CVD Critical Pathways Group 2006 Teleconferences This activity is supported by an educational grant from the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. December 6, 2006

Faculty Gregg C. Fonarow, M D Eliot Corday Professor of Medicine and Cardiovascular Science Director, Ahmanson-UCLA Cardiomyopathy Center UCLA Division of Cardiology UCLA Medical Center Los Angeles, California

Gregg C. Fonarow, M D

Eliot Corday Professor of Medicine

and Cardiovascular Science

Director, Ahmanson-UCLA Cardiomyopathy Center

UCLA Division of Cardiology

UCLA Medical Center

Los Angeles, California

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.

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.

Faculty Disclosure Statement 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. Deborah B. Diercks, MD , of the University of California, Davis Medical Center, has served as a consultant to sanofi-aventis, has received honoraria from Bristol-Myers Squibb Company, sanofi-aventis, and Scios Inc., and has received research support from Biosite Inc.

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.

Deborah B. Diercks, MD , of the University of California, Davis Medical Center, has served as a consultant to sanofi-aventis, has received honoraria from Bristol-Myers Squibb Company, sanofi-aventis, and Scios Inc., and has received research support from Biosite Inc.

Highlights From the 2006 American Heart Association Scientific Sessions Gregg C. Fonarow, MD

Polling Question #1 < 90 minutes 91-120 minutes >120 minutes What is the average door-to-balloon time at your institution?

< 90 minutes

91-120 minutes

>120 minutes

Highlights From the AHA 2006 Scientific Sessions New Registries and Initiatives NCDR-ACTION Registry: Combines the CRUSADE and NRMI registries Door to Balloon (D2B) Initiative: Joint program of AHA, ACC, and other health organizations to reduce door-to-balloon time Time to Treatment—Recent Trials Hospital Delays in Trials of Primary PCI and In-Hospital Fibrinolysis in AMI Reperfusion for ST-Elevation Myocardial Infarction Long-term Outcome of Primary Percutaneous Coronary Interventions vs Prehospital and In-Hospital Thrombolysis for Patients With ST-Elevation Myocardial Infarction RIKS-HIA Registry: Register of Information and Knowledge about Swedish Heart Intensive Care Admissions Pooled Analysis of Randomized Trials of Primary PCI and In-Hospital Fibrinolysis in AMI Other Recent Trials OAT: Occluded Artery Trial CHICAGO Study: Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone APEX MI: Assessment of Pexelizumab in Acute Myocardial Infarction

New Registries and Initiatives

NCDR-ACTION Registry: Combines the CRUSADE and NRMI registries

Door to Balloon (D2B) Initiative: Joint program of AHA, ACC, and other health organizations to reduce door-to-balloon time

Time to Treatment—Recent Trials

Hospital Delays in Trials of Primary PCI and In-Hospital Fibrinolysis in AMI Reperfusion for ST-Elevation Myocardial Infarction

Long-term Outcome of Primary Percutaneous Coronary Interventions vs Prehospital and In-Hospital Thrombolysis for Patients With ST-Elevation Myocardial Infarction

RIKS-HIA Registry: Register of Information and Knowledge about Swedish Heart Intensive Care Admissions

Pooled Analysis of Randomized Trials of Primary PCI and In-Hospital Fibrinolysis in AMI

Other Recent Trials

OAT: Occluded Artery Trial

CHICAGO Study: Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone

APEX MI: Assessment of Pexelizumab in Acute Myocardial Infarction

New Initiatives: NCDR-ACTION Registry; D2B Campaign NCDR-ACTION Registry 1 CRUSADE and NRMI registries to merge to form the National Cardiovascular Data Registry–Acute Coronary Treatment and Intervention Outcomes Network (NCDR-ACTION Registry) Will be largest and most comprehensive national cardiovascular patient database ever developed D2B Program 2 Door to Balloon (D2B) Campaign—joint program of AHA, ACC, and other health organizations Aims to increase percentage of AMI patients who receive primary angioplasty within 90 minutes of hospital presentation to 75%; current figures indicate only 35% do D2B implementation kit contains 6 evidence-based strategies for reducing D2B times 1. ACC News Release. Available at http://www.acc.org/media/releases/highlights/2006/nov06/NCDR_Action.htm. Accessed November 16, 2006. 2. Heartwire. Available at: http://www.theheart.org/article/753305.do. Accessed November 16, 2006.

