병원약사회지 (2010), 제 27 권제 3 호 J. Kor. Soc. Health-Syst. Pharm., Vol. 27, No. 3, 331~ 346 (2010) 학술강좌 Non-ST segment elevation myocardial infarction 의치료 강릉아산병원약제팀 Definition and Statistics Acute coronary syndromes(acs) 은 thrombus 에의하여관상동맥이완전히폐쇄된 ST-segment elevation myocardial infarction(stemi), Thrombus에의하여관상동맥이부분적으로폐쇄되었거나또는일시적인폐쇄와동시에 revascularization 이일어는 Non-ST segment elevation 과 Unstable angina(ua) 로분류된다. 그중에서 Non-ST segment elevation myocardial infarction(nstemi) 은한개또는2개이상의관상동맥질환 (plaque erosion, plaque rupture, fissuring, dissection) 과 Thrombus에의하여혈관이부분적으로폐쇄되고심근에혈액공급이부족하여산소와영양공급이차단되므로심근조직에괴사를초래하는질환이다. 혈액공급의장애로심근에서요구하는산소요구량을충분히공급하지못할때 coronary artery 에긴장도가증가한다. Acute myocardial infarction(ami) 은신속한응급조치를필요로하는질환으로서 1980년까지만해도 AMI환자들은대증적인치료만받아왔었으나현재는미국심장학회인 American college of cardiology(acc) 와 American heart association(aha) 의 evidence-based 안내지침을근거로신속하게환자를치료관리하고있다. 미국AHA가발표한통계에의하면 2006년에미국의심근경색발생률은 8,500,000명이며사망률은 141,462명으로관상동맥질환은미국에서사망률 1위를차지하는위급한질환이지만 2004년부터관상동맥질환으로인한사 망률은급격히감소하기시작하여서 2004년사망률에비교할때 2008년관상동맥질환사망률은 25% 이상감소한것으로나타났다. 감소된주원인은아직확실히밝혀져있지않으나고혈압, 흡연, 고지혈증의지속적인관리와관상동맥질환예방을위한신속한응급치료일것으로여겨지고있다. 2007년미국통계에의하면 (AHA, ASA, Circulation) 총 1,570,000명의 ACS 환자중에서 UA/NSTEMI 환자는 1,240,000명으로추산되며, STEMI 환자는 330,000명으로추산되고있으며, 우리나라는아직구체적인통계자료가없는실정으로 2009년 OECD가발표한자료에의하면우리나라의심근경색사망률은 8.1% 로전체 OECD에가입한국가에서가장높은사망률을나타내고있다. Pathology 대다수의 Acute myocardial infarction(ami) 의원인은관상동맥의부분폐쇄또는완전폐쇄와함께일어나는 Atheromatous plaque 의파열이며이차적으로는 thrombus 생성이그주요원인이다. 관상동맥에형성되는 thombus는 atherosclerotic plaque 가파열되어생성된것으로 atherosclerosis 의초기단계는아직확실히밝혀져있지않지만, Atherosclerosis 의초기단계는혈관벽에 lipid accumulation ( 주로 Low-density lipoprotein cholesterol [LDL-C]) 과그다음단계인 LDL-C 의산화인것으로알려져있다. 그리고활성화된 - 331 -
JKSHP, VOL.27, NO.3 (2010) macrophage 가산화된 LDL-C를받아들여 foam cells(lipid-laden macrophage) 을형성하며병소의진행에따라 Leukocyte 가생성한 Proinflammatory cytokine 이 Extra cellula matrix(collagen) 을분비하여 plaque 가증가하게된다. 증가된 plaque는 ac tivated foam cells(macrophage plus LDL-C) 이분비한 metalloproteinases 와 proteolytic enzyme에의하여 fibrous plaque가파열되어혈액이 collagen 과 fatty acid 에노출되어 platelet이활성화된다. 활성화된 platelet는 thrombin 에의하여활성화된 fibrin 이나 red blood cell 과결합하여점도가증가한 blood clot인 thrombus를형성한다. 