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Management of patients with Unstable Angina Raffaele Bugiardini

om: Thank you …….. Today I will talk about “Management of UA”,an issuue in which there is still much room for uncertainty. CAD is the killer n 1. Everybody knows that Pts with suspected ACS must be evaluated rapidly. Because. Management of patients with Unstable Angina Raffaele Bugiardini.

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Management of patients with Unstable Angina Raffaele Bugiardini

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  1. om: Thank you …….. Today I will talk about “Management of UA”,an issuue in which there is still much room for uncertainty. CAD is the killer n 1. Everybody knows that Pts with suspected ACS must be evaluated rapidly. Because.. Management of patients with Unstable Angina Raffaele Bugiardini

  2. Key Assumptions • The euros available for health care are limited • The medicalprofession must play a significant role in the critical evaluation of the use of diagnostic procedures and therapies

  3. om: .. ..despite the new drugs and devises, as in the natural history of the disease, pts still have a high incidence of death in days that follow the acute events. This rate of death is greatest during the first 30 days. PURSUIT Trial Investigator Prob. of survival Days N Engl J Med 1998;339:436-43

  4. INITIAL EVALUATION AND MANAGEMENT Patients with suspected unstable angina must be evaluated rapidly The physician then must place the evaluation in the context of 2 critical questions: • Are the symptoms a manifestation of an unstable angina? • If so, what is the prognosis?

  5. om: Most of you are GP and frequently recive telephone calls from pts who are concerned that their symptoms may reflect haert disease. Most of these calls regarding chest disconfort do not rapresent an emergency, some yes. There are two critical questions: Are the symptoms a manifestation of ACS ?If so, what is the prognosis ?

  6. om: Answering the question n 1 we have to remember that:… but ansering the Q n 2 we have to remember that…... 1)…..ischemic disconfor at rest rappresent an increased risk of death and non fatal AMI. 2)….the estimation of level of risk is useful for: 1 - selection of site of care ( CCU, monitored step-down unit, out-pt setting) 2-selection of therapy (gp2b/3a inhib.) The slite I showed you before “The presence or absence of the traditional risk factor ordinarily should not be used to determine whether an individual patient should be admitted or treated for ACS. However, the presence of these risk factors does apper to relate to poor outcomes in patients with established ACS.” ACC/AHA Practice Guidelines 2002

  7. Likelihood that Signs and Symptoms Represent an Unstable Angina History Examination ECG Cardiac Markers High Likelihood Intermediate Likelihood Low Likelihood Probable ischemic symptoms Recent cocaine use Typical Angina CAD history Typical Angina, Age >70 yrs, Sex M, Diabetes Mellitus Transient MR Hypotension Diaphoresis, Pulmonary Edema Extracardiac vascular disease Chest disconfort by palpitation T wave flattering New ST-segment deviation or T-wave inversion Fixed Q waves Abnormal ST or T-waves not documented to be new T wave flattering or inversion in laeds with dominant R  cardiac TnI, TnT or CK-MB Normal Normal Normal Modified from Braunwald E et all 1994; AHCPR Pub. 94-0602

  8. LOW RISK PTS INTERMEDIATE RISK PTS Risk StratificationNon Invasive Stress Testing free of ischemia at rest and of CHF for a minimum 12 - 24 hours 2 - 3 days ACC/AHA Practice Guidelines 2002

  9. om: Most of you are GP and frequently recive telephone calls from pts who are concerned that their symptoms may reflect haert disease. Most of these calls regarding chest disconfort do not rapresent an emergency, some yes. There are to critical questions: Are the symptoms a manifestation of ACS ?If so, what is the prognosis ?

  10. The ESSENCE Study Heparin Enoxaparin 40 Combined Endopoint 35 30 25 20 15 10 5 4 6 8 10 12 14 0 2 Time since enrollment (months) Goodman SG, J AM Coll Cardiol 2000;36:693-8

  11. Antman et all developed a 7-point risk score. The risk of developing an adverse outcome ranged from 5% to 41% with the TIMI risk score defined as the sum of the individual prognostic variable. The end point cosidered were: death, (re)-AMI, or recurrent severe ischemia requiring revascularization The score was derived from the TIMI 11 trial. and has been validated in 3 additional trials: ESSENCE TACTICS-TIMI 18 PRISM-PLUS Among pts with UN/NSTEMI there is a progessively greater benefit from new therapy: LMWH, GP2b/3a, invasive strategy, with incrementing risk score. TIMI risk score 1- age > 65 yrs 2- > 3 coronary risk factors 3- more that 2 angina events within 24 hrs 4- prior angiographic obstruction 5- aspirin (in the 7 prior days) 6- ST-segment deviation 7- elevated cardiac markers Antman EM et al. JAMA 2000;284:835-42