NCDR-ACTION Registry 1

CRUSADE and NRMI registries to merge to form the National Cardiovascular Data Registry–Acute Coronary Treatment and Intervention Outcomes Network (NCDR-ACTION Registry)

Will be largest and most comprehensive national cardiovascular patient database ever developed

D2B Program 2

Door to Balloon (D2B) Campaign—joint program of AHA, ACC, and other health organizations

Aims to increase percentage of AMI patients who receive primary angioplasty within 90 minutes of hospital presentation to 75%; current figures indicate only 35% do

D2B implementation kit contains 6 evidence-based strategies for reducing D2B times

D2B: Strategies Associated With a Significant Reduction in Door-to-Balloon Time * P <.05 for all. Bradley EH, et al. N Engl J Med. 2006. November 13. [Epub ahead of print]. 8.6 Having staff in ED and cath lab use and receive real-time feedback 14.6 Having an attending cardiologist always on site 19.3 Expecting staff to arrive at cath lab within 20 minutes after page 15.4 Having the ED activate the cath lab while patient still en route 13.8 Having a single call to a central page operator activate cath lab 8.2 Having emergency medicine physicians activate the cath lab Mean reduction in door-to-balloon time (min)* Strategy

NRMI 2,3,4 452,544 Reperfusion Eligible STEMI Patients 1963 Hospitals Transfer Out Patients n=119,235 Missing Time Intervals n=13,137 Did Not Receive PCI or Fibrinolytic Therapy as Initial Reperfusion n=89,524 Study Population 192,509 Patients 645 Hospitals 230,648 Patients 1860 Hospitals ≥ 20 STEMI Patients Treated Treatment of ≥10 Patients With Primary PCI and ≥10 Patients With Fibrinolytic Therapy © CM Gibson 2006. Pinto DS, et al. Circulation . 2006;114:2019-2025. Adapted with permission from clinicaltrialresults.org. Implications of Hospital Delays for Selection of Reperfusion Strategy in STEMI

Mortality Increases With Increasing PCI-Related Delay © CM Gibson 2006. Pinto DS, et al. Circulation . 2006;114:2019-2025. Adapted with permission from clinicaltrialresults.org. PCI-Related Delay (door-to-balloon–door-to-needle time) (min) In-Hospital Mortality (%) For every 30-minute delay, mortality increases 10% 12 10 8 6 4 2 0 0 20 40 60 80 100 120 140 160 180 200

Advantage of PCI Compared With Fibrinolyisis Decreases as PCI-Related Delay Increases © CM Gibson 2006. Pinto DS, et al. Circulation . 2006;114:2019-2025. Adapted with permission from clinicaltrialresults.org. Odds of Death With Fibrinolysis PCI-Related Delay (door-to-balloon–door-to-needle time) (min) PCI Better Fibrinolysis Better 12 1.5 1.25 1.0 0.8 0.5 60 75 90 105 114 135 150 165 180

Time at Which PCI Loses Superiority in Survival Over Fibrinolysis Varies by Patient Risk © CM Gibson 2006. Pinto DS, et al. Circulation . 2006;114:2019-2025. Adapted with permission from clinicaltrialresults.org. 183 min Met goal without transfer: 100.0% Met goal with transfer: 100.0% (n=10,614 pts; n=191 hospitals) 142 min Met goal without transfer: 98.1% Met goal with transfer: 97.1% (n=3,739 pts; n=91 hospitals) 103 min Met goal without transfer: 89.1% Met goal with transfer: 82.2% (n=16,119 pts; n=244 hospitals) 50 min Met goal without transfer: 7.9% Met goal with transfer: 11.9% (n=5,296 pts; n=117 hospitals) 121+ 154 min Met goal without transfer: 99.8% Met goal with transfer: 100.0% ( n=20,424 pts; n=271 hospitals) 109 min Met goal without transfer: 94.1% Met goal with transfer: 92.8% (n=9,812 pts; n=180 hospitals) 56 min Met goal without transfer: 20.2% Met goal with transfer: 17.3% (n=19,517 pts; n=269 hospitals) 39 min Met goal without transfer: 2.6% Met goal with transfer: 3.6% (n=19,517 pts; n=269 hospitals) 0-120 Age ≥65 years and Non-anterior Infarction Age ≥65 years and Anterior Infarction Age <65 years and Non-anterior Infarction Age <65 years and Anterior Infarction Pre-hospital Delay (Min)

RIKS-HIA Registry: Long-Term Outcome of Primary PCI vs Prehospital and In-Hospital Thrombolysis for STEMI Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA): prospective, observational cohort study of 26,205 consecutive STEMI patients who received reperfusion therapy within 15 hours of onset Patients treated between 1999 and 2004 7084 patients underwent primary PCI; 3078 received prehospital thrombolysis; 16,043 received in-hospital thrombolysis Stenestrad U, et al. JAMA. 2006;296:1749-1756.

