ST-Elevation Myocardial Infarction

1. Tauhid Ahmed Bhuiyan, PharmD PGY-1 Resident King Faisal Specialist and Research Center (KFSH&RC) ST-Elevation Myocardial Infarction (STEMI): A Topic Review and Case Presentation King Faisal Specialist Hospital and Research Center (KFSHRC) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. (UAN# 0833-0000-14-064-L01-P , 0833-0000-14-064-L01-T )

2. Objectives Provide an overview of STEMI in terms of epidemiology, etiology, pathophysiology, and risk factors Identify key diagnostic criteria to diagnose STEMI Review current guideline directed standard of care in the management of STEMI Analyze a patient case related to the topic I do not have financial relationship and no actual or potential conflict of interest in relation to this activity

3. Background STEMI : An acute coronary event that results in complete occlusion of the coronary artery Myocardial Ischemia Myocardial infarction (MI) is the manifestation of prolonged ischemic event Ischemia is associated with Persistent ST segment elevation on electrocardiography (ECG) Release of cardiac biomarkers of myocardial necrosis Emergency requiring immediate medical intervention

4. Spectrum of Acute Coronary Syndrome Fox K. Heart 2004; 90:698-706

5. Epidemiology Estimated annual incidence of myocardial infarction (MI) in the United States: New: 565 K Repeat: 300 K STEMI accounts for 30%-40% ~20%-30% patients die before reaching to the hospital In-hospital and 30-day mortality rates have been estimated to be 8.8% and 18.4%, respectively O’Gara PT et al. Circulation ; 2013; 127

6. Kingdom of Saudi Arabia Osman et al. conducted a prospective observational trial of 205 patients at Prince Sultan Cardiac Center in Riyadh, Saudi Arabia STEMI accounted for 19.5% of diagnosis at admission and has the highest direct medical cost (58K SAR/patient) Gulf RACE – 2 study by AlHabib et al: 9 month prospective, multicenter study Evaluated data on patients with acute coronary syndromes and their long term outcomes in the Arabian Gulf countries STEMI accounted for 45.6% of the cases (N=7930) Osman AM et al. Saudi Med J ; 2011; 32(12):1279-84 Alhabib KF et al. Ann Saudi Med; 2012; 32(2):9-18

7. Etiology Most common : A therosclerotic disease Less common : Coronary embolism Coronary vasospasm (e.g. prinzmetal’s angina) Drug induced (e.g. cocaine, chemotherapeutic agents) Spontaneous coronary dissection or aortic dissection

8. Coronary Circulation Originates from the aorta Right coronary artery bifurcates into: Right marginal artery Posterior descending artery Left coronary artery bifurcates into: Left anterior descending artery (LAD) Circumflex artery http://labelled-diagram-of-the-human-heart.blogspot.com/2009/07/coronary-arteries.html

9. Pathophysiology Rupture of “vulnerable” atherosclerotic plaque Activation of coagulation cascade and fibrin deposition Partial (NSTMI) or totally occlusive (STEMI) coronary vessel Myocardial ischemia and necrosis http://pmtwww.uptodate.com/contents/image?imageKey=PI/60394&topicKey=PI%2F3428&source=outline_link

10. Coagulation cascade http://openi.nlm.nih.gov/imgs/512/349/2496975/2496975_vhrm0402-305-01.png

11. Risk Factors Non-modifiable Age Gender Family history of atherosclerotic coronary artery disease Modifiable Hyperlipidemia Diabetes Mellitus Hypertension Tobacco use Bolooki MH et al. Acute Myocardial Infarction. Available at: http://www.clevelandclinicmeded.com

12. Early Risk Assessments Global Registry of Acute Coronary Event ( GRACE ) risk score: Predicts in-hospital and 6-months mortality rate http://www.outcomes-umassmed.org/grace/acs_risk/acs_risk_content.html Thrombolysis In Myocardial Infarction ( TIMI ) risk score: Estimates overall mortality of STEMI http://www.mdcalc.com/timi-risk-score-for-stemi/ O’Gara PT et al. Circulation ; 2013; 127

