ACUTE CORONARY SYNDROMES: why avoiding discontinuation of dual antiplatelet therapy Giuseppe Biondi-Zoccai Divisione di Cardiologia, Università di Torino, Torino; Meta-analysis and Evidence-based medicine Training in Cardiology (METCARDIO), Torino 15:40-16:05 - 23 maggio 2009 - Roma

the scope of management Preamble: the scope of management

Secondary and long-term prevention Acute thrombosis Sub-acute thrombosis Late restenosis and thrombosis Major adverse cardiac events Other atherothrombotic events (all arterial beds) 24 hours incidence: <0.5% Days to 4 weeks incidence: <1% Up to 12 months incidence: 15% First year incidence: ~20% Life-long Long-term Prevention Short-term Prevention

Introduction: sample case studies

Case study 1 67-year-old man admitted for unstable angina, known for diabetes and symptomatic peripheral artery disease. Coronary angiography showed multivessel disease, subsequently treated with bypass surgery

Case study 2 71-year-old woman with stable angina, known for previous ischemic stroke; coronary angiography showed right coronary artery disease treated with percutaneous paclitaxel-eluting stent implantation

Road map of the presentation What is the evidence supporting dual antiplatelet therapy for 12 months or more? Is there any risk of late thrombosis with drug-eluting stents? What may happen if dual antiplatelet therapy is discontinued? What do the guidelines recommend in patients with acute coronary syndromes or coronary stents?

Road map of the presentation What is the evidence supporting dual antiplatelet therapy for 12 months or more? Is there any risk of late thrombosis with drug-eluting stents? What may happen if dual antiplatelet therapy is discontinued? What do the guidelines recommend in patients with acute coronary syndromes or coronary stents?

CURE – risk of MI, stroke or cardiovascular death (N=12,562) 0.14 Placebo + ASA 20% Relative Risk Reduction P=0.00009 0.12 0.10 Clopidogrel + ASA 0.08 Study subjects had ACS (UA/non–ST-elevation MI) Cumulative Hazard Rate 0.06 The primary outcome occurred in 9.3% of patients in the clopidogrel + ASA group and 11.4% in the placebo + ASA group Clopidogrel, in addition to aspirin (ASA) and other standard therapy, provided a 20% relative risk reduction (RRR) in the combined co-primary end point of MI, stroke, or CV death (95% CI, 0.72–0.90, P=0.00009). Overall, there were 719 (11.4%) first events in the placebo plus ASA group and 582 (9.3%) in the clopidogrel plus ASA group. The hazard rate curves began to separate within the first few hours after therapy initiation and remained separated over the course of the trial. The addition of clopidogrel to ASA and other standard therapy significantly reduced the rate of the co-primary end point of MI, stroke, CV death, or refractory ischemia (16.5% vs 18.8%, RRR 14%, 95% CI, 6.2–20.6, P=0.0005). 0.04 0.02 0.00 3 6 9 12 Months of Follow-up CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

CREDO – 1-year primary outcome Percent death, MI or stroke RRR 26.9% P=0.02 8.5 11.5 12 RRR 19.7% P=NS RRR 37.4% P=0.04 2.9 4.6 8 6.9 5.5 4 CREDO Study: 1-Year Primary Outcome A total of 63% of patients in the clopidogrel group and 61% in the placebo control group completed 12 months of treatment in the CREDO trial. The clopidogrel arm had a 27% reduction in relative risk of the primary outcome of death, MI, or stroke at 1 year compared with the placebo arm (11.5% vs 8.5%, P=.02); the reduction in absolute risk was 3%. The risk of major bleeding by the end of 1 year of clopidogrel therapy was increased, although not significantly. The results of the CREDO trial showed that long-term therapy consisting of clopidogrel plus aspirin significantly reduced the risk of ischemic events at 1 year compared with aspirin alone. Steinhubl SR, Berger PB, Mann JT III, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A randomized controlled trial. JAMA. 2002;288:2411-2420. Day 0 to 28 Day 29 to 365 Cumulative Adapted from Steinhubl SR, et al. JAMA. 2002;288:2411-2420.

