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Journal club 11 1-2012 woest trial

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WOEST trial Journal Club: Triple Therapy vs ASA + Clopidogrel in patients with indication for anticoagulation s/p PCI

WOEST trial Journal Club: Triple Therapy vs ASA + Clopidogrel in patients with indication for anticoagulation s/p PCI

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  • This trial compared two antithrombotic regimens in 517 patients following Palmaz-Schatz coronary artery stenting: ticlopidine (for 4 weeks), aspirin (indefinitely), and heparin (for 12 hours after the procedure) were compared with phenprocoumon, a warfarin derivative (for 4 weeks), aspirin (indefinitely), and heparin (for 5 to 10 days after the procedure). \n\nThe antiplatelet group did better in all clinical end points than the anticoagulation group: stent occlusion, 0.8% versus 5.4% (P < 0.005); major bleeding complications, 0% versus 6.5% (P < 0.001). There was an approximately 80% reduction in the occurrence of acute myocardial infarction (0.8% vs. 4.2%, P = 0.02) and the need for repeat coronary intervention (1.2% vs. 5.4%, P = 0.01) in the antiplateletgroup. At 6months,there was no differencein angiographic restenosis rates (27% for the antiplatelet group and 29% for the anticoagulation group, P = NS).\n
  • The STARS (Stent Antithrombotic Regimen Study) trial compared aspirin alone, aspirin and coumadin, or aspirin and ticlopidine in 1,650 patients after Palmaz –Schatz stent implantation. Similar to the ISAR trial, the combination of aspirin and ticlopidine was associated with the lowest stent thrombosis rate (0.6% in the STARS trial).\n
  • Ticlopidine has been associated with life-threatening neutropenia and has largely been supplanted at many interventional cardiology centers by clopidogrel, a drug chemically related to ticlopidine. Clopidogrel has the same specific mechanism of action as ticlopidine against the ADP-activated pathway of platelet aggregation, but it has a more rapid onset of antiplatelet action, its antiplatelet effect is severalfold more powerful, and it is associated with a lower incidence of neutropenia (0.1%) than ticlopidine (2.4%).\n\nCure focused on Non-ST elevation MI\n\nThe primary end points of MI, stroke, and cardiovascular death from randomization to 1 year were reported. There was a 20% RRR in the primary outcome of MI, stroke, or cardiovascular death, a highly significant result at 12 months in patients treated with clopidogrel. The most pronounced ben- efit was observed in the reduction of MIs, with the largest reductions of 40% in Q-wave or ST-elevation MI, also statistically significant. In parallel with the reduction in large MI was a 43% reduction in the use of fibrinolytic therapy after randomization and an 18% reduction in radiologically confirmed HF.\n\n\n
  • In patients with STEMI treated with lytics prior to PCI, pretreatment with clopidogrel prior to PCI:\n\n46% reduction in the combined MACE endpoint\nNo excess TIMI major or minor bleeding\n
  • Chinese Ministry of Health\n\nThe COMMIT trial used a 75 mg/day dose with no loading dose, unlike CLARITY-TIMI 28, which treated patients with an initial 300 mg loading dose. Despite the lack of a loading dose in COMMIT, the endpoint curves began to diverge as early as day one. \n\nThe risk of any major bleeding did not differ between the clopidogrel and placebo groups. However, minor bleeding was not reported, and it is unknown if the risk of bleeding would be higher had patients undergone revascularization.\n
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  • The trial was discontinued early at the recommendation of the data safety monitoring board due to evidence of superiority on the primary endpoint with oral anticoagulant therapy over clopidogrel plus aspirin (3.90% per year vs. 5.60% per year; relative risk [RR], 1.44; p = 0.0003). Among the individual components of the composite, the oral anticoagulant therapy group had lower rates of stroke (1.4% per year vs. 2.4% per year, p = 0.001) and non-CNS embolism (0.10% per year vs. 0.43% per year, p = 0.005), with no significant difference in myocardial infarction (MI) (0.55% per year vs. 0.86% per year, p = 0.09) or vascular death (2.52% per year vs. 2.87% per year, p = 0.34). \n\nThere was also no difference in total mortality (3.8% per year in both groups). In subgroup analysis, the largest benefit in the primary endpoint was observed in patients who were on oral anticoagulant therapy at study entry (RR, 1.50; p = 0.0005).\n
  • ESC 2010 AF guidelines\n
  • ACCP AF guidelines 2012\n
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  • Note a sudden fall in the use of clopidogrel in both groups possibly because of stopping clopidogrel 30days after bare metal stenting\n
  • The Kaplan Meier curve of the aspirin compliance is comparable to the reversed curve of the bleeding events in the triple therapy group\n
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  • Transcript

    • 1. JOURNAL CLUB THE WOEST TRIAL:ORAL ANTICOAGULATION ± ASA S/P PCI MICHAEL G. KATZ FELLOW IN CARDIOLOGY UNIVERSITY OF ROCHESTER NOVEMBER 1, 2012
    • 2. BACKGROUNDTRIAL AIMSSTUDY DESIGNPOPULATIONRESULTSDISCUSSIONEFFECT ON PRACTICE?
