strive teleconf presentation apr11 2007

ACS Critical Pathways 2007 Teleconferences

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

This activity is co-provided by the Network for Continuing Medical Education and EduPro Resources LLC.

APRIL 11, 2007

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Faculty

Christopher P. Cannon, MDAssociate Professor of Medicine

Harvard Medical School

Senior Investigator, TIMI Study Group

Associate Physician, Cardiovascular Division

Brigham and Women’s Hospital

Boston, Massachusetts

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The Network for Continuing Medical Education and

EduPro Resources LLC require that CME/CNE 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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Christopher P. Cannon, MD, has served as a consultant to Abbott Laboratories, Alnylam Pharmaceuticals, Arena Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Biosite, Bristol-Myers Squibb Company, Eisai Inc., GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Pfizer Inc, sanofi-aventis, Schering-Plough Corporation, Tethys Bioscience, and Vertex Pharmaceuticals. He has received honoraria from Accumetrics, AstraZeneca Pharmaceuticals LP, BGB New York, Bristol-Myers Squibb Company, DIME, Genentech, Inc., Merck & Co. Inc., Pfizer Inc, sanofi-aventis, and Schering-Plough Corporation, and has received research support from Accumetrics, AstraZeneca Pharmaceuticals LP, Merck & Co., Inc., and Schering-Plough Corporation.

The team from Aurora St. Luke's Medical Center reports no such relationships.

Faculty Disclosure Statement

Highlights From the American College of Cardiology

2007 Annual Scientific Session

Christopher P. Cannon, MD

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Highlights From ACC 2007 COURAGE: Clinical Outcomes Utilizing Revascularization and

Aggressive Guideline-Driven Drug Evaluation MERLIN TIMI-36: Metabolic Efficiency with Ranolazine for

Less Ischemia in Non-ST Elevation Acute Coronary Syndromes

Danish Registry: More data on late stent thrombosis in DES-treated patients

An International Risk Prediction Model for Recurrent CV Events in REACH: Reduction of Atherothrombosis for Continued Health

ACUITY: Acute Catheterization and Urgent Intervention Triage StrategY (1 year results)

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COURAGEClinical Outcomes Utilizing Revascularization

and Aggressive Guideline-DrivenDrug Evaluation

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COURAGE: Background

Every year, more than 1 million PCI procedures are performed in the US

– The majority are undertaken electively in patients with stable CAD

Successful PCI of flow-limiting stenoses might be expected to reduce the rate of death, MI or hospitalization for ACS, however:

– Prior studies have shown only that PCI decreases the frequency of angina and improves short-term exercise performance

Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007.

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35,539 patients underwent assessment35,539 patients underwent assessment

1149 to PCI + OMT group

COURAGE: Study Design

32,468 excluded for not meeting inclusion criteria, logistics, or for >1 exclusions

Randomize

1138 to OMT alone group

Primary Outcome: Death or nonfatal MISecondary Outcomes: Death, MI, or stroke

Hospitalization for biomarker (-) ACSCost, resource utilization

Quality of life, including anginaCost-effectiveness

Primary Outcome: Death or nonfatal MISecondary Outcomes: Death, MI, or stroke

Hospitalization for biomarker (-) ACSCost, resource utilization

Quality of life, including anginaCost-effectiveness

Intensive, guideline-driven medical therapy and lifestyle intervention in both groups

N = 2287


3071 met eligibility criteria2287 consented to participate

2.5 to 7 year (mean 4.6 year) follow-up

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COURAGE: Inclusion and Exclusion Criteria

Men and women 1, 2, or 3 vessel disease

(>70% visual stenosis of proximal coronary segment)

Anatomy suitable for PCI CCS class I-III angina Objective evidence of

ischemia at baseline ACC/AHA class I or II

indication for PCI

Uncontrolled unstable angina

Complicated post-MI course Revascularization within 6

months Ejection fraction <30% Cardiogenic shock/severe

heart failure History of sustained or

symptomatic VT/VF Severe non-CV comorbidity

limiting survival


Inclusion Criteria Exclusion Criteria

CCS = Canadian Cardiovascular Society

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COURAGE: Other Criteria Objective Evidence of Ischemia

