Stefano Savonitto, Claudio Cavallini Dipartimento di Cardiologia e Cardiochirurgia Angelo De...

Stefano Savonitto, Claudio CavalliniStefano Savonitto, Claudio Cavallini

Dipartimento di Cardiologia e Cardiochirurgia “Angelo De Gasperis”Dipartimento di Cardiologia e Cardiochirurgia “Angelo De Gasperis”Ospedale Niguarda Ca’ Granda, MilanoOspedale Niguarda Ca’ Granda, Milano

Divisione di Cardiologia, Pr. Osp. Ca’ Foncello, TrevisoDivisione di Cardiologia, Pr. Osp. Ca’ Foncello, Treviso

Come considerare la positività Come considerare la positività dei marker di necrosi dopo dei marker di necrosi dopo

procedure interventistiche coronariche procedure interventistiche coronariche

Elevazione degli indicatori di danno miocardico dopo

rivascolarizzazione percutanea

CK-MB 10-25%

Troponina T o I 20-40%

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

ECS/ACC Consensus document for redefinition of Myocardial infarction

Eur Heart J.2000; 21.1502-13.

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 > 3 times the upper limit of normal would constitute a clinically significant MI

J Am Coll Cardiol 2001; 37:1-66

Post PCI MI- EPIC, EPILOG, Capture, IMPACT II, PURSUIT Spontaneous MI - GUSTO IV ACS, PURSUIT

Minor Myocardial Damage and prognosis:Are spontaneous and PCI-related events differents?

CK-MB/ULN SPONTANEOUS POST- PCI

6-months mortality

Akkerhuis, JACC 2001;37:355a

0-1

>1-3

>3-5

>5-10

>10

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

R.R.R.R. R.R.R.R. pp

0.33

0.54

0.71

0.23

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

CK-RELEASE dopo PCI

Substrato fisiopatologico

Correlati clinici, angiografici e procedurali

Impatto prognostico

Esiste un rapporto di causa/effetto?

Post-PCI CK-MB elevation represents myonecrosis

Ricciardi Circulation 2001; 103:2780-2783

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)

0 10 20 30 40 50 60 70 80 90 1000 10 20 30 40 50 60 70 80 90 100

CKMB (ng/ml)CKMB (ng/ml)

1515

1010

55

00

Hyper-Hyper-enhancementenhancementmass ofmass ofLV (g)LV (g)

Ricciardi Circulation 2001; 103:2780-2783

Correlation of post-PCI CKMB elevation andCorrelation of post-PCI CKMB elevation andLV mass necrosis at contrast-enhanced MRILV mass necrosis at contrast-enhanced MRI

R=0.61R=0.61P=0.02P=0.02

CK-RELEASE dopo PCI



Impatto prognostico


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

Clinical Characteristics associated with Post-ProceduralClinical Characteristics associated with Post-ProceduralCK-MB elevation (CK-MB <16U)CK-MB elevation (CK-MB <16U)

1675 Patients, Mount Sinay Hospital, NY, NY1675 Patients, Mount Sinay Hospital, NY, NYKini A, Kini A, JACCJACC 1999;34:663-71 1999;34:663-71

Elevated CK-MBElevated CK-MB(n=313)(n=313)

Normal CK-MBNormal CK-MB(n=1362)(n=1362)

FemaleFemale

CCS class III-IVCCS class III-IV

Renal failureRenal failure

Systemic AtherosclerosisSystemic Atherosclerosis

Abciximab UseAbciximab Use

Betablocker therapyBetablocker therapy

3737

5252

77

1616

5151

2727

3030

3333

33

1010

3636

4141

0.020.02

0.0010.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

<0.001<0.001

P valueP valueCharactCharact(%)(%)

Age, hypertension,hypercholesterolemia, smoking, diabetes, prior MI,Age, hypertension,hypercholesterolemia, smoking, diabetes, prior MI,prior revascularization, LVEF, CHF, MVD, IABP were found not relatedprior revascularization, LVEF, CHF, MVD, IABP were found not related

to CK-MB elevationto CK-MB elevation

Risk of troponin elevation after PCIRisk of troponin elevation after PCI

a prospective substudy of SYMPHONY a prospective substudy of SYMPHONY

Positive TnIPositive TnI(n=230)(n=230)

