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Evaluating the Risk of Coronary Artery Disease: A Conceptual Approach Texas-Wide Underwriting Conference Cliff Titcomb, MD Hannover Life Re March 19, 2012.

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Presentation on theme: "Evaluating the Risk of Coronary Artery Disease: A Conceptual Approach Texas-Wide Underwriting Conference Cliff Titcomb, MD Hannover Life Re March 19, 2012."— Presentation transcript:

1 Evaluating the Risk of Coronary Artery Disease: A Conceptual Approach Texas-Wide Underwriting Conference Cliff Titcomb, MD Hannover Life Re March 19, 2012

2  How Much Myocardium is Already Lost?  How Much Myocardium is At Short Term Risk?  What is the Predisposition to Disease?  How Much Myocardium Will Likely Be Jeopardized in the Future and in What Time Frame? 2 Risk Assessment Revolves Around 4 Key Questions

3 Why the Questions?  Ultimately, the More Total Myocardium is Lost - the Greater the Risk for Adverse Morbidity and Mortality Outcomes Loss of Pump Reduces Function Losing More Than 40% of the Myocardium is Incompatible with Life Each Event Carries Risk of Fatal Arrhythmia 3

4 Question 1: How Much Myocardium Has Been Lost?

5 Numerous Studies Show an Increase in Mortality with Reduced Ventricular Function  Best Surrogate Marker is the Ejection Fraction  An Alternative is the Left Ventricular End-Diastolic Pressure (LVEDP) Weaker Predictor Subject to Other Factors 5

6 Stahle et al., Ann Thorac Surg, 1997; 64:437-44.


8 Caution - “Stunned” Myocardium  Transient Ventricular Dysfunction Due to Profound Ischemia Reversible with Improved Blood Flow Common in the Early Post Infarction Period Most Recent Evaluation is Probably the Best Estimate of Actual Function 8

9 Question 3: How Much Myocardium is at Short Term Risk?

10 How Much Myocardium is At Short-Term Risk?  Traditionally Referred to Ischemic Burden  Number of Vessels with Hemodynamically Significant Obstructive Disease  Mortality Clearly Varied with Number of “Diseased” Vessels Usually Defined as 50% or Greater Obstruction 10

11 Emond M, et al., Circulation, 1994; 90:2645-57.


13 The Number of Diseased Vessels Does Scale Risk  But Not By the Mechanism Traditionally Thought to Be Operative  Get the Right Answer for the Wrong Reason  Relates to the New Model of CAD

14 Three Elements are Critical in Acute Coronary Events  The Vulnerable Plaque  Endothelial Dysfunction  Thrombosis 14

15 The Relatively Innocent Looking Lesions are the Killers  Tight Stenosis Doesn’t Kill Severe Stenosis Typically Causes Angina -- Not Infarction  For Major Coronary Events Quality Matters More than Quantity in Terms of Atherosclerotic Material  Gradual Obstruction May to Some Extent Be Beneficial Induces the Development of Collaterals Which Can Be Protective 15

16 Vulnerable Plaques  Large Core of Oxidized Lipids Thin Fibrous Cap  Inflammation  Some Degree of Calcium Deposition  Generally Non-Obstructive  Dynamic Continuous Remodeling Dependent on Risk Factors 16

17 Other Critical Elements  Endothelial Function Abnormal Blood Vessel Response to Injury –Spasm Instead of Dilatation –Reduced Production of Nitric Oxide  Thrombosis Final Common Pathway for Acute Events –Adverse Events Result from Clot with Occlusion Hypercoagulable State Increases Risk –Minor Plaque Ruptures Become Major Events –Important with Smoking 17

18 Mechanism - Acute Events  In Most Cases the Critical Step is the Rupture of a Non-Obstructive Vulnerable Plaque Fracture of Fibrous Cap Exposes Lipid Core to Circulating Blood Result is Acute Thrombosis, Endothelial Spasm and Vessel Occlusion  Tightly Stenotic Lesions Cause Only a Minority of Infarctions More Likely to Cause Ischemia –Angina or Equivalent Symptoms 18