– Spontaneous ST-T changes on ECG

– >1 mm ST deviation on treadmill test

– Ischemic imaging defect

Coronary Intervention

– Best practice

– May use all FDA or Health Canada approved devices

– Completeness of revascularization as clinically appropriate


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COURAGE: Risk Factor GoalsVariable Goal

Smoking Cessation

Total Dietary Fat / Saturated Fat <30% calories / <7% calories

Dietary Cholesterol <200 mg/day

LDL-C (primary goal) 60-85 mg/dL

HDL-C (secondary goal) >40 mg/dL

Triglyceride (secondary goal) <150 mg/dL

Physical Activity 30-45 min. moderate intensity 5x/week

Body Weight by BMI Initial BMI Weight Loss Goal 25-27.5 BMI <25 >27.5 10% relative weight loss

Blood Pressure <130/85 mm Hg

Diabetes HbAlc <7.0%


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COURAGE: Optimal Medical Therapy*

Category Agents

Antiplatelet Aspirin Clopidogrel in accordance

with established practice standards

Statin Simvastatin ± ezetimibe or extended-release niacin

ACE Inhibitor or ARB Lisinopril or losartan

Beta blocker Long-acting metoprolol

Calcium channel blocker Amlodipine

Nitrate Isosorbide 5-mononitrate


*Applied to both arms by protocol and case-managed.

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COURAGE: Baseline Demographic Characteristics

Characteristic PCI + OMT (N = 1149) OMT (N = 1138) P value

Age (y)

Sex (n, %)

Male

Female

Race or ethnic (n, %)

White

Black

Hispanic

Other

61.5±10.1

979 (85)

169 (15)

988 (86)

57 (5)

68 (6)

35 (3)

61.8±9.7

968 (85)

169 (15)

975 (86)

57 (5)

58 (5)

47 (4)

.54

.95

.64


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COURAGE: Baseline Characteristics – AnginaCharacteristic PCI + OMT (N = 1149) OMT (N = 1138) P value

Angina CCS class (no, %)

0

I

II

III

Missing data

Duration of angina (months)

Median

Interquartile range

Episodes/week with exertion or at rest within last month

Median

Interquartile range

135 (12)

340 (30)

409 (36)

261 (23)

3 (<1)

5

1-15

3

1-6

148 (13)

341 (30)

425 (37)

221 (19)

2 (<1)

5

1-15

3

1-6

.24

.53

.83


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COURAGE: Survival Free of Death From Any Cause and MI

No. at Risk

OMT 1138 1017 959 834 638 408 192 30PCI+OMT 1149 1013 952 833 637 417 200 35

Years

0 1 2 3 4 5 6

0.0

0.5

0.6

0.7

0.8

0.9

1.0

PCI + OMT: 19%*

OMT: 18.5%* Hazard ratio: 1.0595% CI (0.87-1.27)P = .62

7


Su

rviv

al F

ree

of

Dea

th F

rom

A

ny

Cau

se a

nd

MI

*Cumulative event rates at a median of 4.6 years.

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COURAGE: Cumulative Event Rates at a Median of 4.6 Years

<.0010.51–0.710.6032.621.1Revasc.(PCI or CABG)

.560.84–1.371.0711.812.4Hospitalization for ACS

.190.80–3.041.56 1.8 2.1Stroke

.330.89–1.431.1312.313.2Nonfatal MI

.380.65–1.160.87 8.3 7.6Death

.620.87–1.271.0519.520 Death, MI, stroke

.620.87–1.271.05 18.519Death, MI

Pvalue

95% CI Hazard ratio

OMT(%)

PCI + OMT (%)

Outcome


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COURAGE: Overall Survival

No. at Risk

OMT 1138 1073 1029 917 717 468 302 38PCI+OMT 1149 1094 1051 929 733 488 312 44

Years0 1 2 3 4 5 6

0.0

0.5

0.6

0.7

0.8

0.9

1.0 PCI + OMT: 7.6%*

OMT: 8.3%*

7

Hazard ratio: 0.8795% CI (0.65-1.16)P = .38


Ove

rall

Su

rviv

al

*Cumulative event rates at a median of 4.6 years.

