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Tratamentul cu antiagregante dupa angioplastia coronariana percutanataConf. Dr. Serban BALANESCU, FESCClinica de Medicina Interna si Cardiologie,Spitalul Clinic de Urgenta Bucuresti.
Ce este angioplastia coronariana percutanata ?Definitie: Metoda de revascularizare endovasculara (percutanata)bazata pe dilatarea endovasculara a stenozelor arteriale cu o sonda cu balonasSe folosesc doua tehnici de angioplastie:Cu balonas (angioplastie simpla)Cu implantare de stent (> 95% din cazuri)
Numarul procedurilor de revascularizare prin angioplastie este in crestere fata de CABGHeart Disease & Stroke Statistics: 2007 Update.
Deschizatorii de drumDotter CT.Judkins MP.Circulation 1964;30:654.Zeitler EJ.Vasa 1973;2:401.Gruentzig AR et al.Circulation 1976;54(suppl II):II-81.
Prima PCI primara in IMAGruentzig AR, Senning A, Siegenthaler WE. Nonoperative dilation of coronary artery stenosis: percutaneous transluminal coronary angioplasty.N Engl J Med 1979;301:61 8.Hartzler GO et al. PTCA with and without thrombolytic therapy for treatment of acute myocardial infarction. Am Heart J 1983;106:965-73
Angioplastia induce leziune endoteliala extinsa +/- introducerea unui corp strain (stent) intracoronarMecanismele de crestere a lumenului:Fractura longitudinala a placii ASCompresia placii contra peretelui arterial+/- extractia placii AS prin aterectomie= necesitatea tratamentului antitrombotic dupa PCIStent
Tratamentul cu antiagregante reduce tromboza subacuta de stent fata de anticoagulantele orale0123456ISARFANTASTICSTARSAnticoagulant oral + ASATiclopidina + ASAN.Engl.J.MedCirculationN. Engl. J. Med1996;334:1084 1998;98:15971998;339:1665Tromboza subacuta de stent (%)
Tratamentul cu antiagregante plachetare se asociaza incidenta redusa a hemoragiilor majore dupa PCIBertrand M et al. Circulation 1998;98:1597-603.0510152025Aspirina +anticoagulant oralAspirina + ticlopidinaHemoragii sau complicatii vasculare perifericeEvenimenteadverse cardiace majorep = 0.01Incidenta (%) p = 0.03
CLASSICS: profilul de siguranta si eficienta al clopidogrelului este superior ticlopidinei la 28 zile dupa PCI cu stentBertrand ME et al. Circulation 2000;102:624-9.Sangerare, citopenie, oprirea medicatiei antiplachetare (%)
Inhibitorii receptorilor plachetari de ADP sunt superiori anticoagulantelor dupa PCI cu stentEvenimente cardiace averse(% deces, IMA, revasc.)04812ISARN=517FANTASTICN=485STARSN=1653MATTISN=350Ticlopidine + ASACoumadin + ASA6.21.68.35.72.70.5115.63.6ASACLASSICSN=10201.51.20.9Clopidogrel + ASAClopidogrel LD + ASA
PCI-CURE: tratamentul cu aspirina si clopidogrel reduce riscul de deces si IMA recurent dupa angioplastie (urmarire medie = 8 luni)Mehta SR et al. Lancet 2001;358:257-33.N = 2658 pts cu SCA; clopidogrel (n=1313) vs placebo (n=1345); stenturi la ~82% pts
PCI-CURE: beneficiul clopidogrelului pana la 1 an de la angioplastie la cei stentati si la cei tratati cu angioplastie simplaMehta SR et al. Lancet 2001;358:257-33.N = 2658 pts cu SCA; clopidogrel (n=1313) vs placebo (n=1345); urmarire medie: 8 luni
CREDO: clopidogrelul reduce incidenta decesului, a IM si a AVC la 1 an de la PCI Steinhubl SR et al. JAMA 2002;288:2411-20.N = 2116 pts; SCA la 66% (n=1407); clopidogrel (n=1053) vs placebo (n=1063)
Tipurile de tromboza coronariana dupa angioplastie: intraprocedurala (~0.6%)Medicatie intraprocedurala insuficienta:Heparina < 70 U /kgcLipsa incarcarii cu clopidogrel si aspirinaNeutilizarea inhibitorilor de GP 2b/3aSindrom coronarian acutPlaca AS instabilaFactori procoagulanti
