C di I h i ardiac Ischemia in the Critically Ill

Cardiac
C
di IIschemia
h i
in the Critically Ill
M Jacka
J k MD MS
MSc
U of Alberta
mjacka@ualberta.ca
Summary

Myocardial injury




Common
Deleterious
STEMI - invasive therapy
NSTEMI - non-invasive therapy


Anticoagulation
g
Statin
65 y male post gastrectomy

NSTEM
ACB 10 y ago
DES 2 mo ago
Heparin bleeds
NSTEMI

?ASA ?statin ?plavix ?BB




Diagnosis / Significance

Definition



> 99th ptle of biomarker +
Symptoms/ EKG/ Echo/ Nuclear Med
Categories



I: STEMI
II: NSTEMI
III, IV, V: related to invasive cardiac procedure
Rivers E et al. NEJM 2001; 345: 1368-77
Sepsis
1
p = 0.02
0 75
0.75
Survival
Trop NEG
Trop POS
0.5
0.25
0
2
4
6
8
10
12
14
16
18
20
Ammann P. J AM Coll Cardiol 2003; 41: 2004-9
COPD
1
p = 0.002
0 75
0.75
Survival
Trop NEG
Trop POS
0.5
0.25
0
0
10
20
30
40
50
60
Baillard C. Int Care Med 2003; 29: 584-9
CHF
Horwich TB. Circulation 2003; 108: 833-8
Subarachnoid hemorrhage
Tung P. Stroke 2004; 35(2): 548-52
Mortality vs time by ‘troponin elevation group’
Troponin T < 0.01
ng/L
Trop T > 0.01
ng/L
12.5%
29.5%
Day 30
13.7
34
0.001
Year 1
25
56
0 001
0.001
Year 2
32
66
0.001
Year 3
37
74
0.001
Jacka2
Trop I < 0.15
0 15 mcg/L
Trop I > 0.15
0 15
mcg/L
26%
50%
Babuin et al1
p
ICU
C ((n=1657))
Hospital
( 335)
(n=335)
0.01
Mortality
y vs Troponin
p
Level
60
p=0
0.0007
0007
50
40
30
Mortality
20
10
0
0-0.14
0.15-0.37
> 0.37
Troponin I (mcg/L)
ICU Troponin & Mortality Risk
Lim W. Arch Int Med 2006; 166: 2446-54
Classical MI : Presentation
Inflammation
TNFα
IL-1
IL-6
Coagulation
PAI 1
PAI-1
FVIII
AIII
Plts
‘
‘Stress’
Epi
NEpi
MI
Hypoxia
O2
Inflammation
(& Coagulation)
C
l ti )
Hansson G. N Engl J Med 2005;352:1685-1695
Inflammation and MI




N = 2457
Serology for inflammatory markers
Medical therapy : LMWH vs placebo
Invasive therapy stratified by IL-6
IL 6
Lindmark E. JAMA 2001; 286: 2107-13
Inflammation and Myocardial
y
Injury in Sepsis
Trop > 0
0.1
1 Trop < 0
0.1
1
TNF (pcg/mL)
p
13
5.7
0.0007
Soluble TNF
1.05
0.43
0.0001
IL-1
0.65
1
0.11
IL-6
358
29
0.0007
IL 8
IL-8
85
65
0 26
0.26
CRP
258
144
0.0002
Ammann P. J AM Coll Cardiol 2003; 41: 2004-9
Stress
St
Landesberg G. J Am Coll Cardiol 2001; 37(7): 1839-45
Management (NSTEMI)



Inflammation
Coagulation
Stress/ Catecholamine State
Inflammation
Rho
Nf KB
MMP
PGE2
NO
LeManach Y et al. Anesthesiology 2008; 108: 1141-6
Statin Withdrawal :
ACS
Observational Data
Platelet Receptor Inhibition In Ischemia Syndrome (PRISM)
Statins and ACS: n= 1616
Heeschen C et al. Circulation 2002; 105: 1446-52
How fast do statins work?
8 healthy volunteers, atorvastatin 80 mg OD X 1/52
Laufs U et al. Am J Cardiol 2001; 88: 1306-7
n = 33, dyslipidemia, atorvastatin 80 mg vs placebo
Taneva E et al. Am J Cardiol 2006; 97: 1002-6
n = 120, vascular surgery, atorvastatin 20 mg vs placebo
Durazzo AE et al. J Vasc Surg 2004; 39: 967-76
Mouse volunteers, endothelium
Laufs U et al. Circulation 2000; 102: 3104-10
And…. a word of caution!
Kruger PS. Int Care Med 2008; Epub
Coagulation
Mangano D. NEJM 2006; 354: 353-65
Procoagulant Risk
N = 67000
Privately
ate y contracted
co t acted (by
BAYER!)
“Increased
Increased mortality
mortality,
renal failure, heart
failure,, and stroke
associated with
aprotinin use”
Hiatt WR. NEJM 2006; 355: 2171-3
“ If the FDA asks for bad news
news, then we
have to have to give (it). But if we don’t
have itit, then we can’t
can t give it ”
Bayer senior executive
Hiatt WR. NEJM 2006; 355: 2171-3
Revascularizing with Stents?
Shuchman M. N Engl J Med 2007;356:325-328
Survival after Stenting
Shuchman M. N Engl J Med 2007;356:325-328
Real World Adoption of DES – Brigham
and Women's
Women s Hospital
P-DES
FDA Approval
S-DES
FDA Approval
100
80
%
60
% ≥ 1 DES
% only BMS
40
20
0
Apr
2003
JJun
n
A
Aug
g
Oct
Dec
Feb
Apr
JJun
n
A
Aug
g
2004
Jonas et al. Catheterization and Cardiovascular Interventions 2007;70:175–83
Complications Increase with Off - Label
Use of DES
24
Death, MI or target lesion revascularization
Off-Label
On-Label
18
%
12
6
0
0
2
4
6
8
10
12
Time after initial procedure (months)
No. at Risk
Off-Label 1817 1757 1514 1476 1428 1313 1253
O L b l 1506 1475 1363 1343 1311 1215 1182
On-Label
Win et al. JAMA; 2007;297:2001-9
Aspirin

