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Minimaster Cuore e diabete Prevenzione delle recidive e aderenza alle terapie Cardioprotezione farmacologica: il punto sul clopidogrel Massimo Uguccioni.

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Presentazione sul tema: "Minimaster Cuore e diabete Prevenzione delle recidive e aderenza alle terapie Cardioprotezione farmacologica: il punto sul clopidogrel Massimo Uguccioni."— Transcript della presentazione:

1 Minimaster Cuore e diabete Prevenzione delle recidive e aderenza alle terapie Cardioprotezione farmacologica: il punto sul clopidogrel Massimo Uguccioni Roma

2 Il clopidogrel in associazione allASA nella pratica clinica Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste unindicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca

3 Il clopidogrel in associazione allASA nella pratica clinica Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste unindicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca

4 Clopidogrel Evidence: ACS (Non-STEMI - UA) Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial The CURE Trial Investigators. NEJM. 2001;345: Rate of death, myocardial infarction, or stroke 20% RRR P<0.001 Months of Follow Up Aspirin + Clopidogrel Aspirin + Placebo 12,562 patients with a NSTEMI-ACS randomized to daily aspirin ( mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin ( mg) for 3-12 months (average 9)

5 PCI – Cure Mehta et al. Lancet 2001;358: Steinhubl S et al. JAMA. 2002; 288: MI, Stroke or Death (%) Months From Randomization 27%RRR Placebo*Clopidogrel* % 11.5% up to 12 months plus ASA and other standard therapies Placebo Placebo Clopidogrel Clopidogrel Days of follow-up 12.6% 8.8% P = N = 2658 CV-death or MI (%) 31%RRR P=0.02 N = 2116 CREDO PCI-CURE and CREDO Long-Term Benefits of Clopidogrel in PCI Patients

6 Il clopidogrel in associazione allASA nella pratica clinica Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste unindicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca

7 *Odds ratio in CV death, MI or recurrent ischemia leading to urgent revascularization Time (days) Patients with endpoint (%) %* p=0.03 Clopidogrel (11.6%) Placebo (14.1%) Sabatine M et al. New Eng J Med 2005; 352: 1179–1189. Clopidogrel Reduced Clinical Events by 20% at 30 Days

8 Days (up to 28 days) Clopidogrel (9.3%) Placebo (10.1%) Events (%) RRR=9% p=0.002 RRR = relative risk reduction Chen ZM et al. Oral presentation, ACC Available at: URL: Accessed April Clopidogrel Reduced the Composite of Death, MI or Stroke by 9%

9 Il clopidogrel in associazione allASA nella pratica clinica Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste unindicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca

10 CHARISMA Primary Outcome (MI, Stroke, or CV Death) Cumulative Event Rate (%) Months Since Randomization Placebo + ASA 7.3% First occurrence of fatal or non-fatal MI, fatal or non-fatal stroke, or CV death All patients received ASA (aspirin) mg/day Bhatt DL et al. N Engl J Med 2006;354:1706–1717. RRR: 7.1% [95% CI: -4.5%, 17.5%] P=0.22 Clopidogrel + ASA 6.8% P = 0.22

11 Van de Werf, F. Eur Heart J Suppl :D3-9D Effect of aspirin plus clopidogrel on the primary endpoint (MI, stroke, CV death) in patients with risk factors or established disease

12

13 Absolute benefit and bleeding hazard of combined treatment with clopidogrel plus aspirin

14 Il clopidogrel in associazione allASA nella pratica clinica Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste unindicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca

15 Start and continue clopidogrel 75 mg/d in combination with aspirin for post ACS or post PCI with stent placement patients for up to 12 months for post PCI-stented patients >1 month for bare metal stent, >3 months for sirolimus-eluting stent >6 months for paclitaxel-eluting stent * Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile Clopidogrel Recommendations

16 Il clopidogrel in associazione allASA nella pratica clinica Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste unindicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca

17 Mandelzweig, L. et al. Eur Heart J : ; Comparison of treatment of STEMI patients at discharge in ACS-I and ACS-II in 34 centres European Heart Survey ( )

