Acute Coronary Syndromes

1. Acute Coronary Syndromes Dr. S. McPherson Dr. G. Curry July 11, 2002

2. Chest Pain – the initial presentation 2 questions to be answered: Are the symptoms a manifestation of an ACS? If so, what is likelihood of an adverse outcome?

3. Chest pain – the initial presentation • Early Risk stratification: • Categorize patients with chest pain into high, intermediate, and low risk of ACS • Use of history (anginal symptoms), physical exam, ECG, biochemical markers

4. Historical features Classic characteristics: • Deep chest or arm pain associated with exertion or emotional stress • Resolves promptly with rest or NTG Not characteristic: • Pleuritic • Primarily mid to lower abdominal pain • Pain that is localized with 1 finger • Reproducible pain with palpation or movement • Constant pain X hours • Very brief pain lasting few seconds or less • Pain radiates to lower extremities

5. Incidence of ACS with noncharacteristic symptoms Arch Int Med 1985;145:65-9 • Sharp or stabbing pain 22% • Pleuritic 13% • Reproducible to palpation 7% Med Care 1991; 29:610-27, J Critic epi 1992;85:1254-64 • Traditional risk factors only weakly predictive of ACS • But presence of risk factors relate to poorer outcomes

6. Estimation of the likelihood of ACS

7. Estimation of the risk of adverse outcome

8. Estimation of the risk of adverse outcomes JAMA 1996;276:1568-74 • Looked at 30 day mortality or MI in patients with high, intermediate and low risk UA (AMI and noncardiac CP excluded) • Low risk 0% • Intermediate risk 1.2% • High risk 1.7%

9. Management recommendations • Low risk: expeditious work up as an outpatient (ie within 72 hrs of d/c from ED) • High and intermediate risk admit for further work up

10. The ECG • Progression of changes • Giant R wave • Hyperacute T waves (release of intracellular K+) • ST elevation (current of injury) • Q wave (shift of axis of depolarization) • Inverted T waves (abnormal repolarization

11. Interpreting the ECG • ECG • Inferior  II, III, aVf • Lateral  I, aVL, V5-6 • Anterior  V1-4 • Posterior  ST depression ant V1-3 with large R V1

12. Interpreting the ECG • ECG in association with old LBBB (Sgarbossa) any concordant change >1mm any discordant change > 5mm *same applies for VPB rhythm • 15 lead ECG prognostic value  sensitivity

13. Interpreting the ECG • ST elevation of > 0.1 mV confirmed >90% of the time by biochemical markers to be AMI • Up to 15% of AMI have a normal or nonspecific ECG • ST depression of > 0.05 mV or T wave inversion of > 0.2 mV may represent cardiac ischemia

14. Prognostic value of the ECG

15. Prognostic value of the ECG

16. Biochemical Cardiac Markers • Lab • CK, CKMB • At 24Hrs sensitivity reaches >95% • Specificity problem (high false positive rate) • Doesn’t predict USA • Troponins (TnT, TnI) • T1/2 : 3-8 hrs, but detected for up to 10 days

17. Biochemical markers • Enzyme comparison Markertime to  peak time to normmyoglobin 1-3 6-10 24-36 CK 3-8 10-36 72-96 CK-MB 3-8 9-30 48-72 CK-MB iso 1-3 4-6 18-24 cTnT 2-6 10-24 10-15 days cTnI 2-6 12-24 7-10 days

18. Troponins sensitivity Ebell 2000

19. Troponin the main points • Troponin should NOT determine disposition • General Numbers to remember • 6 -----------------> 60% sensitive • 8 -----------------> 80% sensitive • 10 -----------------> 90% sensitive • Patients with TnT + and CKMB – have worse prognosis (increased death and CV events at 30 days)

20. False + troponin • Troponins: increase levels? • Ischemia/ infarction • Cardiomyopathy • Electrical injury • Pericarditis • Myocarditis • Cardiac contusion • Hypertensive emergencies • End- stage renal failure • Pulmonary embolus

21. Case 1 & 2 • Insert a low risk ACS case and a high or intermediate case and have group decide what to do in light of the previous slides

22. Unstable angina/NSTEMI Canadian Cardiology Classification of Angina • Class I. Ordinary physical activity (e.g., walking or climbing stairs) does not cause angina. • Class II. Slight limitation of normal activity; angina occurs with walking, climbing stairs, or emotional stress. • Class III. Severe limitation of ordinary physical activity; angina occurs on walking one or two blocks on a level surface or climbing one flight of stairs in normal conditions. • Class IV. Inability to carry on any physical activity without discomfort; anginal symptoms may be present at rest.

