Il trattamento delle SCA: la terapia medica. ACS without persistent ST-segment elevation

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1 Il trattamento delle SCA: la terapia medica Manlio Cocozza Responsabile U.O. Cardiologia Clinica Sanatrix Napoli Ischia 25 giugno 24 III Seminario Regionale ARCA Spectrum of Acute Coronary Syndromes Stable Angina Cannon CP Unstable Angina Non-Q wave MI Non ST Elevation ACS CRP Troponin CK-MB ECG - ST Q wave MI ST Elevation MI ECG - ST ACS without persistent ST-segment elevation

2 ACC/AHA Classifications Expert Opinion and Recommendations Treatment options I IIa IIb III Intervention is useful and effective Evidence conflicts/opinions differ but leans toward efficacy Evidence conflicts/opinions differ but leans against efficacy Intervention is not useful/effective and may be harmful JACC 1999; Vol 33, No 7: Five categories of treatment Antiischaemic agents Anti-platelet agents Anti- thrombin agents Fibrinolytics Coronary revascularization

3 TERAPIA ANTITROMBOTICA NELLE SINDROMI CORONARICHE ACUTE NON ST Antiaggreganti piastrinici ASA Clopidogrel Inibitori glicoproteici IIb / IIIa Anticoagulanti Eparina non frazionata Eparina a basso peso molecolare MANAGEMENT OF PATIENTS WITH UA AND NSTEMI ASA should be administred as soon as possible after presentation and continued indefinitely. ( class I; level of Evidence : A) ACC/AHA Unstable Angina and NSTEMI Guideline Update JACC October 22

4 Prevalence of ASA Resistance 325 patients with stable CVD taking ASA 325 mg >7days Clinical Outcomes: Aspirin Responsiveness by Aggregometry And PFA-1 % Death, MI, CVA % Death, MI, CVA Not Aspirin Resistant, N = 39 Aspirin Resistant, N = 17 Log rank χ 2 =5.5, p= P= ASA-R: mean aggregation 7% with µm 1 ADP & 2% with.5 mg/ml AA Gum PA et al. Am J Cardiol 21;88: Days after Treatment ASA Responder N=294 ASA Non- Responder N=32 Clinical Outcomes based on PFA-1 Results Gum PA et al. JACC 23;41:961-5 TERAPIA ANTITROMBOTICA NELLE SINDROMI CORONARICHE ACUTE NON ST Antiaggreganti piastrinici ASA Clopidogrel Inibitori glicoproteici IIb / IIIa Anticoagulanti Eparina non frazionata Eparina a basso peso molecolare

5 CLOPIDOGREL RR 2 % RR 2 % Clopidogrel should be administred to hospitalized patients who are unable to take ASA because of hypersensitivity or maior gastrointestinal intolerance (class I; level of evidence : A) In ACS patients clopidogrel is recommended for acute treatment for at least 9-12 months (class I; level of Evidence : B) i risultati dimostrano effetto precoce di clopidogrel ACC/AHA-ESC Guidelines 22 CLOPIDOGREL In patients for whom a PCI is planned and who are not high risk for bleeding, clopidogrel should be started and continued for at least 1 month (class I ; level of Evidence : A) and for up to 9-12 months (class I; level of Evidence : B) In patients taking clopidogrel in whom elective CABG is planned, the drug should be withheld for 5 days (class I; level of Evidence : B) / % *1 # * +, % -. " % &'( )'! ACC/AHA-ESC Guidelines 22!" # %%& &'(

6 TERAPIA ANTITROMBOTICA NELLE SINDROMI CORONARICHE ACUTE NON ST Antiaggreganti piastrinici ASA Clopidogrel Inibitori glicoproteici IIb / IIIa Anticoagulanti Eparina non frazionata Eparina a basso peso molecolare " # % & ( ( )! + ) / 1 # * " *2 " # * **( 5*** 6 # & 7 8 / # *9 * %! ', -,., ',!,,,,,, # # # + * *# + GP IIb/IIIa IIIa Inhibitors Reduce Mortality in DiabeticPatients with non-st Segment Elevation Acute Coronary Syndromes 3-Day Mortality Diabetic Patients Trial N Odds Ratio & 95% CI Placebo IIb/IIIa PURSUIT PRISM PRISM-PLUS GUSTO IV PARAGON A PARAGON B Pooled Breslow-Day: p= IIb/IIIa Better p=.33 p=.7 p=.17 p=.22 p=.51 p=.93 p= Placebo Better 6.1% 4.2% 6.7% 7.8% 6.2% 4.8% 6.2% 5.1% 1.8% 3.6% 5.% 4.6% 4.9% 4.6% Roffi M. Circulation 21;14:2767