Tipurile de tromboza coronariana dupa angioplastie: subacuta 24h - 28 zile dupa PCI (0.5 5.7%)M, 68 ani, IMA anterior h6 de la debutPCI primara cu stent 2.5 x 13 mm
Tipurile de tromboza coronariana dupa angioplastie: subacuta 24h - 28 zile dupa PCI (0.5 5.7%)C.m. frecvent in primele 10 zile de la PCIOprirea intempestiva a tratamentului antiagregantRezistenta la aspirina sau la clopidogrel Defecte mecanice ale stentului:Lipsa expansionareDisectie rezidualaStent mic si lung in vas mic < 3 mmDiabetici, SCA
Tipurile de tromboza coronariana dupa angioplastie: tardiva > 28 zile 1 anAsociata de obicei cu implantarea de stenturi farmacologic activeLa oprirea precoce (< 1 an) a tratamentului antiplachetar dual (aspirina + clopidogrel)Determinata de lipsa endotelizarii stentului prin intarzierea vindecarii post PCIVirmani R et al. Circulation 2004;109:701-5.
Mecanismele trombozei tardive de stent dupa implantarea de stent farmacologic activLuscher TF et al. Circulation 2007;115:1051-8.
BASKET-LATE: oprirea tratamentului cu clopidogrel dupa 6 luni de la implantarea de DES creste riscul de IMA recurent in primul anPfisterer M et al. JACC 2006;48:2584-91.% pacientip=0.04p=0.09N = 746 pts; DES (n=499) vs stenturi simple (n=244); clopidogrel 6 luni; urmarire = 1 an
Incidenta trombozei tardive de stent in principalele studii cu DES este redusa (~ 1.3%) Mauri L et al. NEJM 2007;356:1020-9.Meta-analiza a cate 4 studii randomizate cu DES rapamicina si paclitaxel vs stenturi simpleAparitia trombozei tardive de stent dupa DES: NECESITATEA PRELUNGIRII TERAPIEI ANTIPLACHETARE DUALE 1 an
Prevenirea trombozei tardive de stent dupa angioplastie este multifactorialaTrombogenitatea stentului material design acoperirea suprafetei metode terapeutice asociate (brahiterapie)BIOCOMPATIBILITATESTENTING MULTIPLUFLUXUL CORONARFactori pacient / leziune diametru vas, lungime stenoza SCA caracteristicile placii activitatea locala plachete / coagulareFactori procedurali subexpansionare apozitie incompleta disectie tromb, protruzie tisulara terapie antitrombotica ineficaceHonda Y, Fitzgerald PJ. Circulation 2003;108:2-5.
OPTIMUS: dublarea dozei de intretinere de clopidogrel la 150 mg/zi creste eficienta antiplachetara in diabetul zaharat de tip IIAngiolillo DJ et al. Circulation 2007;115:708-16.
Care este tratamentul antitrombotic la pacientii tratati cu PCI cu stent care sunt in FiA ? Necesitatea terapiei antiagregante dupa PCI Necesitatea terapiei anticoagulante ptr FiA RISCUL HEMORAGIC ?
Recomandarile de tratament antitrombotic din ghidurile fibrilatiei atrialeFuster V et al. ACC/AHA/ESC Guidelines for the Management of Patients with Atrial Fibrillation. EHJ 2006;27:1979.Clasa IIb
Terapia antiplachetara optima dupa angioplastia coronariana cu stent trebuie sa tina seama de 2 elemente esentiale:Tipul de boala coronariana ptr care se face stentarea:Angina stabila: durata terapiei duale = 1 lunaSindrom coronarian acut inclusiv IMA: durata terapiei duale = 9 luni - 1 anTipul de stent implantat:Stent metalic simplu: durata terapiei duale ~ 1 lunaStent farmacologic activ:Stent cu rapamicina (sirolimus): cp 3 luniStent cu paclitaxel (taxol): cp 6 luniIn lumina riscului de tromboza tardiva de stent farmacologic activ FDA a recomandat in dec 2006 continuarea tratamentului antiplachetar dual pentru cel putin 1 an (nivel de evidenta I_B)Smith SC et al. 2005 Guideline Update for PCI. Circulation 2006. Available at: http://www.americanheart.org.