13. Clinical Presentation D iffer by gender and age Midline anterior and/or retrosternal chest pain/discomfort lasting >20 minutes in duration May radiate to shoulder, arm, back, jaw Unremitting May describes as pressure sensation, fullness, or heaviness Associated symptoms : nausea and vomiting, palpitations, diaphoresis or sweating, dyspnea or shortness of breath, cough, syncope, or low grade fever Patient may present with acute heart failure, tachycardia, bradycardia , or heart block Hypotension or cerebrovascular symptoms in elderly Koda-Kimble MA et al. Myocardial Infarction. In: Applied Therapeutics: The Clinical Use of Drugs, 2009

14. Diagnosis

15. Classic Triad Ischemic symptoms ECG changes Release of cardiac biomarkers

16. New ST-elevation at the J point (at least 2 contiguous leads): ≥ 2 mm (0.2 mV) in men ≥ 1.5 mm(0.15 mV) in women OR ≥ 1 mm (0.1 mV) in other contiguous chest leads or limb leads ST-depression: ≥ 2 precordial leads (V 1 – V 4 ): may indicate transmural posterior injury Established MI Presence of Q waves of ≥ 0.03 s in leads V 1 – V 6 or II, aVL, aVF 12-Lead Electrocardiogram (ECG) V 2 – V 3 O’Gara PT et al. Circulation ; 2013; 127

17. Location of MI http://imgarcade.com/1/septal-mi/

18. Laboratory Markers Biomarkers CK Less specific for cardiac muscle necrosis CK-MB Detectable within 6 hours , falls within 48 hours Troponin I or T Detectable within 6 hours , remains elevated for 7-14 days DiPiro J. Acute Coronary Syndrome. In: Pharmacotherapy: A Pathophysiological Approach, 2011

19. Complications of MI Ventricular remodeling Cardiogenic shock Death Valvular dysfunction Arrhythmias (VF/VT) Heart failure Bradycardia Heart block Pericarditis CVA secondary to LV thrombus Free wall rupture (e.g. VSD, papillary muscle dysfunction) DiPiro J. Acute Coronary Syndrome. In: Pharmacotherapy: A Pathophysiological Approach, 2011

20. Management

21. Goals of Therapy Short term: Early restoration of epicardial blood flow and myocardial perfusion in the infarct zone Relief ischemic chest discomfort and restoration of ECG changes Long term: Prevent death or MI complications Prevent reocclusion or reinfarction DiPiro J. Acute Coronary Syndrome. In: Pharmacotherapy: A Pathophysiological Approach, 2011

22. ACC/aha Classification of recommendations O’Gara PT et al . Circulation ; 2013; 127

23. Management

24. Reperfusion Therapy Prompt and effective reperfusion therapy is the cornerstone for treatment of STEMI Selection of reperfusion depends on chance of achieving early and persistent reperfusion with lowest risk of major complications Guideline recommendation: Should be administered to all eligible patients with STEMI with symptoms onset within the prior 12 hours(Class 1; LOE: A) 12-24 hours for patient with ongoing ischemia (Class IIa; LOE: B) DiPiro J. Acute Coronary Syndrome. In: Pharmacotherapy: A Pathophysiological Approach, 2011

25. Types of Reperfusion Primary Percutaneous Coronary Intervention (PPCI) Fibrinolytics Balloon angiography Strptokinase Alteplase Reteplase Tenecteplase Placement of intracoronary stent: Bare-metal stent (BMS) Drug-eluting stent (DES) O’Gara PT et al . Circulation ; 2013; 127

26. O’Gara PT et al. Circulation ; 2013; 127 Rescue PCI PCI: percutaneous coronary intervention FMC: first medical contact CABG: coronary artery bypass graft Algorithm of therapy