Bhatt DL, et al. J Am Coll Cardiol 2007;49:1982–8 CHARISMA primary end point (MI/stroke/CV death) in pts with previous MI, stroke or PAD* 10 N=9,478 Placebo + ASA 8.8% 8 Clopidogrel + ASA 7.3% 6 Primary outcome event rate (%) 4 RRR: 17.1 % [95% CI: 4.4%, 28.1%] P=0.01 A post hoc analysis of patients (n=9,478) with a previous MI, stroke, or PAD (similar to the entry criteria for the CAPRIE trial) showed a significant 17.1% RRR in favor of clopidogrel plus ASA over ASA alone. 2 * Post hoc analysis 6 12 18 24 30 Months since randomization Bhatt DL, et al. J Am Coll Cardiol 2007;49:1982–8

Overall Relative Risk Reduction CAPRIE - efficacy of clopidogrel in MI, ischemic stroke, or vascular death (N=19,185) Median Follow-up=1.91 years 8.7%* Aspirin Overall Relative Risk Reduction 16 Clopidogrel 12 Aspirin Event Rate (%) Cumulative P=0.045 8 Clopidogrel Study subjects had either recent MI, recent ischemic stroke, or established peripheral arterial disease. The primary outcome analysis in CAPRIE was based on the composite end point of MI, ischemic stroke, or vascular death among all randomized patients (intent-to-treat analysis). Only the first occurrence of these outcomes was counted. The total number of patients randomized was 9,599 for clopidogrel bisulfate and 9,586 for aspirin. Results from the CAPRIE trial demonstrated that clopidogrel had a lower event rate per year compared with aspirin, 5.32% vs 5.83%, respectively, which resulted in an overall risk reduction of 8.7% (P=0.045) vs aspirin. An on-treatment analysis of the primary event cluster showed a relative risk reduction of 9.4% (P=0.046). Although the statistical significance favoring clopidogrel over aspirin was marginal (P=0.045, based on overall incidence of primary outcome events: 9.78% for clopidogrel vs 10.64% for aspirin), and represents the result of a single trial that has not been replicated, the comparator drug, aspirin, is itself effective (vs placebo) in reducing cardiovascular events in patients with recent MI or recent stroke. The cumulative risk curves separated early and continued to diverge during the 3-year follow-up period.[1] 4 3 6 9 12 15 18 21 24 27 30 33 36 Months of Follow-Up ITT analysis. CAPRIE Steering Committee. Lancet. 1996;348:1329-1339.

Road map of the presentation What is the evidence supporting dual antiplatelet therapy for 12 months or more? Is there any risk of late thrombosis with coronary stents? What may happen if dual antiplatelet therapy is discontinued? What do the guidelines recommend in patients with acute coronary syndromes or coronary stents?

Delayed endothelialization in DES: 6-month optical coherence tomography Guagliumi G et al. TCT 2009

Dutch registry – incidence of stent thrombosis from 21,009 patients % van Werkum JW et al. JACC 2009;53:1399-409

Rotterdam-Bern registry – long-term incidence of DES thrombosis 8146 patients treated with DES (sirolimus or paclitaxel- eluting stents) followed for a mean of 1.7 years (up to 3) 0.6% per year Stent thrombosis: Cumulative incidence -> 2.9% rate Late thrombosis -> costant 0.6% yearly rate Daemen J et al. Lancet 2007;369:667–78

Road map of the presentation What is the evidence supporting dual antiplatelet therapy for 12 months or more? Is there any risk of late thrombosis with coronary stents? What may happen if dual antiplatelet therapy is discontinued? What do the guidelines recommend in patients with acute coronary syndromes or coronary stents?

