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

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

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

Rate of death, myocardial infarction, or stroke Clopidogrel Evidence: ACS (Non-STEMI - UA) Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial 12,562 patients with a NSTEMI-ACS randomized to daily aspirin (75-325 mg) or clopidogrel (300 mg load, 75 mg thereafter) plus aspirin (75-325 mg) for 3-12 months (average 9) 3 6 9 12 Rate of death, myocardial infarction, or stroke 20% RRR P<0.001 Months of Follow Up Aspirin + Clopidogrel Aspirin + Placebo Clopidogrel evidence: ACS (non-STEMI and unstable angina) The CURE trial evaluated the efficacy and safety of clopidogrel and aspirin in patients with a non-ST–segment elevation acute coronary syndrome (NSTEMI-ACS). Patients that had presented within 24 hours after the onset of symptoms were randomly assigned to receive 300 mg of clopidogrel immediately, followed by 75 mg once daily (6,259 patients) or placebo (6,303 patients), in addition to aspirin for 3-12 months. The first primary outcome, a composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), or stroke, occurred in 9.3% of the patients in the clopidogrel group and 11.4% in the placebo group corresponding to a significant 20% relative risk (RR) reduction. The second primary outcome, a composite of the first primary outcome along with refractory ischemia, occurred in 16.5% of patients in the clopidogrel group vs. 19% of patients in the placebo group, resulting in a significant 14% RR reduction. The percentage of patients with in-hospital refractory or severe ischemia, heart failure, and revascularization procedures were also significantly lower with clopidogrel. Patients on clopidogrel had a significantly increased risk of major bleeding (4% vs. 3%; RR, 1.38; P=0.001), but no greater incidence of life-threatening bleeding (2% vs. 2%, P=0.13) or hemorrhagic strokes. Reference: Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494-502. The CURE Trial Investigators. NEJM. 2001;345:494-502

PCI-CURE and CREDO Long-Term Benefits of Clopidogrel in PCI Patients 15 Placebo‡ Clopidogrel‡ 15 10 5 100 200 300 400 Days of follow-up 12.6% 8.8% P = 0.002 N = 2658 CV-death or MI (%) 31% RRR Placebo* Clopidogrel* 11.5% 27% RRR 10 8.5% MI, Stroke or Death (%) 5 P=0.02 N = 2116 In the Clopidogrel for the Reduction of Events during Observation (CREDO) trial, 2116 patients scheduled to undergo percutaneous coronary intervention (PCI) or thought to be at high likelihood of undergoing PCI were randomized to a 300mg loading dose of clopidogrel vs. placebo 3-24 hours prior to PCI. Following PCI, all patients received 75mg daily clopidogrel through day 28. From day 28 through 1 year, patients in the loading dose group received 75mg daily placebo. Clopidogrel reduced the 1-year risk of MI, stroke, or death by 27% (95% confidence interval [CI], 3.9%-44.4%; P =.02; absolute reduction, 3%). No significant difference was seen in 28 day combined risk of MI, death, or urgent target vessel revascularization (risk reduction, 18.5%; 95% CI, -14.2% to 41.8%; P =.23). 3 6 9 12 Months From Randomization Mehta et al. Lancet 2001;358:527-533 Steinhubl S et al. JAMA. 2002; 288:2411-2420 †up to 12 months ‡plus ASA and other standard therapies

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

Clopidogrel Reduced Clinical Events by 20% at 30 Days Placebo (14.1%) 15 20%* p=0.03 10 Clopidogrel (11.6%) Patients with endpoint (%) 5 At 30 days, clopidogrel had a significant effect on reducing clinical endpoints1 Clopidogrel reduced the odds of cardiovascular death, recurrent MI or recurrent ischemia leading to urgent revascularization by 20% (odds ratio 0.80; 95% CI [0.65–0.97]; p=0.03)1 Reference 1. Sabatine M et al. New Eng J Med 2005; 352: 1179–1189. 5 10 15 20 25 30 Time (days) *Odds ratio in CV death, MI or recurrent ischemia leading to urgent revascularization Sabatine M et al. New Eng J Med 2005; 352: 1179–1189.

