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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

Trial VignettesContemporary Trials 2

Advanced Angioplasty

London, January 2007

Jonathan Hill, Clinical Senior Lecturer, Consultant Cardiologist

King’s College Hospital, King’s College London.

slide2

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 trials
3 Trials
  • Pharmacotherapy
    • ACUITY PCI
  • Myocardial Infarction Devices
    • VAMPIRE
  • Stem and Progenitor Cells
    • REPAIR-AMI LATE
gregg w stone md for the acuity investigators

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

goals of the acuity pci sub study
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
management strategy n 13 819

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)

3 primary endpoints at 30 days
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
3 primary endpoints at 30 days8
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

components of ischemia pci pts

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

major bleeding non cabg pci pts

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

net clinical outcomes pci pts

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

stone conclusions and clinical implications
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
acuity pci statistical problems
“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
acuity pci statistical problems14
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
acuity pci conclusions
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

trial 2
TRIAL 2
  • Pharmacotherapy
    • ACUITY PCI
  • Myocardial Infarction Devices
    • VAMPIRE
  • Stem and Progenitor Cells
    • REPAIR-AMI LATE
vampire18
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

vampire endpoints
Vampire Endpoints

(Corrected TIMI Frame Count)

vampire results
VAMPIRE Results

Greatest benefit seen with late presenting patients

vampire conclusions
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
30 day mace meta analysis thrombectomy trials
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

trial 3
TRIAL 3
  • Pharmacotherapy
    • ACUITY PCI
  • Myocardial Infarction Devices
    • VAMPIRE
  • Stem and Progenitor Cells
    • REPAIR-AMI (LATE)
slide30

BMC group

1 year

Follow up

1-Yr follow-up (cumulative)§

* These events occurred after bone marrow aspiration and ra

future study refinements
Future study refinements

Benefit seen in patients given cells after 5 days

Benefit seen in patients with EF <49%

repair ami late
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,”
many unanswered questions
ManyUnanswered Questions
  • Efficacy
    • Equivocal at best (Imaging dependent)
  • Cell type
    • Unselected vs Selected
    • Autologous vs Allogeneic
  • Mechanism
    • Paracrine Effects vs Regeneration
repair ami late conclusions
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
conclusions
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