혈관에서 plaque stenosis 가 70-80% 까지진행되어도 atheroclerosis 증세를느끼지못할수있지만 myocardial infarction 이나 stroke 의경우는 50% 이하의 stenosis 에서도그증세를유발할수있다. Diagnosis 임상증상를갖고있는 NSTEMI 환자의진단을위하여가슴통증과함께 12-leads ECG reading 은중요한진단요소이며 NSTEMI는 ST-segment 가 0.5mm 이상감소하였거나증가하였어도 0.6-1.0mm 이하로증가하였고 T-wave inversion 이 1mm 이상으로변화하며 Q-wave를나타내지않는경우이다. 또한심장세포가손상을입었을때혈액순환에분비되는 cardiac biomarkers 인 creatine kinase (CK) 와 Troponin T & I 효소는 NSTEMI 를진단할수있는중요한 laboratory 진단요소로서, CK 효소는 BB, MB, MM의 3가지 isoenzymes 을갖고있으며이중에서 CK-MB 효소는 AMI를진단하는데가장특이성을갖고있다. CK-MB는심근손상이후 3-6시간이내에혈중에나타나며 12-24 시간이내에최고농도에달하고 (CK-MB 정상범위 : < 12IU/L) 48-72시간이내에정상수치로돌아온다. 가장민감한 cardiac marker인 Troponin I & T는심장세포내의 actin 과 myosin 의작용을조절하고있으며세포가손상을입으면말초혈액순환에분산 된다. Troponin 은 2개의 isoenzymes로구성되어있으며증세시작후 6-12시간이내에혈중에나타나며 30시간이내에최고농도에도달한다. Troponin-I isomer 는 7-14일간지속적으로검출되며 Troponin-T isomer 는 10-14일간지속적으로검출된다. 12-leads ECG reading에서 STsegment elevation 이없으며 CK-MB 효소가검출되지않을지라도 30% 의환자에게서 Troponin enzyme이정상수치이상으로검출되어 AMI 진단에사용될수있다. 또다른 cardiac marker로서 myoglobin enzyme이있으나심근세포외에골격근손상이나운동시에도분비되므로비특이적인진단요소로사용된다. 따라서 2007년미국 AHA/ACC의안내지침에의하면새로운 biomarker로서 B-type natriuretic peptide(bnp) 를 ACS 진단에고려할것을추천하였다. BNP 는심실의심근세포가이완할때분비되는신경호르몬으로 STEMI와 UA/NSTEMI의환자들의 short 또는 long term mortality 를예측할수있는효과가있다. 기타진단검사로는 Exercise tolerance test (ETT) 와 Adenosine이나 Dobutamin을사용한 Pharmacologic stress test (PST), 관상동맥질환에서동맥경화의위치와그범위를확인할수있는 Specific imaging 방법인 Cardiac Angiography, 혈관의구조적인이상이나혈관의기형을진단할수있는 Magnetic Resonance Image(MRI) 가있으며 MRI와 Computed Tomography(CT) 둘모두심근경색이발생한위치와그손상부위의크기를진단하는데적합한 Non-invasive tools 이다. NSTEMI 를진단하기위하여위의진단방법중에서 12- leads ECG 와 Cardiac biomarkers 및임상증세인가슴통증중에서 2개를충족하면 NSTEMI라고진단할수있다. Clinical manifestations NSTEMI의임상적인주요증세는 30분이상계속되는가슴통증이나흉부압통으로일부환자는소화불량이나 gastrointestinal symptoms 으로오인될 - 332 -
신혜연 : Non-ST segment elevation myocardial infarction 의치료 수도있다. 가슴통증은그발생부위와특성이비전형적이지만팔, 어깨, 목, 아래턱, 등부위로통증이있을수있으며 shortness of breath(sob), diaphoresis, nausea, vomiting 이있을수도있다. 심신의과로나정신적인긴장이나흥분에의해발생할수도있으며안정시에도올수있다. 심근경색증환자의 15-20% 는통증이없을수도있는데남성의경우는통증이흔히나타나고여성의경우는통증대신 nausea 나 diaphoresis 를나타내며노인의경우는저혈압이나심혈관계증세를나타내는경향이있다. 