Strive Teleconf Presentation March22 2006

CVD Critical Pathways Group 2006 Teleconferences

March 22, 2006

This activity is supported by an educational grant from the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership.

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Faculty

Gregg C. Fonarow, MDEliot Corday Professor of Medicine

and Cardiovascular Science

Director, Ahmanson-UCLA Cardiomyopathy Center

UCLA Division of Cardiology

UCLA Medical Center

Los Angeles, California

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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.

Disclosure Statement

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Gregg C. Fonarow, MD, has served as a consultant to and has received research support and honoraria from Bristol-Myers Squibb Company, GlaxoSmithKline, Merck & Co., Inc., Pfizer Inc, sanofi-aventis, Schering-Plough Corporation, and Scios, Inc.

The team from Aurora Health Care reports no such relationships.

Faculty Disclosure Statement

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Polling Question #1

Did you attend the American College of Cardiology 2006 Annual Scientific Session?

1) Yes, I attended the entire duration of the conference

2) Yes, I attended part of the conference

3) No, I did not attend

Highlights From the American College of Cardiology 2006 Annual

Scientific Session

Gregg C. Fonarow, MD

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Highlights From ACC 2006

CHARISMA: Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization Management and Avoidance

REACH: Reduction of Atherothrombosis for Continued Health

ACUITY: Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial

ExTRACT-TIMI 25: Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction (ExTRACT) – Thrombolysis in Myocardial Infarction (TIMI) 25 study

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Highlights From ACC 2006 (cont.)

OASIS-6: Sixth Organization to Assess Strategies in Acute Ischemic Syndromes

ISAR-REACT 2: Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2 trial

ASTEROID: A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound

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CHARISMA

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Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA):

Study Design

Double-blind treatment up to 1040 primary efficacy events occur*

Aspirin 75–162 mg once daily

Clopidogrel75 mg once daily

Placebo1 tab once

daily

Aspirin 75–162 mg once daily

Fina

l stu

dy v

isit

(fix

ed s

tudy

end

dat

e)

1-m

onth

vis

it3-

mon

th v

isit

Patients 45 years or olderwho are at high risk of atherothrombotic events

R = randomization.

N=15,603

R

Bhatt DL, et al. Am Heart J. 2004;148:263-268.

*Event-driven trial: primary efficacy outcome of vascular death, MI, stroke

Visits every 6 months (12 m, 18 m…),and intermediate phone callsin between(15 m, 21m…)

6-m

onth

vis

it

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Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death)†

Placebo + ASA*7.3%

Clopidogrel + ASA*6.8%

RRR: 7.1% [95% CI: -4.5%, 17.5%]P = 0.22

Months since randomization§

0

2

4

6

8

0 6 12 18 24 30

Cu

mu

lati

ve e

ven

t ra

te (

%)

† First Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death*All patients received ASA 75-162 mg/day§The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo)

Adapted with permission from Bhatt DL, et al. N Engl J Med. 2006;354.

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Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization)†

Placebo + ASA*

17.9%

Clopidogrel + ASA*

16.7%

RRR: 7.7% [95% CI: 0.5%, 14.4%] P = 0.04

Cu

mu

lati

ve e

ven

t ra

te (

%)

0

5

10

15

20

Months since randomization§

0 6 12 18 24 30

*All patients received ASA 75-162mg/day†First Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization§The number of patients followed beyond 30 months decreases rapidly to zero and there are only 38 primary efficacy events that occurred beyond this time (23 clopidogrel and 15 placebo)

Adapted with permission from Bhatt DL, et al. N Engl J Med. 2006;354.

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Overall Population: Secondary Efficacy Results

*Intention to treat analysis†First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death (including hemorrhagic death), or hospitalization for UA, TIA, or a revascularization procedure‡For UA, TIA, or revascularization

Endpoint* – N (%)Clopidogrel +

ASA(n=7802)

Placebo + ASA(n=7801)

RR (95% CI)P

value

Principal Secondary Endpoint† 1301 (16.7) 1395 (17.9) 0.92 (0.86, 0.995) 0.04

All Cause Mortality 371 (4.8) 374 (4.8) 0.99 (0.86, 1.14) 0.90

Cardiovascular Mortality

238 (3.1) 229 (2.9) 1.04 (0.87, 1.25) 0.68

Myocardial Infarction 147 (1.9) 159 (2.0) 0.92 (0.74, 1.16) 0.48

Ischemic Stroke 132 (1.7) 160 (2.1) 0.82 (0.66, 1.04) 0.10

Stroke 149 (1.9) 185 (2.4) 0.80 (0.65, 0.997) 0.05

Hospitalization‡ 866 (11.1) 957 (12.3) 0.90 (0.82, 0.98) 0.02

Bhatt DL, et al. N Engl J Med. 2006;354.