7 GP IIb/III IIIa ANTAGONISTS A platelet GP IIb/IIIa antagonist should be administred, in addition to ASA and heparin, to patients in whom catheterization and PCI are planned. The GP IIb/IIIa antagonist may also be administred prior to PCI (class IIa; level of evidence : A) A platelet GP IIb/IIIa antagonist should be administred to patients already receiving heparin, ASA, and clopidogrel in whom catheterization and PCI are planned (class IIa; level of evidence : B) Eptifibatide or tirofiban should be administred, in addition to ASA and LMWH or UFH, to patients with continuing ischemia, and elevated troponin, or with other high-risk features in whom an invasive management strategy is not planned (class IIa; level of evidence :A) ESC-ACC/AHA Guidelines 22 TERAPIA ANTITROMBOTICA OTTIMALE NELLE SINDROMI CORONARICHE ACUTE NON ST Antiaggreganti piastrinici ASA Clopidogrel Inibitori glicoproteici IIb / IIIa Anticoagulanti Eparina non frazionata Eparina a basso peso molecolare

8 ANTICOAGULATION THERAPY Anticoagulation with subcutaneous LMWH or intravenous UFH should be added to antiplatelet therapy with ASA and / or clopidogrel (class I; level of Evidence : A) Enoxaparin is preferable to UFH as an anticoagulant in patients with UA / NSTEMI, in the absence of renal failure and unless CABG is planned within 24h (class IIa; level of evidence :A) ACC/AHA-ESC Guidelines 22 % eventi (morte, IM) La sospensione della terapia con statine aumenta il rischio di eventi in pazienti con sindrome coronarica acuta Statine sospese 14% No statine 7.5% 6% Statine iniziate 3.7% Statine continuate Follow up (3 gg) La sospensione delle statine triplica il rischio di eventi hard a 3 gg Heeschen et al. Circulation 22;15: '&' 21' ,%. 93& )),%. 82#' 82,%. 76,%. '4,%. *)+ ),%.,%. (5(6,%. 4,%. ',%. *,;. #! " # # # # :,;.! "! " p ! 3 NON ST ELEVATION ACS INVASIVE OR CONSERVATIVE STRATEGY? "& )* +,-+..

9 + + ) Physical examination, (Echocardiogram) ECG monitoring, Blood samples No persistent ST-Segment elevation Heparin (LMWH or UFH), ASA, Clopidogrel*, Betablockers, Nitrates Undetermined diagnosis ASA High risk Low risk Second troponin measurement Gp2b/3a Cor Angiography (PCI CABG) 4 Twice negative Stress test Cor. angiography New ESC guidelines High risk definition TIMI Risk score Age >65 At least three risk factors for coronary artery disease Significant coronary stenosis (eg, prior coronary stenosis > 5%) ST deviation Severe anginal symptoms (eg, > 2 anginal events in last 24 h) Use of aspirin in last 7 days Elevated serum cardiac markers Relationship between TIMI risk score and event rate* 4 %.%,,/ +/ / /./ / *p<.1 by 2 for trend

10 The Global Registry of Acute Coronary Events (GRACE) The GRACE prediction tool was developed using data from 1567 patients in the registry who were discharged from the hospital alive from April 1999 to March 22 and had complete six-month follow-up NINE VARIABLES PREDICTIVE OF SIX-MONTH MORTALITY 13,% ACS AND ECG CHANGES 14,3% 9,% Older age Previus MI History of CHF Increased pulse rate at presentation Lower blood pressure at presentation Elevated initial serum creatinine level Elevated initial serum cardiac biomarker levels ST-segment depression on presenting electrocardiogram Not having a percutaneus coronary intervention performed in the hospital Eagle KA et al. JAMA 24; 291: ,8% 21,9% NO ECG Changes ST Deviation,5 mm ST Deviation >/=1 mm LBBB T wave Inversion Cinetica dei markers cardiaci bio-umorali Mioglobina nell IMA Multipli dei valori di cut-off per IMA Troponine nell IMA CK MB nell IMA Troponine nell angina instabile Limite per la diagnosi Limite superiore di normalità Tempo dall insorgenza dei sintomi (gg)

