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  • Some basics, some reviews, some new. Review of litterature backing up what we do All based on Sept 2000 AHA-ACC recommendations on UA and NTSEMI with addition of last year trials and practical points.
  • Backbone of my lecture www.acc.org
  • Conflicting results between Gusto2b and Timi9b
  • Prevents progression of white clot to red clots by preventing platelets aggregation through fibrinogen to form thrombus
  • Composite end points
  • Very good numbers for PCI and hard to dispute but irrelevant to ER Focus is on prism-plus and pursuit Overall 2% absolute decrease death or MI
  • 3200 pts On average, PTT was around 80
  • Subgroup analysis showing good for + markers Same for trop T Independent of revascularization procedures (PCI or CABG) Heparin with + trop do worst (on right)
  • 1900 pts Composite end-point:MI, death, refractory ischemia Non-weight based heparin NNT: 20 to 25
  • 22 end-points: 3 strong <0.01, 8 weaker 0.01 to 0.05
  • Major bleed: 5 gr of Hgb Cath rate: North America 79% Western Europe 58% Eastern Europe 20%
  • GP 2 b/3a if no cath lab???
  • Not proof that everything is time dependent as in thrombolysis
  • Risk factors for CAD: HTN, diabetes, current smoker, family hx of CAD, hypercholesterolemia Coronary stenosis: still valid model if do not know the answer Severe anginal symptoms: 2 or more episodes within 24 hrs CKMD or troponin
  • People (some cardiologist) want o use GP 2b/3a inh when score is 5 or above
  • Subgroup analysis of UFH vs LMW heparin; different slope
  • Level 5 since database group was comparing UFH to LMW heparin…
  • Personnalize TIMI risk program Do it slowly
  • Considering side-effects…
  • From international group ECG changes or hx of CAD (no markers) Fairly good but not perfect: B-blocker 40% miss, 15% decr mortality = 6% gain Nitrates is highlighted because if CP + heparin + nitro = GP2b/3a inh
  • TACTICS: 97% cath vs 51% cath = 520 extra pts got cath CEP: death, MI, readmission for ACS within 6 months
  • 11% at 6 months
  • 1 nothing 2 stented 3 stent or CABG 4 CABG
  • Just to let you know
  • Is it really justify???
  • ? Definition of UA vs NSTEMI
  • Cocaine coronary blood flow: from 140 to 120 (down to 100 with propranolol)

    1. 1. NSTEMI and antithrombotics Part II Dr. Gilbert Boucher R4 Emergency Medicine McGill
    2. 2. Last time: <ul><li>Review definitions of Non-ST-elevation Myocardial infraction and related items. </li></ul><ul><li>Prognostic factors. </li></ul><ul><li>Current therapies. </li></ul>
    3. 3. Today: <ul><li>Finish anticoagulants. </li></ul><ul><ul><li>Hirudin </li></ul></ul><ul><li>Gp IIb/IIIa inhibitors. </li></ul><ul><ul><li>Their indications… </li></ul></ul><ul><li>Treatment strategies. </li></ul><ul><ul><li>Early vs late angio. </li></ul></ul><ul><li>Special groups. </li></ul>
    4. 4. www.acc.org What's New?   