for MI
LV ejection fraction 40%
Receiving ACE inhibitor 48 h
• 1,023 patients had no heart failure – “Stage B”
– (about 50% of the total were asymptomatic)
The CAPRICORN Investigators. Lancet. 2001;357:1385–1390.
CAPRICORN: Reduced Mortality in
Stage B Post MI
1.00
Carvedilol
(n=504)
Proportion Alive
0.90
Risk Reduction
31%
Placebo
(n=519)
0.80
(3%, 53%)
0.70
0.60
0
0
0.5
1
1.5
Years
2
2.5
Sudden Death(Low EF)
Primary Prevention Trials
MADIT 1
MUSTT
MADIT 2
DEFINITE
SCDHEFT