CVD Critical Pathways Group 2005 Teleconferences

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CVD Critical Pathways Group 2005 Teleconferences
October 19, 2005
This activity is supported by an educational
grant from the Bristol-Myers Squibb/Sanofi
Pharmaceuticals Partnership.
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2
Faculty

• Gregg C. Fonarow, MD

Eliot Corday Professor of Medicine and
Cardiovascular ScienceDirector, Ahmanson-UCLA
Cardiomyopathy CenterUCLA Division of
CardiologyUCLA Medical CenterLos Angeles,
California
3
Disclosure Statement

• The Network for Continuing Medical Education
  requires that CME faculty disclose, during the
  planning of an activity, the existence of any
  personal financial or other relationships they or
  their spouses/partners have with the commercial
  supporter of the activity or with the
  manufacturer of any commercial product or service
  discussed in the activity.

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Faculty Disclosure Statement

• Gregg C. Fonarow, MD, has served as a consultant
  to and has received research support from
  GlaxoSmithKline, Pfizer Inc., and Scios Inc. He
  has also received honoraria from Merck Co.,
  Inc.
• The team from UCLA Healthcare reports no such
  relationships.  

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New ACS Clinical Trial Results Presented at the
European Society of Cardiology (ESC) Congress
2005
Gregg C. Fonarow, MD
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Polling Question 1

• Did you attend the European Society of Cardiology
  (ESC) Congress 2005?
• Yes, I attended the entire duration of the
  conference
• Yes, I attended part of the conference
• No, I did not attend

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Highlights from the ESC 2005

• Assessment of the Safety and Efficacy of a New
  Treatment Strategy for Acute Myocardial
  Infarction (ASSENT-4 PCI)
• Percutaneous Coronary Intervention-Clopidogrel as
  Adjunctive Reperfusion Therapy (PCI-CLARITY)
• Organization to Assess Strategies for Ischaemic
  Syndromes (OASIS-5)
• PROspective pioglitAzone Clinical Trial In
  macroVascular Events (PROactive)

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ASSENT-4 PCI

• Large Acute MI (gt6 mm ST Elevation), lt6 hr Sx
  Onset
• No Upper Age Limit
• Delay in Arriving in Cath Lab gt75 minutes