23. USA/NSTEMI • Definition of Unstable Angina: Rest angina. Angina occurring at rest, lasting longer than 20 minutes, and occurring within 1 week of presentation New-onset angina. Angina of at least class III severity with onset within the last 2 months Increasing angina. Previously diagnosed angina that is more frequent, longer in duration, or increased by one class within the last 2 months of at least class III severity • Definition of NSTEMI: Evidence of myocardial necrosis with rise in biochemical markers

24. Case # 3 • Insert case of classic USA here

25. Anti-ischemic therapy: Bedrest Oxygen NTG Morphine B-blocker CCB ACE Anti-platelet/Anti-thrombotic therapy: ASA Clopidogrel GPIIbIIIA Heparin LMWH Management of UA/NSTEMI

26. Anti-ischemic therapy • Oxygen • No evidence to support administration of O2 to all patients with ACS • Recommended for patients with questionable respiratory status and hypoxia

27. Anti-ischemic therapy Nitrates: • 0.4mg sl or spray q5min • Initiate NTG infusion if above does not resolve pain (contraindicated if hypotension or pt has used Viagra within 24hr); titrate q3min to effect or until SBP < 110mmHg

28. Nitrates – the evidence • Meta-analysis of the small trials (pre-lytic) showed a 35% reduction in mortality • ISIS-4 and GISSI-3 showed no mortality benefit but frequent pre-hospital and hospital use of NTG in the control group • BOTTOM LINE: we all use it, it makes patients feel better, it doesn’t seem to harm most patients

29. Anti-ischemic therapy Morphine: • 1-5 mg iv recommended for patients with ongoing pain post NTG x3 • May give with iv NTG but watch BP • No RTC to validate its benefit or clarify its optimal schedule • Adverse effects: hypotension, N&V (20%), resp depression

30. Anti-ischemic therapy B-Adrenergic blockers: • Metoprolol 5mg iv q5min, if tolerate 15mg start 25mg po 15min after last iv dose • Contrindications: • 1st, 2nd, 3rd degree heart block, LV dysfunction, CHF, asthma, sinus brady, hypotension, cautiously in patients with COPD

31. B-blockers the evidence • Overview of all RPCT (small) showed 13% reduction is progression to AMI, not powered to detect difference if mortality JAMA 1988 • Use in USA extrapolated from mortality reduction proven in AMI, stable angina, heart failure

32. Anti-ischemic therapy Calcium channel blockers: • To control ongoing or recurrent pain when maxed therapy of B-blocker/NTG, NTG/B-blocker not tolerated or variant angina • Do not use nifedipine • Do not use verapamil or diltiazem if evidence of acute CHF • Evidence supports role for symptom control with use as a rate control if B-blocker not tolerated

33. UA/NSTEMI – Antiplatelet therapy • ASA • Clopidogrel • GPIIbIIa inhibitors

34. Anti-platelet therapy ASA: • 160-325mg to chew ASAP • All trials have shown mortality benefit that extends to 2 years • Contraindications: • Allergy • Active bleeding (GI, retinal) • Hemophilia

35. Anti-platelet therapy Clopidogrel • CAPRIE (1996), RCT ASA vs Plavix (N=19,185) • 3 year ischemic stroke, MI or death ARR = 0.5% (NNT = 200) • Plavix equal to ASA but increased side effects (diarrhea, rash, GI bleed)

36. Anti-platelet therapy Clopidogrel: • CURE trial (2001) RCT Plavix + ASA vs ASA • UA/NSTEMI within 24 hr • Death, MI, or stroke 3 and 12 month ARR = 2.2% (NNT = 45) • Excess in major bleed of 1% (NNH = 100) • Risk of bleed with CABG increased in 1st 5 days • Recommended in UA/NSTEMI when noninvasive course is anticipated • BOTTOM LINE: appears to work but not for us to start in the ED

37. Anti-platelet therapy GPIIbIIIa Receptor Antagonists: • Inhibits the cross-linking of platelets by fibrinogen

38. GPIIbIIIa RA • EPIC (abcixamab) NEJM 1994 • PRCT, N=2,099 pts • High risk pts going for PCI (AMI, USA) • Reopro(bolus, bolus +infusion) vs placebo • Placebo vs bolus similar • F/U 30 days • Bolus/infusion: lower rate triple end-point (Death, MI or urgent revascularization) 8.3% vs 12.8% (ARR 4.5%, RRR 35%) • 2 fold increase in major bleeds: 14% vs 6.6 (ARI 7.4%, RRI 112%!!!

