Nessun titolo diapositiva

1
Come considerare la positività dei marker di
necrosi dopo procedure interventistiche
coronariche
Stefano Savonitto, Claudio Cavallini Dipartimento
di Cardiologia e Cardiochirurgia Angelo De
Gasperis Ospedale Niguarda Ca Granda,
Milano Divisione di Cardiologia, Pr. Osp. Ca
Foncello, Treviso
2
Elevazione degli indicatori di danno miocardico
dopo rivascolarizzazione percutanea
CK-MB 10-25 Troponina T o I 20-40
3
ECS/ACC Consensus document for redefinition of
Myocardial infarction
Typical rise and gradual fall (troponin) or more
rapid rise and fall (CK-MB)of biochemical markers
of myocardial necrosis (above 99th percentile)
with at least one of the following. (a) ischemic
symptoms (b) development of Q-wave at ecg (c)
ECG changes indicative of ischemia (d) coronary
artery intervention
     Eur Heart J.2000 21.1502-13.
4
ACC/AHA percutaneous coronary guidelines
The writing committee recommends that a CK-MB
determination be performed on all patients who
have signes or sympthoms suggestive of MI
following the procedure or in patients in whom
there is angiographic evidence of abrupt vessel
closure, important side branch occlusion, or
persistent slow flow. (in these circumstances).,
a CK-MB gt 3 times the upper limit of normal
would constitute a clinically significant MI
J Am Coll Cardiol 2001 371-66
5
Minor Myocardial Damage and prognosis Are
spontaneous and PCI-related events differents?
6-months mortality
CK-MB/ULN
SPONTANEOUS POST- PCI
R.R.
p
R.R.
0-1 gt1-3 gt3-5 gt5-10 gt10
4.1 8.6 2.2 9.0 2.3 14.3 3.9 15.6 4.3
1.3 2.0 1.5 2.3 1.8 4.3 3.4 7.4 6.1
0.33 0.54 0.71 0.23
Spontaneous MI - GUSTO IV ACS, PURSUIT
Post PCI MI- EPIC, EPILOG, Capture, IMPACT II,
PURSUIT
Akkerhuis, JACC 200137355a
6
Problemi nella interpretazione degli studi
ck-release/prognosi

• studi retrospettivi o analisi post-hoc
• selezione dei pazienti (trial clinici)
• inadeguata durata follow-up
• assenza di analisi multivariata
• insufficiente dimensione del campione

7
CK-RELEASE dopo PCI

• Substrato fisiopatologico
• Correlati clinici, angiografici e procedurali
• Impatto prognostico
• Esiste un rapporto di causa/effetto?

8
Post-PCI CK-MB elevation represents myonecrosis

• 14 patients with no previous MI and TIMI 3 flow
  post procedure.
• 9 of these with CK-MB release (median 2.3X ULN)
• Anatomic correlate of myonecrosis seen with
  contrast MRI (median 2.0 grams of myocardium)

Ricciardi Circulation 2001 1032780-2783
9
Correlation of post-PCI CKMB elevation and LV
mass necrosis at contrast-enhanced MRI
15 10 5 0
Hyper- enhancement mass of LV (g)
R0.61 P0.02
0 10 20 30 40 50 60 70 80 90
100
CKMB (ng/ml)
Ricciardi Circulation 2001 1032780-2783
10
CK-RELEASE dopo PCI

• Substrato fisiopatologico
• Correlati clinici, angiografici e procedurali
• Impatto prognostico
• Esiste un rapporto di causa/effetto?