Open-Label Randomization
Superiority power assumptions 15 events rate
in control, 12 in experimental group
No lytic UFH ASA n2,000
TNK Heparin ASA n2,000
Angiography/ PCI
Angiography/ PCI
GP IIb/IIIa not permitted, in patients gt75 y Enox
dosing is 15 mg IV bolus, then 0.75 mg/kg,
Clopidogrel for stented patients
GP IIb/IIIa may be used at MD discretion,
additional UFH per ACT, Clopidogrel for stented
patients
Composite endpoint Death, New Cardiogenic Shock,
or Refractory Cardiac Failure at 90 Days
ASSENT-4 PCI Assessment of the Safety and
Efficacy of a New Treatment Strategy for Acute
Myocardial Infarction.
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ASSENT-4 PCI 30-Day Mortality Results
van de Werf F. Presented at European Society of
Cardiology Congress 2005 September 4-7, 2005
Stockholm, Sweden.
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ASSENT-4 PCI In-hospital Cardiac Events
van de Werf F. Presented at European Society of
Cardiology Congress 2005 September 4-7, 2005
Stockholm, Sweden.
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ASSENT-4 PCI In-hospital Stroke Rates
van de Werf F. Presented at European Society of
Cardiology Congress 2005 September 4-7, 2005
Stockholm, Sweden.
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ASSENT-4 PCI Bleeding Complications
van de Werf F. Presented at European Society of
Cardiology Congress 2005 September 4-7, 2005
Stockholm, Sweden.
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PCI-CLARITY Design
Open-label clopidogrel w/ loading dose recommended
933 underwent PCI during index hosp.
930 underwent PCI during index hosp.
30-day clinical follow-up
PCI-CLARITY Percutaneous Coronary
Intervention-Clopidogrel as Adjunctive
Reperfusion Therapy. Adapted from Sabatine MS,
et al. JAMA. 20052941224-1232.
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PCI-CLARITY CV Death, MI, or Stroke Following
PCI
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Odds Ratio 0.54 (95 CI, 0.35-0.85) P.008
No Pretreatment 6.2
6
46
Percentage With Outcome
4
Clopidogrel Pretreatment 3.6
2
0
0
10
20
30
Days Post-PCI
Adapted from Sabatine MS, et al. JAMA.
20052941224-1232.
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PCI-CLARITY Subgroup Analyses
Adapted from Sabatine MS, et al. JAMA.
20052941224-1232.
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PCI-CLARITY MI or Stroke Before PCI
Reproduced with permission from Sabatine MS, et
al. JAMA. 20052941224-1232.
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PCI-CLARITY CV Death, MI, or Stroke
Randomization ? 30 d
41 ? P.001
12.0
Odds Ratio 0.59 (95 CI, 0.43-0.81)
12
10
7.5
8
4.5 absolute difference
CV Death, MI, or Stroke ()
6
4
Number needed to treat 23
2
n933
n930
n933
n930
0
No Pretreatment
Clopidogrel Pretreatment
Sabatine MS, et al. JAMA. 20052941224-1232.
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PCI-CLARITY Bleeding PCI ? 30 d
TIMI major bleeding Hgb ? gt5 g/dL or ICH TIMI
minor bleeding Hgb ? 3-5 g/dL
Adapted from Sabatine MS, et al. JAMA.
20052941224-1232.
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Meta-Analysis of Clopidogrel Pretreatment
Adapted with permission from Sabatine MS, et al.
JAMA. 20052941224-1232.
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OASIS-5 Design Randomized, Double Blind
Patients with NSTE ACS, Chest discomfort lt24
hours2 of 3 Age gt60, ST Segment ?, ? cardiac
markers
Exclude Age lt21 Any contra-ind to Enox Hem stroke
lt12 mo. Creat gt3 mg/dL/265 umol/L
ASA, Clop, GP IIb/IIa planned Cath/PCI as per
local practice
Randomize
N20,000
Fondaparinux 2.5 mg sc once daily
Enoxaparin 1 mg/kg sc once daily
PCI lt6 h IV Fonda 2.5 mg without IIb/IIa, 0 with
IIb/IIa PCI gt6 h IV Fonda 2.5 mg with and 5.0
without IIb/IIa
PCI lt6 h No additional UFH PCI gt6 h IV UFH
With IIb/IIa 65 U/kgWithout IIb/IIa 100 U/kg
Outcomes
Primary Efficacy Death, MI, refractory ischemia
at 9 days Safety Major bleeding at 9 days Risk
benefit Death, MI, refractory ischemia, major
bleeds 9 days Secondary Above each component
separately at day 30 6 months Hypothesis First
test noninferiority, then test superiority
OASIS-5 Organization to Assess Strategies for
Ischaemic Syndromes. Yusuf S. Presented at
European Society of Cardiology Congress.
September 5, 2005. Stockholm, Sweden.
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OASIS-5 Efficacy Outcomes at Day 9
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Major Bleeding 9 Days
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Bleeding Rates Day 9
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Efficacy Outcomes at Day 30
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Major Bleeding Day 30
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Death/MI/RI/Major Bleeds Day 30
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Efficacy at 6 Months
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Major Bleeding 6 Months
0.06
Enoxaparin
0.05
0.04
Fondaparinux
Cumulative Hazard
0.03
HR 0.72
0.02
-
95 CI 0.63
0.82
Plt0.00001
0.01
0.0
0
20
40
60
80
100
120
140
160
180
Days