October 4 , 2001 Practice Guidelines: Atherosclerotic Cardiovascular Disease   September 1 , 2001 Practice Guidelines: Atrial Fibrillation   April 27 , 2001 Practice Guidelines: Percutaneous Coronary Intervention   April 27 , 2001 Expert Consensus Document: Catheterization Laboratory Standard   April 3 , 2001 Consensus Conference Report: Care of the Patient with Adult Congenital Heart Disease   April 2 , 2001 Expert Consensus Document: Standards for Acquisition, Measurement and Reporting of Intravascular Ultrasound Studies   March 1, 2001 Teaching Slides: ACC/AHA Guidelines for the Management of Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction   January 1, 2001 Consensus Conference Report: Mechanical Cardiac Support 2000: Current Applications and Future Trial Design   November 1, 2000 Clinical Competence Statement: Invasive Electrophysiology Studies, Catheter Ablation, and Cardioversion   October 1, 2000 Clinical Competence Statement: Stress Testing   September 1, 2000 Practice Guidelines: Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction September 1, 2000 Consensus Conference Report: Myocardial Infarction Redefined—A Consensus Document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction   July 1, 2000 Expert Consensus Document: Electron-Beam Computed Tomography for the Diagnosis and Prognosis of Coronary Artery Disease   June 1, 2000 Training Statement: Adult Cardiovascular Medicine (COCATS) Revised 6/00 Task Force #5: Training in Nuclear Cardiology
    5. 5. Anticoagulants <ul><li>UFH </li></ul><ul><li>LMW heparin </li></ul><ul><li>Hirudin </li></ul>
    6. 6. Hirudin <ul><li>Direct thrombin inhibtor. </li></ul><ul><li>For patients with HIT or history of. </li></ul><ul><li>Binds directly to catalytic site of thrombin without going through antithrombin III </li></ul><ul><li>TIMI 7: better than ASA alone in UA… </li></ul><ul><li>Mild improvement compared to UFH but increase in bleeding, no benefit in STEMI. </li></ul><ul><li>Meta-analysis shows OR of 0.90 </li></ul>
    7. 7. Platelet GP IIb/IIIa Receptor Antagonists <ul><li>Activation of platelets leads to configurational change increasing affinity for fibrin and other ligands </li></ul><ul><li>Necessary final step to platelets aggregation. </li></ul><ul><li>Needs 80% blockade to achieve potent antithrombotic effects </li></ul>
    8. 9. GP IIb/IIIa Receptor A ntagonists. <ul><li>Abciximab (reopro) : non-specific binding </li></ul><ul><ul><li>Unclear significance </li></ul></ul><ul><li>Eptifibatide (integrilin), tirofiban (aggrastat): very specific binding achieve >80% within 5 minutes </li></ul><ul><li>Different antagonists can bind at different sites and can paradoxically activates the GPIIb/IIIa receptor </li></ul><ul><ul><li>?what is happening with the oral form. </li></ul></ul>
    9. 10. GP IIb/IIIa Receptor A ntagonists <ul><li>4 main studies </li></ul><ul><li>2 positives </li></ul><ul><li>High-risk features </li></ul><ul><li>11.7% vs 8.7%, </li></ul><ul><li>15.7% vs 14.2% </li></ul>
    10. 11. <ul><li>Infarction </li></ul><ul><li>  </li></ul><ul><li>                                                                                                                 </li></ul>
    11. 12. Numbers… <ul><li>PRISM: Platelet Receptor Inhibition in Ischemic Syndrome Management. </li></ul><ul><ul><li>heparin (non-weight based) vs tiroban X 48hrs </li></ul></ul><ul><li>ECG changes or enzymes or very strong hx of CAD </li></ul><ul><li>Composite end-point better at 48hr but only trend at 30 days. </li></ul><ul><li>MI/death: non-significant at 48 hrs but + at 30 days (3.6 vs 2.3%). </li></ul><ul><li>?Playing/fishing for numbers </li></ul>
    12. 13. PRISM: Lancet 1999 <ul><li>                                            </li></ul>Figure 1: Adjusted hazard ratios (95% CI) for treatment with tirofiban by troponin I quartiles <ul><li>                                            </li></ul>Figure 2: Event-rate curves (mortality, myocardial infarction) for 30-day follow-up for patients with + troponin I