Register of Information and Knowledge about Swedish Heart Intensive Care Admissions (RIKS-HIA): prospective, observational cohort study of 26,205 consecutive STEMI patients who received reperfusion therapy within 15 hours of onset

Patients treated between 1999 and 2004

7084 patients underwent primary PCI; 3078 received prehospital thrombolysis; 16,043 received in-hospital thrombolysis

RIKS-HIA Registry: Comparisons of Thrombolysis and Primary PCI Stenestrad U, et al. JAMA. 2006;296:1749-1756. 2.0 0.79 (0.70–0.88) 3.4 0.88 (0.68–1.14) 4.0 1.00 In-hospital reinfarction (%) Adjusted HR (95% CI) 4 0.68 (0.65–0.70) 5 0.83 (0.80–0.87) 6 1.00 Hospital stay for index event (days) Adjusted HR (95% CI) 4.8 0.61 (0.53–0.71) 9.0 1.02 (0.90–1.17) 9.6 1.00 Readmission for MI in 1st year (%) Adjusted HR (95% CI) 7.6 0.66 (0.60–0.76) 10.3 0.84 (0.74–0.95) 15.9 1.00 Mortality at 1 year (%) Adjusted HR (95% CI) 4.9 0.61 (0.53–0.71) 7.6 0.87 (0.76–1.01) 11.4 1.00 Mortality at 30 days (%) Adjusted HR (95% CI) 3.5 0.61 (0.51–0.73) 5.9 0.90 (0.76–1.06) 8.8 1.00 Mortality at 7 days (%) Adjusted HR (95% CI) Primary PCI, n=7084 Prehospital thrombolysis, n=3078 In-hospital thrombolysis, n=16,043 End point

RIKS-HIA Registry: Time to Reperfusion: 30-Day and 1-Year Mortality Stenestrad U, et al. JAMA. 2006;296:1749-1756. 4.5 8.9 11.4 Time to reperfusion >2 h 1-year mortality (%) 6.7 8.0 11.9 Time to reperfusion <2 h 7.3 11.8 16.3 Time to reperfusion >2 h 3.8 5.6 8.6 Time to reperfusion <2 h 30-day mortality (%) Primary PCI Prehospital thrombolysis In-hospital thrombolysis End point

Estimated Cumulative Mortality for Patients Receiving Reperfusion Treatment Within ≤2 or >2 Hours of Symptom Onset 8892 7675 7519 7417 1155 1020 1004 997 3592 3375 3344 3318 No. at Risk Thrombolysis Prehospital 3993 3571 3530 3490 Posthospital 1155 1077 1066 1060 Primary PCI 979 936 928 916 Mortality curves calculated using Cox regression analysis including propensity score for primary PCI. Reprinted with permission from Stenestrad U, et al. JAMA. 2006;296:1749-1756. 20 15 10 5 0 100 200 300 400 Cumulative Mortality, % Days Reperfusion >2 h In-Hospital Thrombolysis Prehospital Thrombolysis Primary Percutaneous Coronary Intervention (PCI) 20 15 10 5 0 100 200 300 400 Cumulative Mortality, % Days Reperfusion ≤2 h

Pooled Analysis of Randomized Trials of Primary PCI and In-Hospital Fibrinolysis in AMI Pooled analysis of 22 randomized trials (N=6763) published between 1990 and 2002 that tested the efficacy of primary PCI vs fibrinolysis Examined the extent to which time to treatment affects the clinical benefit of primary PCI vs in-hospital fibrinolysis Primary end point: All-cause mortality at 30 days Boersma E, et al. Eur Heart J. 2006;27:779-788.