통증이없는심근경색증은주로당뇨병환자나여성, 노인환자에게많으므로통증이없는경우라고안심하여서는안된다. Initial management 우선환자를침대에안정시키고환자의기도와호흡과혈액순환을정상화하기위하여산소를공급하며SaO2(systemic atrial oxygen saturation) 90% 이상을유지토록권장하고있다. 환자의위급한상태를개선하고사망률을감소시키기위하여신속한의료조치가필요하다. 신속한진단을위하여 EKG를측정이필요하며병원에도착한 NSTEMI 환자에게 antithrombotic therapy 로서 aspirin 325mg (non-enteric coated) 을씹어서삼키도록하며 clopidogrel, GpIIbIIIa inhibitor, Unfractioned heparin(ufh) 이나 low molecular weight heparin(lmwh) 을사용할수있으며환자의병력과혈액검사, Cardiac biomarkers 인 Troponin I/T과 CK-MB수치의분석이필요하다. STEMI 환자의치료와유사한방법으로약물치료를시작하지만약물치료중에서 Fibrinolytic 는 NSTEMI 환자에게그효과가입증되지않고있어서사용을고려하지않는다. Antiischemic agent와가슴의통증을완화하기위하여 NTG(IV/ PO), Beta-blockers(IV/PO), Morphine(IV, prn), ACEI(left ventricular systolic dysfunction 이나 congestive heart disease 를갖고있는환자로서지속적으로고혈압인환자의경우 ) 를사용하며 lipid lowering agent로서 Statins, bile acid resins, ezetimibe, niacin, fibrate 을투여할수있고관상동맥의폐쇄와혈관의손상, 그리고고위험환자들의 MI 위험도에따라필요한 reperfusion treatment 를실시할수있다. Hospital care 병원에서 NSTEMI 환자를치료하기위하여약물요법 (conservative therapy) 과또는수술요법 (invasive therapy) 을사용하고있으며약물요법으로는 antiischemic agents, antithrombotic agent, lipid lowering agents 사용을권장하며수술요법으로는 Percutaneous coronary intervention(pci) 과 Coronary artery bypass graft(cabg) 가권장되고있다. TACTICS- TIMI 18 trial 은출혈위험, 병원치유를위한체류기간, 치료비용에관하여 invasive therapy 와 conservative therapy 를비교하였는데연구결과두치료방법의효과에차이가없었으며위험도가높은환자에게는수술요법이약물요법보다더효과가좋았으며위험도가낮은환자에게는두방법의효과에차이가없는것으로나타났다. Fig. 1, 2는 ACC/AHA (2007년) 안내지침으로 NSTEMI환자를위한약물치료와수술요법 (invasive therapy) 에관한치료순서 (algorithm) 를나타내고있다. Fig. 1 Algorithm for treatment of UNSTEMI - 333 -
JKSHP, VOL.27, NO.3 (2010) Fig. 3 Angioplasty Fig. 2 Algorithm for treatment of USTEM 1) Invasive therapy - Percutaneous coronary intervention(pci) Balloon angioplasty는 1977년스위스의 Andreas Gruntzig가관상동맥에적용한것으로 Fig. 3, 4에서와같이 angioplasty 는 catheter 상에있는balloon을 plaque가있는곳에서부풀리어 plaque 를눌러준후동맥경화부위를부수어서혈액의흐름을복원시킬수있으며 stent는 angioplasty 후에혈관의재협착을방지하기위하여동맥벽을떠바치도록금속구조물을협착부위에삽입하여동맥내혈액흐름을복원유지할목적으로사용하며 drug-eluting stent 와 bare-metal stent 2종류가있다. NSTEMI 환자에게 Early angiography와 Revascularization 이필요한경우는 Hemodynamically instable, Cardiogenic shock, Severe left ventricular dysfunction(lvd), Heart failure(hf), New or Worsening Mitral regurgitation, New ventricular septic defect 가있는고위험군환자로서 Fig. 6에서와같이 UA/NSTEMI 환자에게 early