3. BACKGROUND
LONG TERM ORAL ANTICOAGULATION
IS GENERALLY INDICATED IN:
MOST PATIENTS WITH AF
PATIENTS WITH MECHANICAL
HEART VALVES
CIRCULATION 2006;114;700-752
CIRCULATION 2006;114;450-527
5. ACS/PCI - DAPT AND TRIPLE TX
> 30% OF PTS WITH AF HAVE ISCHEMIC HEART DISEASE
AF OCCURS IN 2 – 21% OF PATIENTS WITH ACS
WHEN THESE PATIENTS UNDERGO PCI, BOTH THE ACC/AHA
GUIDELINES AND THE ESC GUIDELINES CALL FOR SOME
PERIOD OF “TRIPPLE TX”
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 BLEEDING
LANCET 2005; 366: 1607–21
15. DAPT FOR AF
ACTIVE - 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
18. WOEST ESC, Hotline III, Munchen, August 28th, 2012
The WOEST Trial: First randomised trial
comparing 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)
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19. WOEST
Aim of the study
To test the hypothesis that in patients on OAC undergoing PCI,
clopidogrel alone is superior to the combination aspirin and
clopidogrel with respect to bleeding but is not increasing
thrombotic risk in a multicentre two-country study (The
Netherlands and Belgium)
|
20. WOEST
Study Design-1
Inclusion criteria: Exclusion criteria:
1/ Indication for OAC for at least 1 1/ History of intracranial bleeding
year 2/ Cardiogenic shock during
2/ One coronary lesion eligible for hospitalisation
3/ Peptic ulcer in the previous 6 months
PCI
4/ TIMI major bleeding in the previous
3/ 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
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21. WOEST
Study Design-2
1:1 Randomisation:
Double therapy group: Triple therapy group
OAC + 75mg Clopidogrel qd OAC + 75mg Clopidogrel qd + 80mg Aspirin qd
1 month minimum after BMS 1 month minimum after BMS
1 year after DES
1 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
|
22. 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
23. 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 treat
analysis until the day of withdrawal
24. 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%)
34. 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
35. 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
|
36. WOEST
Conclusions
1. First randomized trial to address the optimal antiplatelet therapy in patients on
OAC undergoing coronary stenting
2. In this study which was specifically designed to detect bleeding events, the
bleeding rate was higher than expected
3. Primary endpoint was met: OAC plus clopidogrel causes less bleeding than triple
antithrombotic therapy, but now shown in a randomized way
4. Secondary endpoint was met: with double therapy there is no excess of
thrombotic/thromboembolic events: stroke, stent thrombosis, target vessel
revascularisation, myocardial infarction or death
5. Less all-cause mortality with double therapy
|
37. WOEST
Implications
We propose that a strategy of oral anticoagulants
plus clopidogrel, but without aspirin could be
applied in this group of high-risk patients on OAC
when undergoing PCI
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Notas del editor
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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 &#x2013;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