Atherothrombosis is leading cause of death worldwide.
Atherosclerosis is an ongoing process affecting mainly large- and medium-sized arteries; it can begin in childhood and progresses throughout a person’s lifetime. 1 Stable atherosclerotic plaques may encroach on the lumen of the artery and cause chronic ischemia, resulting in (stable) angina pectoris or intermittent claudication, depending on the vascular bed affected. Unstable atherosclerotic plaques may rupture, leading to the formation of a platelet-rich thrombus that partially or completely occludes the artery and causes acute ischemic symptoms. 2 A large rupture typically results in the formation of a large thrombus that completely occludes the vessel, resulting in an acute vascular event. A smaller rupture may result in a mural thrombus that partially or transiently occludes the artery, causing acute ischemia and, in the long term, contributing to progression of atherothrombosis. References Jager A, Stehouwer CDA. Early detection of diabetic and non-diabetic subjects with increased cardiovascular risk: new risk indicators. Heart and Metabolism . Available at: www.heartandmetabolism.org/HMScardiac_metabolism.htm. (Last accessed 3 March, 2003). Rauch U et al . Ann Intern Med. 2001; 134: 224 – 238.
Patients who present with ST segment depression have at least as great a six-month risk of mortality as those who present with ST-segment-elevation ACS, emphasizing the importance of aggressive in-hospital and post-discharge therapy.
Individual studies and cumulative data strongly suggest the additional benefit of risk reduction in patients with unstable angina when unfractionated heparin is added to treatment with aspirin.
The ESSENCE study was the first major study to demonstrate a reduction in major adverse cardiac events in patients with NSTE-ACS randomized to treatment with the low molecular weight heparin enoxaparin.
In TIMI 11B, patients with NSTE-ACS were randomized to treatment with either the low-molecular-weight heparin enoxaparin (30 mg IV then 1 mg/kg SC q 12 hrs) or unfractionated heparin. At 14 days, the composite primary ischemic endpoint was statistically significantly lower in those treated with enoxaparin, similar to what was observed in the ESSENCE study.
The ACC/AHA Guidelines Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction make several recommendations regarding antithrombin therapy in patients with NSTE-ACS. The use of either unfractionated heparin (UFH) or a low molecular weight heparin (LMWH) is a class I recommendation. Based primarily on the ESSENCE and TIMI 11B studies, a class IIa recommendation was that enoxaparin was preferable to UFH. Whether this preferential recommendation changes as a result of the SYNERY study remains to be determined.
Guidelines for the use of enoxaparin in patients with NSTE-ACS.
Management acute coronary syndrome
ACUTE CORONARY SYNDROME The newest management Nahar Taufiq Jogja International Hospital Yogyakarta
Atherothrombosis* is the Leading Cause of Death Worldwide1 Pulmonary Disease 6.3 Injuries 9 AIDS 9.7 Cancer 12.6 Infectious Disease 19.3 Atherothrombosis* 22.3 0 5 10 15 20 25 30 Causes of Mortality (%)*Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.1 The World Health Report 2001. Geneva: WHO; 2001.Reprod.with permission from Cannon CP. Atherothrombosis slide compendium. Available at: www.theheart.org.