27. Timing to reperfusion therapy Treatment Recommended Time for Initiation of Treatment PCI Door-to-balloon time ≤ 90 min Fibrinolytic agents Door-to-needle time ≤ 30 min Hilleman DE et al. Pharmacotherapy. 2007;27(11):1558-1570

28. Primary pCI (PPCI) http://www.youtube.com/watch?v=S9AqBd4RExk

29. PPCI Indications: ACC/AHA Recommendations COR† LOE† Ischemic symptoms <12 h I A Ischemic symptoms <12 h and contraindications to fibrinolytic therapy irrespective of time delay from FMC I B Cardiogenic shock or acute severe HF irrespective of time delay from MI onset I B Evidence of ongoing ischemia 12 to 24 h after symptom onset IIA B PCI of a non-infarct artery at the time of primary PCI in patients without hemodynamic compromise III: Harm B COR: Classification of recommendation; LOE: level of evidence O’Gara PT et al. Circulation ; 2013; 127

30. pPCI >>> fibrinolytics Greatest survival benefit in high risk patient Higher rates of infarct artery patency with TIMI 3 flow (90%-PCI vs. <60%-fibrinolysis) Reduction in recurrent ischemia/reinfarction 30-day mortality reduction (6.5% to 4.4%) Reduction in stroke (2.0% to 0.7%) Reduced risk of bleeding Van De Wefr F. et al. Circulation. 2002;105: 2813-16 O’Gara PT et al. Circulation ; 2013; 127 TIMI Flow Grade Characteristics No perfusion 1 Penetration without perfusion 2 Partial reperfusion 3 Complete perfusion TIMI: Thrombolysis in Myocardial Infarction

31. Fibrinolytic therapy Acts on converting plasminogen to plasmin  cleaves fibrin  causing clot dissolution and restoration of blood flow Indications : Recommendations COR† LOE† Ischemic symptoms <12 h I A Evidence of ongoing ischemia 12 to 24 h after symptom onset and a large area of myocardium at risk or hemodynamic instability IIa C ST depression, except if true posterior MI is suspected or when associated with ST elevation in lead aVR III: Harm B O’Gara PT et al. Circulation ; 2013; 127 Hilleman DE et al. Pharmacotherapy. 2007;27(11):1558-1570

32. Choice of fibrinolytic agents Adjunctive antiplatelet and/or anticoagulant therapies are indicated, regardless of the choice of fibrinolytic agent Agents Fibrin Specificity Half-life (h) Patency Rate Alteplase (tPA) ( Activase® ) ++ 5 73%-84% Reteplase (rPA) ( Retavase® ) ++ 13-16 84% Tenecteplase ( TNKase ® ) ++++ 20-24 85% Streptokinase ( Streptase® ) No 18-23 60%-68%

33. Efficacy and safety data Hilleman DE et al. Pharmacotherapy. 2007;27(11):1558-1570

34. Dose and administration Agents Dose and Administration Alteplase (tPA)* 90 min infusion : 15 mg bolus, then Infusion 0.75 mg/kg for 30 min (max 50 mg), then 0.5 mg (max 35 mg) over the next 60 min; total dose not to exceed 100 mg; 60 mg administered within first hour, then 20 mg during second and third hour Reteplase (rPA) Two 10 unit boluses, each administered over 2 min, 30 min apart Tenecteplase (TNK) Single bolus administration over 5 sec; dose based on patient weight (max dose 50 mg): <60 kg: 30 mg; 60-69 kg: 35 mg; 70-79 kg: 40 mg; 80-89 kg: 45 mg; and ≥ 90 kg: 50 mg Streptokinase 1,500,000 units IV infusion over 30-60 min Hilleman DE et al. Pharmacotherapy. 2007;27(11):1558-1570 *KFSH&RC formulary