  12. Validation of TIMI Risk Score and Assessment of Treatment Effect According to Score in ESSENCE 45 Unfractionated Heparin (n=1564) 38.1 40 Enoxaparin (n=1607) 35 31 30 Rate of Composite End Point % 25 20 18.3 20 16.8 15.8 15 12.4 12 11.6 10 9.5 7.3 7.2 5 0/1 2 3 4 6/7 5 No. of Risk Factors Antman E, JAMA 2000;284:835-42

  13. Tools for risk stratificationinitial management • Age and History • Symptoms • Standard ECG • Biochemical Markers • Continous ECG

  14. Life table of cumulative risk and time of MI or death during 1 year of follow-up with regard to different types of ST-T segment change ST Elevation and Depression n=78 ST Depression Only n=216 Death or MI % ST Elevation Only n=93 Death or MI % T Wave Inversion Only n=287 No ST or T Wave Change n=237 0 60 120 180 240 300 360 Days Nyman N, J Intern Med 1993;234:293-301

  15. Mortality Rates at 42 Days According to the Time From Onset of Pain to Study Enrollment and the Baseline Cardiac Troponin I Enrolled 0 to 6 hr after Pain Onset Enrolled > 6 to 24 hr after Pain Onset Enrolled 0 to 24 hr after Pain Onset 4 4 3.7 Troponin I 0.4 ng/ml Troponin I <0.4 ng/ml 3.1 3 2.6 2.5 2.4 2 1.7 1.4 1.0 1 0.8 P<0.01 P<0.05 0.5 0.4 0 No CK-MB Elevation No CK-MB Elevation No CK-MB Elevation All Pts All Pts All Pts Risk Ratio 3.8 1.7-8.5 1.8 0.6-5.5 1.8 0.4-7.6 9.5 2.2-4146 3.0 0.97-9.2 5.5 1.1-29.7 95% Confidence Interval Antman EM N Engl J Med 1996; 335:1342-49

  16. Relation between initial negative Troponin and ECG Negative TnT Negative TnI 5% 4% Mortality 3% 2% 1% 60% 0% 20% 40% 80% 100% Patients with Ischemia on ECG Heidenreich J Am Coll Cardiol 2001;38:478-85

  17. Prognostic Significance of different Clinical, ECG and Angiographic Variables for Identifying High Risk Pts with UA Positive predictive value Negative predictive value Sensitivity Specificity (%) (%) (%) (%) 883724838880 329292755989 467567685883 806965878888 Recurrent angina Duration of anginal episodes> 15 min Pain-free interval < 1 h Duration of TMI  60 min/24h High risk coronary lesion Duration of TMI  60 min/24h and high risk coronary lesion Bugiardini R, J Am Coll Cardiol 1995; 25:597-604

  18. Relations among prognosis, duration of ischemia at admission and symptoms Unfavorable clinical Outcome Favorable clinical Outcome Over 180 180 160 140 120 100 80 60 30 0 Fatal or Non fatal MI Other clinical outcome Duration of TMI at admission (min/24 hrs) No Yes No Yes Symptoms Predictive of coronary events Bugiardini R, J Am Coll Cardiol 1995; 25:597-604

  19. Simplified TIMI risk score CRITERIA a - age > 65 yrs b- ST deviation > 0.5 mm c- CK > 2 times normal or TnT high CLASSES Low Risk 0-1 Intermediate Risk 2 High Risk 3 Holper EM et al Am J Cardiol 2001;87:1008-10

  20. Simplified TIMI risk score Unfractionated heparin 30252015105 0 Enoxaparin 29.6 24.8 20.5 17.9 15 14.1 Event rate at day 43 802 870 848 797 307 286 Low (0/1) Inter (2) High (3) Holper EM, Am J Cardiol 2001;87:1008-13

  21. NORMAL REST ECG Abnormal LVEF 2% Normal LVEF 98 % Am Heart J 2000: 139:584

  22. Prognostic value of low risk exercise test 1.0 Chronic Stable Angina .9 .8 Event-free survival Unstable Angina .7 .6 .5 0 500 600 700 100 200 300 400 Days Florenciano-Sandez R. J Am Coll Cardiol 2001;38:1974-9

  23. RESULTS OF THE EXERCISE TEST Patients With CSA (n=86) p Value Patients With UA (n=105) Duration (min) 92 0.0001 74 7711 NS % TMHR 8013 20,9025,835 NS 21,4817,079 Rate-pressure product Positive clinical response 17 (16%) 40 (46%) 0.0001 Positive ECG response 57 (66%) 0.0001 34 (32%) 64 (74%) 0.0001 Positive result 41 (39%) 0.0001 06 Duke index 55 Florenciano-Sandez R. J Am Coll Cardiol 2001;38:1974-9

  24. In patients with suspected ACS and negative ECG-Exercise Stress Test, physycians should proceede to pharmacological stress or cardiac scintigraphy.

