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Trial Vignettes Contemporary Trials 2

Trial Vignettes Contemporary Trials 2. Advanced Angioplasty London, January 2007. Jonathan Hill, Clinical Senior Lecturer, Consultant Cardiologist King’s College Hospital, King’s College London. MY CONFLICTS OF INTEREST ARE. Advisory Board/Speaker Fees Baxter Cell Therapy Miltenyi Biotech

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Trial Vignettes Contemporary Trials 2

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  1. Trial VignettesContemporary Trials 2 Advanced Angioplasty London, January 2007 Jonathan Hill, Clinical Senior Lecturer, Consultant Cardiologist King’s College Hospital, King’s College London.

  2. MY CONFLICTS OF INTEREST ARE • Advisory Board/Speaker Fees • Baxter Cell Therapy • Miltenyi Biotech • Biologics Delivery Systems • Nycomed • Research/Grant Support • Cordis • Boston Scientific • RADI • Miltenyi Biotech

  3. 3 Trials • Pharmacotherapy • ACUITY PCI • Myocardial Infarction Devices • VAMPIRE • Stem and Progenitor Cells • REPAIR-AMI LATE

  4. ACUITY PCI A Prospective Trial of Patients with ACS Undergoing PCI after Randomization to Heparin plus GP IIb/IIIa Inhibitors vs. Bivalirudin With or Without GP IIb/IIIa Inhibitors Gregg W. Stone MD for the ACUITY Investigators

  5. Goals of the ACUITY PCI Sub-study • To examine the outcomes of bivalirudin ± GPIIb/IIIa inhibitors compared to heparin (unfractionated or enoxaparin) + GPIIb/IIIa inhibitors in pts with moderate and high risk ACS undergoing PCI • 3 primary clinical endpoints at 30 days • Angiographic outcomes from a large independent blinded core lab analysis • Specific subgroups and analyses of interest: • Troponin positive pts • Impact of pre-PCI thienopyridine use • “ISAR-REACT-2 like” cohort • Angiographic thrombus

  6. Heparin + IIb/IIIa N = 2,561 Bivalirudin + IIb/IIIa N = 2,609 Bivalirudin alone N = 2,619 Management Strategy (N=13,819) Medical Rx (n=4,491) CABG (n=1,539) 32.2% 11.4% 56.4% PCI (n=7,789)

  7. 3 Primary Endpoints (at 30 Days) 1. Composite net clinical benefit = 2. Ischemic composite or 3. Major bleeding • Death from any cause • Myocardial infarction - During medical Rx: Any biomarker elevation >ULN - Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves - Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves • Unplanned revascularization for ischemia

  8. 3 Primary Endpoints (at 30 Days) 1. Composite net clinical benefit = 2. Ischemic composite or 3. Major bleeding • Non CABG related bleeding • - Intracranial bleeding or intraocular bleeding • -Retroperitoneal bleeding • Access site bleed requiring intervention/surgery • Hematoma ≥5 cm • -Hgb ≥3g/dL with an overt source or ≥4g/dL w/o overt source • -Blood product transfusion - Reoperation for bleeding This is an ACUITY specific definition and differs from TIMI and GUSTO bleeding

  9. p=0.16 p=0.45 p=0.16 p=0.19 p=0.37 p=0.53 p=0.31 P=0.87 Components of Ischemia – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone *Heparin=unfractionated or enoxaparin

  10. Heparin* + IIb/IIIa (N=2561) 6.8% P (log rank) Estimate 0.31 Bivalirudin + IIb/IIIa (N=2609) 7.6% <0.001 Bivalirudin alone (N=2619) 3.5% Major Bleeding (Non-CABG) – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15 10 Event Rate (%) P<0.0001 5 0 0 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

  11. Heparin* + IIb/IIIa (N=2561) 13.5% P (log rank) Estimate 0.10 Bivalirudin + IIb/IIIa (N=2609) 15.1% 0.049 Bivalirudin alone (N=2619) 11.7% Net Clinical Outcomes – PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone 15 P=0.001 10 Event Rate (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization *Heparin=unfractionated or enoxaparin