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Overall Population: Safety Results

*Adjudicated outcomes by intention to treat analysisICH= Intracranial Hemorrhage

Safety Outcome* – N (%)

Clopidogrel + ASA

(n=7802)


RR (95% CI) P value

GUSTO Severe Bleeding

130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09

Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17

Primary ICH 26 (0.3) 27 (0.3) 0.96 (0.56, 1.65) 0.89

GUSTO Moderate Bleeding

164 (2.1) 101 (1.3) 1.62 (1.27, 2.10) <0.001


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Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category

Population RR (95% CI) P value

Qualifying CAD, CVD or PAD 0.88 (0.77, 0.998) 0.046(n=12,153)

Multiple Risk Factors 1.20 (0.91, 1.59)0.20 (n=3284)

Overall Population* 0.93 (0.83, 1.05)0.22 (n=15,603)

0.6 0.8 1.41.2

Clopidogrel Better Placebo Better

1.60.4

* A statistical test for interaction showed marginally significant heterogeneity (P = 0.045) in treatment response for these pre-specified subgroups of patients


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Population N RR (95% CI) P value

Qualifying CV Disease 12,153 0.88 (0.77, 0.998) 0.046

Coronary 5,835 0.86 (0.71, 1.05) 0.13

Cerebrovascular 4,320 0.84 (0.69, 1.03) 0.09

PAD 2,838 0.87 (0.67, 1.13) 0.29

Multiple Risk Factors 3,284 1.20 (0.91, 1.59) 0.20

Overall Population 15,603 0.93 (0.83, 1.05) 0.22

Primary Efficacy Results (MI/Stroke/CV Death)* by Category of Inclusion Criteria

0.6 0.8 1.41.2Clopidogrel Better Placebo Better

1.60.4

* First occurrence of MI (fatal or not), Stroke (fatal or not), or CV Death

Bhatt DL. Presented at: 55th Annual Scientific Session of the American Collegeof Cardiology; March 12, 2006; Atlanta, Ga.

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Multiple Risk Factor Population: Secondary Efficacy Results

*Intention to treat analysis†First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death (including hemorrhagic death), or hospitalization for UA, TIA, or a revascularization procedure‡For UA, TIA, or revascularization

Endpoint* – N (%)Clopidogrel +

ASA(n=1659)


RR (95% CI) P value

Principal Secondary Endpoint† 224 (13.5) 216 (13.3) 1.01 (0.84, 1.22) 0.88

All Cause Mortality 89 (5.4) 62 (3.8) 1.41 (1.02, 1.95) 0.04

Cardiovascular Mortality

64 (3.9) 36 (2.2) 1.74 (1.16, 2.62) 0.01

Myocardial Infarction 40 (2.4) 33 (2.0) 1.19 (0.75, 1.89) 0.45

Ischemic Stroke 27 (1.6) 29 (1.8) 0.91 (0.54, 1.54) 0.73

Stroke 35 (2.1) 36 (2.2) 0.95 (0.60, 1.52) 0.84

Hospitalization‡ 140 (8.4) 147 (9.0) 0.93 (0.74, 1.18) 0.55


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Multiple Risk Factor Population: Safety Results

*Adjudicated outcomes by intention to treat analysis


Clopidogrel + ASA

(n=1659)


RR (95% CI) P value


34 (2.0) 20 (1.2) 1.67 (0.96, 2.88) 0.07

Fatal Bleeding 7 (0.4) 5 (0. 2) 1.71 (0.50, 5.84) 0.38

Primary ICH 7 (0.4) 6 (0.4) 1.14 (0.38, 3.39) 0.81


36 (2.2) 22 (1.4) 1.60 (0.95, 2.71) 0.08


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Documented CV Disease Population: Safety Results

*Adjudicated outcomes by Intention to treat analysis


Clopidogrel + ASA

(n=6062)


RR (95% CI)P

value


95 (1.6) 84 (1.4) 1.14 (0.85, 1.52) 0.39

Fatal Bleeding 19 (0.3) 13 (0.2) 1.47 (0.73, 2.97) 0.28

Primary ICH 19 (0.3) 21 (0.3) 0.87 (0.47, 1.60) 0.65


128 (2.1) 79 (1.3) 1.63 (1.23, 2.15) <0.001


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CHARISMA: Conclusions 7.1% RRR for the primary endpoint (MI/Stroke/CV Death) in the overall

population did not reach statistical significance

7.7% RRR for the secondary endpoint, which included hospitalizations, was statistically significant

The overall outcome was influenced by divergent findings in the two main sub-groups enrolled in the trial

In patients with multiple risk factors only, without clearly established CV disease, dual antiplatelet therapy was not beneficial - excess in CV mortality as well as an increase in bleeding

In patients with documented CV disease (CAD, CVD, or PAD) long-term clopidogrel plus ASA resulted in a significant 12.5% RRR in MI/Stroke/CV Death with no significant increase in severe bleeding compared to ASA alone


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CHARISMA: Clinical Implications

In the acute setting, prior studies have shown the benefit of dual antiplatelet therapy for 1 year post ACS or PCI

For stable patients, CHARISMA failed to demonstrate a reduction in CV death/MI/stroke with dual antiplatelet therapy

CHARISMA may suggest differential long-term effects of dual antiplatelet therapy by patient type:

– NOT Recommended for Primary Prevention

– Potential benefit in Secondary Prevention (CAD, CVD, or PAD) CV death/MI/stroke - 10 events prevented per 1000 patients treated Balanced by 2 severe GUSTO bleeds per 1000 patients treated

