CVD Critical Pathways Group 2006 Teleconferences

1
CVD Critical Pathways Group 2006 Teleconferences

• November 8, 2006
• 1200 Noon ET (900 AM PT)

This activity is supported by an educational
grant from the Bristol-Myers Squibb/Sanofi
Pharmaceuticals Partnership.
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Faculty
Christopher P. Cannon, MDAssociate Professor of
MedicineHarvard Medical SchoolSenior
Investigator, TIMI Study GroupAssociate
Physician, Cardiovascular DivisionBrigham and
Womens HospitalBoston, Massachusetts
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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

• Christopher P. Cannon, MD, has received
  grant/research support from Merck Co., Inc.,
  AstraZeneca Pharmaceuticals LP, and
  Merck/Schering Plough Partnership. He has served
  as a consultant on scientific/advisory boards of
  AstraZeneca Pharmaceuticals LP, Bristol-Myers
  Squibb Company, GlaxoSmithKline, Merck Co.,
  Inc., Merck/Schering Plough Partnership, Pfizer
  Inc, sanofi-aventis, and Schering-Plough
  Corporation. He has received honoraria for CME
  lectures supported by AstraZeneca Pharmaceuticals
  LP, Bristol-Myers Squibb Company, Merck Co.,
  Inc., Millennium Pharmaceuticals, Inc., Pfizer
  Inc, sanofi-aventis, and Schering-Plough
  Corporation.
• John S. Wilson, MD, representing the Allegheny
  General Hospital in Pittsburgh, Pennsylvania,
  reports no such relationships.

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Polling Question 1

• Have the recent reports regarding late-stent
  thrombosis had an impact on your clinical
  practice?
• Yes, I am more likely to use bare-metal stents
  than drug-eluting stents (DES)
• Yes, I am more likely to prescribe an extended
  duration of dual antiplatelet therapy for
  patients with DES
• Yes, both 1 and 2
• No, the studies have not changed my practice

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Highlights From the 2006 Transcatheter
Cardiovascular Therapeutics (TCT) Conference

• Christopher P. Cannon, MD

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Highlights From TCT 2006

• Academic Research Consortium proposed new
  definitions for stent thrombosis
• DEScover Registry prospective, multicenter,
  observational study that characterized PCI
  patients from a broad sampling of hospitals and
  practice
• PREMIER Registry prospective, multicenter
  evaluation of premature discontinuation of
  thienopyridine therapy after DES
• REWARDS Registry registry of 2769 patients
  receiving either Cypher or Taxus stents
  evaluated risk of thrombosis
• STENT Thrombosis Registry multicenter,
  prospective registry to evaluate long-term
  efficacy and safety of DES in real-world patients
  and clinical situations
• ACUITY-PCI Substudy 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

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Academic Research Consortium Proposed
Definitions for Stent Thrombosis
Expanded Stent Thrombosis Definition Timing
Acute Thrombosis 0 24 hrs. post Subacute
Thrombosis gt24 hrs 30 days post Late
Thrombosis 30 days 1 year post Very Late
Thrombosis gt1 year post

• Definite/Confirmed
• Probable
• Possible

Acute/Subacute can also be replaced by early
stent thrombosis. Early stent thrombosis 0-30
days. Cutlip D. Presented at TCT October 2006
Washington, DC.
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Academic Research Consortium Proposed
Definitions for Stent Thrombosis
1. Definite/Confirmed

• Autopsy evidence or angiographic confirmed stent
  thrombosis (definite) is
• considered to have occurred if
• TIMI flow is
• Grade 0 with occlusion originating in the stent
  or segment 5 mm proximal or distal to the stent
  region in the presence of thrombus
• Grade 1, 2, 3 originating in the stent or in the
  segment 5 mm proximal or distal to the stent
  region in the presence of thrombus

• AND at least one of the following criteria within
  48 hrs
• New onset of ischemic symptoms at rest (typical
  chest pain with duration gt20 minutes)
• New ischemic ECG changes suggestive of acute
  ischemia
• Typical rise and fall in cardiac biomarkers (gt2x
  ULN of CK)

The incidental angiographic documentation of
stent occlusion in the absence of clinical
syndromes is not considered a confirmed stent
thrombosis (silent thrombosis). Cutlip D.
Presented at TCT October 2006 Washington, DC.
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Academic Research Consortium Proposed
Definitions for Stent Thrombosis
2. Probable

• Probable stent thrombosis is considered to have
  occurred in the
• following cases
• Any unexplained death within the first 30 days.
• Irrespective of the time after the index
  procedure, any MI in the absence of any obvious
  cause which is related to documented acute
  ischemia in the territory of the implanted stent
  without angiographic confirmation of stent
  thrombosis.