    • 3. BACKGROUND LONG TERM ORAL ANTICOAGULATION IS GENERALLY INDICATED IN: MOST PATIENTS WITH AF PATIENTS WITH MECHANICAL HEART VALVESCIRCULATION 2006;114;700-752CIRCULATION 2006;114;450-527
    • 4. MECHANICAL VALVES
    • 5. ACS/PCI - DAPT AND TRIPLE TX> 30% OF PTS WITH AF HAVE ISCHEMIC HEART DISEASEAF OCCURS IN 2 – 21% OF PATIENTS WITH ACSWHEN THESE PATIENTS UNDERGO PCI, BOTH THE ACC/AHAGUIDELINES AND THE ESC GUIDELINES CALL FOR SOMEPERIOD OF “TRIPPLE TX”
    • 6. ACS DAPT TRIALSISARSTARSCURE } ANTICOAGULATION STUDIESCLARITY-PCICOMMIT
    • 7. ISARANTIPLATELET VS.ANTICOAGULANT THERAPYFOLLOWINGINTRACORONARY STENTINGALL PTS PREVIOUS RECEIVEDHEPARIN AND ASPIRIN PRIORTO PTCATICLOPIDINE/ASPIRIN VSHEPARIN/PHENPROCOUMON/ASPIRINDAPT WINS OVERTRADITIONALANTICOAGULATION N ENGL J MED 1996;334:1084
    • 8. STARSANTIPLATELET ANDANTICOAGULATIONREGIMENS AFTERINTRACORONARYSTENTINGASA ALONE VS ASA +WARFARIN VS ASA +TICLOPIDINEDAPT WINS OVER ASAALONE VS ASA +WARFARIN N ENGL J MED 1998;339:1665
    • 9. CURE N ENGL J MED 2001;345: 494
    • 10. CLARITY-PCI JAMA:2005;294:1224
    • 11. COMMIT GOAL: EVALUATE FOR MOTALITY BENEFIT OF DAPT IN PTS WITH ST ELEVATION APPRX 46,000 PTS ASA 162 MG VS CLOPIDOGREL + ASA 162 DAPT SHOWED BENEFIT WITH NO INCREASE IN MAJOR BLEEDINGLANCET 2005; 366: 1607–21
    • 12. ISAR ISAR STARS CURE STARS CLARITY-PCI COMMITANTICOAGULATION DAPT
    • 13. ISARSTARS
    • 14. DAPT FOR AFACTIVE - W APPROX 6,700 PATIENTS WITH AF ASA 75-100 MG + CLOPIDOGREL 75 MG VS WARFARIN WITH INR 2-3 TRIAL D/C’ED EARLY AT RECOMMENDATION OF SAFETY MONITORING BOARD SUPERIOR COMBINED END- POINT AND LESS STROKE WITH WARFARIN
    • 15. EUR HEART J 2009;30:1038 – 1045
    • 16. CHEST 2012;141;E531S-E575S
    • 17. WOEST ESC, Hotline III, Munchen, August 28th, 2012 The WOEST Trial: First randomised trialcomparing two regimens with and without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting Willem Dewilde, Tom Oirbans, Freek Verheugt, Johannes Kelder, Bart De Smet, Jean-Paul Herrman, Tom Adriaenssens, Mathias Vrolix, Antonius Heestermans, Marije Vis, Saman Rasoul, Kaioum Sheikjoesoef, Tom Vandendriessche, Carlos Van Mieghem, Kristoff Cornelis, Jeroen Vos, Guus Brueren, Nicolien Breet and Jurriën ten Berg The WOEST Trial= What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (clinicaltrials.gov NCT00769938) |
    • 18. WOEST Aim of the studyTo test the hypothesis that in patients on OAC undergoing PCI,clopidogrel alone is superior to the combination aspirin andclopidogrel with respect to bleeding but is not increasingthrombotic risk in a multicentre two-country study (TheNetherlands and Belgium)|
    • 19. WOEST Study Design-1Inclusion criteria: Exclusion criteria:1/ Indication for OAC for at least 1 1/ History of intracranial bleeding year 2/ Cardiogenic shock during2/ One coronary lesion eligible for hospitalisation 3/ Peptic ulcer in the previous 6 months PCI 4/ TIMI major bleeding in the previous3/ Age over 18 year 5/ Contra-indication for aspirin or clopidogrel 6/ Thrombocytopenia (platelet count less than 50,000 per ml) 7/ Pregnancy 8/ Age >80|
    • 20. WOEST Study Design-21:1 Randomisation:Double therapy group: Triple therapy group OAC + 75mg Clopidogrel qd OAC + 75mg Clopidogrel qd + 80mg Aspirin qd1 month minimum after BMS 1 month minimum after BMS 1 year after DES1 year after DES Follow up: 1 year Primary Endpoint: The occurence of all bleeding events (TIMI criteria) Secondary Endpoints: - Combination of stroke, death, myocardial infarction, stent thrombosis and target vessel revascularisation - All individual components of primary and secondary endpoints|