19 Stenotic Lesions are Associated with Outcomes Because of the Company They Keep

20 The Volume of Plaque Matters

21 Question 2 — Really a 2 Part Question  What is Total Plaque Burden? How Many Plaques are There?  What is the Stability of the Plaques That are Present? Are They Likely to Rupture? 21

22 Total Plaque Burden  Traditional Gold Standard – Cardiac Cath Problem: Underestimates Volume of Plaque Really a Lumenogram –Only Sees Inner Surface of Vessel Vessel Remodeling Hides the True Volume of Disease –Vessel expands in Size to Compensate for Disease and Maintain Flow Not Effective at Finding Vulnerable Plaques –Predictive of Events But Poorly Predictive of the Actual Site of an Event 22

23 Traditional Non-Invasive Markers of Plaque Volume Primarily Detect Obstructive Disease Measure Ischemia Don’t Address Vulnerable Plaques

24  Direct Measures Electron Beam CT Scan (EBCT) Intravascular Ultrasound Multi-Detector CT (MDCT) MRA  Indirect Measures Carotid Intima-Media Thickness (IMT) 24 Newer Non-Invasive Measure of Coronary Plaque Burden Direct and Indirect

25 Electron Beam CT (EBCT)  Reflects Overall Plaque Burden Measures Calcium Deposition in Plaque Both Obstructive and Non-Obstructive Lesions  Overall Score is the Most Important Factor Higher the Score the Greater the Likelihood of Obstructive Disease  Distribution of Plaque is also Important  Relative Risk Correlates with Percentile Ranks By Age and Sex Where Do You Stand Relative to Your Peers? 25

26 EBCT  More Predictive of Risk of Cardiovascular Events Than Risk Factor Analysis  Ties the Risk Factors to the Individual Relates Population Data to the End-Organ Results in the Individual Functions for CAD Like LVH for BP or Microalbumin for Diabetes  Identifies the Vulnerable Person Not Necessarily the Vulnerable Plaque 26

27 Shaw et al., Radiology,, 2003; 228:826-33.

28 Raggi et al., Circulation, 2000; 101:850-55.

29 Blaha et al., J Am Coll Cardiol Img, 2009; 2:692-700.

30  Probably the Best Test to Assess Overall Plaque Burden  Visualizes Both Soft and Calcified Plaque Visualizes Lesions not Seen on Angiography  Positive Predictive Value (PPV) is Very Good and Negative Predictive Value (NPV) is Excellent for Significant Obstruction Often Used Clinically to Rule Out Disease Best Visualizes the Left Main and LAD Worst Visualization is in the Circumflex 30 Multidetector CT Angiography

31  Heavy Calcification May Degrade Images  Not All Segments are Visualized Well  Visualization of In-Stent Stenosis is Variable  May not be Adequate for Planning for Surgery False Positives an Issue Visualization of the Vascular Run Off  Radiation Exposure is Significant 31 Multidetector CT Angiography - Problems

32 Schuijf et al., J Am Coll Cardiol Img, 2008; 1:190-9.


34 But is the Plaque Vulnerable ? Quality is as Important as Quantity

35 Plaque Stability Varies with Risk Factor Control  Important Revelation from Statin Studies  Plaques May Look the Same But They Don’t Rupture  Inflammation is a Key Component  Reduction of Inflammation and Stabilization of Plaques Leads to a Marked Decrease in Clinical Event Rates 35

36 C-Reactive Protein  Non-Specific Acute Phase Reactant Measure of Inflammation  Produced in the Liver Induced By Cytokines – Especially Interleukin 6  Highly Sensitive Test (hsCRP) Can Detect Low Grade Inflammation Subdivide the Traditional Normal Range 36

37 C-Reactive Protein  Initially Appeared to Be Much More Predictive of Future Events Than Other Risk Factors  More Recent Studies Suggest Benefit May Be More Modest  Questionable if it Adds Substantially to Risk Assessment When Traditional Risk Factors are Taken into Account  Recent USPSTF analysis showed: RR high risk v low risk = 1.58 RR average risk v low risk = 1.22 37