3. Possible
Possible stent thrombosis is considered to have
occurred with any unexplained death beyond 30
days.
Cutlip D. Presented at TCT October 2006
Washington, DC.
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CYPHER RCT Stent Thrombosis 4-Year Follow-up
Expanded Definition
Definite Probable Possible
Data from 4 pooled RCT SIRIUS, E and C SIRIUS
and RAVEL. Log Rank Test P-value. Cutlip D.
Presented at TCT October 2006 Washington, DC.
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CYPHER RCT Stent Thrombosis 4-Year Follow-up
Expanded Definition
Definite Probable
Data from 4 pooled RCT SIRIUS, E and C SIRIUS
and RAVEL. Log Rank (exact) Test P-value.
Cutlip D. Presented at TCT October 2006
Washington, DC.
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DEScover Registry

• Prospective, multicenter, observational study
  that characterized PCI patients from a broad
  sampling of hospitals and practice
• 6906 patients at 140 medical centers in the US
  undergoing PCI with stenting were followed for up
  to 1 year
• 96 of patients received stents vs 4 who
  received balloon angioplasty
• 5 of patients treated with bare-metal stents
• 95 treated with drug-eluting stents (55
  sirolimus-eluting stent 38 paclitaxel-eluting
  stent)

Williams DO, et al. Circulation. 2006114.
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DEScover Registry Events at 1-Year Bare-Metal
Stents vs Drug-Eluting Stents

• Small, but significant baseline differences in
  the selection of patients for BMS vs DES eg, BMS
  patients were significantly older and had more
  severe disease and more ST-elevation MI at
  presentation
• Data were not randomized
• Small number of patients treated with BMS does
  not allow for valid efficacy comparisons

Williams DO, et al. Circulation. 2006114.
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PREMIER Registry

• Prospectively collected data from 19 centers
  examining the prevalence and predictors of
  thienopyridine discontinuation 30 days after DES
  treatment
• Compared mortality and cardiac hospitalization
  rates for the next 11 months for patients
  continuing vs discontinuing thienopyridine
  therapy
• 2498 MI patients enrolled 500 patients who
  received a DES were available for follow-up

Spertus JA, et al. Circulation.
20061132803-2809.
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PREMIER Registry Factors Associated With
Discontinuing Thienopyridine Therapy

• Nearly 1 in 7 patients (13.6) reported
  discontinuing therapy 1 month postdischarge

Age (per 10 years) Male Non-Caucasian Not
married No high school diploma Avoided care due
to cost Not depressed Pre-existing cardiovascular
disease Anemia No DC medication instructions Not
referred to rehab Discharged on Coumadin
Factors Associated With Discontinuing
Thienopyridine Therapy
0.5
1
2
Odds Ratio
Figure shows the fully adjusted, multivariable,
logistic-regression model for discontinuing
thienopyridine therapy within 30 days of
discharge for an MI treated with a DES. Point
estimates are represented by points, and the 95
CIs are shown as bars.
Spertus JA, et al. Circulation.
20061132803-2809.
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PREMIER Registry Mortality Among Patients
Continuing vs Discontinuing Thienopyridine Therapy
15
Plt.001
Continued Discontinued
10
Mortality ()
5
0
Months
The Kaplan-Meier mortality plots show the rate of
death for those who continued thienopyridine
therapy (solid line) and those who did not
(dashed line). The origin is at the time of the
patients MI, but the lines begin at the 1-month
assessment point.
Spertus JA, et al. Circulation.
20061132803-2809.
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Mortality Data From the BASKET LATE Trial and
PREMIER Registry
PREMIER Registry Data All cause death according
to minimum 30 day thienopyridine therapy duration
()
BASKET LATE Trial Cardiac death in DES vs BMS ()
7.5
2
8
P.09
Plt.0001
6
1.2
1
Patients
4
Patients
2
0.7
0.0
0
0
Stopped thienopyridines
Stayed on thienopyridines
DES
BMS

• In the BASKET LATE Trial, cardiac death trended
  higher in the DES group than in the BMS group
  during the year following clopidogrel
  discontinuation (1.2 vs 0, P.09).
• Data from the PREMIER registry looked exclusively
  at AMI patients who received DES and suggested
  that patients who discontinued thienopyridine
  therapy early within 30 days in this instance
  were significantly more likely to die over the
  next 11 months (Plt.0001).