These data and future trials will help physicians decide which non-acute/stable patients should receive long-term dual antiplatelet therapy


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REACH

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The REACH Registry

The REACH (REduction of Atherothrombosis for Continued Health) Registry has recruited outpatients who have had, or are at high risk of having, symptoms of atherothrombosis

The Registry aims to study a contemporary stable patient population from various regions of the world in order to:

– Describe the characteristics and management of these patients and of each subgroup

– Assess the long-term risk of atherothrombotic events in the global population and in each subgroup

– Assess the amount of “cross-risk” across subgroups

– Compare outcomes within different subject profiles

– Define predictors of risk for subsequent atherothrombotic events

Follow-up planned at 12 and 21 months, extended to 3 and 4 years

Steg PG. Presented at: 55th Annual Scientific Session of the American Collegeof Cardiology; March 12, 2006; Atlanta, Ga.

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North AmericaLatin America

Eastern Europe

Middle East

Asia (incl. Japan)

Australia

27,746

1,931

17,886

846

5,903

2,872

Western Europe

REACH Registry: >67,000 Patients From 5,473 Sites* in 44 Countries

5,048

5,656

*Up to 15 patients/site (up to 20 in the US)

Bhatt DL, et al. JAMA. 2006;295:180-189.

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A Broad Range of the At-Risk Population Is Included

Must include

SignedWritten

InformedConsent

Patients aged 45 yearsor more

At least 1of fourcriteria

1. Documented cerebrovascular diseaseischemic stroke ortransient ischemic attack

2. Documentedcoronary diseaseangina, MI, angioplasty/stent/bypass

3. Documented historicalor current intermittentclaudication associatedwith ABI < 0.9

4. At least 3 atherothromboticrisk factors

1. Male 65 yearsor female 70 years

2. Current smoking> 15 cigarettes/day

3. Type 1 or Type 2diabetes

4. Hypercholesterolemia

5. Diabetic nephropathy

6. Hypertension

7. Ankle Brachial Index(ABI) < 0.9 in eitherleg at rest

8. Asymptomatic carotidstenosis 70%

9. Presence of at leastone carotid plaque

REACH Registry Inclusion Criteria

Bhatt DL, et al. JAMA. 2006;295:180-189.

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1-Year Results: Single vs Multiple and Overlapping Atherothrombotic Locations: The Example of CAD

1.5 1.4 0.9

3.1

13.3

2 1.6

3.7

6.4

20

2.91.4 1.3

4.8

23.3

3.61.8

4

7.4

26.9

0

5

10

15

20

25

30

CV Death Nonfatal MI Nonfatal Stroke Death/MI/Stroke Death/MI/ Stroke/Hosp*

CAD alone

CAD +CVD

CAD+PAD

CAD+CVD+PAD

Rates adjusted for age and risk factors*TIA, unstable angina, other ischemic arterial event including worsening of PAD


(%)

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Major Endpoints as a Function of Single vs Multiple and Overlapping Locations

1 p<0.05; 2 p<0.01; 3 p<0.001 (ref class: CAD alone) 1 p<0.05; 2 p<0.01; 3 p<0.001 (ref class: CAD + CVD)

*TIA, unstable angina, other ischemic arterial event including worsening of PAD

Single arterial bed Polyvascular disease

OverallCAD alone

CVD alone

PAD alone

OverallCAD + CVD

CAD + PAD

CVD + PAD

CAD + CVD + PAD

CV death 1.5 1.5 1.4 1.2 2.4 2.0 2.9(2) 1.8 3.6(3)

Non-fatal MI 1.2 1.4 0.5(3) 1.0 1.5 1.6 1.4 1.3 1.8

Non-fatal stroke 1.5 0.9 3.5(3) 0.6 3.1 3.7 1.3(3) 4.8 4.0

CV death/MI/stroke

3.4 3.1 4.5(3) 2.3 6.0 6.4 4.8(3) 7.0 7.4

CV death/MI/ stroke/hospitalization

12.8 13.3 10.0(3) 18.2(3) 22.0 20.0 23.3(3) 24.4(1) 26.9(3)


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Clinical Implications

These results suggest the need to address atherothrombosis as a “global disease” rather than separately for each vascular bed

All-out efforts are needed to reduce the high event rates experienced by atherothrombotic patients

A more in-depth discussion of REACH will take place during next month’s STRIVE Champion teleconference.

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ACUITY

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Moderate-high risk

ACS

Study Design – First Randomization

An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allclopidogrel

dosing and timingper local practice

UFH orEnoxaparin+ GP IIb/IIIa

Bivalirudin+ GP IIb/IIIa

Bivalirudinalone

R*

Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800)


Medicalmanagement

PCI

CABG

*Stratified by pre-angiography thienopyridine use or administration

Stone GW, et al. Am Heart J. 2004;148:764-775.