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COURAGE: Freedom From Angina During Long-term Follow-up

Time Point (y) PCI + OMT OMT P value

Baseline 12% 13% NS

1 y 66% 58% <.001

3 y 72% 67% .02

5 y 74% 72% NS


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COURAGE: Conclusions

As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, MI, or other major cardiovascular events when added to optimal medical therapy

PCI resulted in better angina relief during most of the follow-up period, but medical therapy was also effective, with no between–group difference in angina-free status at 5 years


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MERLIN TIMI-36Metabolic Efficiency with Ranolazine for Less

Ischemia in Non-ST ElevationAcute Coronary Syndromes

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MERLIN TIMI-36: Background

Despite advances in antithrombotic therapies and invasive technology, risk of recurrent ischemic complications in patients with NSTE-ACS remains substantial

Ranolazine is a novel agent that inhibits the late sodium current thereby reducing cellular sodium and calcium overload; has been shown to reduce ischemia in patients with chronic stable angina

MERLIN TIMI-36 was designed to evaluate the safety and efficacy of long-term treatment with ranolazine compared with placebo in NSTE-ACS

Morrow DA, et al. Am Heart J. 2006;151:1186.

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Follow-up visits: Day 14, Month 4, Q4 Months

Placebo (n = 3,281) Matched IV/PORanolazine (n = 3,279) IV → PO

Standard Therapy for ACS

Morrow DA, et al. Am Heart J. 2006;151:1186.

UA/NSTEMI (N = 6560)1) Rest symptoms within 48 h 2) High-risk features

MERLIN TIMI-36: Study Design

Holter monitoring at enrollment x 7d

Final Visit

Additional end points: Exercise performance, new/worsening heart failure, quality of life, extent of myocardial injury, clinically significant arrhythmia.

DurationEvent-driven

Mean Follow-up: Median, 348 Days

Primary end point: Composite of CV death, MI, or recurrent ischemiaSecondary end point: Composites of CV death, MI, severe recurrent

ischemia; and positive Holter at 30 days

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MERLIN: Efficacy Results

End pointPlacebo

(n = 3281)

Ranolazine(n = 3279)

Hazard Ratio

P value

CV death/recurrent ischemia (primary end point)

23.5 21.8 0.92 .11

CV death/MI 10.5 10.4 0.99 .87

Recurrent ischemia 16.1 13.9 0.87 .030

Morrow D, et al. Presented at: American College of Cardiology 2007 Scientific Sessions; March 27, 2007; New Orleans, Louisiana.

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MERLIN: Safety Results

End pointPlacebo

(n = 3273)Ranolazine(n = 3268)

Hazard ratio

P value

Death, any cause(number of patients)

175 172 0.99 .91

Sudden cardiac death (number of patients)

65 56 0.87 .43

Symptomatic documented arrhythmia

(number of patients)

102 99 0.97 .84

Clinically significant arrhythmia on Holter(% of patients)

83.1% 73.1% 0.89 <.001


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MERLIN: Conclusions

In NSTE-ACS, no difference between ranolazine and placebo in death or MI, but improvements in recurrent ischemia with ranolazine

Reduced need for anginal therapy intensification with ranolazine

No adverse trend in death or arrhythmia with ranolazine; suggestion of possible antiarrhythmic effect with ranolazine

Study supports use of ranolazine in stable disease

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Danish Registry

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Danish Registry: Background

Use of drug-eluting stents (DES) recently associated with increased risk of stent thrombosis

Based on Academic Research Consortium (ARC) definition, Maeng, et al reported on the incident of stent thrombosis in patients treated with DES (sirolimus- and paclitaxel-eluting) and bare-metal stents (BMS) in Western Denmark

Maeng M, et al. Presented at: American College of Cardiology 2007 Scientific Sessions; March 24, 2007; New Orleans, Louisiana.

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Academic Research Consortium: Proposed Definitions for Stent Thrombosis

*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.