11
Condizioni cliniche più frequentemente associate
a rilascio enzimatico

• Età avanzata
• Pregresso infarto miocardico
• Pregresso intervento di bypass aorto-coronarico
• Ipercolesterolemia
• Insuccesso procedurale
• Insufficienza renale cronica
• Aterosclerosi sistemica

12
Clinical Characteristics associated with
Post-Procedural CK-MB elevation (CK-MB lt16U) 1675
Patients, Mount Sinay Hospital, NY, NY Kini A,
JACC 199934663-71
Normal CK-MB (n1362)
Elevated CK-MB (n313)
Charact ()
P value
Female CCS class III-IV Renal failure Systemic
Atherosclerosis Abciximab Use Betablocker therapy
37 52 7 16 51 27
30 33 3 10 36 41
0.02 0.001 lt0.001 lt0.001 lt0.001 lt0.001
Age, hypertension,hypercholesterolemia, smoking,
diabetes, prior MI, prior revascularization,
LVEF, CHF, MVD, IABP were found not related to
CK-MB elevation
13
Risk of troponin elevation after PCI a
prospective substudy of SYMPHONY
TnI gt1.5 ng/ml (Dimension, Dade Behring,
Detection limit 0.05 ng/ml)
Negative TnI (n251)
Positive TnI (n230)
P value
Age, y Female sex () Weight (kg) Current smoking
() Diabetes () Family history of CAD
() hypercholesterolemia () hypertension ()
0.09 0.1 0.02 0.9 0.1 0.01 0.8 0.05
56 (48, 67) 21 86 (76, 99) 38 15 67 55 47
59 (50, 66) 28 83 (74, 94) 38 20 55 54 56
Cantor WJ, submitted
14
Risk of troponin elevation after PCI a
prospective substudy of SYMPHONY
TnI gt1.5 ng/ml (Dimension, Dade Behring,
Detection limit 0.05 ng/ml)
Negative TnI (n251)
Positive TnI (n230)
Medical history ()
P value
Chronic Angina Bypass Surgery Previous
MI Previous PCI Stroke Heart Failure Chronic
Renal Insufficiency
43 16 18 18 2 5 0.4
52 15 23 18 1 3 0
0.05 0.9 0.2 0.9 0.4 0.3 0.5
Cantor WJ, submitted
15
Risk of troponin elevation after PCI a
prospective substudy of SYMPHONY
TnI gt1.5 ng/ml (Dimension, Dade Behring,
Detection limit 0.05 ng/ml)
Negative TnI (n251)
Positive TnI (n230)
Indication ()
P value
Elective Recurr/Refract Ischemia Abrupt
Closure Hemodynamic Instability (re)Infarction Day
s from qualyfying events
0.5 0.05 0.1 0.3 0.001 lt0.001
74 14 1.7 0 11 3 (2, 5)
77 20 0.4 0.4 2 11 (5, 32)
Cantor WJ, submitted
16
Plaque Characteristics associated with
Post-Procedural CK-MB elevation (CK-MB lt16U) 1675
Patients, Mount Sinai Hospital, NY, NY
30 25 20 15 10 5 0
Plt0.001

A
B1
B2
C
N365
N207
N223
N880
Kini A, JACC 199934663-71
17
Angiographic Characteristics associated with
Post-Procedural CK-MB elevation (CK-MB lt16U) 1675
Patients, Mount Sinai Hospital, NY, NY
Plt0.001
30 25 20 15 10 5 0

Plt0.001
Entire Group
Diffuse CAD
Focal CAD
Multivessel Intervention
Single vessel Intervention
Kini A, JACC 199934663-71
18
Risk of troponin elevation after PCI a
prospective substudy of SYMPHONY
TnI gt1.5 ng/ml (Dimension, Dade Behring,
Detection limit 0.05 ng/ml)
Negative TnI (n251)
Positive TnI (n230)
Procedural Charact ()
P value
Multivessel Intervention Target Vessel
(native) Saphenous Vein Graft PTCA Stent Atherecto
my or Laser Abciximab Use Angiographic Success
0.07 N.S. 0.1 0.5 0.002 0.7 0.02 0.07
10 7 92 88 5 26 91
16 3.6 90 77 4 17 86
No difference
Cantor WJ, submitted
19
Device Characteristics associated with
Post-Procedural CK-MB elevation (CK-MB lt16U) 1675
Patients, Mount Sinay Hospital, NY, NY Kini A,
JACC 199934663-71
30 25 20 15 10 5 0