Clopidogrel Reduced the Composite of Death, MI or Stroke by 9% Placebo (10.1%) RRR=9% p=0.002 10 9 Clopidogrel (9.3%) 8 7 6 Events (%) 5 4 3 At 28 days after randomization (mean follow-up 16.5 days), the percentage of patients in the clopidogrel group with the composite endpoint of death, MI or stroke was 9.3% compared with 10.1% in the placebo group Thus, the COMMIT trial demonstrated that clopidogrel reduced the relative risk of the primary composite endpoint of death, recurrent MI or stroke by 9% (p=0.002) Reference 1. Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005. 2 1 7 14 21 28 Days (up to 28 days) RRR = relative risk reduction Chen ZM et al. Oral presentation, ACC 2005. Available at: URL: http://www.commit-ccs2.org. Accessed April 2005.

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

Primary Outcome (MI, Stroke, or CV Death) CHARISMA Primary Outcome (MI, Stroke, or CV Death) Placebo + ASA 7.3% Clopidogrel + ASA 6.8% P = 0.22 Cumulative Event Rate (%) CHARISMA: primary efficacy outcome (MI, stroke, or CV death) The CHARISMA trial randomized 15,603 patients with multiple cardiovascular (CV) risk factors or known CV disease to aspirin (75-162 mg) or aspirin (75-162 mg) + clopidogrel (75 mg) for a mean of 30 months. The primary endpoint was stroke, myocardial infarction (MI), or death from CV causes. The primary endpoint occurred in 6.8% of the clopidogrel + aspirin group and 7.3% of the placebo + aspirin group (relative risk [RR] 0.93; 95% CI, 0.83 to 1.05; P=0.22). There was a trend for increased total events in the primary prevention group (RR 1.2; 95% CI, 0.91 to 1.59; P=0.20) and a modest trend for benefit in those subjects with a history of prior atherothrombotic event (RR 0.88; 95% CI, 0.77 to 0.99; P=0.046). Reference: Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-1717. RRR: 7.1% [95% CI: -4.5%, 17.5%] P=0.22 6 12 18 24 30 Months Since Randomization First occurrence of fatal or non-fatal MI, fatal or non-fatal stroke, or CV death All patients received ASA (aspirin) 75-162 mg/day Bhatt DL et al. N Engl J Med 2006;354:1706–1717.

Effect of aspirin plus clopidogrel on the primary endpoint (MI, stroke, CV death) in patients with risk factors or established disease Van de Werf, F. Eur Heart J Suppl 2007 9:D3-9D

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

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

Clopidogrel Recommendations 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: recommendations Start and continue clopidogrel 75 mg/d in combination with aspirin for up to 12 months in patients after acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) with stent placement (1 month for bare metal stent, 3 months for sirolimus-eluting stent, and 6 months for paclitaxel-eluting stent). I (B) Patients who have undergone PCI with stent placement should initially receive higher-dose aspirin at 325 mg/d for 1 month for bare metal stent, 3 months for sirolimus-eluting stent, and 6 months for paclitaxel-eluting stent. I (B) I=Procedure or treatment SHOULD be performed or administered (B)=Single trial, non-randomized studies Reference: Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, Grundy SM, Hiratzka L, Jones D, Krumholz HM, Mosca L, Pasternak RC, Pearson T, Pfeffer MA, Taubert KA; AHA/ACC; National Heart, Lung, and Blood Institute. AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. Circulation 2006;113:2363-2372. *Clopidogrel is generally given preference over Ticlopidine because of a superior safety profile

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

European Heart Survey (2000-04) Comparison of treatment of STEMI patients at discharge in ACS-I and ACS-II in 34 centres European Heart Survey (2000-04) Mandelzweig, L. et al. Eur Heart J 2006 27:2285-2293;

European Heart Survey (2000-04) Comparison of treatment of N-STEMI patients at discharge in ACS-I and ACS-II in 34 centres European Heart Survey (2000-04) Mandelzweig, L. et al. Eur Heart J 2006 27:2285-2293;

Variations Among Hospitals 430 CRUSADE hospitals Acute Discharge Peterson et al, JAMA 2006;295:1863-1912

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

Diabetes and Medication Use at Discharge % of Patients 100 p=0.008 Non-diabetic (n=3,429) 90.3 76 52.1 53.9 87.50 73.6 65.6 54.5 p=0.08 80 Diabetic (n=1,149) p<0.0001 p=NS 60 40 20 Antiplatelet Beta Blocker ACE Inhibitor Lipid Lowering Yan R et al Am Heart J 2006;152:676