Biondi-Zoccai G et al. EHJ 2006;27:2667-2674 Risk of antiplatelet agent withdrawal in patients with coronary artery diseae Biondi-Zoccai G et al. EHJ 2006;27:2667-2674

Dutch registry – predictors of stent thrombosis from 21,009 patients van Werkum JW et al. JACC 2009;53:1399-409

Risk of adverse events after discontinuation of clopidogrel: medically treated patients with ACS Rate ratio of death or MI for 0-90 days after clopidogrel discontinuation of 1.98 (1.46-2.69, p<0.05) vs 91-180 days Ho PM et al. JAMA 2008;299:532-9

Risk of adverse events after discontinuation of clopidogrel: PCI treated patients with ACS Rate ratio of death or MI for 0-90 days after clopidogrel discontinuation of 1.82 (1.17-2.83, p<0.05) vs 91-180 days Ho PM et al. JAMA 2008;299:532-9

Adjusted rates of death or MI starting at 6 months Duke Registry – clopidogrel and long- term outcomes after DES implantation Adjusted rates of death or MI starting at 6 months Adjusted outcomes were analyzed at 24 months Patients in the DES with clopidogrel group had significantly lower rates of death or MI than did patients in the DES without clopidogrel group Among BMS patients, there were no differences in death or MI Difference = -4.1 ± 3.5 p=0.02 Difference = -0.5 ± 2.7 p=0.70 Endpoint (%) Eisenstein EL et al. JAMA 2007;297:159–68

Impact of duration of clopidogrel after PCI with stents in diabetics Brar SS et al. JACC 2008;51:2220-7

Planned duration of clopidogrel after DES implantation: the Melbourne registry Propensity-adjusted p=0.012 Propensity-adjusted p=0.76 Butler MJ et al. AHJ 2009;157:899-907

Any disagreement among studies: the Milan-Naples-Siegburg registry Airoldi F et al. Circulation 2007;116:745-754

Any disagreement among studies: the J-Cypher registry Kimura T et al. Circulation 2009;119:987-995

Road map of the presentation What is the evidence supporting dual antiplatelet therapy for 12 months? What is the rationale in favor of dual antiplatelet therapy for more than 12 months? Is there any risk of late thrombosis with drug-eluting stents? What do the guidelines recommend in patients with acute coronary syndromes or coronary stents?

ESC NSTE-ACS guidelines 2007 update Bassand J-P et al. Eur Heart J 2007;28:1598–1660.

NSTE-ACS - recommendations for oral antiplatelet drugs (2007) Aspirin is recommended for all patients presenting with NSTE-ACS without contraindication at an initial loading dose of 160 - 325mg (non-enteric) (I-A), and at a maintenance dose of 75 to 100mg long-term (I-A) For all patients immediate 300mg loading dose of clopidogrel is recommended, followed by 75mg clopidogrel daily (I-A). Clopidogrel should be maintained for 12 months unless there is an excessive risk of bleeding (I-A) For all patients with contraindication to aspirin, clopidogrel should be given instead (I-B) Bassand J-P et al. Eur Heart J 2007;28:1598–1660.

Silber S et al. Eur Heart J 2005;26:804-47. ESC PCI 2005 guidelines Silber S et al. Eur Heart J 2005;26:804-47.

for oral antiplatelet drugs (2005) PCI - recommendations for oral antiplatelet drugs (2005) Aspirin is recommended for all patients undergoing PCI (I-A) For all stable patients clopidogrel is recommended after bare-metal stents for 1 month (I-A), drug-eluting stents for 6–12 months and brachytherapy for 12 months (I-C) For patients with NSTE-ACS clopidogrel is recommended for 9–12 months (I-B) Silber S et al. Eur Heart J 2005;26:804-47.

International updates King SB III et al. Circulation 2008;117:261-95.

International updates – US PCI guidelines (2007) For all patients receiving a DES, clopidogrel 75 mg daily should be given for >12 months if patients are not at high risk of bleeding (I-B) For those receiving a BMS, clopidogrel should be given for >1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for >2 weeks) (I-B) Continuation of clopidogrel therapy beyond 1 year may be considered in patients undergoing DES placement (IIb-C) King SB III et al. Circulation 2008;117:261-95.

Take home messages RESEARCH PRACTICE

Take home messages The benefit of dual antiplatelet therapy for 12 months following ACS is well established. Most recent data and guidelines support dual antiplatelet therapy for 12 months in subjects treated with DES without high bleeding risk. Patients at high thombotic but low bleeding risks may benefit from dual antiplatelet therapy beyond 12 months. In any case, compliance should be recommended and verified, to avoid early and/or unsupervised discontinuation

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