11 Patients with recurrent ischemia Recurrent chest pain Dynamic ST-segment changes (ST-segment depression or transient ST segment elevation) Elevated troponin levels Diabetes Early post infarction unstable angina Hemodynamic instability Major arrhythmias (VF, VT) Planning Emergency GpIIB/IIIA and Coronary angiography * <' (-,+. * @?' *=> A B!! "" # # # *1 &2 3!"&2& ", * < < < < < # =4 &) *24 -+! # : <' C' D& '4 *1 &2 3!"&2& ", *

12 ACS with persistent ST-segment elevation + + ) Physical examination, ECG monitoring, Blood samples Persistent ST-Segment elevation Thrombolysis PCI New ESC guidelines

13 ISTITUZIONE UTIC (1962) TREND IN MORTALITA Mortalità pre-utic 3%-4%. Mortalità a 5 anni dalla istituzione delle UTIC 15%- 25% : anni in cui ASA,betabloccanti e fibrinolitici erano sottoutilizzati 27% (Top-Pedersen 1995; Abrahamsson 1998) morte 3gg 17% La prognosi è migliore per i pazienti trattati da cardiologi e in strutture dedicate rispetto a quelli trattati da medici e strutture non specialistiche (Jollis 1994 e 1996) morte inh 19% % Heidenreich P.A. Am J Med. 21;11 LA RIPERFUSIONE FARMACOLOGICA

14 M o r t a l i t à (%) reappraisal of the golden hour absolute benefit per 1 treated patients Boersma et al. Lancet 1996;348: st hour: 65 lives 2nd hour: 37 lives 3rd hour: 26 lives treatment delay (h) MORTALITÀ NEI PRIMI 35 GIORNI DOPO TROMBOLISI IN STUDI CLINICI SU LARGA SCALA % GISSI-1 (SK) 9.2% 8.9% ISIS-2 (SK) GISSI-2 (rt-pa) 6.3% GUSTO I (rt-pa) 7.4% GUSTO III (r-pa) 6.2% ASSENT-2 (TNK-tPA) 5.4% ASSENT-3 (TNK-tPA) 21')+-+'-,;!".E # : ' - ' - + *2F => *2 => 2) # E* )'+ *1 &2 3!"&2& ", *

15 LIMITI DELLA TERAPIA TROMBOLITICA (Class I - level of evidence A ) lisi inefficace nel 25% riperfusione incompleta nel 3% riocclusione precoce nel 1% controindicazioni al trattamento TAMI Study Group. Circulation 199 The GUSTO Angiographic Investigators. N Engl J Med 1993 TIME TT VS CONTROLS RIOCCLUSIONE PRECOCE m o r t a l i t y (%) 2 m % - 4 % - 2% ns TT Controls % mortalità ,5 riocclusione persistenza risultato Hour -1 >1-2 >2-3 >3-6 >6-12 >12-24 Boersma: The Lancet 1996 riocclusione persistenza risultato TAMI Study

16 COMBO THERAPY: FLUSSO TIMI 3 A 6 MINUTI Solo trombolitico (dose piena) Trombolitico (metà dose) + inibitore GP IIb/IIIa 1 TROMBOLISI IN COMBINAZIONE CON INIBITORI GP IIB/IIIA: MORTALITÀ A 3 GIORNI Solo trombolitico (dose piena) Trombolitico (metà dose) + inibitore GP IIb/IIIa Pazienti (%) Mortalità (%) TIMI 14 SPEED INTRO-AMI (n=224) (n=238) (n=35) 2 GUSTO V ASSENT 3 COMPLICANZE EMORRAGICHE MAGGIORI COMPLICANZE EMORRAGICHE NELL ANZIANO (>75 AA) P<.1 p:.5 5 4,5 4 3,5 3 2,5 2 1,5 1, GUSTO V ASSENT 3 trombolisi "combo" % ASSENT trombolisi "combo"