PTCA
PRCA
Stent
PRCA stent
Other devices
PTCA vs non-balloon devices PRCA vs Stent
N534
N174
N420
N477
N70
20
Postprocedural cTnT elevation and total balloon
inflation time Johansen O, Eur Heart J
199819112-7
N 75 patients
12 9 6 3 1
Prevalence ()
Risk Ratio
50 40 30 20 10 0
lt180
181-307
gt307
Total inflation time (sec)
21
Cause di rilascio enzimatico

• Insuccesso procedurale
• Embolia coronarica
• Occlusione acuta transitoria
• Ampia dissezione
• Occlusione di collaterali
• Fenomeno no-reflow
• Ostruzione microvascolare

50-60
22
CK elevations in Coronary Artery
Interventions Angiographic correlates (Dobies R,
AHA 1998)
Prospective study 774 pts Elevated CK (gt160
mu/ml MBgt9.9 ng/ml) 12
Angiographic evidence for CK elevation 92
abrupt closure
40
6
dissection
24
thrombus
distal embolization
6
17
7
side branch occlusion
decreased final TIMI flow
23
PCI, PLATELET AND MICROVASCULAR EMBOLIZATION
Debries and platelet-thrombin-WBC micro-emboli
24
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25
TIMI Myocardial Perfusion Grade andMaximum CK-MB
24 Hours Post-stent
TIMI Grade 3 Flow 100 CTFC mean, 19.2
7.5 median, 17.5, p0.02
TIMI Grade 3 Flow 100 CTFC mean, 14.7
7.6 median, 13
p 0.01
2.5
2.23 2.70
2
1.5
Maximum CK-MB / Upper Limit of Normal
0.78 0.60
1
0.5
n 34
n 24
0
TMPG 3
TMPG 0/1/2
Gibson, AHJ, in press
26
Integrilin Improves MyocardialPerfusion After
Stenting
With Normal Blush DSA gt 5.3 Gray
Blush Circumference
20
69
P0.085
P0.079
15.0 7.7
15
48
11.7 6.9
Circumference (cm)
10
With Normal Blush
5
N16
N27
N24
N32
0
Placebo
Integrilin 180/2/180
Placebo
Integrilin 180/2/180
CM Gibson 2000
27
CK-RELEASE dopo PCI

• Substrato fisiopatologico
• Correlati clinici, angiografici e procedurali
• Impatto prognostico
• Esiste un rapporto di causa/effetto?

28
Clinical Relevance of CK elevation following
PCINorthwestern University Experience 1984-1993
100
Sopravvissutil ()
p lt 0.02
90
Controlli (n 120) CK-MB gtLSN (n 253)
80
1
2
3
4
5
6
TEMPO (anni)
Kong et al. JAMA. 1997
29
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30
Periprocedural CPK Elevation and Mortality in 3
RCTs of GP IIb/IIIa Inhibitors
Topol, Circulation 2000101570.
31
Correlation Between Elevated Cardiac Markers and
Long-term Mortality
mortality at 42 days
mortality at 6 months2
8
20
7.5
19.9
6
15
6.0
14.5
4
12.6
3.7
3.4
10
9.2
2
5
1.7
5.7
1.0
? 1-2
? 2-3
? 3-5
? 5-10
? 10
0
0
lt0.4 lt1.0 lt2.0 lt5.0 lt9.0 ?9.0
Cardiac Troponin 1 (ng/ML)
CK-MB (x ULN)
1. Antman EM, et al. N Engl J Med. 1996 335
1342-1349.2. Alexander JH et al. Circulation.
1999 Suppl 11-629.
32
Probability of 6-month Events By Max CK
Ratio across the spectrum of ACS the GUSTO IIb
study
Probability of Death or MI by Max CK Ratio
Probability of Death by Max CK Ratio
0,25
0,25
ST elevation
Non ST elevation
0,2
0,2
0,15
0,15
0,1
0,1
NonST elevation
0,05
0,05
ST elevation
0
0
0
2
4
6
8
10
12
14
16
18
20
0
5
10
15
20
Max CK Ratio
Max CK Ratio
Savonitto S, JACC 2002, in press
33
Impact on survival of Electrocardiographic
Q-waves and enzimatic myocardial infarction
normal
1-3 x nl
3-5 x nl
5-8 x nl
gt 8 x nl
Q-wave
Stone Circulation 2001104642
34
CK-RELEASE dopo PCI

• Substrato fisiopatologico
• Correlati clinici, angiografici e procedurali
• Impatto prognostico
• Esiste un rapporto di causa/effetto?