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Death, MI, RI, Major Bleedingat 6 Months
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Efficacy and Bleeding byCath Lab vs No
Cath Lab Day 30
Interaction P
Efficacy
With
Cath
Lab
No
Cath
Lab
0.246
Bleeding
With
Cath
Lab
0.745
No
Cath
Lab
EfficacyBleeding
0.808
0.4
0.6
0.8
1
1.2
Enox better
Fonda better
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Efficacy and Bleeding by Prior Heparin
Day 30
Efficacy
Interaction P
Prior Hep
0.727
No Prior
Hep
Bleeding
Prior Hep
0.538
No Prior Hep
Efficacy
Bleeding
Prior Hep
0.767
No Prior Hep
0.4
0.6
0.8
1
1.2
Fonda better
Enox better
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Bleeds at 9 Days Based on Open Label
Heparin Use in Hospital
No Heparin
Fonda
Enox
P value
HR (95 CI)
Bleeding
2.2
5.8
lt0.0001
0.37 (0.31
-
0.45)
Total
1.3
3.1
lt0.0001
0.41 (0.32
-
0.52)
Major
lt0.0001
0.33 (0.25
-
0.44)
0.9
2.8
Minor
lt0.0003
0.44 (0.28
-
0.69)
0.4
0.9
TIMI Major
With Heparin
lt0.0001
0.54 (0.44
-
0.65)
5.
7
10.
4
Total
0.0004
0.66 (0.52
-
0.83)
4.3
6.5
Major
lt0.00001
0.37 (0.26
-
0.53)
1.5
4.0
Minor
0.021
0.63 (0.43
-
0.93)
1.5
2.4
TIMI Major
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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OASIS-5 Early InterventionPCI Performed lt24
hours
Yusuf S. Presented at European Society of
Cardiology Congress. September 5, 2005.
Stockholm, Sweden.
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PROactive Study
5238 enrolled and randomised
2605 assigned pioglitazone
2605 assigned placebo
1 lost to follow-up (moved away) 427
discontinued medication 235 adverse
events 149 withdrew consent 43 other
1 lost to follow-up (moved away) 438
discontinued medication 202 adverse
events 167 withdrew consent 69 other
2605 analysed by Intention to treat 2427
reached final assessment 177 died 1
lost to follow-up
2633 analysed by Intention to treat 2446
reached final assessment 186 died 1
lost to follow-up
PROactive PROspective pioglitAzone Clinical
Trial In macroVascular Events.
Adapted with permission from Dormandy JA, et al.
Lancet. 20053661279-1289.
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Patient Characteristics in PROactive
Retinopathy, nephropathy, neuropathy. Adapted
with permission from Dormandy JA, et al. Lancet.
20053661279-1289.
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Baseline CV Medications in PROactive
Adapted with permission from Dormandy JA, et al.
Lancet. 20053661279-1289.
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PROactive Time to Primary Endpoint
25
Pioglitazone (514 events) Placebo (572 events)
20
15
Proportion of Events ()
10
HR0.90 (95 CI 0.80-1.02) P0.095
5
0
0
6
12
18
24
30
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Time from Randomisation (months)
Death from any cause, nonfatal MI (including
silent MI), stroke, acute coronary syndrome, leg
amputation, coronary revasularisation, or
revascularisation of the leg. Adapted with
permission from Dormandy JA, et al. Lancet.
20053661279-1289.
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PROactive Time to Secondary Endpoint
25
Pioglitazone (301 events) Placebo (358 events)
20
15
Proportion of Events ()
10
5
HR0.84 (95 CI 0.72-0.98) P0.027
0
0
6
12
18
24
30
36
Time from Randomisation (months)
Death from any cause, nonfatal MI (excluding
silent MI), or stroke. Adapted with permission
from Dormandy JA, et al. Lancet.
20053661279-1289.
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First Events in PROactive
MImyocardial infarction. NAnot applicable. This
table describes the events that make up the
primary composite endpoint, so if death is not
the first event, it does not appear. Adapted with
permission from Dormandy JA, et al. Lancet.
20053661279-1289.
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First Events in PROactive
Not adjudicated. Adjudicated cause of
death. Adapted with permission from Dormandy JA,
et al. Lancet. 20053661279-1289.
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Featured Institution UCLA Healthcare Los
Angeles, California
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Polling Question 2
If you participated in a previous teleconference,
how much progress have you made since
then? (Please refer to the checklists on the next
3 slides.)

• We are currently on the same item
• We have since moved to the next checkbox on the
  checklist
• We have progressed by more than one item on the
  checklist
• ACS pathways are up-to-date and regularly followed

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Progress ChecklistImmediate Goals
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Progress ChecklistShort-term Goals/Activities
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Progress ChecklistLong-term Goals/Activities
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Question-and-Answer Session
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Concluding Remarks

• Gregg C. Fonarow, MD
• Next program Wednesday, November 9, 2005at
  1200 Noon Eastern Time (900 AM Pacific)
• Topic Acute Management of MI
• Highlights from TCT 2005
• Faculty Christopher P. Cannon, MD