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1 Welcome to this program sponsored by AstraZeneca The educator, who is presenting on behalf of AstraZeneca, is here to provide educational information pertinent to understanding the risk of a recurrent cardiovascular event in patients with prior myocardial infarction This event does not qualify for continuing medical education (CME), continuing nursing education (CNE), or continuing education (CE) credit AstraZeneca. All rights reserved Last Updated 7/15

2 Understanding the Ongoing Risk of Atherothrombosis Beyond the Culprit Lesion 2

3 Objectives Review the pathophysiology and burden of acute coronary syndrome (ACS) Examine the current evidence for persistent risk for recurrent cardiovascular (CV) events in patients with prior myocardial infarction (MI) Identify and assess risk factors that influence the recurrence of CV events Discuss American Heart Association (AHA) goals for improving CV health 3

4 AHA Heart Disease and Stroke Statistics CHD=coronary heart disease. *Represents prevalence in 212 in patients 2 years of age. Percentages are rates based on age and gender. 45 years of age. 4 Mozaffarian D et al. Circulation. 215;131:e29-e322.

5 Life Expectancy at 6 Years of Age (Years) Reduced Life Expectancy in Patients With Prior MI 3 Framingham Heart Study Cohort years years 15 Healthy* Acute MI 5 Men Women Longitudinal study of subjects 28 to 62 years of age at study onset who were disease free (without CVD) at study entry (n=57) from 1948 to 1991 CVD=cardiovascular disease. *Without a history of CVD. 5 Peeters A et al. Eur Heart J. 22;23:

6 ACS Is the Tip of the Atherothrombotic Iceberg 1,2 Acute Plaque Rupture ACS (UA/NSTEMI/STEMI) CLINICAL SUBCLINICAL Presence of Multiple Coronary Plaques Vascular Inflammation Prothrombotic State UA=unstable angina; NSTEMI=non ST-segment elevation myocardial infarction; STEMI=ST-segment elevation myocardial infarction Goldstein JA. J Am Coll Cardiol. 22;39: Libby P. N Engl J Med. 213;368:

7 Atherosclerosis Is a Chronic and Progressive Disease Healthy Vessel Early Lesion Advanced Lesion Ruptured Lesion INTIMA ENDOTHELIUM MEDIA THROMBUS LUMEN EXTERNA Inflammation plays a major role in all stages of atherogenesis Glagov Hypothesis 7 Libby P et al. J Am Coll Cardiol. 26;48:A33-A46.

8 MI Patients (%) Many MIs Occurred in Lesions That Were <5% Stenosed <5 5-7 >7 Stenosis Prior to MI (%) 12 Falk E et al. Circulation. 1995;92:

9 Cumulative Incidence of MACE (KM%) Recurrent MACE Events Often Originate From Documented Non-culprit Lesions (NCL) 25 The PROSPECT Study* 2 All events 2.4% 15 1 Culprit lesion related events Non-culprit lesion related events 12.9% 11.6% 5 Indeterminate events 2.7% Time From PCI (years) Prospective evaluation of 697 US and European patients with ACS who underwent coronary artery imaging using grayscale and radiofrequency IVUS in addition to angiography after successful and uncomplicated PCI. The median follow-up was 3.4 years 13 KM=Kaplan Meier; MACE=major adverse cardiovascular events (CV death, cardiac arrest, MI, or rehospitalization due to unstable or progressive angina); PCI=percutaneous coronary intervention; PROSPECT=Providing Regional Observations to Study Predictors of Events in the Coronary Tree; IVUS=intravascular ultrasound; CL=culprit lesion. *Some patients had both CL-related and NCL-related events, and some patients had multiple CL-related events, multiple NCL-related events, or both at different times (in which case the first event is represented in the time-to-event curve). Adapted from Stone GW et al. N Engl J Med. 211;364: ; with permission from the Massachusetts Medical Society.