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Moderate-high risk

ACS

Study Design – Second Randomization

An

gio

gra

ph

y w

ith

in 7

2h

Aspirin in allclopidogrel

dosing and timingper local practice

Medicalmanagement

PCI

CABG

Bivalirudinalone

UFH or enoxaparinUFH or enoxaparin

Routine upstream GPI in all ptsGPI started in

CCL for PCI only

R

BivalirudinBivalirudin

R

Routine upstream GPI in all ptsGPI started in

CCL for PCI only



Stone GW, et al. Am Heart J. 2004;148:764-775.

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Primary Endpoint Measures (ITT)

11.7%

7.3%5.7% 5.3%

11.8%

7.7%

Net clinicaloutcome

Ischemic composite Major bleeding

30 d

ay e

ven

ts (

%)

UFH/Enoxaparin+GPI (N=4603) Bivalirudin+GPI (N=4604)

PNI < 0.0001PSup = 0.93

PNI = 0.007PSup = 0.39

PNI = 0.0001PSup = 0.38

UFH/Enoxaparin + GPI vs Bivalirudin + GPIUFH/Enoxaparin + GPI vs Bivalirudin + GPI

Stone G. Presented at: 55th Annual Scientific Session of the American Collegeof Cardiology; March 12, 2006; Atlanta, Ga.

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0 1 2

11.7%11.8% 1.01 (0.90-1.12)<0.001

0.93

Risk ratio±95% CI

Risk ratio±95% CI

Primaryendpoint

Net clinical outcome

Ischemic composite

Major bleeding

Bivalirudin + IIb/IIIa betterBivalirudin + IIb/IIIa better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Bival+ IIb/IIIa

UFH/Enox+ IIb/IIIa

RR (95% CI)P value

(noninferior)(superior)

7.3%7.7% 1.07 (0.92-1.23)0.0150.39

5.7%5.3% 0.93 (0.78-1.10)<0.001

0.38

Upp

er b

ound

ary

noni

nfer

iorit

y

UFH/Enoxaparin + GPI vs Bivalirudin + GPIUFH/Enoxaparin + GPI vs Bivalirudin + GPI


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11.7%

7.3%5.7%

3.0%

10.1%

7.8%

Net clinicaloutcome

Ischemic composite Major bleeding

30 d

ay e

ven

ts (

%)

UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)


PNI <0.0001PSup = 0.015

PNI = 0.011PSup = 0.32

PNI <0.0001PSup <0.0001

UFH/Enoxaparin + GPI vs Bivalirudin AloneUFH/Enoxaparin + GPI vs Bivalirudin Alone


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Bivalirudin alone betterBivalirudin alone better UFH/Enox + IIb/IIIa betterUFH/Enox + IIb/IIIa better

Risk ratio±95% CI

Risk ratio±95% CI

Primaryendpoint

Bivalalone

UFH/Enox+ IIb/IIIa

RR (95% CI)


Ischemic composite

Major bleeding

Upp

er b

oun

dary

non

-infe

riorit

y11.7%10.1% 0.86 (0.77-0.97)

<0.0010.015

7.3%7.8% 1.08 (0.93-1.24)0.020.32

5.7%3.0% 0.53 (0.43-0.65)<0.001<0.001

P value(non inferior)

(superior)

UFH/Enoxaparin + GPI vs Bivalirudin AloneUFH/Enoxaparin + GPI vs Bivalirudin Alone

0 1 2

Upp

er b

ound

ary

noni

nfer

iorit

y


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7.3%

1.3%

4.9%

2.3%2.7%2.4%

5.0%

7.7%

1.5% 1.6%

7.8%

5.4%

Ischemic composite Death Myocardialinfarction

Unplanned revasc for ischemia

30 d

ay e

ven

ts (

%)

UFH/Enox+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612)

Components of the Ischemic Composite

PSup = 0.32 PSup = 0.34 PSup = 0.35 PSup = 0.78

UFH/Enoxaparin + GPI vs Bivalirudin + GPI vs Bivalirudin AloneUFH/Enoxaparin + GPI vs Bivalirudin + GPI vs Bivalirudin Alone


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Major Bleeding Endpoints

PSup= 0.38 PSup< 0.0001PSup= 0.31 PSup < .001

UFH/Enoxaparin + GPI vs Bivalirudin + GPI vs Bivalirudin AloneUFH/Enoxaparin + GPI vs Bivalirudin + GPI vs Bivalirudin Alone

11.8%

5.7%

11.1%

5.3%

3.0%

9.1%

All major bleeding Non-CABG major bleeding(primary endpoint)

30 d

ay e

ven

ts (

%)

Heparin+GPI (N=4603) Bivalirudin+GPI (N=4604) Bivalirudin alone (N=4612)


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Conclusions: Primary ResultsConclusions: Primary Results

UFH/Enox + GP IIb/IIIa

Bivalirudin +GP IIb/IIIa

Bivalirudinalone

Observed Rate RateP

Value

RateP

ValueEndpoint


11.7% 11.8% <0.001 NI 10.1% 0.015 Sup

Ischemic events 7.3% 7.7% 0.007 NI 7.8% 0.011 NI

Major bleeding 5.7% 5.3% 0.001 NI 3.0% <0.001 Sup

NI = noninferiority; Sup = superiority


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Clinical Implications

In patients with moderate-high risk ACS undergoing an early invasive strategy with use of GP IIb/IIIa inhibitors

– Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin

However, compared to either UFH/enoxaparin with GP IIb/IIIa inhibition or bivalirudin with GP IIb/IIIa inhibition

– A bivalirudin-alone strategy results in significantly greater net clinical benefit and enhanced survival free from adverse events at 30 days


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ExTRACT-TIMI 25

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STEMI < 6 hLytic eligible

Lytic choice by MDLytic choice by MD(TNK, tPA, rPA, SK)(TNK, tPA, rPA, SK)

UFH60 U / kg bolus (4000 U)

Inf 12 U / kg / h (1000 U / h)Duration: at least 48 hCont’d at MD discretion

ENOX< 75 y: 30 mg IV bolus

SC 1.0 mg / kg q 12 h (Hosp DC)≥ 75 y: No bolus

SC 0.75 mg / kg q 12 h (Hosp DC)CrCl < 30: 1.0 mg / kg q 24 h

Double-blind, double-dummy

ASAASA

Protocol Design

Day 301° Efficacy Endpoint: Death or Nonfatal MI

1° Safety Endpoint: TIMI Major Hemorrhage

Antman EM, et al. N Engl J Med. 2006;354.

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Primary End Point (ITT)Death or Nonfatal MI

0

3

6

9

12

15

0 5 10 15 20 25 30

Pri

ma

ry E

nd

Po

int

(%)

ENOX

UFH

Relative Risk0.83 (0.77 to 0.90)

P<0.001

Days after Randomization

9.9%

12.0%

Lost to follow-up = 3

17% RRR

Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354.

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Major Secondary End PointDeath or Nonfatal MI or Urgent Revascularization

(ITT)

Sec

on

dar

y E

nd

Po

int

(%)

Days

0

3

6

9

12

15

0 5 10 15 20 25 30

ENOX

UFH

11.7% (1199)

14.5% (1479)

5.3%

6.1%

RR 0.88 (0.79 to 0.98)

P=0.02

48 h

UFH ENOX

280 events19% RRR

RR 0.81 (0.75 to 0.87)

P<0.001

12% RRR


Death or Nonfatal MI – Day 30 Major Subgroups

> Median

< Median

Fibrin-specific

Streptokinase

Prior MI

No Prior MI

DM

No DM

Other

Anterior

0.5 1 2

PRIOR MI

OVERALL

DIABETES

FIBRINOLYTIC

INFARCTLOCATION

ENOX Better UFH BetterRelative Risk

TIME TO Rx

20,479

1123

1721

1720

1318

2312

17

Reduction In Risk (%)

> 75

< 75AGE (y)

206

Female

MaleSEX 1816

All Interaction TestsP = NS

P < 0.0001


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Bleeding Endpoints (TIMI) 30 Days

1.40.9 0.7

2.11.3

0.8

0

2

4

6

8

10UFHENOX

% E

ven

ts

Major Bleed(fatal + nonfatal)

ICH

ARD 0.7%RR 1.53

P<0.001

ARD 0.1%RR 1.27

P = 0.14

NonfatalMajor Bleed

ARD 0.4%RR 1.39

P = 0.014


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Net Clinical Benefit at 30 Days

1 1.250.90.8

Death or Nonfatal MI or Nonfatal ICH

Death or Nonfatal MI or Nonfatal Major Bleed

Death or Nonfatal MI or Nonfatal Disabl. Stroke

ENOX Better UFH BetterRR

UFH (%) ENOX (%) RRR (%)

12.3 10.1 18

12.8 11.0 14

12.2 10.1 17

Prespecified Definitions

P <0.001

P <0.001

P <0.001


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Clinical Implication

A strategy of enoxaparin is preferable to the current standard of unfractionated heparin as the antithrombin to support fibrinolysis, the most common form of reperfusion for STEMI used worldwide.

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48

OASIS-6

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OASIS – 6 Trial: Study Design

12,092 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hours of symptom onset midway through trial)

Randomized. Blinded. Factorial.28% female, mean age 62 years, mean follow-up 3-6 months

Fondaparinux2.5 mg/day for up to 8

days or hospital discharge

Placebo Fondaparinux 2.5 mg/day for up to 8

days or hospital discharge

UFH

Primary Endpoint: Composite of death or reinfarction at 30 days Secondary Endpoint: Composite of death or reinfarction at 9 days and at

final follow-up

Stratum 1 (No UFH) Stratum 2 (UFH)

Yusuf S, et al. JAMA. 2006;295.

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OASIS – 6 Trial: Primary Endpoint

The primary endpoint was lower in the fondaparinux group compared with the control group (9.7% vs.11.2%, HR 0.86, P=0.008)

The results were similar at 9 days (HR 0.83, P=0.003) and at study end (HR 0.88, P=0.008)

9.7%

7.4%

13.4%

11.2%

8.9%

14.8%

0%

3%

6%

9%

12%

15%

30 days 9 days 3-6 monthsFondaparinux (n=6036) Control (n=6056)

Primary Endpoint: Death/Reinfarction (%)

P=0.008 P=0.003 P=0.008

Fre

qu

en

cy


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OASIS – 6 Trial: Primary Endpoint (cont.)