Pfisterer ME. Presented at ACC 2006 Spertus JA,
et al. Circulation. 20061132803-2809. Adapted
with permission from www.clinicaltrialresults.org.

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Angioscopy Follow-up 6 Months After SES or BMS
Implanatation
(N46, 66 lesions 33 SES, 33 BMS)
Grade 0 No neointima
Grade 1 Thin neointima
Grade 2 Full neointima
Visible Thrombus
P.031
100
80
60
Frequency of Persistence of Thrombus ()
40
Plt.001 comparedwith the corresponding segment
in the BMS.
20
0
n7 SES
n7 BMS
Takano M, et al. Eur Heart J. 2006272189-2195.
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Milan/Siegburg Experience
Stent thrombosis after DES (SES or PES)
occurredin 29/2229 pts (1.3) at 9.3 5.6 mos
Several patient and lesion subgroups have a
higher stent thrombosis rate than
identified in RCTs
29.0
8.7
5.5
3.5
3.2
2.6
2.0
1.3
Unstable angina
Prior Brachy Rx
Thrombus
Diabetes
Unprot. left main
Bifurcation
Renal failure
Premature antiplatelet d/c
Iakovou I, et al. JAMA. 20052932126-2130.
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Frequency of and Risk Factors for Stent
Thrombosis After DES Implantation During
Long-Term Follow-up

• 1,911 consecutive DES-treated patients
• Median follow-up 19.4 months
• Incidence of stent thrombosis 7.8 (5 of 64
  patients) with premature interruption of aspirin
  or clopidogrel, or both (vs 0.5 in those
  without, Plt.001)
• MV predictors of late-stent thrombosis
• Premature interruption of antiplatelet therapy
• Renal failure

Park D-W. Am J Cardiol. 200698352-356.
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Correlates and Long-Term Outcomes of
Angiographically Proven Stent Thrombosis With
Sirolimus- and Paclitaxel-Eluting Stents

• 12-month incidence of stent thrombosis 1.27 (38
  patients)
• 8 patients (0.3) had late (gt30 days) stent
  thrombosis
• Clopidogrel discontinuation in 37 of ST
  patients, 11 of non-ST (Plt.001)
• MV predictors of stent thrombosis
• Cessation of clopidogrel
• Renal failure
• Bifurcation lesions
• In-stent restenosis

Kuchulakanti PK. Circulation. 20061131108-1113.
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REWARDS Registry Cypher vs Taxus Stents

• Registry of 2769 patients at Washington Hospital
  receiving either Cypher (n1925) or Taxus stents
  (n844) evaluated risk of thrombosis
• Cypher patients received clopidogrel for at least
  3 months and Taxus patients for at least 6
  months investigators recommended 1 yr of
  treatment for all patients
• At 6 months, clopidogrel compliance was 83.5 in
  the Cypher group, 90.6 in the Taxus group
  (P.043)
• Clopidogrel compliance not significantly
  different between the groups at the time of
  thrombosis

Waksman R. Presented at TCT October 2006
Washington, DC.
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REWARDS Registry Cypher vs Taxus Stents

• Overall incidence of stent thrombosis 1.6
• 1 yr incidence of stent thrombosis 1.9 in
  Cypher group vs 0.8 in Taxus group (P.034)
• Repeat target lesion revascularization 3.2 in
  Cypher group vs 1.8 in Taxus group (P.039)
• No significant differences in in-hospital
  complications
• At 1, 6, 12 months, rates of MACE, target vessel
  revascularization, and target lesion
  revascularization were comparable
• No significant differences in MACE in subgroup
  analyses of complex patients, but greater risk
  of stent thrombosis in the Cypher group

Including ostial lesions, in-stent restenosis,
non-native coronary artery lesions, lesions
longer than 33 mm, type C lesions, chronic total
occlusions, 2 or more DES, acute MI, type 1
diabetes, or prior CABG.
Waksman R. Presented at TCT October 2006
Washington, DC.
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STENT Thrombosis Registry