invasive treatment를실시하면그렇지않은환자와비교할때 ACS 로인한사망률이나심근경색발생률, 재입원율이감소하였음을나타내고있다. Fig. 4 Coronary stent Fig. 5 Coronary artery bypass graft - Coronary artery bypass graft(cabg) Fig. 5에서 CABG는다리의정맥을대용혈관으로사용하여 atherosclerotic coronary artery 의막힌부분을경유하여 aorta 끝에서 coronary artery 끝을연결하여대용혈관으로혈액이우회하여흐르도록복원하는수술로서 left main coronary artery 에협착이있을때, 3개이상의혈관에협착이있을때, 또는 1-2개의 proximal left circum- - 334 -
신혜연 : Non-ST segment elevation myocardial infarction 의치료 flex arteries와 left anterior descending cornary artery 에 70% 이상의협착이있을때 CABG가권장된다. Table 1. 은 ACC/AHA안내지침에서 CABG 수술이권장되는 NSTEMI 환자의상태에관하여요약한내용을나타내고있다. - Management after angiography Fig. 7에서와같이 Angiography를실시한후 CABG, PCI 또는약물치료중에서 ACC/ AHA algorithm 에따라 NSTEMI 환자를치료할것을권장하였으며. PCI를실시할계획이있는경우 NSTEMI 환자에게 aspirin을평생복용할것을권장하며만일 Angiography 전에 clopidogrel 과 Glycoprotein IIb/IIIa inhibitor 를사용하지않았다면 clopidogrel loading dose 300mg과 Fig. 6 Improved outcome in early invasive treatment with NSTEMI Source: :TACTICS Thrombolysis in Myocardial Infarction 18 Investigators, N Engl J Med 2001; 344:1879. cumulative incidence of the primary end point (death, nonfatal myocardial infarction, or rehospitalization for an acute coronary syndrome) during the six-month is lower in the invasive-strategy group than in the conservative treatment group (15.9 versus 19.4 percent) in patients with unstable angina or a non-st elevation myocardial infarction Fig. 7 Invasive treatment followed by pharmacologic treatment Table 1. ACC/AHA Guideline: Coronary artery bypass surgery in patients with NSTEMI - 335 -
JKSHP, VOL.27, NO.3 (2010) Glycoprotein IIb/IIIa inhibitor 사용을권장하고있다. 2) Pharmacologic management(conservative therapy) Acute coronary syndrome을유발하는혈관내 thrombus나 thrombotic occlusion을완화시키기위한여러가지유용한약물치료가있다. (1) Anti ischemic and analgesic for chest pain 심근경색에서가슴통증을완화하여환자를안정시키고교감신경 (hyper-adrenergic response) 의이상상태를완화할수있다. - Providing oxygen Respiratory distress 환자의 SaO2 가 90% 이하인경우, 고위험군저산소혈증환자에게반드시산소를공급하도록권장하고있다. - Nitroglycerin sublingual (NTG-SL) 심근경색으로인한통증을완화하기위하여설하정 (0.6mg) 1정을혀밑에놓아서 5분정도기다린후통증이소실되지않으면응급실로신속히연락하여응급의료팀의지시를따르도록한다. 환자의이송은가족이나친구보다응급의료팀의 ambulance를사용할것을권장하고있다. 