Negative TnINegative TnI(n=251)(n=251)

Age, yAge, y

Female sex (%)Female sex (%)

Weight (kg)Weight (kg)

Current smoking (%)Current smoking (%)

Diabetes (%)Diabetes (%)

Family history of CAD (%)Family history of CAD (%)

hypercholesterolemia (%)hypercholesterolemia (%)

hypertension (%)hypertension (%)

56 (48, 67)56 (48, 67)

2121

86 (76, 99)86 (76, 99)

3838

1515

6767

5555

4747

59 (50, 66)59 (50, 66)

2828

83 (74, 94)83 (74, 94)

3838

2020

5555

5454

5656

0.090.09

0.10.1

0.020.02

0.90.9

0.10.1

0.010.01

0.80.8

0.050.05

P valueP value

TnI >1.5 ng/ml TnI >1.5 ng/ml ((Dimension, Dade Behring, Detection limit 0.05 ng/ml)Dimension, Dade Behring, Detection limit 0.05 ng/ml)

Cantor WJ, submittedCantor WJ, submitted





Chronic AnginaChronic Angina

Bypass SurgeryBypass Surgery

Previous MIPrevious MI

Previous PCIPrevious PCI

StrokeStroke

Heart FailureHeart Failure

Chronic Renal InsufficiencyChronic Renal Insufficiency

4343

1616

1818

1818

22

55

0.40.4

5252

1515

2323

1818

11

33

00

0.050.05

0.90.9

0.20.2

0.90.9

0.40.4

0.30.3

0.50.5

P valueP valueMedical historyMedical history(%)(%)







ElectiveElective

Recurr/Refract IschemiaRecurr/Refract Ischemia

Abrupt ClosureAbrupt Closure

Hemodynamic InstabilityHemodynamic Instability

(re)Infarction(re)Infarction

Days from qualyfying eventsDays from qualyfying events

7474

1414

1.71.7

00

1111

3 (2, 5)3 (2, 5)

7777

2020

0.40.4

0.40.4

22

11 (5, 32)11 (5, 32)

0.50.5

0.050.05

0.10.1

0.30.3

0.0010.001

<0.001<0.001

P valueP valueIndicationIndication(%)(%)



Plaque Characteristics associated with Post-ProceduralPlaque Characteristics associated with Post-ProceduralCK-MB elevation (CK-MB <16U)CK-MB elevation (CK-MB <16U)

1675 Patients, Mount Sinai Hospital, NY, NY1675 Patients, Mount Sinai Hospital, NY, NY

%%

3030

2525

2020

1515

1010

55

00AA B1B1 B2B2 CC

P<0.001P<0.001

N=207N=207 N=223N=223 N=880N=880 N=365N=365

Kini A, Kini A, JACCJACC 1999;34:663-71 1999;34:663-71

Angiographic Characteristics associated with Post-ProceduralAngiographic Characteristics associated with Post-ProceduralCK-MB elevation (CK-MB <16U)CK-MB elevation (CK-MB <16U)

1675 Patients, Mount Sinai Hospital, NY, NY1675 Patients, Mount Sinai Hospital, NY, NY

%% 3030

2525

2020

1515

1010

55

00Multivessel InterventionMultivessel Intervention

P<0.001P<0.001

Single vessel InterventionSingle vessel Intervention

P<0.001P<0.001

Entire Group

Diffuse CAD

Focal CAD

Kini A, Kini A, JACCJACC 1999;34:663-71 1999;34:663-71





Multivessel InterventionMultivessel Intervention

Target Vessel (native)Target Vessel (native)

Saphenous Vein GraftSaphenous Vein Graft

PTCAPTCA

StentStent

Atherectomy or LaserAtherectomy or Laser

Abciximab UseAbciximab Use

Angiographic Success Angiographic Success

1010

77

9292

8888

55

2626

9191

1616

3.63.6

9090

7777

44

1717

8686

0.070.07

N.S.N.S.