11.2%

14.0%

0%

2%

4%

6%

8%

10%

12%

14%

Fondaparinux Placebo

Reduction in Death/MI: Stratum 1(No UFH indicated)

P<0.05

Reduction in Death/MI: Stratum 2(UFH Indicated)

P=NS

The reduction in the primary endpoint at 30 days in the fondaparinux group was driven by Stratum 1, where death/MI occurred less frequently among fonda pts than placebo (11.2 vs. 14%, HR 0.79, p<0.05)

There was no difference in Stratum 2, comparing those patients who received fondaparinux vs those who received UFH (8.3% vs. 8.7%, HR 0.96, p=NS)

p=0.97p=0.97

8.3% 8.7%

0%

2%

4%

6%

8%

10%

12%

14%

Fondaparinux UFH


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OASIS – 6 Trial: Primary Composite Endpoint

Among the components of the composite at 30 days, mortality was lower in the fondaparinux group compared to the control group (7.8% vs. 8.9%, HR 0.87, P=0.03).

Reinfarction was also lower in the fondaparinux group compared to the control group (2.5% vs. 3.0% HR 0.81, P=0.06).

Components of Primary Composite Endpoint (%)

P=0.03

P=0.06


7.8%

2.5%

8.9%

3.0%

0%

2%

4%

6%

8%

10%

Death Reinfarction

Fondaparinux Control

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OASIS – 6 Trial: PCI Substudy at 30 Days

There was no difference in the primary endpoint for patients who were managed with primary PCI (6.1% vs 5.1%, p=0.19).

Guiding catheter thrombosis in the primary PCI cohort occurred more often with fondaparinux compared with control (n=22 vs. n=0, p<0.001)

6.1%

5.1%

0%

2%

4%

6%

8%


Primary Endpoint of Death or MI in PCI Cohort (%)p=0.19


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OASIS – 6 Trial: PCI Substudy (cont.)

There was no difference in severe bleeding at 9 days by treatment group (1.0% fondaparinux vs. 1.3% control, P=NS)

Intracranial hemorrhage occurred in 0.2% in each group

1.0%

1.3%

0%

1%

2%


Severe Bleeding at 9 days (%)P=NS


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There was a higher instance of guiding catheter thrombosis in the PCI cohort treated with fondaparinux compared to control (n=22 vs. n=0, P<0.001)

22

00

5

10

15

20

25


Guiding Catheter Thrombosis P<0.001


Nu

mb

er

of in

sta

nce

s

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Coronary complications occurred in more patients treated with fondaparinux compared to control (n=270 vs. n=225, P=0.04)

Coronary complications include abrupt closure, no reflow, dissection, new angiographic thrombus, perforation, or catheter thrombus

270

225

0

40

80

120

160

200

240

280


Coronary Complications P=0.04


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OASIS – 6 Trial: Conclusions

In patients with STEMI, particularly those not undergoing primary PCI, fondaparinux significantly reduces mortality and reinfarction without increasing bleeding and strokes

Benefits of fondaparinux were observed in Stratum 1 where placebo or no antithrombin was administered

Fondaparinux was not superior to active control UFH overall, but was more beneficial in those patients not undergoing direct PCI

Fondaparinux trended to produce less severe bleeding Fondaparinux was associated with a hazard in those

patients who underwent PCI, including guiding catheter thrombosis

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ISAR-REACT 2

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ISAR-REACT 2 Trial: Study Design

Primary Endpoint: Composite of death, MI, and urgent target vessel revascularization (TVR) due to myocardial ischemia within 30 days

Secondary Endpoint: In-hospital major and minor bleeding

2022 patients with an episode of angina within the preceding 48 hours and an elevated troponin T level or new ST-segment depression of ≥0.1 mV or transient (<20 minutes)

ST-segment elevation of ≥0.1 mV or new or presumed new bundle-branch block; significant angiographic lesions in a native coronary vessel or venous bypass graft

amenable to and requiring a PCI Placebo Controlled. Randomized. Blinded.

24% female, mean age 66 years, mean follow-up 30 days

Abciximab(usual bolus or infusion dose)

n=1012

Placebon=1010

Pre-treatment with high dose (600mg) clopidogrel at least 2 hours pre-procedure

Kastrati A, et al. JAMA. 2006;295.

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Adapted with permission from Kastrati A, et al. JAMA. 2006;295. Published online March 13, 2006.

ISAR REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR

20

15

10

5

0

0 5 10 15 20 25 30Days After Randomization

Cu

mu

lati

ve R

ate

of

Pri

mar

y E

nd

Po

int,

%

Placebo GroupAbciximab Group

Log-Rank P=.03

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Abbreviations: CI, confidence interval; MI, myocardial infarction; RR, relative risk.

Adapted with permission from Kastrati A, et al. JAMA. 2006;295.Published online March 13, 2006.