Anti-platelet Adherence Patients (%) MATRIX Registry

Independent Predictors of Late Thrombosis Late DES Thrombosis Independent Predictors of Late Thrombosis Iakovou JAMA 2005; 293: 2126-30

*Antiplatelet Therapy Discontinuation Stent Thrombosis Rates Selected Patient Characteristics *Antiplatelet Therapy Discontinuation Prior Brachy Renal Failure Bifurcation ULM Diabetes UA The incidence of stent thrombosis according to selected patient characteristics was 29% in pts with premature antiplatelet therapy discontinuation, 8.7% in prior brachytherapy at the target vessel, 5.5% with renal failure, 3.5% in bifurcations, 3.2% in unprotected left main treated, 2.6% in diabetes, and 1.3% in unstable angina Jeremias P et al Circulation 2004; 293:2126 *Premature discontinuation

Premier Registry 19-center study – 500 DES treated 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 Spertus, J. A. et al. Circulation 2006;113:2803-2809

Premier Registry 19-center study Cardiac rehospitalization from 1 to 12 months after MI in relation to thienopyridine therapy at 1 month Premier Registry 19-center study Spertus, J. A. et al. Circulation 2006;113:2803-2809

Duke Databank 6-Month Landmark Analysis Adjusted Cumulative Rates of Death or Nonfatal MI DES-C BMS-C DES+C BMS+C 2 4 6 8 Percent Cumulative Incidence Rate 12 18 24 0.70 -0.5 BMS+C BMS-C 0.44 1.2 DES-C BMS-C 0.01 -2.9 DES+C BMS-C 0.16 -2.4 DES+CBMS+C 0.02 -4.1 DES+C DES-C p % (95% CI) 7.2 5.5 6.0 3.1 CONTEXT: Recent studies of drug-eluting intracoronary stents suggest that current antiplatelet regimens may not be sufficient to prevent late stent thrombosis. OBJECTIVE: To assess the association between clopidogrel use and long-term clinical outcomes of patients receiving drug-eluting stents (DES) and bare-metal stents (BMS) for treatment of coronary artery disease. DESIGN, SETTING, AND PATIENTS: An observational study examining consecutive patients receiving intracoronary stents at Duke Heart Center, a tertiary care medical center in Durham, NC, between January 1, 2000, and July 31, 2005, with follow-up contact at 6, 12, and 24 months through September 7, 2006. Study population included 4666 patients undergoing initial percutaneous coronary intervention with BMS (n = 3165) or DES (n = 1501). Landmark analyses were performed among patients who were event-free (no death, myocardial infarction [MI], or revascularization) at 6- and 12-month follow-up. At these points, patients were divided into 4 groups based on stent type and self-reported clopidogrel use: DES with clopidogrel, DES without clopidogrel, BMS with clopidogrel, and BMS without clopidogrel. MAIN OUTCOME MEASURES: Death, nonfatal MI, and the composite of death or MI at 24-month follow-up. RESULTS: Among patients with DES who were event-free at 6 months (637 with and 579 without clopidogrel), clopidogrel use was a significant predictor of lower adjusted rates of death (2.0% with vs 5.3% without; difference, -3.3%; 95% CI, -6.3% to -0.3%; P = .03) and death or MI (3.1% vs 7.2%; difference, -4.1%; 95% CI, -7.6% to -0.6%; P = .02) at 24 months. However, among patients with BMS (417 with and 1976 without clopidogrel), there were no differences in death (3.7% vs 4.5%; difference, -0.7%; 95% CI, -2.9% to 1.4%; P = .50) and death or MI (5.5% vs 6.0%; difference, -0.5%; 95% CI, -3.2% to 2.2%; P = .70). Among patients with DES who were event-free at 12 months (252 with and 276 without clopidogrel), clopidogrel use continued to predict lower rates of death (0% vs 3.5%; difference, -3.5%; 95% CI, -5.9% to -1.1%; P = .004) and death or MI (0% vs 4.5%; difference, -4.5%; 95% CI, -7.1% to -1.9%; P<.001) at 24 months. However, among patients with BMS (346 with and 1644 without clopidogrel), there continued to be no differences in death (3.3% vs 2.7%; difference, 0.6%; 95% CI, -1.5% to 2.8%; P = .57) and death or MI (4.7% vs 3.6%; difference, 1.0%; 95% CI, -1.6% to 3.6%; P = .44). CONCLUSIONS: The extended use of clopidogrel in patients with DES may be associated with a reduced risk for death and death or MI. However, the appropriate duration for clopidogrel administration can only be determined within the context of a large-scale randomized clinical trial. Months Eisenstein, E et al. JAMA 2007; 297(2):159-68