0.10.1

0.50.5

0.0020.002

0.70.7

0.020.02

0.070.07

P valueP value

No differenceNo difference

Procedural CharactProcedural Charact(%)(%)



Device Characteristics associated with Post-ProceduralDevice Characteristics associated with Post-ProceduralCK-MB elevation (CK-MB <16U)CK-MB elevation (CK-MB <16U)

1675 Patients, Mount Sinay Hospital, NY, NY1675 Patients, Mount Sinay Hospital, NY, NYKini A, Kini A, JACCJACC 1999;34:663-71 1999;34:663-71

%%

3030

2525

2020

1515

1010

55

00PTCA*PTCA* PRCA**PRCA** StentStent PRCA+PRCA+

stentstent

N=174N=174 N=420N=420 N=477N=477 N=534N=534

OtherOtherdevicesdevices

N=70N=70*PTCA vs non-balloon devices**PRCA vs Stent

Postprocedural cTnT elevation and total balloon inflation timePostprocedural cTnT elevation and total balloon inflation timeJohansen O, Johansen O, Eur Heart JEur Heart J 1998;19:112-7 1998;19:112-7

PrevalencePrevalence(%)(%) 5050

4040

3030

2020

1010

00

1212

99

66

33

11

Risk RatioRisk Ratio

Total inflation time (sec)Total inflation time (sec)

<180<180 181-307181-307 >307>307

N= 75 patientsN= 75 patients

Cause di rilascio enzimatico

• Insuccesso procedurale

• Embolia coronarica

• Occlusione acuta transitoria

• Ampia dissezione

• Occlusione di collaterali

• Fenomeno “no-reflow”

• Ostruzione microvascolare

50-60%

CK elevations in Coronary Artery InterventionsAngiographic correlates (Dobies R, AHA 1998)

Prospective study: 774 ptsElevated CK (>160 mu/ml; MB>9.9 ng/ml) = 12%Prospective study: 774 ptsElevated CK (>160 mu/ml; MB>9.9 ng/ml) = 12%

Angiographic evidence for CK elevation = 92%

dissection

thrombus

side branchocclusion

decreased finalTIMI flow

distalembolization

abruptclosure

40%

24%

6%

6%17% 7%

PCI, PLATELET AND MICROVASCULAR EMBOLIZATION

Debries and platelet-thrombin-WBC micro-emboli

TIMI Myocardial Perfusion Grade andMaximum CK-MB 24 Hours Post-stent

0

0.5

1

1.5

2

2.5

TMPG 3 TMPG 0/1/2

Max

imu

m C

K-M

B /

Up

per

Lim

it o

f N

orm

al

2.23 + 2.70p = 0.01

n = 24 n = 34

TIMI Grade 3 Flow: 100%

CTFC: mean, 14.7 + 7.6

median, 13

TIMI Grade 3 Flow: 100%

CTFC: mean, 19.2 + 7.5

median, 17.5, p=0.02

0.78 + 0.60

Gibson, AHJ, in press

Integrilin Improves MyocardialPerfusion After Stenting

0

20

40

60

80

% W

ith

No

rma

l Blu

sh

69%

48%

P=0.085

Placebo Integrilin

180/2/180

N=16N=16 N=27N=27

% With Normal Blush % With Normal Blush

DSA > 5.3 GrayDSA > 5.3 Gray

0

5

10

15

20

Cir

cu

mfe

ren

ce (

cm

)N=24N=24N=32N=32

Placebo Integrilin

180/2/180

11.7+ 6.9

15.0+ 7.7

P=0.079

Blush CircumferenceBlush Circumference

CM Gibson 2000CM Gibson 2000

CK-RELEASE dopo PCI



Impatto prognostico


100

90

801 2 3 4 5 6

TEMPO (anni)

Sop

ravv

issu

til (

%)

p < 0.02

Controlli (n = 120)CK-MB >LSN (n = 253)

Kong et al. JAMA. 1997

Clinical Relevance of CK elevation following PCINorthwestern University Experience 1984-1993