18 Mandelzweig, L. et al. Eur Heart J : ; Comparison of treatment of N-STEMI patients at discharge in ACS-I and ACS-II in 34 centres European Heart Survey ( )

19 Variations Among Hospitals 430 CRUSADE hospitals Acute Discharge Peterson et al, JAMA 2006;295:

20 Paradoxical Discharge Care Patterns (n = 74,217 patients in CRUSADE)

21 % of Patients Diabetes and Medication Use at Discharge Non-diabetic (n=3,429) Diabetic (n=1,149) p=0.008 p=0.08 p< p=NS AntiplateletBeta Blocker ACE InhibitorLipid Lowering Yan R et al Am Heart J 2006;152:676

22 Anti-platelet Adherence MATRIX Registry Patients (%)

23 Late DES Thrombosis Independent Predictors of Late Thrombosis Iakovou JAMA 2005; 293:

24 * *Antiplatelet Therapy DiscontinuationDiabetes Prior Brachy Renal Failure BifurcationULMUA *Premature discontinuation Stent Thrombosis Rates Selected Patient Characteristics Jeremias P et al Circulation 2004; 293:2126

25 Spertus, J. A. et al. Circulation 2006;113: Mortality from 1 to 12 months after MI in relation to thienopyridine therapy at 1 month after MI Premier Registry 19-center study – 500 DES treated 13.6% stop therapy in 30 days

26 Spertus, J. A. et al. Circulation 2006;113: Cardiac rehospitalization from 1 to 12 months after MI in relation to thienopyridine therapy at 1 month Premier Registry 19-center study

27 DES-C BMS-C DES+C BMS+C Percent Cumulative Incidence Rate BMS+C BMS-C DES-C BMS-C DES+C BMS-C DES+CBMS+C DES+C DES-C p p % (95% CI) Months Eisenstein, E et al. JAMA 2007; 297(2): n=4666 Duke Databank 6-Month Landmark Analysis Adjusted Cumulative Rates of Death or Nonfatal MI

28 Wallentin, L. Eur Heart J Suppl :D38-44D; Incidence of DES thrombosis among 8146 patients in the Bern/Rotterdam cohorts study

29 Windecker, S. et al. Circulation 2007;116: Antiplatelet treatment at the time of DES thrombosis in 152 patients

30 Results: Baseline characteristics Characteristic Entire cohort (n=5,838) Clopidogrel users with appropriate adherence (n=4,548) (n=4,548) Clopidogrel users with inappropriate adherence (n=1,290)p-value Age, years Female gender, %332421<0.01 Previous history of myocardial infarction, % Previous history of hypertension, % Previous history of diabetes, % <0.01 Previous history of abnormal lipids, % Previous history of heart failure, % Medicare, % Drug eluting stents, %

31 Results: Predictors of inappropriate clopidogrel use PredictorsOR (95% C.I) Age0.97 ( ) Female gender0.79 ( ) Diabetes1.2 ( ) Medicare insurance1.5 ( )

32 Results: Incidence of MI by adherence to clopidogrel HR 1.35( )p=0.009

33 Dual anti-platelet discontinuation DM ACS / AMI Low EF Renal Failure Bifurcations Longer stent length Residual dissection Small stent diameter Stent underexpansion Malapposition Patient Factors Lesion Factors Who Should Not Get DES in 2007? Predictors of Stent Thrombosis

34 UA/NSTEMI Groups at Discharge Medical Rx No Stent Bare Metal Stent Drug-Eluting Stent ASA mg/d indefinitely Clopidogrel 75 mg/d > 1 mo (Class I, LOE A) up to 1 yr (Class I, LOE B) ASA mg/d indefinitely Clopidogrel 75 mg/d > 1 mo (Class I, LOE A) up to 1 yr (Class I, LOE B) ASA mg/d for 1 mo then mg/d indefinitely Clopidogrel 75 mg/d for at least 1 mo and up to 1 yr (Class I, LOE B) ASA mg/d for 1 mo then mg/d indefinitely Clopidogrel 75 mg/d for at least 1 mo and up to 1 yr (Class I, LOE B) ASA mg/d for 3-6 mo then mg/d indefinitely Clopidogrel 75 mg/d for at least 1 yr (Class I, LOE B) ASA mg/d for 3-6 mo then mg/d indefinitely Clopidogrel 75 mg/d for at least 1 yr (Class I, LOE B) Indication for Anticoagulation Add Warfarin (Class IIb, LOE B) Continue dual antiplatelet Rx Yes No Anderson HV et al. ACC/AHA UA/NSTEMI Guideline Revision. JACC 2007; 50:e1–157 ACC/AHA 2007: Long-Term Treatment