Epilog
Dotter si Judkins in SUA primele dilatatii perifericeTehnica lor preluata de Zeitler si adusa in Germania de unde a invatat-o Gruentzig.Gruentzig a miniaturizat catetere pentru dilatatie si a realizat prima angioplastie coronariana la Zurich in septembrie 1977: 30 ANI.Indicatii foarte limitate: leziuni focale in segmente rectilinii, fara bifurcatii si calcificariRiscul de ocluzie coronariana acuta si IMA : necesarul salii operatorii
Abstract. Hartzler GO et al. AHJ 1983Successful percutaneous transluminal coronary angioplasty (PTCA) was performed during evolving acute myocardial infarction (AMI) in 41 patients. Catheterization was performed within 1 hour of presentation, from 1 to 12 hours (mean 3.3) following symptom onset. In 17 of 29 patients with a totally occluded coronary artery, successful thrombolytic therapy was followed by PTCA of a residual high-grade atheromatous stenosis. Successful PTCA without prior thrombolytic therapy was employed in 11 of 12 subtotal coronary stenoses producing acute infarction syndromes and in two patients having critical coronary stenoses not immediately responsible for AMI. Three patients experienced early in-hospital reocclusion with reinfarction. One death occurred in a patient presenting with cardiogenic shock. All remaining patients had prompt pain relief, subsequent stable clinical courses, and no clinical or late angiographic evidence of coronary reocclusion. Dramatic improvement of regional and global left ventricular function was evident in 22 of 27 patients undergoing late left ventricular angiography. At follow-up, 94% of patients remained free of angina although three required repeat dilatation of recurrent stenoses. We concluded that PTCA may be performed with or without thrombolytic therapy in selected patients with AMI and may reduce the likelihood of late reocclusion following successful thrombolytic therapy. The use of an ADP receptor antagonist in combination with aspirin has dramatically reduced the risk of subacute stent thrombosis and thus, the occurrence of clinical ischemic events.3 main trials, STARS, ISAR and FANTASTICS, clearly showed that subacute stent thrombosis drops to less than 1% at one month follow-up when ticlopidine was used together with aspirin.
Bertrand ME, Legrand V, Boland J et al. (1998) Randomized multicenter comparison of conventional anticoagulant versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study. Circulation 98:1597-1603. Leon MB, Baim DS, Popma JJ et al. (1998) A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. NEJM 339:1665-71. Schmig A, Neumann F-J, Kastratt A et al. (1996) A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. NEJM 334:1084-1089.
This reduction of subacute stent thrombosis leads to a significant reduction of major cardiac events.Several recent studies have measured the rate of major cardiac events (death, myocardial infarction and revascularisation) in patients undergoing coronary interventional procedures, following anticoagulant therapy or antiplatelet therapy using an ADP receptor antagonist, in combination with aspirin (Schmig et al. 1996, Bertrand et al. 1998, Urban et al. 1998, Leon et al. 1998). In each trial, the major cardiac event rate was significantly lower in patients given aspirin + ticlopidine (range 0.5% to 5.7%), compared with aspirin + anticoagulant therapy (range 2.7% to 11%).
Bertrand ME, Legrand V, Boland J et al. (1998) Randomized multicenter comparison of conventional anticoagulant versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study. Circulation 98:1597-1603. Hall P, Nakamura S, Maiello L et al. (1996) A randomised comparison of combined ticlopidine and aspirin therapy alone after successful intravascular ultrasound-guided stent implantation. Circulation 93:215-222. Leon MB, Baim DS, Popma JJ et al. (1998) A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. NEJM 339:1665-71. Schmig A, Neumann F-J, Kastratt A et al. (1996) A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. NEJM 334:1084-1089. Urban P, Macaya C, Rupprecht H-J et al. (1998) Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients. Circulation 98:2126-2132.