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

11

00 3030 6060 9090 120120 150150 180180 210210 240240 270270 300300

Days From InterventionDays From Intervention

Fre

edo

m F

rom

Dea

th o

r M

IF

reed

om

Fro

m D

eath

or

MI cTnI <1.5 ng/mLcTnI <1.5 ng/mL

cTnI >1.5 ng/mLcTnI >1.5 ng/mL

PP =0.0028=0.0028

__

Elevated TnI and prognosis after PCI: Elevated TnI and prognosis after PCI: a prospective evaluation from the SYMPHONY STUDYa prospective evaluation from the SYMPHONY STUDY


N=230N=230

N=251N=251

EPICEPIC

EPILOGEPILOG

EPISTENTEPISTENT

Periprocedural CPK Elevation Periprocedural CPK Elevation and Mortality in 3 RCTs of and Mortality in 3 RCTs of GP IIb/IIIa InhibitorsGP IIb/IIIa Inhibitors

Topol, Circulation Topol, Circulation 2000;101:570.2000;101:570.

Correlation Between Elevated Cardiac Markers and Long-term Mortality

1. Antman EM, et al. N Engl J Med. 1996; 335: 1342-1349.2. Alexander JH et al. Circulation. 1999; Suppl 1:1-629.

5.7%

9.2%

12.6%

14.5%

19.9%

1-2 2-3 3-5 5-10 10

% mortality at 42 days

<0.4 <1.0 <2.0 <5.0 <9.0 9.0

2

4

6

8

0

% mortality at 6 months2

1.7%

3.4%

3.7%

6.0%

7.5%

1.0%

5

10

15

20

0

Cardiac Troponin 1 (ng/ML) CK-MB (x ULN)

Probability of Death by Max CK Ratio

0

0,05

0,1

0,15

0,2

0,25

0 2 4 6 8 10 12 14 16 18 20

Max CK Ratio

ST elevationNon ST elevation

Probability of Death or MI by Max CK Ratio

0

0,05

0,1

0,15

0,2

0,25

0 5 10 15 20

Max CK Ratio

NonST elevation

ST elevation

Probability of 6-month Events By Max CK RatioProbability of 6-month Events By Max CK Ratioacross the spectrum of ACS: the GUSTO IIb studyacross the spectrum of ACS: the GUSTO IIb study

Savonitto S, JACC 2002, in pressSavonitto S, JACC 2002, in press

0 1.0 2.0Time (years)

0

40

20

60

80

100

Cu

mu

lati

ve s

urv

ival

(%

)

Q-wave

3-5 x nl

1-3 x nl

normal

5-8 x nl

Impact on survival of Electrocardiographic Q-waves and enzimatic myocardial infarction

Stone; Circulation 2001;104:642Stone; Circulation 2001;104:642

> 8 x nl

CK-RELEASE dopo PCI



Impatto prognostico


CK- Release dopo PCI

Causa di una prognosi peggiore..

… o marker di un rischio coronarico più grave?

Microinfarti e prognosi

CK-RELEASE AND CAUSES OF DEATH

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

CK-release e prognosi avversa: potenziali meccanismi

• Microinfarti = microrientri = suscettibilità a eventi aritmici

• Microembolizzazione: compromissione di circoli collaterali preformati = suscettibilità all’ischemia acuta e alle aritmie

• Microembolizzazione = alterata funzione del microcircolo

Coronary Microvascular Dysfunctionin DCM

Prognosis

Neglia et al, Eur Heart J; 2000 (abs)

PET MBF dip ≤ 1.36 ml/min/g

Epidemiology and prognostic impactEpidemiology and prognostic impactof biochemical marker elevations of biochemical marker elevations

after percutaneous coronary interventionsafter percutaneous coronary interventions

A multicenter survey sponsored by the Italian Working Group on

Atherosclerosis, Thrombosis and Vascular Biologyand the

Italian Society of Invasive Cardiology (GISE))

Chairmen:Chairmen:Claudio Cavallini, MDClaudio Cavallini, MD,, Ospedale S. Maria dei Battuti, TrevisoOspedale S. Maria dei Battuti, Treviso

Stefano Savonitto, MD, Stefano Savonitto, MD, Ospedale Ospedale Niguarda Ca’ Granda, MilanNiguarda Ca’ Granda, Milan