  12. Stone Conclusions and Clinical Implications • In patients with moderate and high risk ACS undergoing PCI • Replacing upstream heparin with bivalirudin in pts treated with GP IIb/IIIa inhibitors provides similar clinical and angiographic outcomes • Replacing heparin and GP IIb/IIIa inhibitors with bivalirudin alone (with provisional IIb/IIIa inhibitor use in <10% of pts) results in similar rates of ischemia with reduced hemorrhagic complications, thereby improving overall event-free survival

  13. “Noninferiority in ACUITY lies in the eyes of the beholder” Sanjay Kaul, AHA 2006 Non inferiority definitions challenged Benefit of composite endpoint driven entirely by bleeding (ACUITY definition) ACUITY PCIStatistical Problems

  14. ACUITY PCIStatistical Problems • Should ACUITY have non inferiority design if active control not consistently shown to be superior to heparin. • Non inferiority trials previously not used for combination of efficacy and safety outcomes • Non inferiority margins too wide • ACUITY 25% (high chance of type 1 error) • SYNERGY 10%, A to Z 15% • FDA turned down REPLACE-2 on this basis

  15. Users Equivalent to GPI Cheaper than GPI Safer than GPI Clear advantages in specific subsets Direct thrombin inhibitor has potent antiplatelet effect Detractors Confusing, overspun and underwhelming Inappropriate use of non inferiority Low clopidogrel and Reopro use Not applicable to UK practice We should wait for ISAR REACT 4 ACUITY PCI Conclusions - Non inferior to GPI

  16. TRIAL 2 • Pharmacotherapy • ACUITY PCI • Myocardial Infarction Devices • VAMPIRE • Stem and Progenitor Cells • REPAIR-AMI LATE

  17. VAMPIRE

  18. VAMPIRE Inherent problem of many thrombectomy studies is randomisation occurring prior to angiography 355 Patients recruited 180 TVAC vs 175 Non-TVAC Matched demographics, lesion and procedural characteristics

  19. Vampire Endpoints (Corrected TIMI Frame Count)

  20. 90 % TIMI 2-3 after TVAC aspiration

  21. VAMPIRE Results Greatest benefit seen with late presenting patients

  22. VAMPIRE 8 Month MACE

  23. No adverse events with use of TVAC Better blush scores and TIMI flow especially in late reperfusion No difference in MACE Limitations Underpowered Short follow up to detect CHF difference VAMPIRE Conclusions

  24. 30 day MACE Meta analysis thrombectomy trials Still no convincing evidence for use of thrombectomy catheters routinely in PPCI from 30 day MACE data. ? Need for larger and longer term CHF endpoint studies

  25. TRIAL 3 • Pharmacotherapy • ACUITY PCI • Myocardial Infarction Devices • VAMPIRE • Stem and Progenitor Cells • REPAIR-AMI (LATE)

  26. REPAIR AMI

  27. REPAIR AMI

  28. Primary Endpoint

  29. CADILLAC and ADMIRAL comparison

  30. BMC group 1 year Follow up 1-Yr follow-up (cumulative)§ * These events occurred after bone marrow aspiration and ra

  31. Future study refinements Benefit seen in patients given cells after 5 days Benefit seen in patients with EF <49%

  32. REPAIR AMI LATE • BMC improves combined cardiovascular outcome at 12 months • 12 events in placebo group vs 2 in BMC group (p=0.06) • “Our study was not powered to detect clinical differences, but it appears that intracoronary infusion of bone marrow, in addition to improving left ventricular ejection fraction, may also reduce cardiovascular events at 1 year,”

  33. ManyUnanswered Questions • Efficacy • Equivocal at best (Imaging dependent) • Cell type • Unselected vs Selected • Autologous vs Allogeneic • Mechanism • Paracrine Effects vs Regeneration

  34. Zealots Time for PanEuropean study Large infarcts given bone marrow cells after 5 days do best What further evidence do you need to proceed Sceptics Trivial changes in EF Not powered to show clinical difference No mechanistic explanation Not applicable to UK practice Germans do it better REPAIR AMI Late Conclusions

  35. Conclusions • ACUITY PCI • BIVALIRUDIN NON INFERIOR • IMPROVED BLEEDING OUTCOME • VAMPIRE • THROMBECTOMY DOES NOT CHANGE MACE • REPAIR-AMI LATE • SMALL CHANGES IN LVEF • TIME FOR CLINICAL ENDPOINT STUDY

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