10 Non-culprit Lesions Can Lead to Coronary Events Initial Angiography and IVUS of Non-culprit Lesions Angiography Before and After Emergent Angioplasty Total occlusion Post-balloon angioplasty B Angiography showed luminal irregularities and IVUS showed multiple lesions at different stages of progression Angiography revealed a culprit lesion at the same site where preexisting atherosclerotic disease was noted on IVUS 14 Reprinted from Yamagishi M et al. J Am Coll Cardiol. 2;35:16 111; with permission from Elsevier.

11 Patients With Prior MI (%) Prevalence of Prior MIs in Patients Presenting With an MI NCDR ACTION Registry-GWTG NSTEMI STEMI Over the entire study period, 29% of NSTEMI and 19% of STEMI patients had a prior MI Time (Quarters) Observational study of 319,152 patients with a final diagnosis of STEMI (n=124,535) or NSTEMI (n=194,617) from 446 US hospitals ACTION Registry-GWTG=Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With The Guidelines; NCDR=National Cardiovascular Data Registry. 15 Reprinted from Shen L et al. Am Heart J. 214;167:84 845; with permission from Elsevier.

12 Cumulative 4-Year Incidence of CV Death, MI, or Stroke (KM%) Patients With a History of Prior Ischemic Events Had a High Risk of CV Events at 4 Years % Risk Factors Only (n=873) REACH Registry 12.2% Stable Atherosclerosis Without Ischemic Event at Baseline (n=15,264) 18.3% Prior Ischemic Event* at Baseline (n=21,89) International, prospective, observational study of 45,227 patients 45 years of age at risk for or with atherothrombosis. The cohort was enrolled from 29 countries and followed annually for 4 years from 23 to 28 *Prior ischemic event is defined as an MI or stroke. REACH=Reduction of Atherothrombosis for Continued Health. 16 Bhatt DL et al. JAMA. 21;34:

13 Cumulative 3-Year Risk of Death, MI, or Stroke* (%) Patients Free of MI for 1 Year Continued to Be at Risk for CV Events Over the Next 3 Years 3 APOLLO Study Sweden (n=77,976) England (n=7238) France (n=1757) US (n=53,99) Retrospective 4-country analysis of patients who survived without a further MI for 1 year following hospitalization for MI in 22 to 211. Results are based on data from national linked electronic health records and disease registries as well as administrative data *Adjusted for differences in study populations. 17 Rapsomaniki E et al. Presented at: European Society of Cardiology Meeting; August 3-September 3, 214; Barcelona, Spain.

14 Risk of HF in Patients With Recurrent MI (HR) Risk of HF in Patients With Recurrent MI (HR) Recurrent MI Increased Risk of Heart Failure 6 CARE Study 1 6 Framingham Heart Study Overall First MI before 7 years of age Original Offspring Original Offspring Retrospective analysis of 3,86 stable, post-mi patients without a history of HF enrolled between 1989 and patients developed recurrent MI Retrospective analysis of data on the occurrence of MI and HF from a longitudinal study initiated in 1948 consisting of an original cohort (n=579) and their adult children and spouses (offspring cohort, n=513). Overall, 22 subjects in the original cohort and 92 subjects in the offspring cohort developed a recurrent MI 2,3 18 CARE=The Cholesterol and Recurrent Events trial; HF=heart failure; HR=hazard ratio. 1. Lewis EF et al. J Am Coll Cardiol. 23;42: Hopenfeld B et al. Catheter Cardiovasc Interventions. 213;81(suppl S1):A-7.Abs S Framingham Heart Study website. Accessed April 15, 215.

15 Risk of Combined Death or New Heart Failure* (HR) Residual Risk of Death or New HF Remained High at 1 Year After Recurrent MI VALIANT Study HR on day of recurrent MI: 23. ( ) HR 1 month after recurrent MI: 4.7 ( ) HR 1 year after recurrent MI: 2.3 ( ) Months Since Recurrent MI Retrospective analysis of a cohort of 1,599 patients with left ventricular dysfunction, HF, or both following a first MI enrolled between 1998 and patients had a recurrent MI *Adjusted for different patient characteristics. VALIANT=Valsartan in Acute Myocardial Infarction Trial. 19 Adapted from Thune JJ et al. Eur J Heart Fail. 211;13: ; with permission from the John Wiley & Sons, Inc.