Expanded Stent Thrombosis Definition

Timing

Acute Thrombosis*: 0 – 24 hrs. post

Subacute Thrombosis*: >24 hrs – 30 days post

Late Thrombosis: 30 days – 1 year post

Very Late Thrombosis: >1 year post

1. Definite/Confirmed2. Probable3. Possible

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The incidental angiographic documentation of stent occlusion in the absence of clinical syndromes is not considered a confirmed stent thrombosis (silent thrombosis).


1. Definite/Confirmed

Autopsy evidence or angiographic confirmed stent thrombosis (definite) is considered to have occurred if:1. TIMI flow is:

a) Grade 0 with occlusion originating in the stent or segment 5 mm proximal or distal to the stent region in the presence of thrombus

b) 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:2. New onset of ischemic symptoms at rest (typical chest pain with duration

>20 minutes)3. New ischemic ECG changes suggestive of acute ischemia4. Typical rise and fall in cardiac biomarkers (>2x ULN of CK)

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Probable stent thrombosis is considered to have occurred in the following cases:1. Any unexplained death within the first 30 days.2. 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.

Possible stent thrombosis is considered to have occurred with any unexplained death beyond 30 days.

3. Possible

2. Probable

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Danish Registry: Results

End pointBMS (%)

(n = 8847)DES (%) (n = 3268)

Adj. RR

P value

Target lesion revascularization

7.1 4.6 0.57 <.0001

Overall probable, possible, or definite stent thrombosis (ARC definition)

2.15 1.8 0.92 NS

Definite stent thrombosis, 12-15 months

0.009 0.09 10.9 .029

Overall death 6.2 4.4 0.90 .29

Overall MI 3.0 3.2 1.14 .31

MI, 12-15 months Data notPresented

Data notPresented 4.0 <.0001


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Danish Registry: Conclusions

After 15 months, the investigators noted no overall differences in rates of stent thrombosis or death and MI between DES and BMS

After clopidogrel was discontinued at 12 months, rates of stent thrombosis and MI were significantly higher in DES-treated patients

These findings are consistent with other recent studies


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REACH Update: An International Risk Prediction

Model for Recurrent CV EventsReduction of Atherothrombosis for Continued Health (International Risk Reduction Model

for Recurrent CV Events)

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REACH CV EventsPrediction Model: Background

The capability of CV risk factors to predict recurrent CV events in a “real world” setting not well characterized

REACH is an international, prospective cohort of 68,236 patients with either established atherosclerotic arterial disease (CAD, PAD, CVD) or at least 3 risk factors for atherothrombosis

REACH provides a global, well-defined, outpatient population with known CV disease

Wilson PW. Presented at: American College of Cardiology 2007 Scientific Sessions; March 27, 2007; New Orleans, Louisiana.

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REACH CV EventsPrediction Model: Methods

A prediction model was developed based on 18,802 men and 9,430 women with known CV disease (CAD, CVD, and/or PAD) at entry from North America/Western Europe– Full baseline and 10-year data were available

At 1 year, 709 CV events (CV death, MI, stroke) in men and 417 in women were reported

A single sex-adjusted model was developed since results were similar in separate sex models


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REACH: Multivariable-adjusted HR and P Value for Variables Considered

Variable (unit) HR per unit P value

Gender (male) 1.02 .7087

Age (year) 1.03 <.0001

Smoking (current vs other) 1.42 <.0001

Diabetes (yes/no) 1.60 <.0001

1, 2 or 3 vasc. beds (CAD, CVD, PAD) 1.00, 1.20, 1.44 .0013

CV event in past year (yes/no) 1.47 <.0001

Cardiac failure (yes/no) 1.78 <.0001

Statins (yes/no) .72 <.0001

Acetyl salicylic acid (yes/no) .87 .0352

Hypertension therapy (yes/no) 1.18 .2187


Number at risk: 27,632; Number of events: 1,126.