35
CK- Release dopo PCI
Causa di una prognosi peggiore.. o marker di
un rischio coronarico più grave?
36
Microinfarti e prognosi
37
CK-RELEASE AND CAUSES OF DEATH

• SUDDEN DEATH
• SUBSEQUENT REVASCULAR.
• MYOCARDIAL INFARCTION
• NO CARDIAC ORIGIN

38
CK-release e prognosi avversa potenziali
meccanismi

• Microinfarti microrientri suscettibilità a
  eventi aritmici
• Microembolizzazione compromissione di circoli
  collaterali preformati suscettibilità
  allischemia acuta e alle aritmie
• Microembolizzazione alterata funzione del
  microcircolo

39
Coronary Microvascular Dysfunctionin
DCMPrognosis
PET MBF dip 1.36 ml/min/g
Neglia et al, Eur Heart J 2000 (abs)
40
Epidemiology and prognostic impact of biochemical
marker elevations after percutaneous coronary
interventions A multicenter survey sponsored by
the Italian Working Group on Atherosclerosis,
Thrombosis and Vascular Biology and the Italian
Society of Invasive Cardiology (GISE) Chairmen C
laudio Cavallini, MD, Ospedale S. Maria dei
Battuti, Treviso Stefano Savonitto, MD, Ospedale
Niguarda Ca Granda, Milan Roberto Violini, MD,
Ospedale San Camillo, Rome
41
Primary objective
To evaluate prospectically the prognostic impact
of CK-MB elevations gt2x ULN after PCI on total
mortality at 24 months
Secondary objectives

• To assess the incidence and risk determinants
• of enzyme and marker elevations after PCI
• To assess the predictive value of each marker
• of necrosis and inflammation, and their
• combination on the aggregate of death,MI
• and clinical restenosis
• To assess the risk of early (subacute stent
• thrombosis) and late (clinical restenosis) events
• and their association with biochemical variables
• and predefined genetical polimorphisms

42
Inclusion criteria
All of the patients undergoing PCIs during the
study period
Exclusion criteria
Only patients not willing to participate in the
study
The study monitors will compare the study
enrollment log with the Cath lab PCI log
centers enrolling lt90 of their patients will be
axcluded from the study
PCI procedures and pharmacological
interventions are to be carried out according to
local routine
43
Baseline immediately prior to PCI
Blood sampling
6 to 10 hours after the procedure
16 to 24 hours after the procedure
Both plasmas and sera will be stored from each
sampling, together with the cells for genetic
determinations. All biological material will be
sent to the central laboratory for biochemical
and genetic determinations.
44
Mass CK-MB TnI C-reactive protein Serum
Creatinine (substudy)
Biochemical markers
PlA1/PlA2 polimorphism for the platelet GPIIIa
receptor Polimorphism for the platelet GPIa
receptor Polimorphism I/D for the ACE gene
Genetic determinations
45
ARRUOLAMENTO NEI VARI CENTRI
TREVISO GENOVA MILANO Niguarda MERCOGLIANO BRESCIA
(O.C.) CUNEO COTIGNOLA PAVIA UDINE NOVARA ROMA
PARMA LEGNANO BOLZANO BRESCIA (P.A.) MIRANO

46
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47
Conclusioni

• Rilascio enzimatico dopo PCI o CABG
  frequente
• Significato prognostico ? sfavorevole (
  in gt 5-10 volte LSN)
• Raccomandazione prevenire
• Come trattare? prevenzione secondaria