ISAR REACT 2: 30-Day Ischemic Events

No. (%)

EventAbciximab(n=1012)

Placebo(n=1010)

RR (95% CI)

Death, MI, or urgent target vessel revascularization

90 (8.9) 120 (11.9) 0.75 (0.58-0.97)

Death or MI 87 (8.6) 116 (11.5) 0.75 (0.57-0.97)

Death 11 (1.1) 16 (1.6) 0.69 (0.32-1.47)

MI 82 (8.1) 106 (10.5) 0.77 (0.59-1.02)

Q-wave MI 11 (1.1) 14 (1.4) 0.78 (0.36-1.72)

Urgent target vessel revascularization

10 (1.0) 12 (1.2) 0.83 (0.36-1.92)

Aortocoronary bypass surgery 3 (0.3) 1 (0.1) 2.99 (0.24-157)

PCI 7 (0.7) 11 (1.1) 0.64 (0.25-1.63)

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ISAR REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in Subsets With and Without

Elevated Troponin Levels (>0.03 µg/L)

Adapted with permission from Kastrati A, et al. JAMA. 2006;295.Published online March 13, 2006.

20

15

10

5

0

0 5 10 15 20 25 30Days After Randomization

Cu

mu

lati

ve R

ate

of

Pri

mar

y E

nd

Po

int,

%

Placebo GroupAbciximab Group

Troponin >0.03 µg/LLog-Rank P = .02

Troponin <0.03 µg/LLog-Rank P = .98

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Error bars indicate 95% confidence intervals.

Adapted with permission from Kastrati A, et al. JAMA. 2006;295. Published online March 13, 2006.

ISAR REACT 2: 30-Day Incidence and Relative Risk of Death, MI, or Urgent

TVR in Subgroups

Abciximab PlaceboAll Participants 90/1012 (8.9) 120/1010 (11.9)Troponin Level >0.03 µg/L 67/513 (13.1) 98/536 (18.3) ≤0.03 µg/L 23/499 (4.6) 22/474 (4.6)

Clopidogrel Pretreatment Duration >3 h 27/475 (5.7) 35/461 (7.6) ≤3 h 63/537 (11.7) 85/549 (15.5)

Diabetes Yes 26/252 (10.3) 32/284 (11.3) No 64/760 (8.4) 88/726 (12.1)

Primary End Point,No. of Events/Total No. (%)

0.4 1 2Relative Risk

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ISAR-REACT 2 Trial: Secondary Endpoint

1.4%

4.2%

2.5%

1.4%

3.3%

2.0%

0%

1%

2%

3%

4%

5%

Major Bleeding Minor Bleeding Transfusion

Abciximab Placebo

In-hospital Major and Minor Bleeding (%)p=NS

Kastrati A, et al. JAMA. 2006;295. Published online March 13, 2006.

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ISAR-REACT 2 Trial: Summary

For patients undergoing PCI for a non-ST-segment elevation ACS who were treated with high dose clopidogrel (600 mg) at least 2 hours before the procedure, treatment with abciximab was associated with a reduction in death, MI, or urgent target vessel revascularization within 30 days.

A subgroup analysis showed that the benefit of abciximab therapy was largely confined to patients with an elevated troponin level as there was no significant difference in the incidence of the primary endpoint among patients without an elevated troponin level.

There were no significant differences in in-hospital TIMI major bleeding (1.4% in each group, P = NS) or TIMI minor bleeding (4.2% abciximab vs 3.3% placebo, P = NS)

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ASTEROID

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Follow-up IVUS at 24 monthsn=349

ASTEROID Trial: Study Design

Primary Endpoint: 1) Change in percent atheroma volume and 2) change in nominal atheroma volume in the 10 mm subsegment with the greatest disease severity at baseline.

Secondary Endpoint: Change in normalized total atheroma volume for the entire artery.

Withdrawn during treatment (n=125)

1,183 patients screened for the presence of a coronary angiographic evaluated lesion >20%; IVUS target vessel stenosis <50% and not being treated with

angioplasty with a minimum length of 40 mm; and statin-naïve. Excluding those with:

Uncontrolled triglyceride levels (≥500mg/dL) or poorly controlled diabetes (glycosylated hemoglobin levels ≥10%).

Open-label; mean age 58.5 years; mean follow-up at 2 years; 29% female.

All enrolled patients: 40 mg rosuvastatin, IVUS of a single vessel not intervened upon at baseline

n=507

Nissen SE, et al. JAMA. 2006;295. Published online March 13, 2006.

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ASTEROID Trial: Principal Findings

LDL Levels were reduced from 130.4 mg/dL at baseline to a mean of 60.8 mg/dL at 2 year follow-up (P<0.001), with 75% of patients achieving an LDL <70 mg/dL.

HDL levels were increased from 43.1 mg/dL at baseline to a mean of 49.0 mg/dL at follow-up (P<0.001).

LD

L/H

DL

mg

/dL

Mean LDL level decrement and HDL level increment (mg/dL)

p<0.001

p<0.001


43.1

60.849.0

130.4

0

22

44

66

88

110

132

LDL Levels HDL Levels BaselineFollow-up

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ASTEROID: Example of Regression of Atherosclerosis in a Patient in the Trial

Adapted with permission from Nissen S, et al. JAMA. 2006;295. Published online March 13, 2006.