Roberto Violini, MD,Roberto Violini, MD, Ospedale San Camillo, RomeOspedale San Camillo, Rome

Primary objectivePrimary objective

Secondary objectivesSecondary objectives

To evaluate prospectically the prognosticTo evaluate prospectically the prognosticimpact of CK-MB elevations >2x ULNimpact of CK-MB elevations >2x ULNafter PCI on total mortality at 24 monthsafter PCI on total mortality at 24 months

•To assess the incidence and risk determinantsTo assess the incidence and risk determinantsof enzyme and marker elevations after PCIof enzyme and marker elevations after PCI•To assess the predictive value of each markerTo assess the predictive value of each markerof necrosis and inflammation, and their of necrosis and inflammation, and their combination on the aggregate of death,MI combination on the aggregate of death,MI and clinical restenosisand clinical restenosis•To assess the risk of early (subacute stentTo assess the risk of early (subacute stentthrombosis) and late (clinical restenosis) eventsthrombosis) and late (clinical restenosis) eventsand their association with biochemical variablesand their association with biochemical variablesand predefined genetical polimorphismsand predefined genetical polimorphisms

Inclusion criteriaInclusion criteria

Exclusion criteriaExclusion criteria

All of the patients undergoing PCIsAll of the patients undergoing PCIsduring the study periodduring the study period

Only patients not willing toOnly patients not willing toparticipate in the studyparticipate in the study

The study monitors will compare the study enrollment log The study monitors will compare the study enrollment log with the Cath lab PCI log: centers enrolling <90% of theirwith the Cath lab PCI log: centers enrolling <90% of their

patients will be axcluded from the study patients will be axcluded from the study

PCI procedures and pharmacological interventionsPCI procedures and pharmacological interventionsare to be carried out according to local routineare to be carried out according to local routine

Blood samplingBlood samplingBlood samplingBlood sampling

Baseline: immediately prior toBaseline: immediately prior to PCIPCI

Baseline: immediately prior toBaseline: immediately prior to PCIPCI

6 to 10 hours after the procedure 6 to 10 hours after the procedure 6 to 10 hours after the procedure 6 to 10 hours after the procedure

16 to 24 hours after the procedure16 to 24 hours after the procedure16 to 24 hours after the procedure16 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 laboratoryfor biochemical and genetic determinations.

BiochemicalBiochemicalmarkersmarkers

Mass CK-MBMass CK-MBTnITnIC-reactive proteinC-reactive proteinSerum Creatinine (substudy)Serum Creatinine (substudy)

GeneticGeneticdeterminationsdeterminations

PlAPlA11/PlA/PlA22 polimorphism for polimorphism for

the platelet GPIIIa receptorthe platelet GPIIIa receptor

Polimorphism for the Polimorphism for the platelet GPIa receptorplatelet GPIa receptor

Polimorphism I/D Polimorphism I/D for the ACE genefor the ACE gene

TREVISO GENOVAMILANO Niguarda

MERCOGLIANOBRESCIA (O.C.)CUNEOCOTIGNOLAPAVIAUDINENOVARAROMA PARMALEGNANO BOLZANOBRESCIA (P.A.)MIRANO

ARRUOLAMENTO NEI VARI CENTRI

3168

78104

200216

232253

270291296

336400408416

440

0 100 200 300 400 500

0

500

1000

1500

2000

2500

3000

3500

4000

4500

1 2 3 4 5 6 7 8 9 10

enrolment

Month (yr 2000)

4039 patients4039 patients

Enrolment in the Italian PCI -BM (Biochemical Marker) studyEnrolment in the Italian PCI -BM (Biochemical Marker) study16 participating centers16 participating centers

Ist patientIst patientFebruary 1February 1stst

Last patientLast patientOctober 31October 31

Conclusioni• Rilascio enzimatico dopo PCI o CABG: frequente

• Significato prognostico ?: sfavorevole (++ in > 5-10 volte LSN)

• Raccomandazione : prevenire

• Come trattare? : prevenzione secondaria

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Stefano Savonitto, Claudio Cavallini Dipartimento di Cardiologia e Cardiochirurgia Angelo De...

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