Atherothrombosis: A Generalized and Progressive Disease Atherothrombosis Unstable angina ACS MI Ischemic stroke/TIA Atherosclerosis Critical leg ischemia Intermittent claudication CV death Stable angina/Intermittent claudication MI = Myocardial infarction ACS = Acute coronary syndromesAdapted from Libby P. Circulation 2001; 104: 365–372 CV = Cardiovascular
Initial Recognition and Managementin the Emergency Department
P Ex ED Evaluation of PatientsBrief Physical Examination in the ED1. Airway, Breathing, Circulation (ABC)2. Vital signs, general observation3. Presence or absence of jugular venous distension4. Pulmonary auscultation for rales5. Cardiac auscultation for murmurs and gallops6. Presence or absence of stroke7. Presence or absence of pulses8. Presence or absence of systemic hypoperfusion (cool, clammy, pale, ashen)
P Ex ED Evaluation of PatientsDifferential Diagnosis of STEMI: Life-ThreateningAortic dissection Tension pneumothoraxPulmonary Boerhaave syndromeembolus (esophageal rupture withPerforating ulcer mediastinitis)
P Ex ED Evaluation of PatientsDifferential Diagnosis of STEMI: Other Cardiovascular and Nonischemic Pericarditis LV hypertrophy with Atypical angina strain Early repolarization Brugada syndrome Wolff-Parkinson-White syndrome Myocarditis Deeply inverted T- Hyperkalemia waves suggestive of a Bundle-branch blocks central nervous system lesion or Vasospastic angina apical hypertrophic Hypertrophic cardiomyopathy cardiomyopathy
P Ex ED Evaluation of PatientsDifferential Diagnosis of STEMI: Other Noncardiac Gastroesophageal Cervical disc or reflux (GERD) and neuropathic pain spasm Biliary or pancreatic pain Chest-wall pain Somatization and Pleurisy psychogenic pain disorder Peptic ulcer disease Panic attack
Dx ElectrocardiogramI IIa IIb III If the initial ECG is not diagnostic of STEMI, serial ECGs or continuous ST-segment monitoring should be performed in the patient who remains symptomatic or if there is high clinical suspicion for STEMI.
Dx ElectrocardiogramI IIa IIb III Show 12-lead ECG results to emergency physician within 10 minutes of ED arrival in all patients with chest discomfort (or anginal equivalent) or other symptoms of STEMI.I IIa IIb III In patients with inferior STEMI, ECG leads should also be obtained to screen for right ventricular infarction.
Dx Laboratory ExaminationsI IIa IIb III Laboratory examinations should be performed as part of the management of STEMI patients, but should not delay the implementation of reperfusion therapy. Serum biomarkers for cardiac damage Complete blood count (CBC) with platelets International normalized ratio (INR) Activated partial thromboplastin time (aPTT) Electrolytes and magnesium Blood urea nitrogen (BUN) Creatinine Glucose Complete lipid profile
Dx Biomarkers of Cardiac DamageI IIa IIb III Cardiac-specific troponins should be used as the optimum biomarkers for the evaluation of patients with STEMI who have coexistent skeletal muscle injury.I IIa IIb III For patients with ST elevation on the 12-lead ECG and symptoms of STEMI, reperfusion therapy should be initiated as soon as possible and is not contingent on a biomarker assay.
Tx OxygenI IIa IIb III Supplemental oxygen should be administered to patients with arterial oxygen desaturation (SaO2 < 90%).I IIa IIb III It is reasonable to administer supplemental oxygen to all patients with uncomplicated STEMI during the first 6 hours.
Nitroglycerin TxI IIa IIb III Patients with ongoing ischemic discomfort should receive sublingual NTG (0.4 mg) every 5 minutes for a total of 3 doses, after which an assessment should be made about the need for intravenous NTG.I IIa IIb III Intravenous NTG is indicated for relief of ongoing ischemic discomfort that responds to nitrate therapy, control of hypertension, or management of pulmonary congestion.
Tx NitroglycerinI IIa IIb III Nitrates should not be administered to patients with: • systolic pressure < 90 mm Hg or ≥ to 30 mm Hg below baseline • severe bradycardia (< 50 bpm) • tachycardia (> 100 bpm) or • suspected RV infarction.I IIa IIb III Nitrates should not be administered to patients who have received a phosphodiesterase inhibitor for erectile dysfunction within the last 24 hours (48 hours for tadalafil).
Tx Analgesia Morphine sulfate (2 to 4 mg intravenouslyI IIa IIb III with increments of 2 to 8 mg intravenously repeated at 5 to 15 minute intervals) is the analgesic of choice for management of pain associated with STEMI.
Tx AspirinI IIa IIb III Aspirin should be chewed by patients who have not taken aspirin before presentationI IIa IIb III with STEMI. The initial dose should be 162 mg (Level of Evidence: A) to 325 mg (Level of Evidence: C) Although some trials have used enteric-coated aspirin for initial dosing, more rapid buccal absorption occurs with non–enteric-coated formulations.