    • 21. WOEST Study Design-3- Power calculation was based on the largest retrospective study by Karjalainen1 addressing this issue.- We anticipated a 12% bleeding rate in the triple therapy group and a 5% bleeding rate in the double therapy group- Power was chosen to be 80% and α level 5%. The total patient number is estimated at n = 496- The study is designed as a superiority trial- All events were adjudicated by a committee blinded to treatment allocation 1 Eur Heart J 2007;28:726-32
    • 22. WOEST 573 patients underwent 1:1 randomization Study flow chart 284 were assigned to 289 were assigned to Double therapy group Triple therapy group No PCI (n=3) No PCI (n=1) Withdrawn informed consent (n=2)* Withdrawn informed consent (n=2)* Lost to follow up (n=1) Lost to follow up (n=1) Did not meet inclusion criteria (n=1) Did not meet inclusion criteria (n=2) 279 patients were included in 284 patients were included in Intention to treat analysis Intention to treat analysis* withdrawn informed consent; in double group 2 patients and triple group 1 patient were included in intention to treatanalysis until the day of withdrawal
    • 23. WOEST Baseline Characteristics Double therapy n=279 (%) Triple therapy n=284 (%) Age 70.3 (±7.3) 69.5(±8.0) Male gender 214 (76.7%) 234 (82.4%) BMI (kg/m2) 27.5 (±4.3) 27.9 (±4.2) Current Smoker 60 (21.5%) 42 (14.8%) Diabetes 68 (24.4%) 72 (25.4%) Hypertension 193 (69.2%) 193 (68.0%) Hypercholesterolemia 191 (68.5%) 205 (72.2%) History of MI 96 (34.4%) 100 (35.2%) History of Heart Failure 71 (25.4%) 70 (24.6%) History of Stroke 49 (17.6%) 50 (17.6%) History of PCI 86 (30.8%) 101 (35.6%) History of CABG 56 (20.1%) 74 (26.1%) History of GI bleeding 14 (5.0%) 14 (4.9%) Indication for OAC AF/Aflutter 164 (69.5%) 162 (69.2%) Mechanical valve 24 (10.2%) 25 (10.7%) Other (pulmonary embolus, 48 (20.3%) 47 (20.1%) EF<30%, Apical thrombus...) ACS at baseline 69 (25.0%) 86 (30.6%)
    • 24. WOEST Procedural Characteristics Double therapy n=279 (%) Triple therapy n=284 (%) PCI vessel LAD 111(39.9%) 118 (41.8%) RCX 59 (21.2%) 76 (27.0%) RCA 92 (33.1%) 72 (25.5%) Arterial/Venous Graft 16 (5.7%) 16 (5.6%) INR on the day of PCI 1.86 (±0.9) 1.94 (±1.1) LVEF <=30% 40 (21.1%) 37 (18.1%) Stent type No 5 (1.8%) 4 (1.4%) BMS 89 (32.0%) 86 (30.3%) DES 181 (65.1%) 183 (64.4%) BMS + DES 3 (1.0%) 11 (3.8%) Femoral access 204 (73.4%) 208 (74.6%) Radial access 74 (26.6%) 71 (25.4%) Angioseal 166 (59.5%) 167 (59.4%) Other closure device 43 (15.4%) 29 (10.3%) Peri-produral OAC continuation 128 (45.9%) 113 (39.8%) Peri-procedural LMWH 66 (23.7%) 68 (23.9%) Peri-Procedural GPIIbIIIa 25 (8.9%) 26 (9.1%) Peri-Procedural Fondaparinux 3 (1.0%) 2 (0.7%)
    • 25. WOEST Primary Endpoint: Total number of TIMI bleeding events 50 % Triple therapy group 44.9% Double therapy group Cumulative incidence of bleeding 40 % 30 % 19.5% 20 % 10 % p<0.001 HR=0.36 95%CI[0.26-0.50] 0% 0 30 60 90 120 180 270 365 Days n at risk: 284 210 194 186 181 173 159 140 279 253 244 241 241 236 226 208|
    • 26. WOEST Primary Endpoint: Bleeding events TIMI classification50.0% 44.9 p<0.00137.5 p<0.001 27.2 Double therapy group Triple therapy group 25.0 p<0.001 19.5 16.7 3D-kolom 3 11.2 p=0.159 12.5 6.5 5.8 3.3 0 TIMI Minimal TIMI MinorTIMI Major TIMI bleeding Any