39. GPIIbIIIa RA • CAPTURE (abcixamab) Lancet 1997 • PRCT, N=1050 pts (stopped early) • Pts with refractory USA, after cath and before plasty • Reopro vs placebo , 18-24hrs before plasty, and 1 hr after • F/U 30 days then 6 months • Composite endpoint at 30 days(Death, MI, urgent intervention ): 2.6% vs 5.5% (ARR 2.9%, RRR 53%) • At 6 months: no difference! (decreased early events only) • Major bleeding: 3.8% vs 1.9% (ARI 1.9%, RRI 50%)

40. GPIIbIIIa RA • CAPTURE (substudy) • Predictive value of TnT • Increased TnT(>0.1 ng/ml): 30.9% • F/U 6 months: Death or MI • TnT +ve • Reopro 9.5% vs placebo 23.9% (ARR 14.4%, RRR 60% • TnT –ve • Reopro 7.5% vs 9.4% (not significant) • Conclusion: TnT +ve identifies a high risk population that seems to benefit from GIIb-IIIa’s

41. GPIIbIIIa RA • PRISM-PLUS (tirofiban) NEJM 1998 • PRCT, N=1,570 pts • Non-ST segment elevation ACS and likely to go to catheterization • Heparin vs tirofiban vs combination • Tirofiban alone arm stopped (increased mortality at 7 days) • F/U 7 and 30 days and 6 months • Composite endpoint (Death, MI or recurrent ischemia): 7 days: 12.9 vs 17.9% (p=0.004), 30 days: not significant, 6 months: 27.7 vs 32.2% (p=0.02)

42. GPIIbIIIa RA • PURSUIT (eptifibatide) • PRCT, N=10,948 pts • Eligible if ECG changes : transient ST elevation, ST depression, T wave inversion, or positive CKMB • Eptifibitide vs placebo • F/U 30 days and 6 months • Double endpoint (Death or MI): 30 days: 14.2 vs 15.7% (ARR 1.5%, RRR 10%), 6 months: 12.1 vs 13.6% (ARR 1.5%, RRR 11%) • Medical Management: US benefit, Europe and Latin America no benefit • Didn’t work in females!!!!!

43. GPIIbIIIa RA • GUSTO IV • PRCT, N=7800 pts • ECG changes, +ve troponin level • Early revascularization strongly discouraged • Abcixamab vs placebo (24-48 hr infusion) • No difference in MI or Death

44. GPIIbIIIa RA BOTTOM LINE: • They are definitely indicated as an adjunct to PCI • Role in UA/NSTEMI is questionable, there appears to be a small reduction in death or MI in high risk groups (ongoing or recurrent pain, dynamic ST changes) • Not enough evidence for us to start in the ED

45. Anti-thrombotic therapy Unfractionated Heparin: • 5000 Unit bolus then 1000 unit/hr • Evidence is scanty: • Theroux et al (1993) RCT ASA+hep vs ASA • Decreased rates of MI (fatal and nonfatal) 3% (NNT = 33%) • RISC (1990) ASA vs UFH vs UFH +ASA • ASA + UFH had lowest events in 1st 5 days

46. Anti-thrombotic therapy LMWH: • ESSENCE (1997) RCT enoxaparin vs UFH • No difference in mortality • Composite endpoint of death, MI or recurrent angina, ARR = 3.2% (NNT=33) • TIMI 11B (1999) RCT enoxaparin vs UFH • Composite endpoint death, MI, urgent need for PTCA, ARR = 2.1% (NNT = 50) • 2 trials (1 dalteparin, 1 nadroparin) had neutral or unfavorable trends

47. Anti-thrombotic therapy

48. Case #4 • Insert case for AMI here

49. Diagnosis of AMI • WHO def’n (2 of 3): • Ischemic type chest discomfort • Rise & fall in serum cardiac markers • Changes on ECG • ST elevation 91% specific, 46% sensitive for MI

50. Management of AMI • Routine measures: • Supplemental O2 • Iv access • ECG interpreted within 10 minutes of arrival to ED