    13. 14. Numbers… <ul><li>Prism-plus: Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms </li></ul><ul><li>THE study </li></ul><ul><li>ST changes or + enzymes </li></ul><ul><li>Tiroban alone dropped due to too much mortality </li></ul><ul><ul><li>4.6% vs 1.1 and 1.5%??? (remember PRISM study) </li></ul></ul><ul><li>At 7 days, composite end-point: 17.9% vs 12.9% </li></ul><ul><li>22% CEP reduction at 30 days ( absolute 3.8% ) </li></ul><ul><li>19% CEP reduction at 6 months ( absolute 4.4% ) </li></ul>
    14. 15.                                                           Figure 10
    15. 16. Numbers… <ul><li>PURSUIT: Eptifibatide </li></ul><ul><ul><li>Platelet Glycoprotein IIb/IIIa in Unstable Angina:Receptor Suppression Using Integrilin Therapy. </li></ul></ul><ul><ul><li>11 000 pts </li></ul></ul><ul><ul><li>+ ECG changes or enzymes rise </li></ul></ul><ul><li>Death or MI at 30 days: 15.7% vs 14.2% </li></ul><ul><ul><li>9.1% vs 7.6% at 4 days </li></ul></ul><ul><ul><li>11.6% vs 10.1% at 7 days </li></ul></ul><ul><ul><li>Major bleed increased by 1.5% </li></ul></ul><ul><li>Cath rate overall: 60% </li></ul>
    16. 17. Real Numbers! <ul><li>GUSTO IV:Lancet June 2001 </li></ul><ul><li>Abciximab: 7800 pts without PCI </li></ul><ul><li>Same mortality at 30 days: 8-9% </li></ul><ul><ul><li>Despite all sorts of subgroup analysis… </li></ul></ul>
    17. 18. Antithrombotics: 1, 2 or 3 agents??? <ul><li>  </li></ul>
    18. 20. Cardiogenic shock… BAD!!! <ul><li>Circulation 1999: GUSTO IIb </li></ul><ul><li>200 pts with NSTEMI and shock </li></ul><ul><ul><li>Incidence of 2.5% </li></ul></ul><ul><li>73% mortality </li></ul><ul><li>But median time to shock 76 hrs… </li></ul><ul><ul><li>9.6 hrs in STEMI </li></ul></ul>
    19. 21. Last words: <ul><li>Journal of Emergency Medicine </li></ul><ul><ul><li>October 2000: </li></ul></ul><ul><ul><li>“ The effect of early ED treatment with GPIIb/IIIa inhibitors has never been formally studied until now”. </li></ul></ul><ul><ul><li>EARLY trial will compare early ED, vs late C CU vs catheterization laboratory </li></ul></ul>
    20. 22. TIMI score <ul><li>JAMA, August 16, 2000 </li></ul><ul><li>Databases of ESSENCE and TIMI11B </li></ul><ul><li>12 variables, 7 significants </li></ul><ul><ul><li>Age > 65yo </li></ul></ul><ul><ul><li>3 risk factors for CAD </li></ul></ul><ul><ul><li>Prior coronary stenosis of > 50% </li></ul></ul><ul><ul><li>St deviation </li></ul></ul><ul><ul><li>Severe angina symptoms </li></ul></ul><ul><ul><li>ASA use within 7 days </li></ul></ul><ul><ul><li>Elevated serum cardiac markers </li></ul></ul>
    21. 23. <ul><li>GP IIb/IIIa inh for score 5 or above??? </li></ul>                                           Figure 1. TIMI Risk Score   Rates of all-cause mortality, myocardial infarction, and severe recurrent ischemia prompting urgent revascularization through 14 days after randomization were calculated for various patient subgroups based on the number of risk factors present in the test cohort (the unfractionated heparin group in the Thrombolysis in Myocardial Infarction [TIMI] 11B trial; n = 1957) (see Table 1). Event rates increased significantly as the TIMI risk score increased ( P <.001 by   2 for trend).