응급의료팀이도착할때까지 NTG을 3정까지사용할것을권장하고있으며통증이지속적이거나재발한경우는 intravenous morphine과또는 intravenous nitroglycerine 을사용할것을권장하고 intra venous NTG 10mcg/min 을매 5-10 분간격으로 5-10mcg/min 씩증량하여통증을조절한다. 고용량에서혈압이조절되지않거나저혈압, 두통, tachycardia가오면중단해야한다. NTG는심근경색에의한통증을완화하기위하여사용하며평활근에서 nitrosothiol을형성하여 cyclic guanosine monophosphate(c- GMP) 을생성하여평활근을이완시키고정맥혈관을이완하여 preload와 pulmonary capillary wedge pressure를감소시키므로혈압과 pulmonary congestion을조절할수있다. NTG 를사용할때환자의 systolic blood pressure(sbp) 가 90 mmhg 이하일경우, 또는 severe bradycardia (Heart rate < 50 bpm), tarchycardia(heart rate > 100 bpm), right ventricle infarction ( 우심실경색 ) 인경우또는발기부전을치유하기위하여 24 시간이내에 phosphodiesterase inhibitor인 sildenafil, 48시간이내에 tardalafil을복용한환자에게는금기이다. 지속적인 ischemic 상태인환자나 24시간후에임상적증상이소실된환자에게는 nitroglycerine topical agent 사용이권장한다. - Morphine sulfate 환자의통증을치유하기위한선택적인약물로서혈압과심장의대사요구량을낮추고 hyperadrenergic state를감소시키는것으로알려져있다. 그러나사망률을감소시키는효과는없는것으로나타났으며 (Antman et al. JACC 2004). Morphine 사용량은정맥으로 2-4mg을사용하고매 5-15 분간격으로반복하여 2-8mg 씩정맥으로증가하여사용할수있다. Morphine은심장질환이나심근파열이있는환자의경우 non-selective COX-2 inhibitors나 selective COX-2 inhibitors NSAIDS를병용사용하지말것을권장하고있고과민성이있거나 systolic blood pressure 90mmhg 이하이거나 diastolic blood pressure 50mmhg 이하인경우도금기이다 - Beta-blockers Beta-blockers는심박동율, 혈압, 심장수축력을감소하므로심근의산소요구량과심근경색증의증세를감소시켜사망률을낮추고동맥경화의진행을지연시키는효과가있는것으로나타났으며, 심근대사, 관상미세혈관, 측부혈액흐름 (collateral blood flow), 심근혈액흐름, oxygen-hemoglobin친화성을개선할수있는것으로나타났다. MI, left ventricular dysfunction(lvd) 환자에게 nitrate나 calcium channel blockers(ccb) 를사용하기전에 Beta-blocker에대한금기가없으면 Beta-block- - 336 -
신혜연 : Non-ST segment elevation myocardial infarction 의치료 er를투여하고평생사용할것을권장하고있다. Metoprolol의경우 5mg 을천천히 1-2 분에걸쳐정맥으로투여하고 (max. 5mg) 다음은경구로 25-50mg 을매 6시간마다 48시간동안사용하고그이후부터경구로 metoprolol 100mg 을하루 2번사용한다. 경구제제는정맥주사제제사용후 15분이내에투여하며사용되는 Beta-blockers는 Betaselectivity가있는약물이선호되고있다. Betablocker를사용할때과거나현재환자의병력중에서당뇨병, 고지혈증, air-way diseaser ( 예 :asthma, compulsive obstructive pulmonary disease) 이있는경우는 B-blockers의사용이환자에게유리한지불리한지를검토한후사용하도록권장하고있다. 