  25. Comparison of Stress Echocardiography and Stress Myocardial Perfusion Scintigraphy for CAD SPECT 100% Stress-Echo 89% 90% 81% 80% 72% 60% 40% 20% Sensitivity Specificity O’Keefe J Am J Cardiol 1995;75:25D-34D

  26. Do not judge yourself harshly. Without mercy for ourselves we cannot love the world. The Buddha

  27. Relations among complex stenosis morphology, transient myocardial ischemia, and in-hospital outcome in pts with UA In hospital adverse outcome (+) (o) (+) (o) 280 210 180 150 120 90 60 30 0 280 210 180 150 120 90 60 30 0 Duration of TMI at admission (min/24 hrs) Duration of TMI at admission (min/24 hrs) (+) (o) Complex morphology Bugiardini R et al Am J Cardiol 1991;67:460-464

  28. The Canadian ESSENCE ST Segment Monitoring Substudy 1.00 0.95 No ST Shift 0.90 P=0.0226 Event-free Survival (Proportion) 0.85 0.85 ST Shift 100 0 50 150 200 250 300 350 Days from Randomization Goodman SG J Am Coll Cardiol 2000;36:1507-13

  29. Independent predictors of multivessel disease, complex lesion morphology, intracoronary thrombus or either of latter two Multivessel disease Complex lesion morphology Complex lesion or IC thrombus IC thrombus Odds ratio p Value Odds ratio p Value Odds ratio p Value Odds ratio p Value Age > 65 years 4.66 0.03 Hypertension 11.87 0.02 Transient ischemia 6.82 7.10 0.0004 0.0003 3.33 0.09 9.47 0.04 Severe recurrent pain Patel DJ Eur Heart J 2001; 22:1991-96

  30. If exercise ECG is so bloody good, why is it abnormal so infrequently during dobutamine echocardiography when ischemia (inducible wall motion abnormality) is present ?

  31. Rates of hard events per years as a function of the result of stress SPECT in pts with low, intermediate, and high Duke treadmill scores groups 10.0 9.0 Normal 8.0 Mild Abnl 7.1 Mod-Sev Abnl 6.0 Hard Event Rate per Year (%) 5.3 4.0 3.5 3.2 2.9 2.0 1.4 0.5 0.6 0.0 Low Intermadiate High Duke Treadmill Score Hachamovitch R, Circulation 2002; 105:823-829

  32. Clinical suspicion of ACS Physical examination, echocardiogram, ECG monitoring, blood samples Persistent ST-segment elevation NoPersistent ST-segmentelevation Thrombolysis PCI Aspirin, clopidogrel, LMW heparin, Beta-blockers, nitrates High Risk Low Risk Glycoprotein IIb/IIIa, coronary angiography Second troponin measurement Negative Positive Stress Test, coronary angiography Hamm CW Lancet 2001;358:1533-38

  33. Early Conservative Strategy? • Early Invasive Strategy?

  34. Comparison of Outcomes (death or MI in non-Q-wave MI) in VANQWISH 25% 24% 20% 18.6% 15% 10.4% 10% 7.8% 5.7% 5% 3.3% 0% At Discharge At 1 Month At 1 Year V Invasive (n=462) V Conservative (n=458) Boden H, N Engl J Med 1998; 339:1091-9

  35. FRISC II TRIAL 0.16 0.14 0.12 0.10 Probability of death or myocardial infarction 0.08 Non-invasive group 0.06 Invasive group 0.04 0.02 120 180 240 300 360 0 60 Time since start of open-label dalteparin (days) Wallentin L, Lancet 2000;356:9-16

  36. Early Invasive Strategy coronary angiography class I - Level Evidence A • Recurrent angina-ischemia at rest or with low level activities despite intensive anti-ischemic therapy • Elevated TnT or TnI • New or presumably new ST-segment depression • Recurrent angina/ischemia with CHF symptoms • High-risk findings on noninvasive stress testing • Depressed LV systolic function • Hemodynamic Instability • Sustained Ventricular Tachycardia • PCI within 6 months • Prior CABG ACC/AHA Practice Guidelines 2002