    22. 24.                                                                                             Figure 2. Validation of TIMI Risk Score and Assessment of Treatment Effect According to Score   Rates of all-cause mortality, myocardial infarction, and severe recurrent ischemia prompting urgent revascularization through 14 days after randomization were calculated for the enoxaparin and unfractionated heparin groups in the Thrombolysis in Myocardial Infarction (TIMI) 11B trial and the Efficacy and Safety of Subcutaneous Enoxaparin in Unstable Angina and Non-Q-Wave MI trial (ESSENCE), based on the TIMI risk score. The pattern of increasing event rates with increasing TIMI risk score was confirmed in all 3 validation cohorts ( P <.001 by   2 for trend). C statistics were 0.65 for the unfractionated heparin group and 0.61 for the enoxaparin group in TIMI 11B; and 0.65 for the unfractionated heparin group and 0.59 for the enoxaparin group in ESSENCE. The rate of increase in events as more risk factors were present was significantly lower in the enoxaparin group in both studies (for TIMI 11B, P = .01; for ESSENCE, P = .03). Positive values for absolute risk difference (ARD) and number needed to treat to prevent 1 event (NNT) indicate calculations favoring enoxaparin, while negative values indicate calculations favoring unfractionated heparin.
    23. 25. As Dr. Lang would said… <ul><li>Auto-validation on its own cohort </li></ul><ul><li>Retrospective </li></ul><ul><li>Specific (but large) group </li></ul><ul><li>That would make it a level…4 if we want to use it as a Clinical decision rule to know whether or not to use GP IIb/IIIa inhibitors. </li></ul>
    24. 26. TIMI Risk Calculator For Unstable Angina In the blue column, please enter the patient's age, and then answer each clinical question with a Y (for yes) or an N (for no).  The patient's risk appears at the bottom of the blue column.
    25. 27. Cost $$$$ <ul><li>Tiroban: 950$/3 days </li></ul><ul><li>Abciximab: 2000$/treatment </li></ul><ul><ul><li>But how come we are almost never using streptokinase anymore… are we reasonable??? </li></ul></ul>
    26. 28. What about: Plavix vs GP IIb/IIIa? 18.8% vs 16.5% 17.9 vs 12.9% JUST a thought  …
    27. 29. But back to standard of care… The classics: How do we do? <ul><li>In-hospital drugs treatment (%), 1998 </li></ul><ul><li>USA Canada World </li></ul><ul><li>Intravenous heparin 79 88 73 </li></ul><ul><li>Aspirin 91 92 92 </li></ul><ul><li>B-blockers 57 73 63 </li></ul><ul><li>Calcium antagonists 59 53 53 </li></ul><ul><li>Intravenous nitrates 68 40 51 </li></ul>
    28. 30. Angio: stat or later <ul><ul><li>TACTICS: N Engl J Med 2001; 344:1879-1887, Jun 21, 2001 </li></ul></ul><ul><ul><li>2220 patients, within 48 hours vs selectively </li></ul></ul><ul><ul><li>all got ASA, heparin, GPIIb/IIIa inh </li></ul></ul><ul><ul><li>15.9% vs 19.4% at 6 months </li></ul></ul><ul><ul><li>6% more CABG , 520 extra caths/1100 pts </li></ul></ul><ul><ul><li>MI: 4.8% vs 6.9% </li></ul></ul><ul><ul><li>Pre GPIIb/IIIa inhibitors: TIMI3b (1995) </li></ul></ul><ul><ul><ul><li>Early 18.1% vs 16.2% late </li></ul></ul></ul><ul><ul><ul><li>Decr length of stay </li></ul></ul></ul><ul><ul><li>VANQWISH Investigators: 920 pts </li></ul></ul><ul><ul><ul><li>Early 7.8% vs 3.3% late at hospital discharge </li></ul></ul></ul>
    29. 31. More does not equal better <ul><li>Lancet 1998; 352: 507–14 </li></ul><ul><li>8 000 pts, various countries (Brazil, USA, Canada, Australia, Hungary, Poland) </li></ul><ul><ul><li>59% vs 21% angio rate </li></ul></ul><ul><ul><li>Same overall MI/death rate : 4.7% at 7 days </li></ul></ul><ul><li>Late angio: decreased rate of overall cardiovascular event (including stroke) despite higher recurrent angina </li></ul>