• STENT (Strategic Transcatheter Evaluation of New
  Therapies) multicenter, prospective US registry
  to evaluate long-term efficacy and safety of DES
  in real-world patients and clinical situations
• Established in 2003 gt20,000 patients enrolled
• Second phase of registry to begin early 2007
  will enroll approximately 10,000 new patients
  undergoing DES implantation

Simonton C. Presented at TCT October 2006
Washington, DC.
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STENT Thrombosis Registry 9-Month Clinical
Outcomes

• Evaluated all patients enrolled from May 2003 to
  September 2005 and completing 9-month follow-up
• Patients undergoing repeat PCI within the target
  lesion for restenosis of a DES were eligible

Simonton C. Presented at TCT October 2006
Washington, DC.
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STENT Thrombosis Registry 9-Month Clinical
Outcomes
DES Restenosis Patients Unadjusted Outcomes
25.0 20.0 15.0 10.0 5.0 0.0
DES-Rx NON DES-Rx
19.8
Pgt.05 for all
15.4
11.6
Percent of Patients
10.3
8.1
5.1
5.1
3.5
3.5
0.0
Death
MI
TVR
MACE
SAT
Simonton C. Presented at TCT October 2006
Washington, DC.
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ACUITY-PCI Substudy

• Prospective trial of 7789 moderate- and high-risk
  patients with ACS from the ACUITY trial who
  underwent PCI
• Patients randomized to heparin plus GP IIb/IIIa
  inhibitors vs bivalirudin with or without GP
  IIb/IIIa inhibitors
• Use of drug-eluting stents was approximately 60
  in all 3 groups
• Primary end point at 30 days non-CABG major
  bleeding
• Other end points Death, MI, unplanned
  revascularization, and ischemic composite,
  combining these net clinical benefit, combining
  ischemic and bleeding events

Stone GW. Presented at TCT October 2006
Washington, DC.
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ACUITY-PCI Composite Ischemia
Heparin IIb/IIIa vs Bivalirudin IIb/IIIa vs
Bivalirudin Alone
15
10
P.36
Event Rate ()
Estimate
P (log rank)
5
Heparin IIb/IIIa (N2561)
8.4
Bivalirudin IIb/IIIa (N2609)
.15
9.4
.45
Bivalirudin alone (N2619)
8.9
0
0
5
10
15
20
25
30
35
Days from Randomization
Heparin unfractionated or enoxaparin. Stone
GW. Presented at TCT October 2006 Washington,
DC.
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ACUITY-PCI Major Bleeding (Non-CABG)
Heparin IIb/IIIa vs Bivalirudin IIb/IIIa vs
Bivalirudin Alone
15
Estimate
P (log rank)
Heparin IIb/IIIa (N2561)
6.8
Bivalirudin IIb/IIIa (N2609)
.31
7.6
lt.001
Bivalirudin alone (N2619)
3.5
10
Event Rate ()
Plt.0001
5
0
0
5
10
15
20
25
30
35
Days from Randomization
Heparin unfractionated or enoxaparin. Stone
GW. Presented at TCT October 2006 Washington,
DC.
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ACUITY-PCI Net Clinical Outcomes
Heparin IIb/IIIa vs Bivalirudin IIb/IIIa vs
Bivalirudin Alone
15
P.001
10
Event Rate ()
P (log rank)
Estimate
5
13.5
Heparin IIb/IIIa (N2561)
.10
Bivalirudin IIb/IIIa (N2609)
15.1
.049
Bivalirudin alone (N2619)
11.7
0
0
5
10
15
20
25
30
35
Days from Randomization
Heparin unfractionated or enoxaparin. Stone
GW. Presented at TCT October 2006 Washington,
DC.
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Featured Institution
Allegheny General HospitalPittsburgh,
Pennsylvania
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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.)

• 1) We are currently on the same item
• 2) We have since moved to the next checkbox on
  the checklist
• 3) 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 RemarksChristopher P. Cannon, MD
Next programWednesday, December 6, 2006 300
PM ET (1200 Noon PT)TopicHighlights From the
2006 American Heart Association Scientific
Sessions FacultyGregg C. Fonarow, MD