Διάρκεια διπλής αντιαιμοπεταλιακής αγωγής Νικόλαος Γ.Πατσουράκος Καρδιολόγος, Επιμελητής Α ΕΣΥ Τζάνειο Γενικό Νοσοκομείο Πειραιά
International ACS guidelines: Recommendations on duration of dual antiplatelet therapy Region/Country EU EU EU USA USA Canada Organisation ESC/EACTS ESC ESC AHA/ACC AHA/ACC CCS Guideline topic Myocardial Outpatient antiplatelet revascularisation 1 NSTE-ACS 2 STEMI 3 STEMI 4 UA/NSTEMI 5 therapy 6 Publication year 2010 2011 2012 2013 2012 update 2011 Clinical scenario Ticagrelor: Class of recommendation, LOE Recommended duration of DAPT NSTEMI/ UA, PCI managed STEMI, PCI managed NSTEMI/UA STEMI, primary PCI STEMI, primary PCI NSTEMI/UA, medically managed NSTEMI/UA, PCI managed ACS, medically managed ACS, PCI managed I B I B I B I B I B I B I B I B I B 1 year 1 year 1 year Up to 1 year 1 year Up to 1 year 1 year Up to 1 year 1 year ACS, acute coronary syndrome; ACC, American College of Cardiology; AHA, American Heart Association; CCS, Canadian Cardiovascular Society; DAPT, dual antiplatelet therapy; EACTS, European Association for Cardio-Thoracic Surgery; ESC, European Society of Cardiology; LOE, level of evidence; NSTE-ACS, non-st-elevation acute coronary syndrome; NSTEMI, non-st-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina. 1. Wijns W, et al. Eur Heart J 2010;31:2501 2555; 2. Hamm CW, et al. Eur Heart J 2011;32:2999 3054; 3. Steg G, et al. Eur Heart J 2012;33:2569 2619; 4. O Gara PT, et al. Circulation 2013;127:e362 425; 5. Jneid H, et al. Circulation 2012;126:875 910; 6. Bell AD, et al. Can J Cardiol 2011;27:208 211.
Predictors of DES Thrombosis: Considerations for Prolonged Dual Antiplatelet Therapy (DAPT) Clinical Angiographic Advanced age Acute coronary syndrome Diabetes Low ejection fraction Prior brachytherapy Renal failure Long stents Multiple lesions Overlapping stents Ostial or bifurcation lesions Small vessels Suboptimal stent results
Cumulative mortality in STEMI patients (%) Despite improvements in survival rates, ~1 in 8 patients will die within 3 years of a STEMI Prospective study of 3-year outcomes in a consecutive series of STEMI patients (n=6820) 40 1985 1990 1990 2000 2000 2008 30 20 10 27% 25% 13% Overall log-rank p<0.001 0 0 1 2 3 Time from event (years) Nauta ST, et al. PLoS One 2011;6:e26917
Cumulative mortality in NSTEMI patients (%) Survival rates post-nstemi have not markedly improved ~1 in 8 patients will die within 3 years of a NSTEMI Prospective study of 3-year outcomes in a consecutive series of NSTEMI patients (n=7614) 40 1985 1990 1990 2000 2000 2008 30 20 10 Overall log-rank p<0.001 15% 14% 12% 0 0 1 2 3 Time from event (years) Nauta ST, et al. PLoS One 2011;6:e26917.
5-year mortality rate (%) ~1 in 5 patients with ACS will have died within 5 years of their index event GRACE study: Analysis of UK and Belgian patients with ACS 25 22 20 19 18 15 10 5 0 STEMI (n=1403) NSTEMI (n=1170) UA (n=850) Post-discharge deaths occurred in 68%, 86% and 97% of STEMI, NSTEMI and UA patients, respectively. ACS, acute coronary syndromes; GRACE, Global Registry of Acute Coronary Events; MI, myocardial infarction; NSTEMI, non-st-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina. Fox KA, et al. Eur Heart J 2010;31:2755 2764.
Dual Anti-Platelet Therapy (DAPT) Randomized Trial And Several Registries Suggesting A Benefit With Prolonged Use Of DAPT CURE: 22% reduction in adverse clinical events with DAPT (31% reduction in patients that underwent PCI with stents) Only BMS were used in this study. The Bern-Rotterdam Experience: 65% of stent thromboses (ST) occurred within the first 6 months after PCI and DES. The annual rate of ST according to this registry was 0.6% out to 4 years. Duke Database: Increased incidence of death or MI in DES patients if DAPT was discontinued within 6 months. The Tycoon Registry: 4 late ST when DAPT was discontinued after 1 year (with DES). None ST if DAPT continued out to 2 years.