    30. 32. What do we find anyway on angio… <ul><li>Typically shows the following profile: </li></ul><ul><ul><li>1) no severe epicardial stenosis in 10% to 20% </li></ul></ul><ul><ul><li>2) 1-vessel stenosis in 30% to 35% </li></ul></ul><ul><ul><li>3) multivessel stenosis in 40% to 50% </li></ul></ul><ul><ul><li>4) significant ( .50%) left main stenosis in 4% to 10%. </li></ul></ul>
    31. 33. Next: early statin ???!!!… <ul><ul><li>Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) </li></ul></ul><ul><li>JAMA April 2001 </li></ul><ul><li>2000 pts </li></ul><ul><ul><li>Atorvastatin 80mg/d between 24 and 96hrs of admission. </li></ul></ul><ul><ul><li>17.4% vs 14.8% at 4 months, mostly recurrent symptomatic ischemia requiring rehospitalization. </li></ul></ul>
    32. 34. Risk stratification <ul><li>Noninvasive stress testing in low-risk patients who have been free of ischemia at rest or with low-level activity and of CHF for a minimum of 12 to 24 h. (Level of Evidence: C) </li></ul>
    33. 35.                                                                                                                                                               
    34. 36. Risk stratification <ul><li>Stress test only if free of: </li></ul><ul><ul><li>ST-segment abnormalities </li></ul></ul><ul><ul><li>bundle-branch block </li></ul></ul><ul><ul><li>LV hypertrophy </li></ul></ul><ul><ul><li>Intraventricular conduction defect </li></ul></ul><ul><ul><li>Paced rhythm </li></ul></ul><ul><ul><li>Preexcitation </li></ul></ul><ul><ul><li>Digoxin effect. </li></ul></ul><ul><ul><li>Otherwise need imaging: echo or thallium… </li></ul></ul>
    35. 37. Special groups <ul><li>Women: more atypical symptoms </li></ul><ul><ul><li>?better outcome in UA then men </li></ul></ul><ul><li>Elderly: More disease </li></ul><ul><li>Diabetics: Increased risk for any ACS </li></ul><ul><li>Post-CABG: low threshold angio </li></ul><ul><li>All same protocols and numbers… </li></ul>
    36. 38. Cocaine users <ul><li>Coronary vasospasms </li></ul><ul><ul><li>Worsen by minimal atherosclerosis </li></ul></ul><ul><ul><li>Reversed by CCB </li></ul></ul><ul><ul><li>ST-changes in 38% of pts in detox centers </li></ul></ul><ul><li>Detoxify by cholinesterase in liver and plasma </li></ul><ul><ul><li>Less available in infants or elderly </li></ul></ul><ul><li>Increased platelets sensibility </li></ul><ul><li>Decrease antithrombin III and protein C </li></ul>
    37. 39. Cocaine users as per AHA <ul><li>NTG and CCB for ST changes </li></ul><ul><li>Angio if persistent ST elevation or if thrombus found </li></ul><ul><ul><li>Thrombolysis if not available </li></ul></ul><ul><li>B-blockers if sBp > 150 or HR > 100 </li></ul><ul><ul><li>Labetolol preferred </li></ul></ul>
    38. 40. B-blockers for cocaine users??? <ul><ul><li>Annals of Internal Medicine . Jun 1990 </li></ul></ul><ul><ul><li>30 volunteers </li></ul></ul><ul><li>In cath lab </li></ul><ul><li>Cocaine followed by propranolol </li></ul><ul><li>No change in Hr or BP but: </li></ul><ul><ul><li>50% incr in coronary resistance with 20% decr in flow </li></ul></ul><ul><ul><li>No mention of benzos??????? </li></ul></ul>
    39. 41. Conclusion <ul><li>Troponemia is a bad sign. </li></ul><ul><li>Lots of studies/numbers out there </li></ul><ul><li>Stratification is probably the way to go to target selected population but can we rely on present evidences… </li></ul>
    40. 42. Questions?