이유는 B-blockers는고혈당, 고지혈증을일으키는부작용이있으며 asthma 나 COPD 치료에사용되고있는 B-agonists의작용을감소시킬수있기때문이다. B-blockers는 severe bronchospastic disease, AV block (PR >0.24 second), second or third degree heart block, decompensate bradycardia (HR<60 bpm), Shock, SBP가100mmhg 이상인경우나 active airway disease, cocaine남용으로유발된 ischemia의경우는사용금기이다. - Calcium channel blockers: Calcium channel blockers(ccb) 중에서 nondihydropyridine인 verapamil과 diltiazem은말초혈관확장과관상동맥확장작용이있으며심장전도를감소시켜심방과심실의불응기를지연시킬수있으므로 left ventricular systolic dysfunction 이있는환자에게사용하지말아야한다. CCB는심근의산소요구량을감소시키며심근에혈액공급량을증가시키고평활근을수축하며혈관을이완하여혈액흐름에대한혈관의저항을감소시킨다. 말초에대한작용은말초혈관을이완하여 systemic vascular resistan와혈압을감소하여심장에미치는영향을줄일수있다. Dihydropyridine중에서 amlodipine이나 felodipine은다른 CCB와다르게 LVD에안전하게사용할수있는것으로나타났다. Verapamil이나 diltiazem은 nitrate나 B-blockers 를사용할수없거나이미사용중인환자에게사용할수있으며, 환자가정상적인 ejection fraction을갖고있으며 pulmonary congestion이없는경우사용할수있다. Diltiazem을사용할경우는 0.25mg/kg (actual body weight 사용 ) 을약 2 분간동안정맥으로투여하고필요하면 5mg/hour 씩계속정맥투여한다. 환자가안정되면경구제 (immediate release form) 로교체하여투여하며퇴원할때는경구제 (sustained release form) 로투여한다. - Angiotensin converting enzyme inhibitors (ACEI): ACEI 는 heart failure(hf), acute MI, diabetes mellitus(dm) 환자에게사용할때사망률과이환률을효과적으로감소하는것으로나타났다. HOPE study에의하면 ramipril은만성관상동맥질환 (chronic CAD) 환자의사망, 심근경색증, 뇌졸증발생률을유의성있게감소하는것으로나타났다. ACEI 의기전은명확히밝혀지지않았지만평활근에서 growth-mediating properties를억제하며동맥경화성 plaque를파열되지않도록하고 endothelial function을개선하는것으로알려져있다. ACEI 는 nitrate나 B-blockers를사용하였음에도불구하고조절되지않는고혈압을조절하기위하여사용하도록권장하고있으며금기가없다면당뇨병이나좌심실의 ejection fraction이 40% 이하인경우의 LVD이나 HF를갖고있는 NSTEMI 환자에게평생사용하도록권장하고있다. 그러나 ACEI 를사용할수없는경우는대용약으로 angiotensin receptor blockers(arb) 를사용하도록권장하고있다. 이약의부작용으로는가래가없는마른기침이약을복용한후수시간안에발생할수있으며약을단약한후에도3개월까지지속될수있다. 한연구에의하면 ACEI 로인한부작용으로기침발생률이높아서백인에게는 5-10% 이며중국인의경우는약 50% 라고발표하였다. 따라서 american college of chest physician(accp) 에의하면 ACEI 의부작용인기침이발생하면중단할것이권유하며안전한대용제로 ARB나 hydralazine, isosorbide 사용이 - 337 -
JKSHP, VOL.27, NO.3 (2010) 권장되고있다. (2) Antiplatelet agents Antiplatelet treatmen은환자가병원에도착할때가능한신속하게투여해야하는약물로써 Table 2. 는 antiplatelet treatment에관한 ACC/AHA 안내지침이며 NSTEMI환자에게 aspirin, clopidogrel, Glycoprotein IIb/IIIa inhibitors, heparin 과같은 antiplatelet의치료시기와대용에관하여나타내고있다. - Aspirin Aspirin은 cyclooxigenase-1 enzyme과 cyclooxigenase-2 enzymes에모두작용하여비가역적으로 arachidonic acid에서 thromboxane A2합성을차단하여 platelet aggregation 을억제하는기전을갖고있는 antiplatelet agent로서이약물의 platelet inhibition 기간은약 8~10 일이다. 