Pooled analysis of 22 randomized trials (N=6763) published between 1990 and 2002 that tested the efficacy of primary PCI vs fibrinolysis

Examined the extent to which time to treatment affects the clinical benefit of primary PCI vs in-hospital fibrinolysis

Primary end point: All-cause mortality at 30 days

Pooled Analysis: Primary PCI vs In-Hospital Fibrinolysis Reproduced with permission from Boersma E, et al. Eur Heart J. 2006;27:779-788. 30-day death in patients randomized to primary PCI compared with fibrinolysis according to presentation delay (left panel) and PCI-related delay (right panel) Primary PCI was associated with significantly lower 30-day mortality relative to fibrinolysis, regardless of treatment delay Presentation Number of 30-day delay (h) patients death (%) FL PPCI 0-1 747 6.0 4.7 >1-2 2000 6.2 4.2 >2-3 1712 7.3 5.1 >3-6 1640 9.5 5.6 >6-12 664 12.7 8.5 All patients 6763 7.9 5.3 PCI-related Number of 30-day delay (min) patients death (%) FL PPCI 0-35 1417 8.2 2.8 >35-50 1292 6.8 5.4 >50-62 1425 5.4 4.8 >62-79 1280 9.5 6.9 >79-120 1349 9.6 6.6 All patients 6763 7.9 5.3 0.63 (0.42, 0.84) OR and 95% Cl 0.0 0.5 1.0 1.5 PPCI better FL better 0.0 0.5 1.0 1.5 PPCI better FL better OR and 95% Cl

Primary End Points: Death, MI, or NYHA class IV Heart Failure PCI With Stenting n=1082 Medical Therapy n=1084 2166 patients with angiography on day 3-28 post-MI with evidence of total occlusion of the infarct-related artery with poor or absent antegrade flow (TIMI flow grade 0 or 1); and met a criterion for increased risk, defined as ejection fraction <50%, proximal occlusion of a major epicardial vessel with a large risk region, or both Exclusions: NYHA class III or IV heart failure, shock, serum creatinine concentration >2.5 mg/dL, angiographically significant left main or 3-vessel coronary artery disease, angina at rest, or severe ischemia on stress testing. Randomized. 22% women, mean age 59 years, mean follow-up 3 years, mean EF 48% at baseline Concomitant medications: Aspirin, anticoagulation if indicated, ACE inhibitors, beta blockers, and lipid-lowering therapy, unless contraindicated Occluded Artery Trial (OAT): PCI vs Medical Therapy for Persistent Occlusion After MI Hochman JS, et al. N Engl J Med. 2006. November 14. [Epub ahead of print]. Adapted with permission from clinicaltrialresults.org.

Primary End Points: Death, MI, or NYHA class IV Heart Failure

OAT: Baseline Characteristics of the Study Population * P =.02. Hochman JS, et al. N Engl J Med. 2006. November 14. [Epub ahead of print]. 252/1084 (23) 117/1084 (11) 32/1084 (3) 39/1082 (4) 24/1082 (2) 53/1084 (5) 4/1084 (0.4) 246/1084 (23)* 236/1081 (22) 127/1082 (12) 46/1081 (4) 42/1081 (4) 26/1081 (2) 51/1081 (5) 5/1082 (0.5) 200/1082 (18) History, no/total no (%) Angina MI Cerebrovascular disease Peripheral-vessel disease Heart failure PCI CABG Diabetes 845 (78) 239 (22) 845 (78) 237 (22) Sex, no. (%) Men Women 58.7 ±11.1 58.6 ± 10.8 Age, y Medical Therapy Group (n=1084) PCI Group (n=1082) Characteristic

OAT: Baseline Characteristics of the Study Population *Investigators at the study site reported the ejection fraction if a left ventriculogram was not obtained. Hochman JS, et al. N Engl J Med. 2006. November 14. [Epub ahead of print]. 48.0 ±11.0 554/1075 (52) 206/1075 (19) 47.4 ±11.3 597/1075 (56) 236/1075 (22) Ejection Fraction* Mean <50%, no/total no(%) <40%, no/total no (%) 191/1075 (18) 192/1074 (18) Multivessel disease, no/ total no (%) 932/1084 (86) 939/1082 (87) ST-segment elevation or Q-wave or R-wave loss 681/1039 (66) 700/1037 (68) ST-segment elevation 427/1084 (39) 423/1082 (39) Current cigarette smoker, no/total no (%) Medical Therapy Group (n=1084) PCI Group (n=1082) Characteristic