38 Danesh et al., NEJM, 2004; 350:1387-97..

39 C-Reactive Protein — Practical Issues  Variability Recommendation is Using Average of 2 Samples at Least 2 Weeks Apart  Lack of Specificity Other Causes of Inflammation –Likely for Levels > 10 mg/L –Measure again if levels are questionable 39

40 Park et al., Circulation, 2002; 106:2073-7..

41  Risk of All Cause Mortality is Increased 40-50% of Deaths in RA are From CV Disease  Inflammation Appears to Be the Mechanism The Disease Process in the Rheumatoid Joint is Similar to That in the Plaque Increased Adhesion Molecules and Inflammatory Cells with Production of Cytokines  Seropositive Status Increases CV Risk Risk Increased with Elevated CRP and ESR, Joint Swelling, RA Nodules, Vasculitis, Lung Disease  EBCT Scores are Higher with RA 41 Plaque Stability - Rheumatoid Arthritis

42  Risk of Myocardial Infarction is Increased Traditional Risk Factor Analysis Does Not Work as Well to Assess Risk  Increased Number of Vulnerable Plaques  More Likely to Have Silent Disease –Higher Risk of Sudden Death  Risk Higher with Longer Duration and Greater Severity of RA Disease  Risk of CHF is Increased  Treatment with Disease Modification Drugs Seems to Improve Risk 42 Plaque Stability - Rheumatoid Arthritis

43 Giles et al., Arthritis Res Ther, 2009; 11:ePub

44 Question 3: What is the Individual’s Predisposition to Disease?

45 A Key Step in Customizing the Mortality Assessment is Linking the Disease Process to the Individual Critical Step is Identifying the Age of Diagnosis or Age Standardized Percentile Rank for Disease Burden

46 Age Related Disease Burden Does 2 Things:  Provides an Estimate of the Slope of Initial Progression By Extrapolation, the Likely Future Course  Provides a Context for Interpreting Risk Factors Ties the Risk Factors to the Individual Terms such as High or Low are Relative Values and Depend on Context for Meaning 46

47 Need to Interpret Baseline and Individual Factors in Light of the Pattern Mortality with the Disease


49 van Domburg et al., Eur Heart J, 2009; 30:453-8.

50 van Domburg et al., Eur Heart J, 2009; 30:453-8



53 Peduzzi et al., Am J Cardiol, 1998; 81:1393-99

54 Goldberg et al., Am J Cardiol, 1998; 82:1311-7

55 van Domburg et al., Eur Heart J, 2009; 30:453-8.

56  Overall Plaque Burden  Stability of the Plaques That are Present  Current Ventricular Function and Likely Cardiac Reserve 56 Questions 1 and 2 - Establish the Baseline

57  Age of Onset - Sets the Track and the Slope of Progression Over Time  Without Disease Modification this Historical Slope of Progression Will Likely Continue Going Forward 57 Question 3 – Permits Estimation of the Likely Future Course

58 The Younger the Onset, the Higher the Overall Level of Risk Now and in the Future

59 Weintraub et al., Circulation, 2003; 107:1271-7.


61 61 Age of Onset Severity of Disease Effect of Predisposition 456555

62 Risk Factors Must Also Be Evaluated in Light of Individual Predisposition to Disease

63 Normal vs. Abnormal is Not a Numeric Value or Even a Population Average It is a Level That Produces An End Organ Effect in An Individual

64 Question 4: How Much Myocardium Will Become at Risk in the Future and How Soon Will It Occur?

65 Factors that Affect Risk May or May Not Be Modifiable

66  Equivalent to Having a Previous MI in a Non- Diabetic  Risk is Worse in Type 1 DM  Extensive Disease is More Likely  Outcomes are Worse in Diabetics for Any Given Extent of Disease If Present with Unstable Angina – More Likely to Have an MI If Have an MI – Twice as Likely to Die 66 Diabetes - Increases Mortality Risk


68 Smoking  Converts Minor Plaque Ruptures into Major Events Effect is Primarily on Thrombosis Leg of the Triad  Active Smokers Have Highest Risk  Risk Persists into Older Ages  Quitters Have Reduced Risk Some Studies Suggest Relative Risk Post MI is Lower in Quitters Than Lifelong Nonsmokers Reason: Major Risk Factor Leading to Events Has Been Removed 68

