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Stefano Savonitto, Claudio Cavallini

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

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Stefano Savonitto, Claudio Cavallini

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  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 procedureor 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

  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 >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 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 2001;37:355a

  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; 103:2780-2783

  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) R=0.61 P=0.02 0 10 20 30 40 50 60 70 80 90 100 CKMB (ng/ml) Ricciardi Circulation 2001; 103:2780-2783

  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 <16U) 1675 Patients, Mount Sinay Hospital, NY, NY Kini A, JACC 1999;34:663-71 Normal CK-MB (n=1362) Elevated CK-MB (n=313) Charact (%) P value Female CCS class III-IV Renal failure Systemic Atherosclerosis Abciximab Use Betablocker therapy 0.02 0.001 <0.001 <0.001 <0.001 <0.001 37 52 7 16 51 27 30 33 3 10 36 41 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 >1.5 ng/ml (Dimension, Dade Behring, Detection limit 0.05 ng/ml) Negative TnI (n=251) Positive TnI (n=230) 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 >1.5 ng/ml (Dimension, Dade Behring, Detection limit 0.05 ng/ml) Negative TnI (n=251) Positive TnI (n=230) Medical history (%) P value Chronic Angina Bypass Surgery Previous MI Previous PCI Stroke Heart Failure Chronic Renal Insufficiency 0.05 0.9 0.2 0.9 0.4 0.3 0.5 43 16 18 18 2 5 0.4 52 15 23 18 1 3 0 Cantor WJ, submitted

  15. Risk of troponin elevation after PCI a prospective substudy of SYMPHONY TnI >1.5 ng/ml (Dimension, Dade Behring, Detection limit 0.05 ng/ml) Negative TnI (n=251) Positive TnI (n=230) Indication (%) P value Elective Recurr/Refract Ischemia Abrupt Closure Hemodynamic Instability (re)Infarction Days from qualyfying events 0.5 0.05 0.1 0.3 0.001 <0.001 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 <16U) 1675 Patients, Mount Sinai Hospital, NY, NY 30 25 20 15 10 5 0 P<0.001 % A B1 B2 C N=365 N=880 N=223 N=207 Kini A, JACC 1999;34:663-71

  17. Angiographic Characteristics associated with Post-Procedural CK-MB elevation (CK-MB <16U) 1675 Patients, Mount Sinai Hospital, NY, NY P<0.001 30 25 20 15 10 5 0 % P<0.001 Entire Group Diffuse CAD Focal CAD Multivessel Intervention Single vessel Intervention Kini A, JACC 1999;34:663-71

  18. Risk of troponin elevation after PCI a prospective substudy of SYMPHONY TnI >1.5 ng/ml (Dimension, Dade Behring, Detection limit 0.05 ng/ml) Negative TnI (n=251) Positive TnI (n=230) Procedural Charact (%) P value Multivessel Intervention Target Vessel (native) Saphenous Vein Graft PTCA Stent Atherectomy 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 <16U) 1675 Patients, Mount Sinay Hospital, NY, NY Kini A, JACC 1999;34:663-71 30 25 20 15 10 5 0 % PTCA* PRCA** Stent PRCA+ stent Other devices *PTCA vs non-balloon devices **PRCA vs Stent N=534 N=477 N=420 N=174 N=70

  20. Postprocedural cTnT elevation and total balloon inflation time Johansen O, Eur Heart J 1998;19:112-7 N= 75 patients 12 9 6 3 1 Prevalence (%) Risk Ratio 50 40 30 20 10 0 <180 181-307 >307 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 (>160 mu/ml; MB>9.9 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. 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, p=0.02 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

  25. Integrilin Improves MyocardialPerfusion After Stenting % With Normal Blush DSA > 5.3 Gray Blush Circumference 20 P=0.085 69% P=0.079 15.0+ 7.7 15 48% 11.7+ 6.9 Circumference (cm) 10 % With Normal Blush 5 N=16 N=27 N=32 N=24 0 Placebo Integrilin 180/2/180 Placebo Integrilin 180/2/180 CM Gibson 2000

  26. CK-RELEASE dopo PCI • Substrato fisiopatologico • Correlati clinici, angiografici e procedurali • Impatto prognostico • Esiste un rapporto di causa/effetto?

  27. Clinical Relevance of CK elevation following PCINorthwestern University Experience 1984-1993 100 Sopravvissutil (%) p < 0.02 90 Controlli (n = 120) CK-MB >LSN (n = 253) 80 1 2 3 4 5 6 TEMPO (anni) Kong et al. JAMA. 1997

  28. Elevated TnI and prognosis after PCI: a prospective evaluation from the SYMPHONY STUDY 1 _ cTnI <1.5 ng/mL 0.9 N=251 cTnI >1.5 ng/mL 0.8 N=230 0.7 Freedom From Death or MI 0.6 P =0.0028 0.5 0.4 0.3 0 30 60 90 120 150 180 210 240 270 300 Days From Intervention Cantor WJ, submitted

  29. EPIC EPILOG EPISTENT Periprocedural CPK Elevation and Mortality in 3 RCTs of GP IIb/IIIa Inhibitors Topol, Circulation 2000;101:570.

  30. 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  5-10  10  3-5 0 0 <0.4 <1.0 <2.0 <5.0 <9.0 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 1:1-629.

  31. 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

  32. Impact on survival of Electrocardiographic Q-waves and enzimatic myocardial infarction 100 80 60 Cumulative survival (%) 40 20 0 0 1.0 2.0 Time (years) normal 1-3 x nl 3-5 x nl 5-8 x nl > 8 x nl Q-wave Stone; Circulation 2001;104:642

  33. CK-RELEASE dopo PCI • Substrato fisiopatologico • Correlati clinici, angiografici e procedurali • Impatto prognostico • Esiste un rapporto di causa/effetto?

  34. CK- Release dopo PCI Causa di una prognosi peggiore.. … o marker di un rischio coronarico più grave?

  35. Microinfarti e prognosi

  36. CK-RELEASE AND CAUSES OF DEATH • SUDDEN DEATH • SUBSEQUENT REVASCULAR. • MYOCARDIAL INFARCTION • NO CARDIAC ORIGIN

  37. 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

  38. Coronary Microvascular Dysfunctionin DCMPrognosis PET MBF dip ≤ 1.36 ml/min/g Neglia et al, Eur Heart J; 2000 (abs)

  39. 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: Claudio Cavallini, MD,Ospedale S. Maria dei Battuti, Treviso Stefano Savonitto, MD, Ospedale Niguarda Ca’ Granda, Milan Roberto Violini, MD,Ospedale San Camillo, Rome

  40. Primary objective To evaluate prospectically the prognostic impact of CK-MB elevations >2x 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

  41. 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 <90% of their patients will be axcluded from the study PCI procedures and pharmacological interventions are to be carried out according to local routine

  42. 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.

  43. 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

  44. 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

  45. Enrolment in the Italian PCI -BM (Biochemical Marker) study 16 participating centers 4039 patients Month (yr 2000) Ist patient February 1st Last patient October 31

  46. The end 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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