16 Recurrent MI Was Associated With Increased Risk of Stroke Risk of Stroke After Recurrent MI vs No Recurrent MI Adjusted* HR (95% CI) P-value Stroke 3.68 ( ) <.1 Ischemic 3.49 ( ) <.1 Hemorrhagic NA NA Reduced risk Increased risk Single-center, observational study of 17 STEMI patients from Amsterdam who received primary PCI with stenting between 23 and 28. During follow-up of ~5 years, 24 patients had a recurrent MI 2 *Adjusted HRs were calculated using Cox regression analyses including the occurrence of recurrent MI as a time-dependent covariate adjusting for predictors of the clinical outcomes. Predictors of clinical outcomes were determined by performing stepwise backward selection Cox regression analyses. Two hemorrhagic strokes were reported in the recurrent MI group and 2 in the no recurrent MI group. NA=not available due to low number of events. Kikkert WJ et al. Am J Cardiol. 214;113:

17 Cumulative Incidence of All-Cause Mortality (KM%) 5-Year All-Cause Mortality Was Doubled in Patients With Recurrent MI 2 OACIS Registry Reinfarction (n=353) 15.9% 15 1 HR 2.26; 95% CI 1.56, 3.122; P<.1 6.3% 5 No reinfarction (n=7517) Time After Discharge (years) Prospective, observational, multicenter study of 787 Japanese patients with acute MI enrolled between 1998 and 28. During the 5-year follow-up period (median 3.9 years), 353 patients experienced a recurrent MI OACIS=Osaka Acute Coronary Insufficiency Study. 21 Adapted from Nakatani D et al. Circ J. 213;77: ; with permission from the Japanese Circulatory Society.

18 Factors Associated With the Risk of Recurrent CV Events After an Acute MI Severity of Disease 1 Multivessel disease Calcification of the culprit vessel Comorbidities 1,2,4 Dyslipidemia Hypertension Diabetes mellitus Chronic kidney disease PAD RISK FACTORS CV History 1-3 Previous MI Previous CABG Previous stroke or TIA Patient Characteristics 2,4-6 Obesity Older age Smoking 22 CABG=coronary artery bypass graft; PAD=peripheral artery disease; TIA=transient ischemic attack. 1. Kikkert WJ et al. Am J Cardiol. 214;113: Nakatani D et al. Circ J. 213;77: Ulvenstam A et al. Stroke. 214;45: Thune JJ et al. Eur J Heart Fail. 211;13: Leander K et al. Cardiovasc Prev Rehabil. 27;14: Rea T et al. Ann Intern Med. 22;137:494-5.

19 Patients With a Prior MI (%) History of MI Is a Predictor of Recurrent MI The OACIS Registry Observational, Single-Center Study HR (95% CI) ( ) 1.47 ( ) P-value % 15% 19.8% 17.9% 1% 12.% 9.5% 5% % No Recurrent MI (n=7517) Recurrent MI (n=353) No Recurrent MI (n=146) Recurrent MI (n=24) Nakatani 1 Follow-up ~5 years Kikkert 2 Follow-up ~5 Years Nakatani D et al. Circ J. 213;77: Kikkert WJ et al. Am J Cardiol. 214;113:

20 Non-fatal Reinfarction Rate (%) Re-infarction Rate (%) Risk of Recurrent MI in Patients With Multivessel Disease (MVD) SVD MVD 8 P=.3 8 P=NR 6 5.9% 6 6.1% P= % % 2 1.3%.6% 3 days 1 year 5 Years Retrospective analysis of 82 patients with SVD (n=314) or MVD (n=56) treated with primary angioplasty for acute MI between 1998 and 22 1 Prospective study of 288 STEMI patients with SVD (n=154) or MVD (n=134) treated with bare metal stent for primary PCI between 25 and 27 2 NR=not reported; SVD=single vessel disease Corpus RA et al. Am Heart J. 24;148: Tarantini G et al. Coron Artery Dis. 21;2:78-86.