Tx Clopidogrel in Non STEMI Cumulative events (myocardial infarction, stroke, or cardiovascular death) Cumulative hazard rate 0.14 Placebo * (n =6,303) 20% 0.12 0.10 0.08 Clopidogrel * (n = 6,259) 0.06 p < 0.0001 0.04 0.02 0.00 0 3 6 9 12 Months of follow-up *On top of standard therapy (including acetylsalicylic acid)The CURE Trial Investigators. N Engl J Med 2001; 345: 494–502
Tx Clopidogrel in Non STEMI 1 0.9Bleeding rate (%) 0.8 0.7 0.6 0.4 0.2 0.2 0.1 0 Fatal Intracranial Require surg Drop of Hb interv > 5 g/dl The CURE Investigators. N Engl J Med 2001;345:494-502
Tx Clopidogrel in Non STEMI Primary endpoint ‡ ) during 24 hours 0.025 0.020 PlaceboCumulative hazard 0.015 0.010 Clopidogrel 0.005 P=0.003rates 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 Hours after randomization ‡ Cardiovascular death, myocardial infarction, stroke and severe ischemia Yusuf S et al. Circulation 2003; 107: 966–972
Tx Clopidogrel in STEMI Placebo (10.1%) 10 reinfarction or stroke before first Proportion with death, 9 8 Clopidogrel (9.3%) discharge (%) 7 6 RRR=9% 5 P=0.002 4 3 2 1 0 0 7 14 21 28 Time since randomization (days) COMMIT= ClOpidogrel and Metoprolol in Myocardial Infarction Trial COMMIT Collaborative Group. Lancet 2005;366:1607-21
CLARITY-TIMI 28: angka kejadian kumulative dalam 30 hari 15 Placebo 20%End point * (%) 10 Clopidogrel 5 P=0.03 0 0 5 10 20 25 30 Days * Cardiovascular death, recurrent MI, or recurrent ischemia leading to the need for urgent revascularization Sabatine MS et al for the CLARITY-TIMI 28 Investigators. N Engl J Med 2005;352:1179-89
CLARITY-TIMI 28: Tingkat keamanan dalam 30 hari ASA + CLO ASA P=0.24 4 P=0.80 3.4 P=0.12 3 2.7% of patients 2 1.9 1.7 1.6 1 0.9 0 Major bleeding Minor bleeding Major or minor bleeding
Tx Onset of antiplatelet Agent Dose Onset Aspirin Dosis 80 - 320 mg1 15 - 30 minutes Clopidogrel 75 mg maintenance dose2 Max at 3-7 days 300 mg loading dose3 Max at 24 to 48 h 600 mg loading dose4 Max at 2 h 900 mg loading same with 600 mg loading dose3 dose Ticlopidine 250 mg 2x perhari5 50% pada 5 hari dan maksimum 8-11 hari1 Dabaghi SF et al. Am J Cardiol 1994;74:720-3. 2. Savcic M et al. Semin Thromb Hemost 1999;25:15-19 3 Quinn MJ, Fitzgerald DJ. Circulation 1999;100:1667-72 4. Hochholzer W et al. Circulation2005;111:2560-4 5. Lubbe DF, Berger PB. J Interv Cardiol
Tx Beta-Blockers Oral beta-blocker therapy should beI IIa IIb III administered promptly to those patients without a contraindication, irrespective of concomitant fibrinolytic therapy or performance of primary PCI.I IIa IIb III It is reasonable to administer intravenous beta- blockers promptly to STEMI patients without contraindications, especially if a tachyarrhythmia or hypertension is present.
Summary of Trials of Beta-Blocker Therapy Phase of Total No. RR (95% CI) Treatment Patients Acute 28,970 0.87 (0.77-0.98) treatment Secondary 24,298 0.77 (0.70-0.84) prevention Overall 53,268 0.81 (0.75-0.87) 0.5 1 2 Relative risk (RR) of death Beta blocker Placebo better betterAntman E, Braunwald E. Acute Myocardial Infarction. In:Braunwald E, Zipes DP, Libby P, eds. Heart Disease: Atextbook of Cardiovascular Medicine, 6th ed.,Philadelphia, PA: W.B. Sanders, 2001, 1168.
Tx Reperfusion Therapy and Recommendations STEMI
Tx ReperfusionThe medical system goal is to facilitate rapidrecognition and treatment of patients with STEMIsuch that door-to- needle (or medical contact–to-needle) time for initiation of fibrinolytic therapycan be achieved within 30 minutes or that door-to-balloon (or medical contact–to- balloon) time forPCI can be kept within 90 minutes.