69 Myers et al., J Am Coll Cardiol, 1999; 33:488-98.

70 Kinjo et al., Circ J, 2005; 69:7-12.

71 Lipids  Multiple Studies Have Demonstrated Increased Risk with Elevated Lipids  Control Clearly Reduces Risk  Reduction in Acute Event Rates Occurs At Minimum within Months May Occur Within Weeks or Sooner  Cholesterol/HDL Ratio is the Best Single Lipid Measure 71

72 Clin Chem, 47;2001.


74 Hypertension  Multiple Potential Adverse Effects Progression of Atherosclerosis Mechanical Stress That May Destabilize Plaques Development or Progression of LVH Synergistic Effect with Diabetes  Effects Greater with Systolic BP  Pulse Pressure is Important  Overall Relative Risk is Modest in Most Studies – Probably Maximum of 1.3-1.4 74

75 Type of Therapy  Choice of CABG v PTCI is Still Somewhat Controversial Some Data Suggests That Outcome is Better with CABG for Three Vessel and Left Main Disease –Especially if High Risk with Reduced EF –Diabetics –Older Individuals  Outcomes are Probably Equivalent for One and Two Vessel Disease  Benefit of CABG for Diabetics Continues to 10 Years 75

76 Type of Therapy — Invasive  Stents Clearly Improve Short-Term Outcomes Reduced Restenosis Rate Restenosis is Reduced Further with Drug Eluting Stents (DES) –DES is Associated with Late Stent Thrombosis (Rare) –No Real Survival Benefit of DES vs Bare Metal Stents Limited Benefit Long Term –Most Adverse Outcomes Result from Progression of Disease in Vessels without a Stent 76

77 Type of Therapy — Invasive  Outcomes Better with Use of Internal Mammary Artery (LIMA) Hazard Ratio – 1.34 with a Vein Graft Alone –Data Suggests Two IMA is Better Than One (HR=0.81) Now Standard of Care for Bypass  Radial Arteries also Superior to Vein Grafts May Not Be as Good as Using Both LIMA and RIMA

78 Type of Therapy — Non-Invasive  Clear Benefit of Medical Therapy – Multiple Studies  Different Types – Benefit Additive Statins Beta-Blockers ACE Inhibitors Aspirin/Platelet Agents Anticoagulation 78

79 For Stable CAD w Multivessel Disease and Good EF - Mortality Outcomes are Similar for Medical Therapy, PTCI and CABG More Interventions with Med Rx and PTCI

80  C-Reactive Protein (CRP)  B-Natriuretic Peptide (BNP)  Troponin  WBC Count  Microalbuminuria  Cystatin C  Midregional Proadrenomedullin (MR-proADM)  Fibrinogen  IL-6 80 New Biomarkers

81  Individually Have Shown Some Increase in Hazard Ratios in Multivariate Analysis  For the Most Part the Effect on the Disease Classification Has Been Modest  Combinations of Markers Have Been Tried with Mixed Results Some Combos Have Shown Some Improvement of Risk Assessment  B-Natriuretic Peptide Appears to Be the Best of the Current Group 81 New Biomarkers

82  Peptide Hormone Released from Ventricles in Response to Myocyte Stretch  Associated with Regional or Global Ventricular Dysfunction  Provides Value Independent of EF  Found to Be a Predictor of Long-Term Increase in Mortality in Multiple Scenarios Stable Coronary Disease (RR 2.4) Acute Coronary Syndromes (RR 2.4) Myocardial Infarction 82 B-Natriuretic Peptide

83 Kragelund et al., N Engl J Med, 2005; 352:666-75.

84 84  Has a Variety of Effects Smooth Muscle Cell Proliferation Reduces Inflammation Vascular Calcification Renin-Angiotensin System Blood Pressure  Low Levels are Associated with: Increasing Age Female Sex Non-White Race Diabetes Hypertension Current Smoking Lower Physical Activity Winter Season 25-Hydroxyvitamin D