BackgroundCombination therapy with the ADP receptor antagonist ticlopidine plus aspirin has emerged as standard careafter coronary stenting. Clopidogrel, a new ADP receptor antagonist, has greater molar potency than ticlopidine andbetter safety/tolerability.Methods and ResultsPatients (n=1020) were randomized after successful stent placement and initiated on a 28-dayregimen of either (1) 300-mg clopidogrel loading dose and 325 mg/d aspirin on day 1, followed by 75 mg/d clopidogreland 325 mg/d aspirin; (2) 75 mg/d clopidogrel and 325 mg/d aspirin; or (3) 250 mg BID ticlopidine and 325 mg/daspirin. The primary end point consisted of major peripheral or bleeding complications, neutropenia, thrombocytopenia,or early discontinuation of study drug as the result of a noncardiac adverse event during the study-drug treatment period.The primary end point occurred in 9.1% of patients (n531) in the ticlopidine group and 4.6% of patients (n531) in thecombined clopidogrel group (relative risk 0.50; 95% CI 0.31 to 0.81; P50.005). Overall rates of major adverse cardiacevents (cardiac death, myocardial infarction, target lesion revascularization) were low and comparable betweentreatment groups (0.9% with ticlopidine, 1.5% with 75 mg/d clopidogrel, 1.2% with the clopidogrel loading dose; P5NSfor all comparisons).ConclusionsThe safety/tolerability of clopidogrel (plus aspirin) is superior to that of ticlopidine (plus aspirin)(P50.005). The 300-mg loading dose was well tolerated, notably with no increased risk of bleeding. Secondary endpoint data are consistent with the hypothesis that clopidogrel and ticlopidine have comparable efficacy with regard tocardiac events after successful stenting. (Circulation. 2000;102:624-629.)
Superior efficacy of ADP receptor antagonists in coronary stentingLooking across several stenting trials,1,2,3,4 the event rates seen in all three arms of CLASSICS were consistent with those in the ticlopidine + aspirin arms from the earlier trials, reinforcing the message that combination antiplatelet therapy with an ADP receptor antagonist plus aspirin is superior to full anticoagulation plus aspirin or aspirin alone in preventing subacute occlusion following coronary stenting. Further, the efficacy of clopidogrel in stent patients appears to be similar to that of ticlopidine.
Schomig A et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996;334:10841089.Bertrand ME et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study. Circulation 1998;98:15971603.Leon MB et al. A clinical trial comparing three antithrombotic drug regimens after coronary artery stenting. N Engl J Med 1998;339:16651671.Urban P et al. Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients. The multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation 1998;98:21262132.
Background Despite the use of aspirin, there is still a risk of ischaemic events after percutaneous coronary intervention (PCI). We aimed to find out whether, in addition to aspirin, pretreatment with clopidogrel followed by long-term therapy after PCI is superior to a strategy of no pretreatment and short-term therapy for only 4 weeks after PCI.Methods 2658 patients with non-ST-elevation acute coronary syndrome undergoing PCI in the CURE study had been randomly assigned double-blind treatment with clopidogrel (n=1313) or placebo (n=1345). Patients were pretreated with aspirin and study drug for a median of 6 days before PCI during the initial hospital admission, and for a median of 10 days overall. After PCI, most patients (>80%) in both groups received open-label thienopyridine for about 4 weeks, after which study drug was restarted for a mean of 8 months. The primary endpoint was a composite of cardiovascular death, myocardial infarction, or urgent target-vessel revascularisation within 30 days of PCI. The main analysis was by intention to treat. Findings There were no drop-outs. 59 (45%) patients in the clopidogrel group had the primary endpoint, compared with 86 (64%) in the placebo group (relative risk 070 [95% CI 050097], p=003). Long-term administration of clopidogrel after PCI was associated with a lower rate of cardiovascular death, myocardial infarction, or any revascularisation (p=003), and of cardiovascular death or myocardial infarction (p=0047). Overall (including events before and after PCI) there was a 31% reduction cardiovascular death or myocardial infarction (p=0002). There was less use of glycoprotein IIb/IIIa inhibitor in the clopidogrel group (p=0001). At follow-up, there was no significant difference in major bleeding between the groups (p=064). Interpretation In patients with acute coronary syndrome receiving aspirin, a strategy of clopidogrel pretreatment followed by long-term therapy is beneficial in reducing major cardiovascular events, compared with placebo.
