Implications of Universal MI Definition for Clinical Trials

Transcription

1 Implications of Universal MI Definition for Clinical Trials Stephen D. Wiviott, MD Chairman, Clinical Events Committee TIMI Study Group Cardiovascular Division Brigham and Women s Hospital Harvard Medical School

2 Disclosures CME Honoraria: Eli Lilly, Daiichi Sankyo; Accumetrics, Astra-Zeneca, Pfizer, Merck, Bayer. Consultancies: Sanofi-Aventis, BMS, Portola, Astra-Zeneca, Medco, ARENA Research Funding: Eli Lilly, Daiichi Sankyo, Merck- Schering Plough TIMI Study Group Receives Research Funding From: Eli Lilly, Daiichi Sankyo, Merck, Schering Plough, Sanofi- Aventis, AstraZeneca, Accumetrics

3 Looks like a duck Quacks Like a duck How Are Endpoints Defined?

4 Looks like a duck Quacks Like a duck How Are Endpoints Defined?

5 Definition Harmonization Efforts ARC Stent Thrombosis Universal MI BARC Bleeding Comprehensive ACC/AHA FDA - CDISC

6 Implications The move toward standardized definitions is strong. Regulatory agencies (FDA) are likely to adopt UMI definitions as part of their standard definition portfolio This puts tremendous pressure on investigators and sponsors to use these definitions completely many already are using draft regulatory definitions

7 Adjudication of Events Event Triggers CRF Completion Central Labs? Source Document Collection

8 Adjudication of Events Source Document Collection CRF Completion Central Labs CEC Process Definitions Confirmed Event

9 The Entire Process Matters Triggers Is event identified or reported? Examples PPMI, surgical bleed ecrf Are specific details of event captured to allow for proper adjudication? Source Documents Are documents specific enough for confirmation of event? Do additional documents exist? Process Strict adherence to formalized definitions or best clinical judgement? Definition Does the event fit the formal definition of the event from the specific protocol?

10 Universal MI Definition Evidence of myocardial necrosis in a clinical setting consistent with Myocardial Ischemia

11 Universal MI Preferably Troponin (99 th % URL) With PCI or CABG Tn > 99 th URL is evidence of myocardial necrosis BIOMARKERS > 3x /5x URL by convention

12 Clinical Trial Lessons Definitions should fit the goals and structure of the trial Can we/ Should we reasonably expect that a trial of an antibiotic for pneumonia or a weight loss drug should collect 99 th URL of Troponin world-wide? Can we reasonably expect a registry to provide such information?

13 99 th Percent URL of Tn Cardiovascular Trials? Self-Report/ Registry Unaffiliated Hospitals Affiliated Hospitals Clinical Core Lab Investigators

14 Clinical Trial Lessons Consider core laboratories whenever possible/practical Majority of spontaneous events are not at sites that can collect bloods for core! Collect prospectively 99 th reference limits at all participating centers on case record forms, and with every event reported

15 Universal MI

16 Procedural MI Using Late Gadolinium Enhancement for measure of myonecrosis ctni LGE - LGE+ MI- 6 0 NPV 100% MI PPV 19% CK-MB Spec 22% Sens 100% MI NPV 93% MI+ 2 3 PPV 60% Spec 93% Sens 60% CCS Lim et al JACC 2011

17 Procedural MI Using Late Gadolinium Enhancement for measure of myonecrosis ctni CK-MB LGE - LGE+ Using ROC analysis, best test characteristics for correlation MI- 6 0 NPV 100% with MRI MYONECROSIS: MI PPV 19% CK-MB > 2x 99 th ULN Spec 22% Sens 100% CTNI >40 x 99 th ULN MI NPV 93% Implication 3x is not a magic number for either marker MI+ 2 3 PPV 60% Spec 93% Sens 60% CCS Lim et al JACC 2011

18 Prasad et al Circ CI 2009 Procedural MI No clear cut-point for troponin following PCI

19 Universal MI Classification Application of ESC/ACC/AHA/WHF Universal MI Classification Supplemental classification of all (total) CEC-adjudicated MI endpoints (N = 1,218) Reviewers blinded to treatment allocation. Classification by Universal Def. MI Type Type 1: Spontaneous MI Type 2: Secondary MI Type 3: Sudden death due to MI w/out biomarkers Type 4a: Peri-PCI Type 4b: Confirmed stent thrombosis (angio/autopsy) Type 5: Peri-CABG Determination of peak CKMB and/or troponin Morrow et al Circ 2010

20 % of MIs Morrow et al Circ 2010 Universal MI Classification MI Endpoints Universal MI Classification MI Type using ESC/ACC/AHA/WHF Categorization N = 1,218 MI Type 1 Type 2 Type 3 Type 4a Type 4b Type 5 Spont. Secondary SCD Peri-PCI Stent thro. CABG N = 397 N = 43 N = 6 N = 603 N = 162 N = 7

21 % of MIs Morrow et al Circ 2010 Universal MI Classification MI Endpoints Peak Biomarker MI Size using ESC/ACC/AHA/WHF Categorization N = 1,163 MI with CKMB/cTn data <2xULN 2 - <3xULN 3 - <5xULN 5 - <10xULN >=10xULN N = 109 N = 70 N = 212 N = 331 N = 441

22 Cumulative Incidence (%) Morrow et al Circ 2010 Universal MI Classification Efficacy Analysis by Universal MI Classification CLOPIDOGREL PRASUGREL 29% % % 6.4 Type 1 Type 2 Type 3 Type 4 Type 5 Spont. Secondary SCD PCI-related Peri-CABG p < a 4a b 4b 0 0.1

23 Cumulative Incidence (%) Morrow et al Circ 2010 Universal MI Classification Efficacy Analysis Peak Biomarker CLOPIDOGREL PRASUGREL 25% 23% % % % p 1 - <2xULN 2 - <3xULN 3 - <5xULN 5 - <10xULN >=10xULN

24 Summary Myocardial Infarction is a key endpoint in clinical trials Accurate classification and adjudication is important in understanding clinical trial results Rational conduct of clinical trials suggests that endpoints should fit the goals and mechanisms of the trials rather than forcing a single process on all trials Universal Definitions are A PART of standardizing reporting. A universal definition does not assure direct comparisons

25 Summary Use of troponin 3x URL (or 1x URL) will result in very high rates of procedural MI. Planning blood collection, case report forms, collecting laboratory values prospectively will assist in implementing UMI definitions