OAT: Estimated 4-Year Cumulative Event Rates Hochman JS, et al. N Engl J Med. 2006. November 14. [Epub ahead of print]. .83 0.77–1.40 1.03 9.4 9.1 Death .92 0.64–1.49 0.98 4.5 4.4 NYHA class 4 HF .08 0.96–2.16 1.44 5.0 6.9 Nonfatal MI .13 0.92–2.00 1.36 5.3 7.0 All MI .20 0.92–1.45 1.16 15.6 17.2 Death, MI, HF P 95% CI HR Medical (%) PCI (%) Outcome

CHICAGO: Effect of Pioglitazone vs Glimepiride on CIMT in Type 2 Diabetes CIMT has been shown to highly correlate with risk of future CV events CHICAGO: Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone Randomized, double-blind, comparator-controlled trial in 462 adults with type 2 diabetes; CIMT images captured by ultrasound 72-week treatment period (1-week follow-up) 232 patients received pioglitazone 15-45 mg/d 230 received glimepiride 1-4 mg/d Main outcome measure: absolute change from baseline to final visit in mean posterior-wall CIMT CIMT = carotid artery intima-media thickness. Mazzone T, et al . JAMA . 2006. November 13. [Epub ahead of print].

CIMT has been shown to highly correlate with risk of future CV events

CHICAGO: Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone

Randomized, double-blind, comparator-controlled trial in 462 adults with type 2 diabetes; CIMT images captured by ultrasound

72-week treatment period (1-week follow-up)

232 patients received pioglitazone 15-45 mg/d

230 received glimepiride 1-4 mg/d

Main outcome measure: absolute change from baseline to final visit in mean posterior-wall CIMT

CHICAGO: Progression of Mean and Maximum CIMT at Week 72 Mazzone T, et al . JAMA . 2006. November 13. [Epub ahead of print]. – 0.013 (–0.024 to 0.002) Difference (95% CI) .02 +0.012 – 0.001 Primary end point, mm P Glimepiride Pioglitazone Mean CIMT: End Point – 0.024 (–0.042 to 0.006) Difference (95% CI) .008 +0.026 +0.002 Progression of maximum CIMT, mm P Glimepiride Pioglitazone Maximum CIMT: End Point

APEX-AMI: Outcomes at 30 Days (Revised End Points and Time Frame) Armstrong PW. Presented at: American Heart Association 2006 Scientific Sessions; November 14, 2006. *Primary end point, revised from 90-day all-cause mortality in original protocol. No significant differences. 9.19 8.99 Death, shock, or HF 3.92 4.06 All-cause mortality* Placebo, n=2885 (%) Pexelizumab, n=2860 (%) End point

*Original primary end point, later revised to 30-day all-cause mortality. No significant differences. Armstrong PW. Presented at: American Heart Association 2006 Scientific Sessions; November 14, 2006. APEX-AMI: Outcomes at 90 Days 1.36 1.18 Stroke 3.04 2.39 Reinfarction 3.36 3.47 Cardiogenic shock 4.76 4.82 Incident heart failure 4.93 4.51 All-cause mortality* Placebo, n=2885 (%) Pexelizumab, n=2860 (%) End point

Featured Institution University of California, Davis Medical Center Sacramento, California

Polling Question #2 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 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

Progress Checklist: Immediate Goals Circulate discharge plan and other tools to all cardiology, ED, and CV nursing staff for comments  Circulate pathways to all cardiology, ED, and CV nursing staff for comments  Develop draft pathways  Assemble team and set up meeting of working group 

Progress Checklist: Short-term Goals/Activities Grand rounds/conference: Cardiology/IM  Grand rounds/conference: Emergency Dept.  Grand rounds/conference: Nursing  Circulate memo  Launch critical pathways  Finalize critical pathways 

Progress Checklist: Long-term Goals/Activities  NRMI  AHA Get With the Guidelines  ACC National Cardiovascular Data Registry  CRUSADE  GRACE  REACH  Other Monitor data: Which registry? 

Question-and-Answer Session

Concluding Remarks Gregg C. Fonarow, MD Next Program Christopher P. Cannon, MD Wednesday, January 17, 2007 12:00 Noon Eastern Time (9:00 AM Pacific Time)