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ASTEROID Trial: Primary Endpoint

The first co-primary endpoint, change in percent atheroma volume, was reduced by a mean of 0.98% (from 39.6% at baseline to 38.6% at 2 year follow-up, absolute change of -0.98%, P<0.001).

Co-primary Endpoint of change in % atheroma volume (%)

% A

the

rom

a V

olu

me

p<0.001


38.6%39.6%

0

10

20

30

40

Baseline Follow-up

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ASTEROID Trial: Primary Endpoint cont.

Regression in percent atheroma volume was observed in 63.6% of patients; whereas, progression was observed in 34.6%.

63.6

34.6

0

8

16

24

32

40

48

56

64

Regression Progression

Regression vs. progression change in % atheroma volume (%)

% p

atie

nts


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ASTEROID Trial: Primary Endpoint cont.

Co-primary Endpoint of nominal atheroma volume in the 10 mm subsegment with the greatest disease

severity at baseline (mm3)

mm

3

59.065.1

0

10

20

30

40

50

60

70

Baseline 2-Year Follow-up

P<0.001

The other co-primary endpoint, change in nominal atheroma volume in the 10 mm subsegment with the greatest disease severity at baseline, was also reduced (from 65.1 mm3 at baseline to 59.0 mm3 at 2 year follow-up, an absolute change of -6.1 mm3, P<0.001).


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ASTEROID Trial: Secondary Endpoint

212.2197.5

0

30

60

90

120

150

180

210

240

Baseline Follow-up

Mean Normalized Total atheroma volume (mm3) At follow-up, total

atheroma volume was reduced from 212.2 mm3 at baseline to 197.5 mm3 (an absolute change of -14.7 mm3).

mm

3


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ASTEROID Trial: Adverse Events

4.3%

3.7%

0

1

2

3

4

5

Musculoskeletal Cardiovasculardisorders

Musculoskeletal complaints (3.7%) and cardiovascular disorders (4.3%) were the adverse events that resulted in study drug discontinuation.

There were no cases of rhabdomyolysis.

Adverse events resulting in study drug discontinuation (%)

%


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Adapted with permission from Nissen S, et al. JAMA. 2006;295. Published online March 13, 2006.

Relationship Between Mean LDL-C Levels and Median Change in % Atheroma Volume for

Several Intravascular Ultrasound Trials

-1.2

-0.6

0

0.6

1.2

1.8

50 60 70 80 90 100 110 120

Mean Low-Density Lipoprotein Cholesterol, mg/dL

Med

ian

Ch

ang

e in

Per

cen

t A

ther

om

a V

olu

me,

%

REVERSALPravastatinCAMELOT

Placebo

A-PlusPlacebo

REVERSALAtorvastatin

ASTEROIDRosuvastatin

r2 = 0.97P<.001

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ASTEROID Trial: Limitations

No control group Those patients with a >50% stenosis within

the target segment were excluded. It is unknown whether statin-naïve patients

are more likely to have a larger amount of atheroma regression compared to those already receiving statin therapy.

Nissen S, et al. JAMA. 2006;295. Published online March 13, 2006.

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ASTEROID Trial: SummaryAmong patients with angiographic coronary disease, treatment with

intensive statin therapy with rosuvastatin 40 mg was associated with atherosclerosis regression on IVUS at 2 year follow-up.

Prior IVUS studies have shown a reduction in atherosclerosis progression with intensive statin therapy compared with a more moderate lipid lowering regimen.

The authors attribute the regression in atheroma volume to the very large reductions in LDL and increases in HDL.

It should be noted that regression in atheroma volume in the most diseased 10 mm subsegment was observed even in patients with an average LDL of 100mg/dL (-6.9 mm3, P<0.001) and in those with an average HDL <35 mg/dL (-5.9 mm3, P<0.001).

The impact of aggressive lipid lowering on clinical events was not fully evaluated in this trial.

Nissen S, et al. JAMA. 2006;295. Published online March 13, 2006.

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Featured InstitutionAurora Health Care

Milwaukee, Wisconsin

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Polling Question #2

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

4) ACS pathways are up-to-date and regularly followed

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.)

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Progress Checklist:Immediate Goals

Assemble team and set up meeting of working group

Develop draft pathways

Circulate pathways to all cardiology, ED, and CV nursing staff for comments

Circulate discharge plan and other tools to all cardiology, ED, and CV nursing staff for comments

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Progress Checklist:Short-term Goals/Activities

Finalize critical pathways

Launch critical pathways

Circulate memo

Grand rounds/conference: Cardiology/IM

Grand rounds/conference: Emergency Dept.

Grand rounds/conference: Nursing

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Progress Checklist:Long-term Goals/Activities

Monitor data: which registry?

NRMI AHA Get With The Guidelines ACC National Cardiovascular Data Registry CRUSADE GRACE REACH Other

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Question-and-Answer Session

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Concluding RemarksGregg C. Fonarow, MD

Next program:Wednesday, April 19, 2006 - 3PM ET (12N PT)

Topic:Preliminary Findings From the REACH Registry

Faculty:Gregg C. Fonarow, MD

Strive Teleconf Presentation March22 2006

Health & Medicine

Transcript of Strive Teleconf Presentation March22 2006