  37. Early Conservative Strategy • Coronary angiography is reserved for patients with: • Evidence of recurrent ischemia • - angina at rest or with minimal activity • - dynamic ST-segment changes • Strongly positive stress-test • (despite vigorous medical therapy) ACC/AHA Practice Guidelines 2002

  38. Early Invasive Strategy coronary angiography class I - Level Evidence A • Recurrent angina-ischemia at rest or with low level activities despite intensive anti-ischemic therapy • Elevated TnT or TnI • New or presumably new ST-segment depression • Recurrent angina/ischemia with CHF symptoms • High-risk findings on noninvasive stress testing • Depressed LV systolic function • Hemodynamic Instability • Sustained Ventricular Tachycardia • PCI within 6 months • Prior CABG ACC/AHA Practice Guidelines 2002

  39. Initial Clinical Presentation Possible UA IMA UA + + +/- + Angina + + - ? ECG + + - - Cardiac Markers Pharmacological test Reperfusion Therapy CCU CPU

  40. The odds ratio for increased mortality with a positive troponin T for clinical trials and cohort studies 0.1 1 10 100 Clinical Trials Antman Hamm Ohman Luscher Summary Cohort Studies Gokhan Cin Hamm Hamm Mockel Pettijohn Ravkilde Ravkilde Stubbs Summary Heidenreich J Am Coll Cardiol 2001;38:478-85

  41. Crude and adjusted Relative Risk of Death or Myocardial Infarction by 42 Days Crude Relative Risk OR (95% CI) Adjusted Relative Risk OR (95% CI) p Value p Value Age, by decade 1.51 (1.3,1.9) 0.0001 1.5 (1.2, 1.8) 0.0004 _ _ 0.9 Gender, female 0.9 (0.7, 1.5) 1.5 (0.3, 0.7) 0.6 S3 or rales 3.4 (1.2, 9.2) 0.02 ST segment depression 2.0 (1.4, 3.0) 0.03 0.0004 1.6 (1.1, 2.5) Complicated angina 0.004 1.5 (1.0, 2.3) 0.03 1.8 (1.2, 2.8) 1.4 (0.9, 2.0) 0.2 1.3 (0.9, 2.0) 0.2 CK-MB < 5 IU/ml _ _ 0.5 1.1 (0.8, 1.5) CTnI, by category _ _ CRP, by category 1.0 (0.9, 1.1) 0.3 Salomon J Am Coll Cardiol 2001;38:969-79

  42. Why are the guidelines so misleading? • Composition of members • Selection bias • Peer pressure

  43. The purpose of this study was to compare the effects of nitrates and calcium channel blockers on electrocardiografic (ECG) ischemia during exercise in a group of women admitted to our laboratories because of the occurrence of effort angina associated with ST depression. The results of this investigation demonstrate that simply acquired ECG variables during exercise stress testing on drugs contain diagnostic information, and may reflect the underlying pathogenetic substrate of angina.

  44. NCA p<0.001 CAD RPP (103 U) AT 0.1 mV ST p<0.001 p<0.001 RPP (103 U) AT 0.1 mV ST 

  45. 0.3 0.2 0.1 0.3 0.0 0.2 18 19 20 21 22 23 24 25 26 27 28 0.3 0.3 0.1 0.2 0.2 0.0 18 19 20 21 22 23 24 25 26 27 28 0.1 0.1 0.0 0.0 18 19 20 21 22 23 24 25 26 27 28 16 17 18 19 20 21 22 23 24 25 26 27 28 ISDN Verapamil Baseline EST NCA Patients EST on drug ST  (mV) CAD Patients ST  (mV) RPP (103 U) RPP (103 U)

  46. NCA CAD p<0.001 Time of exercise (sec) p<0.001 p<0.001 Time of exercise (sec)

  47. om:. is the result of the…. In wich the use of an agressive medical therapy (GP 2b/3a inhibitor Intelegrin ) didn’t change the rate of death when used indistriminately. So we cannot use all drugs for all pts. And we need to select them for the therapeutic approch. PURSUIT Trial Investigator Prob. of survival Days N Engl J Med 1998;339:436-43

  48. TIMI Risk Score 40,9 26,2 Rate of composite end point % 19,9 13,2 8,3 4,7 6/7 N° of Risk Factors Antman EM et al. JAMA 2000;284:835-42

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