Incidence of DES thrombosis among 8146 patients in the Bern/Rotterdam cohorts study Wallentin, L. Eur Heart J Suppl 2008 10:D38-44D;

Antiplatelet treatment at the time of DES thrombosis in 152 patients Windecker, S. et al. Circulation 2007;116:1952-1965

Results: Baseline characteristics Entire cohort (n=5,838) Clopidogrel users with appropriate adherence (n=4,548) Clopidogrel users with inappropriate adherence (n=1,290) p-value Age, years 63.311.6 63.511.5 62.711.9 0.04 Female gender, % 33 24 21 <0.01 Previous history of myocardial infarction, % 18 0.92 Previous history of hypertension, % 55 54 57 0.18 Previous history of diabetes, % 28 27 32 Previous history of abnormal lipids, % 48 0.95 Previous history of heart failure, % 10 9 11 0.01 Medicare, % 58 59 0.08 Drug eluting stents, % 84 85 0.49

Results: Predictors of inappropriate clopidogrel use OR (95% C.I) Age 0.97 (0.97-0.98) Female gender 0.79 (0.69-0.91) Diabetes 1.2 (1.0-1.4) Medicare insurance 1.5 (1.26-1.81)

Results: Incidence of MI by adherence to clopidogrel HR 1.35(1.08-1.70)p=0.009

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

ACC/AHA 2007: Long-Term Treatment UA/NSTEMI Groups at Discharge Medical Rx No Stent Bare Metal Stent Drug-Eluting Stent ASA 75-162 mg/d indefinitely Clopidogrel 75 mg/d > 1 mo (Class I, LOE A) up to 1 yr (Class I, LOE B) ASA 162-325 mg/d for 3-6 mo then 75-162 mg/d indefinitely Clopidogrel 75 mg/d for at least 1 yr (Class I, LOE B) ASA 162-325 mg/d for 1 mo then 75-162 mg/d indefinitely Clopidogrel 75 mg/d for at least 1 mo and up to 1 yr (Class I, LOE B) Indication for Anticoagulation Yes No Add Warfarin (Class IIb, LOE B) Continue dual antiplatelet Rx Anderson HV et al. ACC/AHA UA/NSTEMI Guideline Revision. JACC 2007; 50:e1–157

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 : 50th (25th-75th) Medical (n=1569): 281 days (120-417) PCI (n=1568): 310 days (182-410) All-cause death/MI after stopping clopidogrel Determined for each 90 day period Ho PM, et al. JAMA 2008; 299(5):532-539

PCI Therapy: Event rates after stopping clopidogrel Interval after stopping clopidogrel 0-90 days 91-180 181-270 271-360 361-450 Patients at risk 1277 1147 565 332 220 Events 56 25 7 4 3

Medical Therapy: Event rates after stopping clopidogrel Interval after stopping clopidogrel 0-90 days 91-180 181-270 271-360 361-450 Patients at risk 1247 1079 524 335 238 Events 118 46 26 5 8

Risk of adverse events in 0-90 day interval after stopping clopidogrel 1.96 (1.39-2.76) 1.93 (1.12-3.34) 1.86 (1.00-3.45) 1.92 (1.07-3.44) 1.89 (1.24-2.88) 3.0 Incidence Rate Ratio 2.0 Findings consistent for AMI outcome and combined AMI and mortality 1.0 Mortality/ AMI AMI >9 months clopidogrel DM Non-DM Reference period is 91-180 day interval after stopping clopidogrel Ho PM, et al. JAMA 2008; 299(5):532-539

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 Angiolillo, D. J. et al. Circulation 2007;115:708-716

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

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

Flow chart to determine the risk of stent thrombosis in non cardiac surgery Expert opinion Riddell, J. W. et al. Circulation 2007;116:e378-e382

Chirurgia odontoiatrica

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

AHA/ACC/SCAI/ACS/ADA Science Advisory

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.

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