Ontstolling in de dagelijkse praktijk casuïstiek Alles wat u wilt weten over ontstolling en plaatjesremming bij CAD, hartfalen, AF en stents (VKA, NOAC, aspirine, clopidogrel, prasugrel en ticagrelor) Jur ten Berg, cardioloog 1 2016
Disclosures • Advisory / consulting fees: AstraZeneca, Eli Lilly, Daiichi Sankyo, the Medicines Company, Accumetrics, Boehringer-Ingelheim, BMS • Research grants: ZonMw, AstraZeneca
Casus I • Patiënt 65 jaar • Asymptomatisch . “ Krijg ik ook een hartinfarct, fam belast voor HVZ” • Hypertensie sinds 50 e , ACE-remmer • Rookt, hypercholesterolemie (TCh 6; LDL 3,5 mmol/l) • Vader 55 AMI en 70 colon ca • ASA? 1. Ja 2. nee 3
Eerste 6 studies meta-analyse ATT Antithrombotic Trialist Collaboration 2009
Casus I • Per 10.000 treated for 10 years • 72 events (CV death, MI, or stroke) prevented • 51 cancer deaths prevented • 47 major bleedings (149 GI bleeds) incurred • 9 hemorrhagic strokes incurred • Effect man=woman • DM not sufficient risk • Bleeding as severe as MI? 6
Tailoring therapy according to baseline risk • Framingham coronary heart disease risk score: 10-jr MI/death • ESC’s SCORE: 10 -jr fatal atherosclerotic event 5% fatal ~ 15% (x3) total events • Patient 17% risk (ESC’s SCORE): antwoord 1: ja aspirine
Casus II HF en SR • Patiënt 50 jr • Hypertensie, ACE-remmer • Gedilateerde cardiomyopathie, geen CAD • Echo: EF 30%, atria gedilateerd Vraag: 1. OAC 2. ASA 3. Nix 8
Hartfalen en SR ASA vs warfarin vs No ASA vs warfarin No placebo • Death, non-fatal MI, non-fatal stroke: Warfarin = aspirin • Major bleeding: warfarin higher • Stroke: warfarin lower • Wash studie: no medication similar to ASA or warfarin
1212 Wel indicatie! Very low EF
Casus III Hf en coronairlijden • Patiënt 60 jr • Hypertensie, ACE-remmer • AF en CVA 1990 • Ischemische cardiomyopathie • Stabiel AP II CCS, PCI DES 2013 • Echo: EF 30%, murale trombus, atria gedilateerd • ECG: SR, lichte ST-T afw 1. OAC 2. ASA 3. OAC en ASA 11
1212 NOAC = VKA. When combined NOAC plus APT use lower dose NOAC
Casus IV • Man 55 jaar, DM II, in 2012 OWI, hypertensie met GFR = 48 ml/min, rookt. • STEMI 4 oktober 2016 DES proximale LAD, 9 oktober PCI Cx en diffuus RCA • Geen recidief, geen bloeding • 4 oktober 2017 polikliniek a) P2Y12 remmer (ticagrelor) had al gestopt moeten zijn b) Nu stop c) Nog jaren continueren 13
BMS versus 1st and 2nd generation DES Results from a registry of 18,334 unselected patients* Stent thrombosis; 1 st year and for the period Stent thrombosis after the 1 st year (separately) % 3 % 3 HR adj. 95% CI P value n BMS HR adj. 95% CI P value n BMS 1,47 – 2,86 2,01 – 11,1 2,05 <0,001 18.334 o-DES 4,72 <0,001 18.334 o-DES 0,56 – 1,19 0,32 – 3,25 0,82 0,30 n-DES 1,01 0,98 n-DES 2 2 1 1 0 0 0 1 2 3 0 1 2 3 Jaren na procedure Jaren na procedure * patients undergoing coronary stenting 14 Tada T, et al. JACC Cardiovasc Interv 2013
Meta-analysis 12,536 pts randomized to stop DAPT at 3, 6 or 12 months vs. 12 or 24 months Trial EXCELLENT PRODIGY REAL/ RESET ZEST-LATE Primary endpoint Composite of cardiac Composite of all-cause MI or cardiac death Composite of cardiac death, death, MI, or ID-TVR death, MI or CVAs MI, ST, ID-TVR and TIMI major or minor bleeding Time to randomization At index PCI 1 month after index PCI 12 months after index At index PCI PCI DAPT duration Extended DAPT 12 months 24 months 24 months 12 months Group Control DAPT Group 6 months 6 months 12 months 3 months Longest FU 12 months 24 months 24 months 12 months Kort DAPT even veilig als lang DAPT Collet J et al. Lancet. 2014 Jul 15. pii: S0140-6736(14)60612-7. doi: 10.1016/S0140-6736(14)60612-7
DAPT duration in Stable Coronary Artery Disease According to ESC Guidelines (not our patient!) Myocardial revascularization Guidelines (2014) Recommendations for antithrombotic treatment in patients with SCAD undergoing PCI I A DAPT is indicated for at least 1 month after BMS implantation I B DAPT is indicated for 6 months after DES implantation Shorter DAPT duration (<6 months) may be considered after DES implantation in patients at high IIb A bleeding risk I A Life-long single antiplatelet therapy, usually ASA, is recommended I C Instruction of patients about the importance of complying with antiplatelet therapy is recommended IIb C DAPT may be used for more than 6 months in patients at high ischemic risk and low bleeding risk Pas op: • Studies merendeel low risk patienten • Geen power om een verschil in stent trombose aan te tonen 16 Windecker et al. Eur Heart J 2014;35(37):2541-619