85  Deficiency was Present in 22% of the NHANES III Population Age 18 up (16,603)  Self Reported CV Disease is Higher with Lower Levels in NHANES III RR=1.20  Relative Risk of MI is Increased Comparing Lowest to Highest Quartile Levels RR=2.09  Multiple Studies Show an Increase in All-Cause and CV Mortality (Highest v Lowest Quartiles) When Controlling for Other Risk Factors 85 25-Hydroxyvitamin D

86 Melamed et al., Arch Intern Med, 2008; 168:1629-37.

87 Dobnig et al., Arch Intern Med, 2008; 168:1340-9.

88 Exercise Tolerance and Heart Rate Recovery  Important Considerations in Long-Term Prognosis  Survival Rate Decreases in Proportion to Reduction of Exercise Duration and VO 2 Max  HR Recovery Adds Additional Information to That Supplied by Exercise Tolerance 88

89  Even Mild Renal Insufficiency (Serum Creatinine > 1.4 mg/dl-1.5 mg/dl/123.8 umol/L-132.6 umol/L) is Associated with a Worsened Outcome with CAD Common Finding in the Elderly  Outcome is Worse with Overt Renal Failure  Increased Risk Occurs in Multiple Scenarios Chronic Stable Angina Acute Coronary Syndrome Myocardial Infarction CABG and PTCI 89 Renal Insufficiency

90 Left Ventricular Hypertrophy (LVH)  Associated with Coronary Disease Itself and Comorbid Conditions Like Hypertension  In CAD, Increases Risk Compared to Those Without LVH Relative Risk - 1.5-1.8 Range  Certain Treatments May Decrease LV Mass Unclear if Reducing Mass Reduces Risk 90

91 Ventricular Arrhythmias  Ventricular Fibrillation in the Setting of an Acute Event Does Not Reduce Long-Term Survival Provided No Ongoing Arrhythmias  Sustained Ventricular Tachycardia, Even in the First 24 Hours, is an Adverse Prognostic Indicator Associated with Larger Infarcts, LV Aneurysm Non-Sustained VT is a Much Weaker Predictor of Adverse Outcome 91

92 Ventricular Arrhythmias  Mortality Risk is Increased with Even Relatively Few PVCs Present Beyond the Setting of the Acute Event Outcome Depends Heavily on Presence of Ongoing Ischemia and Especially Status of Ventricular Function No Good Evidence That Treatment Affects Survival

93  Incident AF Occurs in 5-13% of Acute Infarctions in Recent Studies (Higher in Older Ones) New AF has a Higher Risk than Chronic AF  Older Age, Heart Failure, Elevated Heart Rate, Hypertension Increased the Risk of Developing AF  AF Increases the Risk of Stroke and In-Hospital Mortality Post MI  AF Increases Long-Term Mortality Even When Controlling for Co-Morbid Conditions RR is in the 1.25-1.35 Range 93 Atrial Fibrillation

94 Peripheral or Cerebrovascular Disease  Indicators of Diffuse Vascular Involvement  Outcomes are Worse for Those With CAD and Peripheral or Cerebrovascular Disease RR Approximately 1.5  Diffuse Vascular Disease is Associated with Risk Factor Profiles That Magnify Risk Diabetes Smoking 94

95 Homocysteine  Data is Mixed Retrospective Studies Suggested Very High Relative Risk Prospective Studies – Generally Less Impressive  Overall Association with Increased Risk is Probably Mild to Moderate  Other Factors Technical Problems with Assay Difficulties with Collection Expensive  Does Not Appear That Lowering Level Reduces Risk 95

96 Lipoprotein (a)  Genetics Play a Large Role in Determining Level – Important in Some Groups  Homology with Plasminogen  Risk Tied to LDL Cholesterol Levels  Difficult to Treat Does Not Respond to Statins Benefit – Estrogens, Nicotinic Acid  Relatively Weak Predictor May Be More Important in Select Cases 96

97 Clin Chem, 47;2001.

98 Age of Onset Severity of Disease Where the Questions Fit 456555 1, 2 3 4 Baseline Amount of Disease Initial Progression Slope Future Rate of Progression

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