35. Contraindications to fibrinolytic therapy O’Gara PT et al. Circulation ; 2013; 127

36. Adjuvant therapies

37. Dual Antiplatelet therapy/DAPT

38. Platelet activation and mechanisms of adverse clinical outcome Alexopoulos D. Int J Card ; 2013; 163:249-55

39. Aspirin Irreversibly inhibits cyclooxygenase-1 and 2 enzymes  decreased formation of prostaglandin and thromboxane A 2  inhibit platelet aggregation ACC/AHA Recommendations PPCI 162-325 mg loading dose (IB) followed by ASA 81 mg daily (indefinitely) (IA) Fibrinolysis 162-325 mg loading dose (IA) followed by ASA 81 mg daily (indefinitely) (IA) O’Gara PT et al. Circulation ; 2013; 127

40. thienopyridines Prevents P2Y 12 component of ADP receptors on the platelet surface  blocking activation of GPIIb/IIIa receptor complex, thereby reduce platelet aggregation ACC/AHA Recommendations PPCI: Clopidogrel: 600 mg PO as early as possible or at the time of PCI (IB) followed by 75 mg daily (IB) Prasugrel: 60 mg as early as possible or at the time of PCI (IB) followed by 10 mg daily (IB) Ticagrelor: 180 mg as early as possible or at the time of PCI (IB) followed by 90 mg twice a day [ Note: maintenance therapy continue for 1 year for both BMS/DES ; dose of ASA should not exceed 100 mg with ticagrelor as DAPT] Fibrinolytics: Clopidogrel: Age ≤ 75 years: 300 mg loading dose (IA) followed by 75 mg daily for at least 14 days (IA) to 1 year in absence of bleeding (IC) Age >75 year: 75 mg once (IA) then daily for at least 14 days (IA) up to 1 year (IC) in absence of bleeding O’Gara PT et al. Circulation ; 2013; 127

41. Comparative advantage/disadvantage Agents Characteristics Contraindications Onset of Action Potency Variable Response Clopidogrel ( Plavix® ) Produrg, binds irreversibly Hypersensitivity , active pathological bleeding ++ + ++++ Prasugrel ( Effient ® ) Produrg, binds irreversibly Hypersensitivity, active pathological bleeding , prior TIA or stroke, age ≥ 75 years or body weight <60 kg ++++ +++ ̶ Ticagrelor ( Brilinta ® ) Nonthienopyridine, r eversible binding Hypersensitivity , active pathological bleeding , severe hepatic impairment ++++ +++ ̶ Alexopoulos D. Int J Card ; 2013; 163:249-55

42. Major trials—outcome comparison Alexopoulos D. Int J Card ; 2013; 163:249-55

43. Anticoagulation therapy

44. Caterina RD et al. Thromb Haemost ; 2013; 109:769-86

45. PPCI ACC/AHA Recommendations Unfactionated Heparin (UFH) With GP IIb/IIIa receptor antagonist planned: 50-70 U/kg IV bolus to achieve ACT (IC) With no GP IIb/IIIa receptor antagonist planned: 70-100 U/kg IV bolus to achieve ACT (IC) Bivalirudin (preferred over UFH in high bleeding risk patients) 0.75 mg/kg IV bolus then 1.75 mg/kg/h infusion with or without prior treatment with UFH (dose adjustment to 1mg/kg/h with CrCl <30 mL/min) (IB) Fondaparinux: not recommended as sole agent for PPCI (IIIB: Harm) O’Gara PT et al. Circulation ; 2013; 127 ACT: activated clotting time Anticoagulation

46. Fibrinolytic therapy O’Gara PT et al. Circulation ; 2013; 127

47. GP IIb/iiia receptor antagonist

48. Clinical Use Block the final common pathway of platelet aggregation (inhibiting cross-linking of platelets through fibrinogen bridges) Rationale to use in combination with UFH: Reduce likelihood of reinfarction Prevent distal embolization of thrombi during PPCI Should not be administered for medical management of the patients with STEMI not undergoing PCI Administration of GP IIb/IIIa inhibitors should be avoided, if possible, with bivalirudin due to increased bleeding risk Beygui F et al. Eur Heart J Supp ; 2005; 7: 110-114 DiPiro J. Acute Coronary Syndrome. In: Pharmacotherapy: A Pathophysiological Approach, 2011