DAPT N=9000 Previous studies underpowered Designed in response to FDA-request Study drug R treatment ends 12 month observational 3 month observational Thienopyridines + Aspirin period: Open-label period: Thienopyridine + Aspririn Off Thienopyridine + Placebo + Aspirin required On Aspririn Time in months after index stent 0 12 30 33 procedure (not scale) Free from MI, stroke, repeat revascularization and bleeding, adherent to P2Y12 18 Mauri et al. NEJM DOI:10.1056/NEJMoa1409312
DAPT Primary endpoint Death, MI, Stroke % 8 5,9 6,5 6 5,6 4 4,3 2 HR 95% CI P value n 12 months 0,59 – 0,85 0,29 <0,001 9.961 30 months 0 0 12 15 18 21 24 27 30 33 Maanden na randomisatie 19 Mauri et al. NEJM DOI:10.1056/NEJMoa1409312
DAPT Primary endpoint Stent Thrombosis % 8 HR 95% CI P value n 12 months 6 0,17 – 0,48 1,03 0,03 9.961 30 months 4 2 1,4 1,4 0,7 0 0,4 0 12 15 18 21 24 27 30 33 Maanden na randomisatie 20 Mauri et al. NEJM DOI:10.1056/NEJMoa1409312
DAPT Primary endpoint Not-Stent Thrombosis Myocardial Infarction % 10 HR 95% CI P value n 12 months 8 0,45 – 0,78 0,59 <0,001 9.961 30 months 6 55% of the MI 2,9 benefit is NOT related to stent 4 thrombosis 1,8 0 0 12 15 18 21 24 27 30 33 Maanden na randomisatie 21 Mauri et al. NEJM DOI:10.1056/NEJMoa1409312
DAPT Bleedings 12 months % 4 30 months <0,001 3,1 0,001 <0,001 3 2,6 2,5 0,004 2 1,7 1,6 1,5 1,5 0,15 1,0 1 0,8 0,6 0,38 0,1 0,1 0 TIMI Moderate Severe BARC BARC BARC Moderate or Type 2 Type 3 Type 5 Severe 22
DAPT Cause for difference in mortality? 12-30 M mortality Thienopyridine Placebo P value Absolute N=5.020 N=4.941 Difference All cause mortality 98 (2,0%) 74 (1,5%) 0,052 24 (0,5%) Cardiac 45 (0,9%) 47 (1,0%) 0,98 -2 (-0,1%) Vascular 5 (0,1%) 5 (0,1%) 0,98 0 (-) Non-cardiovascular 48 (1,0%) 22 (0,5%) 0,002 26 (0,5%) (bleeding, trauma, cancer) 23 Mauri et al. NEJM DOI:10.1056/NEJMoa1409312
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
age of 65 years or older, diabetes mellitus requiring medication, a second prior spontaneous myocardial infarction, multivessel coronary artery disease, or chronic renal dysfunction, defined as an estimated creatinine clearance of less than 60 ml per minute. N= 21.000 An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
An Academic Research Organization of Brigham and Women’s Hospital and Harvard Medical School
Reduction in CV death, MI or stroke with ticagrelor by time from P2Y 12 inhibitor withdrawal Time from P2Y 12 inhibitor withdrawal to HR (95% CI) P value randomization 0.70 (0.57, 0.87) ≤30 days 0.75 (0.61, 0.92) 27% RRR n=7181 0.73 (0.61, 0.87) <0.001 0.90 (0.72, 1.12) >30 days to 1 year 0.82 (0.65, 1.02) 14% RRR n=6501 0.86 (0.71, 1.04) 0.11 0.96 (0.73, 1.26) >1 year 1.06 (0.81, 1.38) n=5079 RRR 1.01 (0.80, 1.27) 0.96 P-interaction 0.0097 Ticagrelor 90 mg 0.7 0.9 1.1 Ticagrelor 60 mg Ticagrelor better 1.0 Placebo better Pooled Bonaca MP et al. Eur Heart J 2016; 37(14): 1133-42 27
Casus IV • Man 40 jaar, DM I, hypertensie met GFR = 48 ml/min, rookt, fam HVZ • STEMI 4 oktober 2016 DES proximale LAD, 9 oktober PCI Cx en diffuus RCA • Geen recidief, geen bloeding • 4 oktober 2017 polikliniek a) P2Y12 remmer (ticagrelor) had al gestopt moeten zijn b) Nu stop c) Nog jaren continueren PEGASUS: age of 65 years or older, diabetes mellitus requiring medication, a second prior spontaneous myocardial infarction, multivessel coronary artery disease, or chronic renal dysfunction, defined as an estimated creatinine clearance of less than 60 ml per minute. DAPT: no event first year 28
Casus V • Vrouw 87 jaar, 57 kg, hypertensie, maag bloeding ulcus 2013 • NSTEMI en PCI DES prox LAD succesvol 21 sept 2016 a) 1 jaar DAPT b) 6 maanden DAPT c) 3 maanden DAPT I A DAPT is indicated for at least 1 month after BMS implantation I B DAPT is indicated for 6 months after DES implantation Shorter DAPT duration (<6 months) may be considered after DES implantation in patients at high IIb A bleeding risk 29 I A Life-long single antiplatelet therapy, usually ASA, is recommended
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