CONTEXT: Following percutaneous coronary intervention (PCI), short-term clopidogrel therapy in addition to aspirin leads to greater protection from thrombotic complications than aspirin alone. However, the optimal duration of combination oral antiplatelet therapy is unknown. Also, although current clinical data suggest a benefit for beginning therapy with a clopidogrel loading dose prior to PCI, the practical application of this therapy has not been prospectively studied. OBJECTIVES: To evaluate the benefit of long-term (12-month) treatment with clopidogrel after PCI and to determine the benefit of initiating clopidogrel with a preprocedure loading dose, both in addition to aspirin therapy. DESIGN, SETTING, AND PARTICIPANTS: The Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a randomized, double-blind, placebo-controlled trial conducted among 2116 patients who were to undergo elective PCI or were deemed at high likelihood of undergoing PCI, enrolled at 99 centers in North America from June 1999 through April 2001. INTERVENTIONS: Patients were randomly assigned to receive a 300-mg clopidogrel loading dose (n = 1053) or placebo (n = 1063) 3 to 24 hours before PCI. Thereafter, all patients received clopidogrel, 75 mg/d, through day 28. From day 29 through 12 months, patients in the loading-dose group received clopidogrel, 75 mg/d, and those in the control group received placebo. Both groups received aspirin throughout the study. MAIN OUTCOME MEASURES: One-year incidence of the composite of death, myocardial infarction (MI), or stroke in the intent-to-treat population; 28-day incidence of the composite of death, MI, or urgent target vessel revascularization in the per-protocol population. RESULTS: At 1 year, long-term clopidogrel therapy was associated with a 26.9% relative reduction in the combined risk of death, MI, or stroke (95% confidence interval [CI], 3.9%-44.4%; P =.02; absolute reduction, 3%). Clopidogrel pretreatment did not significantly reduce the combined risk of death, MI, or urgent target vessel revascularization at 28 days (reduction, 18.5%; 95% CI, -14.2% to 41.8%; P =.23). However, in a prespecified subgroup analysis, patients who received clopidogrel at least 6 hours before PCI experienced a relative risk reduction of 38.6% (95% CI, -1.6% to 62.9%; P =.051) for this end point compared with no reduction with treatment less than 6 hours before PCI. Risk of major bleeding at 1 year increased, but not significantly (8.8% with clopidogrel vs 6.7% with placebo; P =.07). CONCLUSIONS: Following PCI, long-term (1-year) clopidogrel therapy significantly reduced the risk of adverse ischemic events. A loading dose of clopidogrel given at least 3 hours before the procedure did not reduce events at 28 days, but subgroup analyses suggest that longer intervals between the loading dose and PCI may reduce events. BackgroundThe US Food and Drug Administration recently issued a warning of subacute thrombosis and hypersensitivityreactions to sirolimus-eluting stents (Cypher). The cause and incidence of these events have not been determined.Methods and ResultsWe present findings of a 58-year-old man who died of late stent thrombosis 18 months afterreceiving 2 Cypher stents for unstable angina. Although angiographic and intravascular ultrasound results at 8 monthsdemonstrated the absence of neointimal formation, vessel enlargement was present. An autopsy showed aneurysmaldilation of the stented arterial segments with a severe localized hypersensitivity reaction consisting predominantly of Tlymphocytes and eosinophils.ConclusionsThe known pharmacokinetic elution profile of Cypher stents and the presence of polymer fragmentssurrounded by giant cells and eosinophils suggest that a reaction to the polymer may have caused late stent thrombosis.Careful long-term follow-up of patients with vessel enlargement after Cypher stent placement is recommended.(Circulation. 2004;109:701-705.)