21 Risk of CV Events in Patients With a History of Prior Ischemic Events and Diabetes REACH Registry 1,2 4-Year Event Rate for CV Death, MI, or Stroke * Diabetes (n=7987) No Diabetes (n=13,93) P-Value Risk of CV Death, MI, or Stroke at 4 Years 22.5% 15.9% <.1 International, prospective, observational study of 45,277 subjects 45 years of age at risk for or with atherothrombosis, of which 21,89 had a prior history of MI or stroke. This cohort was enrolled from 29 countries and was followed annually for 4 years from 23 to 28 *Event rates adjusted for age and gender. 1. Bhatt DL et al. JAMA. 21;34: Bhatt D et al. Presented at: European Society of Cardiology Congress 21; 28 August 3, 21; Stockholm, Sweden.

22 Rate of Non-fatal Recurrent MI or Death (%) Risk of Nonfatal Recurrent MI or Death by HbA1c Level Year Rate of Nonfatal Recurrent MI or Death in Patients With or Without Diabetes (n=25) (<4.4) ( ) ( ) (4.8) (4.9-5.) ( ) ( ) (>6.2) HbA1c Level (%) A prospective study of 35 patients with (n=74) or without (n=231) diabetes who survived a previous acute MI. Patients were evaluated over 5.5 years for the occurrence of non-fatal recurrent MI or death in relation to HbA1c level at admission 29 HbA1c=hemoglobin A1c. Adapted from Tenerz A et al. J Intern Med. 23;254:494 53; with permission from the John Wiley & Sons, Inc.

23 Relative Risk (95% CI) of Fatal or Non-fatal Reinfarction* Risk of Recurrent MI by Total Cholesterol Levels 1 Men 1 Women P< (1.1, 75.) (.8, 61.8) (.97, 6.4) 1.4 (.6, 3.7) P< (1.4, 1.) (.5, 36.2) <2 mg/dl (n=39) mg/dl (n=53) mg/dl (n=47) Total Cholesterol Level 275 mg/dl (n=26) The prospective, longitudinal Framingham Heart Study of 374 patients who survived their first MI and had available cholesterol measurements evaluated the risk of fatal or non-fatal reinfarction and long-term survival (mean 1.5 years) by total cholesterol level *Multivariate analysis: adjustments made for age, systolic blood pressure, presence of diabetes, relative weight, smoking status, and electrocardiographic result. Calculated using Cox proportional hazards regression. Reference category. P-value as compared to reference group. Reprinted from The Coronary Drug Project Research Group. J Am Coll Cardiol. 1984;4(6): ; with permission 3 from Elsevier. <2 mg/dl (n=13) mg/dl (n=23) mg/dl (n=3) Total Cholesterol Level 275 mg/dl (n=24)

24 Percent Events (%) Risk of Recurrent Major Coronary Events by Blood Pressure Recurrent Major Coronary Events Over 5 Years by Blood Pressure Group 4 Systolic Diastolic BP (mmhg) < n= < men in the Coronary Drug Project with a history of 1 or more prior MIs were evaluated over 5 years for recurrent major coronary events (defined as definite non-fatal MI and fatal coronary events) in relation to diastolic and systolic blood pressure Reprinted from The Coronary Drug Project Research Group. J Am Coll Cardiol. 1984;4(6): ; with permission 31 from Elsevier.

25 Cumulative Non-fatal Reinfarction Rate (%) Risk of Recurrent MI in Patients Who Continue Smoking Cumulative Non-fatal Reinfarction Rate in Relation to Smoking Status at 3 Months Continued to smoke Stopped smoking 2 1 No. stopped No. continued Follow-up Years male patients who survived their first MI between 1968 and 1977 were evaluated for risk of non-fatal reinfarction and long-term survival (maximum of 1.5 years) in relation to smoking status after MI Adapted from Aberg A et al. Br Heart J. 1983;49: ; with permission from the BMJ Publishing Group, Ltd and the British 32 Cardiovascular Society