Inhibits cyclo-oxygenase


both COX-1 (constitutive) and COX-2
Platelet aggregation response returns after
20% recovery i.e., within 2-4 days
Sanderson et al. Ann Intern Med 2005;142:370-80
ASA ‘resistance’
resistance

Causes


Compliance
Dosage <75 mg/day

No advantage to doses > 150 mg/day routinely but
325 mg/day required in perioperative period
Sanderson et al. Ann Intern Med 2005;142:370-80
Mueller RL. Best Pract Res Clin Haem 2004;17:23-53
ASA – Drug
g Interaction with
NSAIDs

NSAIDs block access of ASA to its binding
site on COX-1
Sanderson et al. Ann Intern Med 2005;142:370-80
Thienopyridines

Clopidogrel (Plavix)



Permanent alteration in the platelet P2Y12 ADP
Inhibition of ADP-induced platelet activation and
aggregation
C ll
Collagenand
d th
thrombin-induced
bi i d
d activation
ti ti also
l
inhibited
Jacobson AK. Best Pract Res Clin Haem 2004;17:55-64
Thienopyridenes
Lau WC and Gurbel PA Pharmaceut Res 2006;23:2691-2708
Stress
St
Beta Blockade History : MI
n
RRR
BHAT : JAMA 1982
247(12): 1707-14
3837
27%
Hjalmarson: Lancet 1981
2(8251): 823-7
1395
36%
Anon : NEJM 1981
304(14):801-7
1884
45%
Patience, Patients!
10


CAST study
n = 1689
8
6
placebo
4
Tx
2
0
Echt DS. NEJM 1991; 324: 781-8
Mortality
Non-fatal MI
0.08
8
0.04
0.04
0.02
0.02
Risk
HR(95%CI)=0.70(0.56-0.86), p=0.0007
0.06
HR(95%CI)=0.83(0.70-0.99), p=0.035
0.06
0.08
8
Primary Outcome
Metoprolol
# at Risk 0
P 4177
M 4174
0.0
0.0
Placebo
10
20
30
0
10
20
30 Days
3915
3959
3873
3909
3853
3879
4177
4174
3923
3976
3882
3922
3859
3889
P
M
All Death
0.0
02
0.01
Risk
0.03
HR(95%CI)=1.33(1.02-1.74), p=0.032
Metoprolol
0.0
Placebo
0
No. at Risk
4177
P
4174
M
10
20
30 Days
4116
4113
4091
4066
4069
4038
0.0
020
Stroke
Metoprolol
0.010
Placebo
0.0
0.005
Risk
0.015
HR(95%CI)=2.17(1.26-3.73), p=0.005
0
No. at Risk
4177
P
4174
M
10
20
30 Days
4102
4085
4076
4038
4055
4011
Myocardial infarction
Biomarker increase X ULN in patients with MI
Biomarker X
ULN
Metoprolol
(N=4174)
Placebo
(N=4177)
P
< 4.3
86
92
0.65
> 4.3
74
129
0.0001
• Nonfatal myocardial infarctions
–
–
–
–
36% experienced ischemic symptoms (64% asymptomatic)
16% CHF
7% went on to coronary revascularization
3% nonfatal cardiac arrest
Independent
p
postoperative
p
p
predictors of death
Predictor
HR
95% CI
stroke
12 74
12.74
7 77-20
7.77
20.88
88
hypotension
4.32
3.22-5.80
symptomatic MI
3.51
2.02-6.11
y p
MI
asymptomatic
2.80
1.87-4.19
bradycardia
1.99
1.35-2.92
bleeding
l
1.54
1.09-2.16
Summary

Myocardial injury




Common
Deleterious
Invasive therapy - STEMI
Non-invasive therapy


Anticoagulation
g
Statin
Thank you!