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Characterization of the Myocardial Infarction Endpoints, Impact of Event Adjudication, and Ticagrelor Effects in the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Kenneth W. Mahaffey Daniel M. Wojdyla Stefan K. James Hugo A. Katus Steen Husted Gabriel Steg - PowerPoint PPT Presentation
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Kenneth W. MahaffeyDaniel M. WojdylaStefan K. JamesHugo A. KatusSteen HustedGabriel StegChristopher P. CannonRichard C. Becker
Claes HeldNardev KhurmiDebra MontgomeryAnders HimmelmannRobert A. HarringtonLars Wallentin
for the PLATO investigators
Characterization of the Myocardial Infarction Endpoints, Impact of Event Adjudication, and Ticagrelor Effects in the Platelet Inhibition and Patient Outcomes (PLATO) Trial
Background
• Clinical Events Committees (CEC) are common for endpoint adjudication
• In PLATO, a CEC prospectively defined, systematically identified and adjudicated all events
• In this report, we explore:
– Types of MI events reported by site investigators and CEC
– The concordance between the site investigators and CEC
– The treatment effects observed
Worldwide Country ParticipationArgentinAustraliaAustriaBelgiumBrazil BulgariaCanada
GreeceHong KongHungaryIndiaIndonesiaIsraelItaly
Portugal RomaniaRussiaSingaporeSlovakiaSpainSweden
SwitzerlandSouth AfricaSouth KoreaTaiwanThailandTurkeyUkraine
United KingdomUnited States
ChinaCzech RepublicDenmarkFinlandFranceGeorgiaGermany
MalaysiaMexicoThe NetherlandsNew ZealandNorwayPhilippinesPoland
Event Adjudication Process
Suspected events identified from:1. eCRF data (biomarkers; procedures; etc.)2. Monitors during site visits3. Endpoint Office personnel4. Independent Clinical Adjudication
Committee
1. Notification via Endpoint Office2. Source documents from site
when necessary3. Review of all clinical data DisagreeAgree
Phase 2 —Committee
reviewDONE
Phase 1 — MD Reviews
MI DefinitionsAbbreviated
Non-procedural MI:
CK-MB > ULN or Troponin > 99th % AND one of the following:1. Ischemic Symptoms2. ECG changes indicative of ischemia3. New Q-waves
PCI:
CK-MB≥ 3x ULN with 24 hours from a normal or decreasing level or new Q-waves
CABG:
CK-MB≥ 10x ULN or CK-MB≥5x ULN and new Q-waves
Silent MI: New Q-waves without symptoms
Events reported by PIN = 2705
Cardiac Ischemic Event FormSTEMI/NSTEMI* diagnosis
N = 1198
Cardiac Ischemic Event Form‘Other’ diagnoses**
N = 1507
Adjudicated as MI by CEC
N = 862
Not adjudicated as MI by CEC
N = 336
Adjudicated as MI by CEC
N = 187
Not adjudicated as MI by CEC
N = 1320
Not reported on Cardiac Ischemic
Event formN = 251
MI events adjudicated by CEC
N = 1300
* Include events with final diagnosis “Other” with text suggesting MI
**Include events with final diagnosis “Unstable Angina”, “Stable Angina”, and “Other” with text not suggesting MI
Event Level AnalysisCEC
Yes No
Investigator Reported
Yes 862 336
No 438** —
Comparisons: CEC and Site Investigator
** Includes 187 events reported in CIE form but with final diagnosis not STEMI or NSTEMI and 251 events that were not reported in CIE form.
Patient Level AnalysisCEC
Yes No
Investigator Reported
Yes 762 272
No 385 17205
Using the first event for patient with multiple MI events reported or adjudicated
Patient Level Analysis– Overall,
96% agreement– Of those reported by
site investigator,
74% agreement– Of those reported by
CEC
66% agreement
60%
18%
7%
15%
Non-procedural
PCI related
CABG related
Stent throm-bosis related
85%10%
3%1%
Non-proceduralPCI
related
CABG related
Other
CEC MIs Investigator Reported MIs
DisagreementsCEC and Site Investigator
Total Ticagrelor Clopidogrel0
100
200
300
400
500
438
215 223
Reported by CEC but not Site Investigator
Reported by Site Investigator but not CEC
Total Ticagrelor Clopidogrel0
100
200
300
400
500
336
184152
TypeTotal # Events
# EventsTicagrelor
# EventsClopidogrel
HR (95% CI)Tic. vs Clop.
Any 1107 (100%) 508 599 0.840 (0.746 – 0.945)
Non Silent 1097 (99%) 504 593 0.842 (0.748 – 0.948)
Silent 11 (1.0%) 5 6 0.829 (0.253 – 2.716)Non-Procedure Related 652 (59%) 303 349 0.861 (0.738 – 1.005)
Procedure Related 304 (27.5%) 144 160 0.895 (0.715 – 1.122)
PCI Related 223 (20%) 99 124 0.794 (0.609 – 1.034)
CABG Related 82 (7%) 45 37 1.212 (0.784 – 1.872)Associated with Stent Thrombosis 172 (15.5%) 69 103 0.666 (0.491 – 0.903)
Treatment Effect by Type of MI CEC MIs
The first event of each type counted.On patient with one silent and on non-silent MI
Ticagrelor ClopidogrelHR (95% CI) (Tic vs. Clo)
CEC
All MI 508 599 0.840 (0.746–0.945)
STEMI 117 159 0.731 (0.576–0.928)
NSTEMI 356 404 0.875 (0.758–1.008)
Not evaluable 45 57 0.785 (0.531–1.160)
Q-wave 42 46 0.909 (0.598–1.381)
Non Q-wave 333 375 0.881 (0.761–1.022)
Not evaluable 160 208 0.763 (0.621–0.938)
Site Investigator
All MI 459 516 0.883 (0.779–1.001)
STEMI 156 196 0.791 (0.641–0.976)
NSTEMI 287 307 0.929 (0.791–1.091)
Other 29 31 0.931 (0.561–1.545)
Treatment Effect: CEC and Site Investigator
0 60 120 180 240 300 3600%
1%
2%
3%
4%
5%
Days since randomization
Even
t rat
e
Non-proceduralHR 0.86 (0.74–1.01)
PCI relatedHR 0.79 (0.61–1.03)
CABG relatedHR 1.21 (0.78–1.87)
Treatment Effect by MI TypeCEC MIs
Ticagrelor Clopidogrel
Limitations
• This was pre-specified analysis from PLATO but the trial was not powered to evaluate treatment effect in MI alone or in subtypes of MI
• Reporting of MI by site investigators used different format than the CEC adjudication forms so direct event level comparisons were difficult
• We did not contact sites to determine reasons for why the CEC and the site investigators disagreed on individual MI events
Summary
• In PLATO, ticagrelor significantly reduced MI compared with clopidogrel
• The CEC procedures identified more MI endpoints than reported by the Site Investigators particularly procedural related MIs
• A consistent treatment effect was observed across most MI subtypes and for events reported by Site Investigators or CEC
• Comparison of the CEC and Site Investigator showed:– CEC identified 438 events (215 ticagrelor; 223 clopidogrel) not
reported by the investigators– CEC disagreed with Site Investigator reporting for 336 events
(184 ticagrelor; 152 clopidogrel)
• Understanding CEC procedures, MI definitions and treatment effects across MI subtypes is important in interpreting trial results