26 Relative Risk Risk of Recurrent MI or Fatal CHD by Body Mass Index (BMI) 2.5 Relative Risk for Recurrent Events Over Median 3-Year Follow-up by BMI Group* Body-mass index No. of events Person-years Age-adjusted rates Healthy Weight Overweight Class I Obesity Class II-III Obesity subjects who survived their first acute MI between 1986 and 1996 were evaluated over a median of 3 years for recurrent acute MI and fatal CHD in relation to BMI group *Adjusted for age, sex, tobacco use, physical activity, congestive heart failure, and aspirin use. The rate is per 1 person-years, directly standardized to the age distribution of the entire study population. 33 Reprinted from Rea TD et al. Am J Cardiol. 21;88: ; with permission from Elsevier

27 Risk of Recurrent MI or Fatal CHD in Patients With Prior MI and CKD Probability of a CHD Event P<.1 comparing no CKD*, prior MI group vs CKD*, no prior MI group The ARIC Study CKD*, prior MI (n=21) No CKD*, prior MI (n=366) CKD*, no prior MI (n=25) No CKD*, no prior MI (n=11,66) Follow-up Years Prospective follow-up of over 1 years from 1987 to 21 of 12,243 subjects. The cohort was re-examined approximately every 3 years *Stage 3 CKD (estimated glomerular filtration rate [egfr] 3-59 ml/min/1.73 m 2 ). Definite or probable hospitalized MI or definite fatal CHD. ARIC=Atherosclerosis Risk in Communities; CKD=chronic kidney disease. 34 Reprinted from Wattanakit K et al. J Am Coll Cardiol. 26;48: ; with permission from Elsevier.

28 Cumulative incidence (%) Cumulative incidence (%) Risk of a Recurrent MI by Age and Sex Cumulative 7-Year Incidence of Recurrent Acute MI* Stratified by Age and Sex 3 Men (n=236,317) Women (n=135,32) Years since first acute MI Years since first acute MI 387,452 patients identified from national hospital and mortality-linked records in England with 3 days survival post-first or recurrent acute MI between 24 to 21 were evaluated for risk of recurrent acute MI and long-term survival *Recurrent acute MI was defined as a second MI. Adapted from Smolina K et al. Circ Cardiovasc Qual Outcomes. 212;5:532 54; with permission from the American Heart 35 Association, Inc.

29 C L I N I C A L Q U E S T I O N In your practice, how often do you see a patient with prior MI who has multiple risk factors? 36

30 Cumulative Incidence of Recurrent MI (KM%) Number of Risk Factors Incrementally Increased the Risk of Recurrent MI 2 OACIS Registry risk factors* (n=28) 2 risk factors* (n=157) Years After Discharge 1 risk factor* (n=3764) No risk factors (n=2328) Prospective, observational, multicenter study of 787 Japanese patients (median age 66.2 years) with acute MI enrolled between 1998 and 28. During the 5-year follow-up period (median 3.9 years), 353 patients experienced a recurrent MI *Risk factors=diabetes, age, and prior MI. 37 Adapted from Nakatani D et al. Circ J. 213;77: ; with permission from the Japanese Circulatory Society.

31 C L I N I C A L Q U E S T I O N What goals should we set with our patients to address risk factors for recurrent MI? 38

32 AHA Goal for the Current Decade By 22, to improve the cardiovascular health of all Americans by 2%, while reducing deaths from CVDs and stroke by 2% This goal will be assessed against 7 PREDETERMINED METRICS for ideal health, defined as the presence of optimal levels of all metrics 4 HEALTH BEHAVIORS 3 HEALTH FACTORS (in the absence of drug treatment) Not smoking Having sufficient physical activity A healthy diet pattern Appropriate energy balance as represented by normal body weight Optimal total cholesterol Blood pressure Fasting plasma glucose 39 Mozaffarian D et al. Circulation. 215;131:e29-e322.

33 Summary Atherosclerosis is a diffuse and progressive disease that results in persistent CV risk MIs can occur in vessels not perceived to be at risk Patients with a history of MI remain at high and persistent risk of recurrent events Numerous risk factors can contribute to the recurrence of CV events such as multivessel CAD, diabetes mellitus, CKD, and older age AHA goals for improving CV health encompass behavioral and health factors 4

34 AstraZeneca is committed to conducting business with the highest standards of integrity and professionalism If you have any comments about this presentation, please contact AstraZeneca at Thank you for your participation today. This concludes today s program 41