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ACS Prior MI PAD Acute ischaemic stroke or TIA Type 2 diabetes at high risk of CV events n=18,624 n=21,162 n>13,500 n=9600 n=17,000 Study status: Complete Study status: Enrolment complete Study status: Enrolment complete Study status: Recruiting Study status: Recruiting ACS, acute coronary syndromes; CV, cardiovascular; MI, myocardial infarction; PAD, peripheral arterial disease; TIA, transient ischaemic attack.
PEGASUS-TIMI 54 study design Patients who had a MI 1 3 years ago AND have at least one additional atherothrombotic risk factor* (n=21,162) Ticagrelor 60 mg BID + 75 150 mg ASA Ticagrelor 90 mg BID + 75 150 mg ASA Placebo + 75 150 mg ASA Minimum of 12 months follow up (quarterly in Year 1, then semi-annually) Primary efficacy endpoint: CV death, MI or stroke Primary safety endpoint: TIMI major bleeding *Atherothrombotic risk factors defined as age 65 years, diabetes, a second prior MI, evidence of multivessel coronary artery disease or chronic non-end-stage renal dysfunction; Ticagrelor is only indicated in patients with acute coronary syndromes for up to 1 year of treatment. ASA, acetylsalicylic acid; BID, twice daily; CV, cardiovascular; MI, myocardial infarction; TIMI, Thrombolysis In Myocardial Infarction. Bonaca MP, et al. Am Heart J 2014;167:437 444.e5.
Second Generation Drug-Eluting Stents Implantation Followed by Six Versus Twelve-Month - Dual Antiplatelet Therapy- The SECURITY Randomized Clinical Trial. BACKGROUND: Optimal duration of DAPT following 2 nd -generation DES implantation is still debated. OBJECTIVES: To test the non-inferiority of 6 versus 12 months dual antiplatelet therapy (DAPT) in patients undergoing percutaneous coronary intervention with 2 nd -generation drug-eluting stent (DES). METHODS: The SECURITY trial was a 1:1 randomized, multicenter, international, investigator-driven, non-inferiority study conducted from July 2009 to June 2014. Patients with a diagnosis of stable or unstable angina or documented silent ischemia undergoing revascularization with at least one 2 nd -generation DES were eligible. Primary endpoint was a composite of cardiac death, myocardial infarction, stroke, definite or probable stent thrombosis or BARC type 3 or 5 bleeding at 12 months. The main secondary endpoint was a composite of cardiac death, myocardial infarction, stroke, definite or probable stent thrombosis or BARC type 2, 3 or 5 bleeding at 12 and 24 months. RESULTS: Overall 1399 patients were enrolled in the study and randomized to receive 6-month (n = 682) vs. 12-month (n = 717) DAPT. Primary composite endpoint occurred respectively in 4.5% vs. 3.7% (risk difference, 0.8%; 95% CI: - 2.4% to 1.7%; p = 0.469) at 12 months. Being the upper limit of the 95% CI lower than the pre-set margin of 2% the non-inferiority hypothesis was confirmed (p < 0.05). Moreover no differences were observed in the occurrence of the secondary endpoint at 12 months (5.3% vs. 4.0%, difference: 1.2%; 95% CI: -1.0 to 3.4, p = 0.273) and between 12 and 24 months (1.5% vs. 2.2%, difference: -0.7%; 95% CI: -2.1 to 0.6, p = 0.289). Finally, no differences were present in definite or probable stent thrombosis at 12 months (0.3% vs. 0.4%; difference: -0.1%; 95% CI: -0.7 to 0.4; p = 0.694) and between 12 and 24 months of follow-up (0.1% vs. 0%; difference: 0.1%; 95% CI: -0.1 to 0.4; p = 0.305). CONCLUSIONS: In a low-risk population, as the one included in this study, the non-inferiority hypothesis (6 versus 12 months) DAPT following 2 nd -generation DES implantation appears accepted regarding the incidence of cardiac death, MI, stroke, definite/probable stent thrombosis and BARC type 3 or 5 bleeding at 12 months Colombo, Chieffo, Frascheri J.Am.Coll Cardio 2014 sep 9
Dual-antiplatelet treatment beyond 1 year after drug-eluting stent implantation (ARCTIC-Interruption): a randomised trial Background Optimum duration of dual antiplatelet treatment (DAPT) after coronary stenting remains uncertain, with an unknown efficacy to safety ratio of extended treatment leading to discrepancies between international guidelines and clinical practice. We assessed whether DAPT continuation beyond 1 year after coronary stenting is beneficial. Methods This analysis was a planned extension of the previously published ARCTIC-Monitoring trial, in which we randomly allocated 2440 patients to a strategy of platelet function testing with antiplatelet treatment adjustment or a conventional strategy after coronary stenting with drug-eluting stent (DES). We recruited patients (aged 18 years or older) scheduled for planned DES implantation at 38 centres