Treatment Delayed is Treatment Denied Symptom Call to PreHospital ED-JIH Cath LabRecognition Medical System Increasing Loss of Myocytes Delay in Initiation of Reperfusion Therapy
Reperfusion Options for STEMI Patients Select Reperfusion Treatment. If presentation is < 3 hours and there is no delay to an invasive strategy, there is no preference for either strategy.Fibrinolysis generally preferred Early presentation ( ≤ 3 hours from symptom onset and delay to invasive strategy) Invasive strategy not an option Cath lab occupied or not available Vascular access difficulties No access to skilled PCI lab Delay to invasive strategy Prolonged transport Door-to-balloon more than 90 minutes > 1 hour vs fibrinolysis (fibrin-specific agent) now
Reperfusion Options for STEMI Patients Select Reperfusion Treatment. If presentation is < 3 hours and there is no delay to an invasive strategy, there is no preference for either strategy.Invasive strategy generally preferred Skilled PCI lab available with surgical backup Door-to-balloon < 90 minutes• High Risk from STEMI Cardiogenic shock, Killip class ≥ 3 Contraindications to fibrinolysis, including increased risk of bleeding and ICH Late presentation > 3 hours from symptom onset Diagnosis of STEMI is in doubt
TxAntithrombin Therapy Studies and Recommendations NonSTEMI
Comparison of Heparin + ASA vs ASA Alone Theroux RISC Cohen 1990 ATACS Holdright Gurfinkel Summary Relative Risk 0.67 (0.44-0.1.02) 0.1 1 10 Heparin + ASA RR: ASA Alone 55/698=7.9% Death/MI 68/655=10.4%ASA indicates acetylsalicylic acid; RISC, Research on InStability in Coronary artery disease; ATACS, Antithrombotic Therapy in AcuteCompany Syndromes; RR, relative risk; and MI, myocardial infarction.Data from Oler A, Whooley MA, Oler J, et al. Adding heparin to aspirin reduces the incidence of myocardial infarction and death inpatients with unstable angina: a meta-analysis. JAMA. 1996;276:811-815. Slide reproduced with permission from Cannon CP.Atherothrombosis slide compendium. Available at: www.theheart.org.
TIMI 11B: Enoxaparin vs. Heparin in NSTE-ACS 20 Unfractionated Heparin 16.7 %Urgent Revascularization Enoxaparin (Lovenox) 16 Death, MI or 12 14.2 % 8 p = 0.03 4 Relative Risk Reduction = 15% 0 2 4 6 8 10 12 14 Days Adapted from Antman EM, et al. Circulation. 1999;100:1593-1601.
ACC/AHA Recommendations for Antithrombin Therapy in Patients with NSTE-ACS• Class I – Anticoagulation with subcutaneous LMWH or intravenous UFH should be added to antiplatelet therapy – Dose of UFH 60-70 U/kg (max 5000) IV followed by infusion of 12-15 U/kg/hr (initial max 1000 U/hr) titrated to aPTT 1.5-2.5 times control – Dose of enoxaparin 1 mg/kg subcutaneously q12 hr; the first dose may be preceded by a 30-mg IV bolus• Class IIa – Enoxaparin is preferable to UFH as an anticoagulant unless CABG is planned within 24 hours Available at: www.acc.org/clinical/guidelines/unstable/unstable.pdf.