49. Choice of agents Agent Molecule Dose Contraindications Abciximab ( ReoPro ®) Monoclonal antibody Bolus: 0.25 mg/kg Infusion: 0.125 mg/kg/hr x 12 hrs Active bleeding, thrombocytopenia, prior stroke, renal dialysis ( eptifibatide ) Eptifibatide Integrilin ®) Peptide Bolus: 180 mcg/kg x 2 Infusion: 2 mcg/kg/min x 18-24 hrs (1 mcg/kg/min if CrCL <50) Tirofiban ( Aggrastat ®) Non-peptide Bolus: 25 mcg/kg Infusion: 0.15 mcg/kg/min x 18 hrs Beygui F et al. Eur Heart J Supp ; 2005; 7: 110-114

50. Post PCI Management

51. Routine Medical Therapies Therapy Indications Contraindications (CI) ACC/AHA Recommendations B-blockers Ini tiated in the first 24 hours in all patient s without CI CHF, shock, reactive airway disease, PR interval >0.24 secs , 2 nd or 3 rd degree AV block, HR <60 bpm , SBP <90 mmHg IB ACEI Initiated in the first 24 hours for patients with anterior infarction, LV dysfunction (EF ≤ 0.40) or HF SBP <100 mmHg, intolerant to ACEI, bilateral renal stenosis, serum potassium >5.5 mmol/L, ARF, Pregnancy IA ARB For patient intolerant to ACE Same as ACEI IB O’Gara PT et al . Circulation ; 2013; 127 DiPiro J. Acute Coronary Syndrome. In: Pharmacotherapy: A Pathophysiological Approach, 2011

52. Routine Medical Therapies Therapy Indications Contraindications (CI) ACC/AHA Recommendations Aldosterone Antagonists LVEF ≤ 0.40 and either DM or HF who are already on ACEI and b-blockers Hypotension , hyperkalemia (serum potassium >5.0 mmol/L), SCr >2.5 mmol/L or CrCl <30 mL/min IB Statin High intensity statin to a ll patients without CI Serum transaminase 3X ULN, Pregnancy, active liver disease IB Nitroglycerin Patient with ongoing ischemic discomfort, hypertension and HF Hypotension , use of sildenafil/vardenafil within 24 h or tadalafil within 48 h ̶ O’Gara PT et al . Circulation ; 2013; 127 DiPiro J. Acute Coronary Syndrome. In: Pharmacotherapy: A Pathophysiological Approach, 2011

53. Patient Case

54. Case 1

55. Subjective C/C: “chest pain” HPI: RS is a 59 yrs old Philippino male with no prior cardiac history presented at the emergency room at 22:04 after having retrosternal chest pain for ~1.5 hours Described chest pain as compressive in nature , radiating to both arms and associated with sweating Denied any history of shortness of breath, nausea, and vomiting PMHx: Hypertension (x 3 years) on amlodipine 10 mg by mouth daily, and aspirin 81 mg by mouth daily SHx: KFSH employee; current smoker FHx: unknown Allergy: NKA

56. On Admission: Vitals : BP: 123/70 mmHg; HR: 76 bpm; RR: 25 br/min ; Temp: 36.6 C; O 2 Sat: 98% 3L nasal cannula Physical Exams: unremarkable CVS: S 1 + S 2 + 0 Chest: clear; equal air entry with normal breath sounds Ext: no significant changes, no JVD CNS: no abnormality detected Abd: not distended Height: 148 cm; Weight: 87 kg (standing) ECG : ST segment abnormalities in V 2 -V 6 , and anterior leads Chest X-Ray : mild increase in the interstitial marking but no definite pneumonic infiltration or pleural effusion Objective