in France. After 1 year of follow-up, patients without contraindication to interruption of DAPT were eligible for a second randomisation to this second phase of the study (ARCTIC-Interruption). Using a computergenerated randomisation sequence (1:1; stratified by centre), we allocated patients to a strategy of interruption of DAPT where the thienopyridine was interrupted and single aspirin antiplatelet treatment was maintained (interruption group) or a strategy of DAPT continuation for 6 18 months (continuation group). The primary endpoint was the composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularisation, analysed by intention to treat. Findings Between Jan 4, 2011, and March 3, 2012, 1259 eligible patients were randomly allocated to treatment in ARCTIC- Interruption: 624 to the interruption group and 635 to the continuation group. After a median follow-up of 17 months (IQR 15 18), the primary endpoint occurred in 27 (4%) patients in the interruption group and 24 (4%) patients in the continuation group (hazard ratio [HR] 1 17 [95% CI 0 68 2 03]; p=0 58). STEEPLE major bleeding events occurred more often in the continuation group (seven [1%] patients) compared with the interruption group (one [<0 5%] patient; HR 0 15 [0 02 1 20]; p=0 073). Major or minor bleedings were also more common in the continuation group compared with the interruption group (12 [2%] patients vs three [1%] patients; HR 0 26 [0 07 0 91]; p=0 04). Interpretation Our finding suggests no apparent benefit but instead harm with extension of DAPT beyond 1 year after stenting with DES when no event has occurred within the first year after stenting. No conclusion can be drawn for high-risk patients who could not be randomised. The consistency between findings from all trials of such interruption suggests the need for a reappraisal of guidelines for DAPT after coronary stenting towards shorter duration of treatment. The Lancet, Early Online Publication, 16 July 2014 doi:10.1016/s0140-6736(14)60612-7
Long-Term P2Y12-Receptor Antagonists in Post-Myocardial Infarction Patients: Facing a New Trilemma? Physicians considering prescription of P2Y12-receptor antagonist for longterm (>1 year) protection of patients post-myocardial infarction face the trilemma of selecting between clopidogrel, prasugrel, or ticagrelor. Differential ischemic benefits derived from relevant trials may assist in tailoring treatment, although the different bleeding definitions applied make any meaningful comparison of each agent's bleeding potential very difficult. Considering the available data and recognizing the significant limitation of observations obtained thus far from subgroup analyses, prasugrel appears to provide higher anti-ischemic protection than clopidogrel. Alexopoulos et allj Am Coll Cardiol 2016 Sep;68(11):1223-32
Figure 1. Master Treatment Algorithm for Duration of P2Y 12 Inhibitor Therapy in Patients With CAD Treated With DAPT
2016 ACC/AHA Duration of DAPT Guideline Focused Update Perioperative Management Timing of Elective Noncardiac Surgery in Patients Treated With PCI and DAPT
Perioperative Management Timing of Elective Noncardiac Surgery in Patients Treated With PCI and DAPT COR LOE Recommendations I B-NR Elective noncardiac surgery should be delayed 30 days after BMS implantation and optimally 6 months after DES implantation. I C-EO In patients treated with DAPT after coronary stent implantation who must undergo surgical procedures that mandate the discontinuation of P2Y 12 inhibitor therapy, it is recommended that aspirin be continued if possible and the P2Y 12 platelet receptor inhibitor be restarted as soon as possible after surgery. IIa C-EO When noncardiac surgery is required in patients currently taking a P2Y 12 inhibitor, a consensus decision among treating clinicians as to the relative risks of surgery and discontinuation or continuation of antiplatelet therapy can be useful.
Perioperative Management Timing of Elective Noncardiac Surgery in Patients Treated With PCI and DAPT (cont d) COR LOE Recommendations IIb C-EO Elective noncardiac surgery after DES implantation in patients for whom P2Y 12 inhibitor therapy will need to be discontinued may be considered after 3 months if the risk of further delay of surgery is greater than the expected risks of stent thrombosis. Elective noncardiac surgery should not be performed within 30 days after BMS III: Harm B-NR implantation or within 3 months after DES implantation in patients in whom DAPT will need to be discontinued perioperatively.
Figure 6. Treatment Algorithm for the Timing of Elective Noncardiac Surgery in Patients With Coronary Stents