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REACH CV Events Prediction Model: Results/Conclusions

Statin therapy, number of vascular beds affected, diabetes, smoking, cardiac failure and history of CV event(s) <1 year were significantly associated with next CV event

This prediction model is the first to estimate risk for recurrent CV events in outpatients

Risk factors, burden of disease, and treatment are all related to increased risk for a subsequent CV event


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ACUITY: One Year ResultsAcute Catheterization and Urgent Intervention

Triage StrategY

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ACUITY: Patient Follow-up at 1 Year*

Heparin + GP IIb/IIIa4,603

Bivalirudin + GP IIb/IIIa4,604

Bivalirudin alone4,612

All patientsN = 13,819

25 Withdrawn62 Lost to Follow-up

Heparin + IIb/IIIa4,516 (98.1%)

1-year FU

Bivalirudin + IIb/IIIa4,502 (97.8%)

1-year FU

Bivalirudin alone4,521 (98.0%)

1-year FU



R

*End points adjudicated: Composite ischemia(death, MI, unplanned revasc) and stent thrombosis

Stone GW. Presented at: American College of Cardiology 2007 Scientific Sessions; March 26, 2007; New Orleans, Louisiana.

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0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

25

Isch

emic

Co

mp

osi

te (

%)

Days From Randomization

10

20UFH/Enoxaparin + IIb/IIIa

Bivalirudin + IIb/IIIaBivalirudin alone

EstimateP

(log rank)

30-day

7.4%.367.8%.347.9%

—

EstimateP

(log rank)

16.3%.3816.5%.3116.4%

1-year

—

P = .55

Bivalirudin alone vs Hep + GPIHR [95% CI] = 1.05 (0.95-1.17)

Bivalirudin + GPI vs Hep + GPIHR [95% CI] = 1.05 (0.94-1.16)

ACUITY: Ischemic Composite End Point(Death, MI, unplanned revascularization for ischemia)

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


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0 30 60 90 120 150 180 210 240 270 300 330 360 3900

3

4

5

Ste

nt

Th

rom

bo

sis

(%

)


2

1

ACUITY: Stent Thrombosis (Protocol Defn.)

Drug-eluting Stents (DES) vs Bare-Metal Stents (BMS)Drug-eluting Stents (DES) vs Bare-Metal Stents (BMS)

EstimateP

(log rank)

≥1 DES (N = 4630).38

2.2%

1-year

All BMS (N = 2528) 2.3%

All (N = 7158) 2.2%


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Mo

rtal

ity

(%)


0 30 60 90 120 150 180 210 240 270 300 330 360 3900

5

15

30

10

25

20

1-yearEstimate

Major Bleed only (without MI) (N = 551) 12.5%28.9%Both MI and Major Bleed (N = 94)

3.4%No MI or Major Bleed (N = 2,557)MI only (without Major Bleed) (N = 611) 8.6%

ACUITY: Impact of MI and Major Bleeding(non-CABG) in the First 30 Days on Risk of

Death Over 1 Year

28.9%

12.5%

8.6%

3.4%


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ACUITY: Conclusions• In patients with moderate and high risk ACS

undergoing an early invasive strategy with the use of GP IIb/IIIa inhibitors

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

• Compared to either UFH/enoxaparin with GP IIb/IIIa inhibitors or bivalirudin with GP IIb/IIIa inhibitors

• A bivalirudin alone strategy results in marked reduction of bleeding at 30 days, and similar rates of mortality and composite ischemia at 1 year

• The results of this study further establish the important relationship between iatrogenic bleeding complications and subsequent mortality in patients with ACS

Stone GW. Presented at: American College of Cardiology 2007 Scientific Sessions;March 26, 2007; New Orleans, Louisiana.

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Featured InstitutionAurora St. Luke’s Medical Center

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 RemarksChristopher P. Cannon, MD

Next ProgramChristopher P. Cannon, MD

Wednesday, May 16, 200712:00 Noon Eastern Time

(9:00 AM Pacific Time)

The AHA/ACC/SCAI/ACS/ADA Science Advisory on Prevention of Premature Discontinuation of Dual Antiplatelet

Therapy in Patients With Coronary Artery Stents

strive teleconf presentation apr11 2007

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