57. eCG (day of admission)

58. Labs (day of admission) Chemistry: CBC with differential: unremarkable Enzymes: Na: 136 Cl: 103 Urea: 4.9 Glucose: 8.60 Ca (t): 2.22 K: 4.2 CO2: 22 Cr: 104 Mg: 0.91 PO4: 1.09 CK: 294 TrT: <0.01 Pro-BNP: 25 ALT: 22 AST: 21.4 Alk phos: 59

59. Assessment/Plan He was diagnosed with anteroseptal STEMI and was sent to the cath lab for PPCI Medication: Heparin 7000 units (80 units/kg) IV push once Plan: Immediate PCI Admit to CCU after PCI for routine medical care Catheterization (23:56): PCI LM: Normal LAD: mid 99% followed by diffuse 20% lesion LCx: Large dominant mild irregularities, OM-2 has Ostial 20% stenosis RCA: small non dominant proximal 20% stenosis Impression: single vessel coronary artery disease (LAD) PCI to Mid LAD: Resolute integrity (DES) deployed Post intervention angio showed excellent result with TIMI 3 flow

60. Mid LAD Occlusion LAD Occluded 99%

61. Stent Deployment Resolute Integrity

62. Reperfusion following stent TIMI 3 Flow

63. post Pci – Day 1 Vitals: unremarkable except tachypnea (RR:21-23 br/min) Labs: ECHO: LV is normal in size. Apex, anterior septum, and anterior wall are akinetic with partial loss of wall thickness. LV systolic function moderately reduced; EF 40-45% A/P: Started on Metoprolol 25 mg PO twice a day, Atorvastatin 40 mg PO daily, and Isosorbide dinitrate 20 mg twice a day Continued aspirin and clopidogrel CK: 2343 TrT: 6.930 ALT: 45.6 AST: 242.6 Na: 137 Cl: 101 Urea: 3.9 Glucose: 5.89 Ca (t): 2.040 K: 4.5 CO2: 25 Cr: 99 Mg: 0.88 PO4: 1.09 Trig: 2.247 Chol: 4.757 HDL: 0.91 LDL: 3.0 HbA1c: 0.061

64. eCG (05:58)

65. Vitals: Labs: Plan: Patient is walking and doing well; plan to transfer to A4 Discharge medications: Aspirin 81 mg PO daily Clopidogrel 75 mg PO daily Metoprolol 25 mg PO twice a day Isosorbide dinitrate 20 mg PO twice a day Atorvastatin 40 mg PO daily post Pci– Day 2 Na: 137 Cl: 102 Urea: 5.9 Glucose: 5.96 Ca (t): 2.090 K: 4.4 CO2: 24 Cr: 104 Mg: 0.84 PO4: 0.98 CK: 902 TrT: 2.780 BP:120’s/70’s HR: 50’s-60’s RR: 15-18 Temp: 36.8 O 2 Sat: 95% RA

66. Summary ST segment elevation MI/STEMI is a medical emergency which is the result of complete occlusion of the coronary artery causing myocardial infarction Since atherosclerotic disease is the most common cause of STEMI, the pathophysiology is mainly due to the rupture of “vulnerable plaque” Clinical presentation of STEMI may differ by gender and age. However, in general patient presents with midline anterior and/or retrosternal pain Diagnosis of STEMI is based on: Clinical symptoms, ECG changes, and release of cardiac biomarkers

67. Goals of management is to restore blood flow to the infarct artery as promptly as possible to minimize infarct size Recommended time frame for PPCI in a skilled PCI capable facilities is ≤ 90 minutes otherwise fibrinolysis is preferred DAPT is indicated irrespective of modes of reperfusion therapy For PCI, anticoagulation therapy is provided once before procedure, whereas, the duration of therapy is longer in patients treated with fibrinolysis UFH: 48 h, then other modes of anticoagulation Enoxaparin: 8 days or until discharge Summary (cont)