17 Mortalità (% ) TROMBOLISI PRE-OSPEDALIERA: MORTALITÀ A 5 ANNI % GREAT.5 J Am Coll Cardiol 1997; 3: % Pre-ospedaliera 19%.15 RaMI 47% Int J Cardiol 1998; 65 (S1): Ospedaliera Percutaneous Corononary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost( almost) everything? Nallamothu BK Am J of Card 23 'G-))! # : <' C' D& '4 Nallamothu BK Am J of Card 23 *1 &2 3!"&2& ", *

18 CARESS IN AMI Combined Abciximab RE-canalization Synergistic Study IN Acute Myocardial Infarction Abciximab + rpa High risk ST AMI n=18 Primary Care CCU Abciximab + rpa TERAPIA ANTITROMBOTICA / ANTICOAGULANTE OTTIMALE NELLE SINDROMI CORONARICHE ACUTE CON TRATTO ST Aspirina Eparina Inibitori glicoproteici IIb/IIIa (?) Delayed conditional PCI Immediate PCI Primary end-point: 3 day combined end-point of: death, re-ami, refractory ischemia + : + * ) + ( ) + * *! 4 + ( < '. * * =/ >?.!'@A-! ; : ) ESC GUIDELINES 23 Management of acute myocardial infarction with ST-segment elevation! "# % &' %( " )! ' *+ %! '* I - level of evidence A

19 TERAPIA ANTITROMBOTICA / ANTICOAGULANTE OTTIMALE NELLE SINDROMI CORONARICHE ACUTE CON TRATTO ST Aspirina Eparina Inibitori glicoproteici IIb/IIIa (?) EPARINA + ASA NELLE SINDROMI CORONARICHE ACUTE Differenti studi nel periodo tra il 1988 e il 1995 hanno dimostrato che l eparina non frazionata (generalmente attraverso un infusione e.v. continua), associata all ASA, riduce la frequenza degli eventi cardiovascolari maggiori (morte, IM) di circa il 25-3%, rispetto all ASA da solo, nei pazienti con sindromi coronariche acute. TERAPIA ANTITROMBOTICA / ANTICOAGULANTE OTTIMALE NELLE SINDROMI CORONARICHE ACUTE CON TRATTO ST Aspirina Eparina Inibitori glicoproteici IIb/IIIa (?)

20 Role of IIb/IIIa inhibitors Gusto V patients rpa abcix+1/2 rpa Death 5,9% 5,6% remi 3,5% 2,3% * Stroke,9% 1,% ICH,6%,9% ICH >75y 1,1% 2,1% * any bleeding 13,7% 24,6% * GUSTO V Investigators Lancet 21;357: Role of IIb/IIIa inhibitors Assent 3 TNK+UHF 1/2TNK+abcix Death 6,% 6,6% reinfarction 4,2% 2,2% * Ref. ischemia 6,2% 3,5% * Major bleeds 2,2% 4,3% * ASSENT 3 Investigators Lancet 21;358: ESC GUIDELINES 23 Management of acute myocardial infarction with ST-segment elevation the clinical benefit and safety of the combination of abciximab with half-dose fibrinolytics and reduced doses of heparin has been tested in in two large trials, the routine use of a reduced dose fibrinolytic with abciximab or other glycoprotein IIb/IIIa can not be recommended. Class III level of evidence A Routine Prophylactic Terapies in the Acute Phase RECOMANDATION Aspirin mg (no enteric-coated formulation) I.V. BB if no controindication ACE oral formulation since first day (high risk patients) ACE oral formulation since first day (all patients if no contr.) Nitrates Cacium antagonists Magnesium Lidocaine I X X IIa X IIb X X III X X Evidence A A A A A B B

21 News: guidelines change! Time is muscle and the more time one waits to open an occluded artery, the greater the loss of myocardium and the greater the chance of death. The results of large clinical trials of statin drugs show that lower LDL significantly improving outcomes for patients. New American College of Cardiology and American Heart Association guidelines for the management of patients with ST-elevation MI are adopting an aggressive approach. The recommendations call for early reperfusion and statins for those with a low-density lipoprotein of 1 mg/dl or greater. Scheduled to be published in the July 21, 24 issue of the Journal of the American College of Cardiology