Guidelines for the Use of Enoxaparin in Patients with NSTE-ACS• 1 mg/kg SQ q12 hours (actual body weight) – An initial 30 mg IV dose can be considered• Adjust dosing if CrCl <30 cc/min – 1 mg/kg SQ q24 hours• Do not follow PTT; do not adjust based on PTT• Stop if platelets ↓ by 50% or below 100,000/mm3• If patient to undergo PCI: – 0-8 hours since last SQ dose: no additional antithrombin therapy – 8-12 hours since last SQ dose: 0.3 mg/kg IV immediately prior to PCI
Applying Classification of Recommendations and Level of EvidenceClass I Class IIa Class IIb Class IIIBenefit >>> Risk Benefit >> Risk Benefit ≥ Risk Risk ≥ Benefit Additional studies with Additional studies with No additional studies focused objectives broad objectives needed; needed needed Additional registry data would be helpful Procedure/TreatmentProcedure/ Treatment IT IS REASONABLE to should NOT beSHOULD be perform Procedure/Treatment performed/administeredperformed/ procedure/administer MAY BE CONSIDERED SINCE IT IS NOTadministered treatment HELPFUL AND MAY BE HARMFULshould is reasonable may/might be considered is not recommendedis recommended can be useful/effective/ may/might be reasonable is not indicatedis indicated beneficial usefulness/effectiveness is should notis useful/effective/ is probably recommended or unknown /unclear/uncertain is not beneficial indicated or not well established useful/effective/beneficial may be harmful
Applying Classification of Recommendations and Level of EvidenceLevel A Class I Class IIa Class IIb Class IIIMultiple (3-5) • Recommen- • Recommen- • Recommen- • Recommen-population risk dation that dation in favor dation’s dation thatstrata evaluated procedure or of treatment or usefulness/ procedure or treatment is procedure efficacy less treatment notGeneral useful/ being useful/ well useful/effectiveconsistency of effective effective established and may bedirection and • Sufficient • Some • Greater harmfulmagnitude of evidence from conflicting conflicting • Sufficienteffect multiple evidence from evidence from evidence from randomized multiple multiple multiple trials or meta- randomized randomized randomized analyses trials or meta- trials or meta- trials or meta- analyses analyses analyses
Applying Classification of Recommendations and Level of EvidenceLevel B Class I Class IIa Class IIb Class IIILimited (2-3) • Recommen- • Recommen- • Recommen- • Recommen-population risk dation that dation in favor dation’s dation thatstrata evaluated procedure or of treatment or usefulness/ procedure or treatment is procedure efficacy less treatment not useful/effective being useful/ well established useful/effective • Limited effective • Greater and may be evidence from • Some conflicting harmful single conflicting evidence from • Limited randomized evidence from single evidence from trial or non- single randomized trial single randomized randomized or non- randomized trial studies trial or non- randomized or non- randomized studies randomized studies studies
Applying Classification of Recommendations and Level of EvidenceLevel C Class I Class IIa Class IIb Class IIIVery limited (1- • Recommen- • Recommen- • Recommen- • Recommend-2) population dation that dation in favor dation’s ation thatrisk strata procedure or of treatment or usefulness/ procedure orevaluated treatment is procedure efficacy less treatment not useful/ being well established useful/effective effective useful/effective • Only diverging and may be • Only expert • Only diverging expert opinion, harmful opinion, case expert opinion, case studies, or • Only expert studies, or case studies, or standard-of- opinion, case standard-of- standard-of- care studies, or care care standard-of- care
Contraindications and Cautions for Fibrinolysis in STEMIAbsolute • Any prior intracranial hemorrhageContraindications • Known structural cerebral vascular lesion (e.g., arteriovenous malformation) • Known malignant intracranial neoplasm (primary or metastatic) • Ischemic stroke within 3 months EXCEPT acute ischemic stroke within 3 hours NOTE: Age restriction for fibrinolysis has been removed compared with prior guidelines.
Contraindications and Cautions for Fibrinolysis in STEMIAbsolute • Suspected aortic dissectionContraindications • Active bleeding or bleeding diathesis (excluding menses) • Significant closed-head or facial trauma within 3 months
Contraindications and Cautions for Fibrinolysis in STEMIRelative • History of chronic, severe, poorly controlledContraindications hypertension • Severe uncontrolled hypertension on presentation (SBP > 180 mm Hg or DBP > 110 mm Hg) • History of prior ischemic stroke greater than 3 months, dementia, or known intracranial pathology not covered in contraindications • Traumatic or prolonged (> 10 minutes) CPR or major surgery (< 3 weeks)
Contraindications and Cautions for Fibrinolysis in STEMIRelative • Recent (< 2 to 4 weeks) internal bleedingContraindications • Noncompressible vascular punctures • For streptokinase/anistreplase: prior exposure (> 5 days ago) or prior allergic reaction to these agents • Pregnancy • Active peptic ulcer • Current use of anticoagulants: the higher the INR, the higher the risk of bleeding