Non-fatal MI was higher in the DES group compared with the BMS group (4.1% vs. 1.3%, p=0.04).
Also, cardiac death trended higher in the DES group than in the BMS group (1.2% vs. 0%, p=0.09).
OBJECTIVES We sought to define the incidence of late clinical events and late stent thrombosis in patientstreated with drug-eluting (DES) versus bare-metal stents (BMS) after the discontinuation ofclopidogrel as well as their timing and outcome.BACKGROUND There is growing concern that delayed endothelialization after DES implantation may lead tolate stent thrombosis and related myocardial infarction (MI) or death. However, event ratesand outcomes after clopidogrel discontinuation versus BMS are unknown.METHODS A consecutive series of 746 nonselected patients with 1,133 stented lesions surviving 6months without major events were followed for 1 year after the discontinuation ofclopidogrel. Patients were assigned randomly 2:1 to DES versus BMS in BASKET (BaselStent Kosten Effektivitts Trial). The primary focus of this observation was cardiac death/MI.RESULTS Rates of 18-month cardiac death/MI were not different between DES and BMS patients.However, after the discontinuation of clopidogrel (between months 7 and 18), these eventsoccurred in 4.9% after DES versus 1.3% after BMS implantation. Target vessel revascularizationremained lower after DES, resulting in similar rates of all clinical events for this timeperiod (DES 9.3%, BMS 7.9%). Documented late stent thrombosis and related death/targetvessel MI were twice as frequent after DES versus BMS (2.6% vs. 1.3%). Thrombosis-relatedevents occurred between 15 and 362 days after the discontinuation of clopidogrel, presentingas MI or death in 88%.CONCLUSIONS After the discontinuation of clopidogrel, the benefit of DES in reducing target vesselrevascularization is maintained but has to be balanced against an increase in late cardiac deathor nonfatal MI, possibly related to late stent thrombosis. (J Am Coll Cardiol 2006;48:2584-91
BackgroundAfter treatment with clopidogrel, patients with type 2 diabetes mellitus (T2DM) have reduced plateletinhibition compared with patients who are not diabetic. Whether platelet inhibition can be enhanced by increasingclopidogrel maintenance dosage in T2DM patients is unknown. The aim of this pilot study was to assess the functionalimpact of a high maintenance dose in T2DM patients with suboptimal clopidogrel-induced antiplatelet effects.Methods and ResultsT2DM patients on chronic dual antiplatelet therapy were screened to identify suboptimalclopidogrel responders. The latter were randomized to 30-day treatment with a standard (75 mg; n20) or high (150mg; n20) daily maintenance dose. Platelet function was assessed at 3 time points: baseline, 30 days afterrandomization, and 30 days after resuming standard dosing. Platelet function parameters included adenosinediphosphateinduced (20 and 5 mol/L) maximal and late platelet aggregation, inhibition of platelet aggregation,platelet disaggregation, and P2Y12 reactivity index. A total of 64 T2DM patients were screened to identify 40 suboptimalresponders. After randomization, maximal adenosine diphosphateinduced (20 mol/L) platelet aggregation wassignificantly reduced in the 150-mg group compared with the 75-mg group (P0.002; primary end point). However,suboptimal clopidogrel response was still present in 60% of patients on the 150-mg regimen. All other platelet functionparameters showed enhanced clopidogrel-induced antiplatelet effects with 150 mg, which returned to baseline valuesafter resumption of standard dosing.ConclusionsA 150-mg maintenance dose of clopidogrel is associated with enhanced antiplatelet effects compared with75 mg in high-risk T2DM patients. However, enhanced ex vivo platelet reactivity continues to persist, the clinicalimplications of which are unknown and need to be evaluated in large-scale clinical trials. (Circulation. 2007;115:708-716.)
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