    • 27. WOEST Locations of TIMI bleeding: Worst bleeding per patient 48 50 Double therapy Triple therapy Noord 38 30(N=) 25 20 20 25 16 8 7 13 3 3 0 Intra-Cranial Acces site GI Skin Other GI=gastro intestinal; Other bleeding consists of eye, urogenital, respiratory tract, retroperitoneal, mouth, PMpocket bleeding
    • 28. WOEST Forest plot of primary endpoint Hazard Ratios Factor Group Triple Double P-value for interaction age age75 <75 years FALSE 79 200 194 82 >75 years TRUE 200 79 82 194 0.9157 0.9157 gender male female no 50 65 65 male yes 234 214 214 0.8217 0.8217 ACS t0acs no 195 207 207 yes 86 69 0.721 69 0.7210 AF/AFlut 162 164 indication AF/AFlut oacind3cat 162 164 OAC Mechanical 25 24 Mechanical valve 24 0.1116 25 0.1116 valve Other 47 48 0.7761 47 48 Other 0.7761 Stent des BMS No 90 94 94 type DES 194 184 184 0.7894 0.7894 Overall Overall 284 279 279 0.1 0.4 1 double therapy better <=> triple therapy better
    • 29. WOEST Compliance to OAC, aspirin and clopidogrel Double therapy group Triple therapy group100 %75 %50 % OAC Clopidogrel25 % Aspirin 0% 0 30 60 90 120 180 270 365 0 30 60 90 120 180 270 365 Days Days
    • 30. WOEST Bleeding in triple therapy group and aspirin compliance Free from bleeding curve Triple therapy group 100 % Double therapy group 75 %free fromany TIMI bleeds 50 % Triple therapy group OAC 25 % Clopidogrel Aspirin 0% 0 30 60 90 120 180 270 365 0 30 60 90 120 180 270 365 Days Days n at risk: 284 210 194 186 181 173 159 140 279 253 244 241 241 236 226 208
    • 31. WOEST Secondary Endpoint (Death, MI,TVR, Stroke, ST) 20 % Triple therapy group 17.7% Double therapy group 15 % Cumulative incidence 11.3% 10 % 5% p=0.025 HR=0.60 95%CI[0.38-0.94] 0% 0 30 60 90 120 180 270 365 Days n at risk: 284 272 270 266 261 252 242 223 279 276 273 270 266 263 258 234
    • 32. WOEST Secondary Endpoint9.0 Double ther p=0.876 Triple thera 7.3 Noord p=0.027 6.8 6.4 6.8 p=0.382 4.7 4.5 p=0.128 p=0.165 3.3 3.2 2.9 2.6 2.3 1.5 1.1 0 Death MI TVR Stroke STMI=any myocardial infarction; TVR= target vessel revascularisation (PCI + CABG); ST= stent thrombosis
    • 33. WOEST All-Cause Mortality 7.5 % Triple therapy group Double therapy group 6.4% Cumulative incidence of death 5% HR=0.39 95%CI[0.16-0.93] p=0.027 2.6% 2.5 % 0% 0 30 60 90 120 180 270 365 Days n at risk: 284 281 280 280 279 277 270 252 279 278 276 276 276 275 274 256
    • 34. WOEST Limitations- The study was powered to show superiority on the primary bleeding endpoint, but not to show non-inferiority on the secondary endpoint- Open label trial design with its inherent bias- Classification of smaller bleeding, although well defined and blindly adjudicated, may be subjective|
    • 35. WOEST Conclusions1. First randomized trial to address the optimal antiplatelet therapy in patients on OAC undergoing coronary stenting2. In this study which was specifically designed to detect bleeding events, the bleeding rate was higher than expected3. Primary endpoint was met: OAC plus clopidogrel causes less bleeding than triple antithrombotic therapy, but now shown in a randomized way4. Secondary endpoint was met: with double therapy there is no excess of thrombotic/thromboembolic events: stroke, stent thrombosis, target vessel revascularisation, myocardial infarction or death5. Less all-cause mortality with double therapy |
    • 36. WOEST ImplicationsWe propose that a strategy of oral anticoagulantsplus clopidogrel, but without aspirin could beapplied in this group of high-risk patients on OACwhen undergoing PCI|