Clinical need for determination of vulnerable plaques Robert L Wilensky, MD Professor of Medicine Hospital of the University of Pennsylvania

Robert L. Wilensky, MD DISCLOSURES Grants/Contracted Research GlaxoSmithKline Ownership Interest (Stocks, Stock Options or Other Ownership Interest) Johnson & Johnson I intend to reference unlabeled/ unapproved uses of drugs or devices in my presentation. I intend to reference a darapladib which is in Phase III clinical trial evaluation.

Acute coronary syndromes: US prevalence and incidence 2006 7.9 million with history of Myocardial Infarction Incidence 1.37 million hospital discharges for ACS 810,000 for Myocardial Infarction 537,000 for Unstable Angina 18,000 Myocardial Infarction and Unstable Angina 610,000 new MIs and 325,000 recurrent MIs 29%–32% STEMI Lloyd-Jones D, et al. Circulation. 2009;119(3):e21-181

Mortality rate after a first MI 1-year (%) 5-year (%) 40–69 years of age White men 8 15 White women 12 22 Black men 14 27 Black women 11 32 ≥70 years of age 50 56 26 28 62 Lloyd-Jones D, et al. Circulation. 2009;119(3):e21-181

Rate of recurrent MI or fatal CHD 5-year (%) 40–69 years of age White men 14 White women 18 Black men 27 Black women 29 ≥70 years of age 24 30 32 Lloyd-Jones D, et al. Circulation. 2009;119(3):e21-181

Mortality: Fast Stats 1990–1999 in-hospital acute MI mortality declined from 11.2% to 9.4% Annual mortality rate 16% for MI Sudden death rate 4–6 times higher in persons with history of MI than general population Ischemic heart disease is a leading cause of chronic congestive heart failure Lloyd-Jones D, et al. Circulation. 2009;119(3):e21-181

Leading Causes of Death in the United States – 2005 http://www.cdc.gov/nchs/FASTATS/lcod.htm (accessed May 19, 2009) Lloyd-Jones D, et al. Circulation. 2009;119(3):e21-181

Younger age in women is associated with increased risk of adverse outcome in acute coronary syndromes One-year death, MI and revascularization rates Circulation 2004;110:III-1936.

Clinical studies summary: Angiography in infarct-related artery Content Points: In a review of coronary plaque disruption, Falk et al31 collated data from studies by Ambrose et al,33 Little et al,34 Nobuyoshi et al,35 and Giroud et al.36 The slide summarizes the number of patients with MI caused by rupture of plaques causing either > 70%, 50%-70%, or < 50% stenosis. In 68% of cases, the coronary event was caused by plaques causing < 50% stenosis.

Unstable angina resulting in sudden death

Unstable angina is associated with widespread neutrophil activation. N Engl J Med 2002;347:5

VBWG

VBWG

PROVE-IT: Estimates of the HR for 2° secondary end points and the individual components of the 1° end point Figure 4. Estimates of the Hazard Ratio for the Secondary End Points and the Individual Components of the Primary End Point in the High-Dose Atorvastatin Group, as Compared with the Standard-Dose Pravastatin Group. CI denotes confidence interval, CHD coronary heart disease, and MI myocardial infarction. Revascularization was performed at least 30 days after randomization. Cannon C et al. N Engl J Med 2004;350:1495

REACH: 1-yr CV event rates as a function of number of symptomatic disease locations Steg, P.G. et al. JAMA 2007;297:1197

COURAGE trial PCI+OMT OMT Death 7.6% 8.3% MI 13.2% 12.3% ACS 12.4% 11.8% Total: 19.0% 18.5% 4.6 year follow-up Figure 2. Kaplan-Meier Survival Curves. In Panel A, the estimated 4.6-year rate of the composite primary outcome of death from any cause and nonfatal myocardial infarction was 19.0% in the PCI group and 18.5% in the medical-therapy group. In Panel B, the estimated 4.6-year rate of death from any cause was 7.6% in the PCI group and 8.3% in the medical-therapy group. In Panel C, the estimated 4.6-year rate of hospitalization for acute coronary syndrome (ACS) was 12.4% in the PCI group and 11.8% in the medical-therapy group. In Panel D, the estimated 4.6-year rate of acute myocardial infarction was 13.2% in the PCI group and 12.3% in the medical-therapy group. Boden W et al. N Engl J Med 2007;356:1503

Braunwald, E. J Am Coll Cardiol 2006;47:C101 Proposed algorithm for the detection of plaques likely to result in acute coronary syndromes or death Braunwald, E. J Am Coll Cardiol 2006;47:C101

Potential for new medications to reduce atherosclerosis risk Numerous large pharmaceutical companies are no longer pursuing agents to reduce atherosclerosis risk. clinical trials.gov- Atherosclerosis studies: 739 Number of novel medications being studied: 12 Number of on-going studies 14

Summary A significant number of patients with coronary artery disease will suffer recurrent events despite optimal medical therapy. No current diagnostic approach can locate the lesion with increased likelihood of rupture. Evaluation of high-risk lesions in high risk patients will require a combination of non-invasive and focused invasive imaging.