35 Ho PM, et al. JAMA 2008; 299(5): Is There Clinical Evidence of Clopidogrel Rebound? Study Population: –127 VHA Hospital ACS Registry: Oct 2003-March 2005 –Admitted with ACS between 10/03 to 9/04 –Discharged on clopidogrel Total duration of clopidogrel treatment : 50 th (25 th -75 th ) –Medical (n=1569): 281 days ( ) –PCI (n=1568): 310 days ( ) All-cause death/MI after stopping clopidogrel –Determined for each 90 day period

36 Interval after stopping clopidogrel 0-90 days days days days days Patients at risk Events PCI Therapy: Event rates after stopping clopidogrel

37 Interval after stopping clopidogrel 0-90 days days days days days Patients at risk Events Medical Therapy: Event rates after stopping clopidogrel

38 Mortality/ AMI >9 months clopidogrel Incidence Rate Ratio ( ) 1.93 ( ) 1.86 ( ) ( ) 1.89 ( ) DMNon-DM Reference period is day interval after stopping clopidogrel Ho PM, et al. JAMA 2008; 299(5): Risk of adverse events in 0-90 day interval after stopping clopidogrel

39 Angiolillo, D. J. et al. Circulation 2007;115: Platelet aggregation (A) and inhibition of platelet aggregation (B) (baseline and 30 days) after stimulus with ADP in doses of 75 mg and 150 mg in diabetic patients

40 Il clopidogrel in associazione allASA nella pratica clinica Pazienti con N-STEMI e/o PCI Benefici nei pazienti con STEMI Esiste unindicazione in prevenzione primaria? Pazienti con stent (BMS e DES) Uso del clopidogrel nel mondo reale Terapia anti-aggregante e chirurgia non cardiaca

41 Presentazione del caso clinico Uomo di 55 anni ex-fumatore; accusa tosse persistente. Rx torace: opacità vicino al bronco lobare superiore destro Tre mesi prima SCA trattata con impianto di DES sulla DA prossimale Si rende necessaria una biopsia bronchiale Riddell, J. W. et al. Circulation 2007;116:e378-e382

42 Flow chart to determine the risk of stent thrombosis in non cardiac surgery Expert opinion

43 Chirurgia odontoiatrica

44 Gestione del caso clinico Si decide per la sospensione del clopidogrel cinque giorni prima della biopsia con ripresa con dose da carico il primo giorno postoperatorio La terapia con aspirina non viene sospesa Riddell, J. W. et al. Circulation 2007;116:e378-e382

45 AHA/ACC/SCAI/ACS/ADA Science Advisory

46 Summary and Recommendations 1. Patients should be specifically instructed before hospital discharge to contact their cardiologist before stopping any anti-platelet therapy 2. Healthcare providers who perform invasive or surgical procedures and are concerned about periprocedural and postprocedural bleeding must be made aware of the potentially catastrophic risks of premature discontinuation of thienopyridine 3. For patients treated with DES who are to undergo subsequent procedures that mandate discontinuation of thienopyridine therapy, aspirin should be continued if possible and the thienopyridine restarted as soon as possible after the procedure because of concerns about late-stent thrombosis.

47 Conclusions While in-hospital antiplatelet therapy is improving, still potential for optimization –More complete treatment, particularly high risk –More appropriate drug dosing in diabetics? Greater potential for improving outpatient care –Better patient adherence –Better understanding of optimal therapy duration –Protocols for safe drug withdrawal


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