전체 platelet중 10% 정도가매일보충되며, 반감기가 15-20분인 aspirin 75mg/daily 로는충분히 platelet aggregation을억제할수있지만, aspirin을불규칙적으로사용하고있는 NSTEMI 환자인경우는효과가충분치않아 12개월이내에심근경색증재발로입원하거나사망하는비율이 4배증가하는것으로보고되었다 (AHA, Circulation. 2007). 그러나외국의 Cairns, Lewis, Theroux, Pooled, Wallentin 연구에의하면 NSTEMI 환자에게 aspirin을사용하여 placebo와비교한결과 aspirin은사망이나심근경색을일으킬수있는상대적인위험 (relative risk) 을감소하였다. 따라서 aspirin은 NSTEMI 환자에게사용할때사망률을감소 (mortality benefit) 할수있는유익한효과가있는 antiplatelet agent로서 NSTEMI 환자가병원에도착후심근경색증으로진단을받으면가능한빠른시간에초기용량 aspirin 160-325mg/daily 을사용하고유지용량 aspirin 75-325mg/daily을평생사용할것을권장한다. ( 예외 : aspirin 사용에내성이있거나금기인경우 ). - Tienopyridines Adenosine diphosphate inhibitors(adp) 로서비가역적으로 Platelet aggregation을억제한다. Clopidogrel (Plavix ) 활성적인대사체로 platelet-signal pathway를비가역적으로영구히손상시키는것과관련이있다. Clopidogrel 75mg/daily은충분히 antiplatelet 작용을갖고있지만불규칙하게복용할경우사망률과이환률 (mortality and morbidity) 를증가시키는것과관련이있다 (AHA, Circulation. 2007). 또한 clopidogrel은환자에따라서다양하게반응하므로불완전하게 platelet aggregation을억제할수도있다. 따라서 clopidogrel은 aspirin에내성이있거나금기 ( 과민성, 위장관내성 ) 인환자로서 NSTEMI 회복기에있는환자에게최소 1개월동안 clopidogrel 75mg/daily을사용할수있으며 (level of evidence A) 이상적으로는 1년정도사용할것을권장하고있다 (Level of evidence B). CAPRIE 연구에서 NSTEMI 환자를대상으로 ischemic stroke, MI, vascular death 위험률 (risk ratio) 에관하여 clopidogrel과 aspirin효과를비교하였는데 clpidogrel의경우 aspirin에비하여위험률이 8.8% 감소하였으며 CURE study에서는 aspirin과 clopidogrel의병용투여의효과를비교하였는데 aspirin단독투여에비하여 aspirin과 clopidogrel 병용투여는위험률을 20% 나더감소한것으로나타났다. Clopidogrel은 ticlopidine에비하여작용시간이빠르며부작용이적은장점이있다. 그러나 aspirin과병용하면심혈관계질환을예방하는효과가증가하지만출혈이지속하는시간도함께증가하는부작용이있으므로주의하여야하며특히고용량의 atorvastatin을사용할경우 atorvastatin(cyp 3A4 inhibitor) 은 clopidogrel(cyp 2B6 inhibitor) 의대사를 90% 이상억제하는것으로나타났으므로두약물의병용사용에주의하여야한다 (Circulation,AHA 2007) Ticlopidine(Ticlid ) Clopidogrel에내성이있는환자에게 clopidogrel 의대용제로사용할수있으며초기용량은 500 mg 을경구로사용하고유지용량은 250mg 을하루에두번음식과함께복용한다. Tclopidine의최대효과는 - 338 -
신혜연 : Non-ST segment elevation myocardial infarction 의치료 투여후 3-5일이내에나타나며제산제를사용하면그작용발현이느려지는약물상호작용이있다. Ticlopidine은 neutropenia, thombocytopenia purprea, aplastic anemia를유발할수있으므로복용처음 3개월동안매 2주마다 complete blood count (CBC) test를실시하여부작용을검토하며만일간기능이상이의심될경우처음 4개월동안간기능검사 (LFT) 를받도록권장하고있으며출혈의증세나징후를검토하여야한다. Prasugrel Platelet aggregation을억제하는신약으로심혈관계질환으로인한사망이나심근경색증, 뇌졸증을감소하는것으로나타났으며 (TRION TIMI-38 research, 2001) 약효는 clopidogre보다우수하지만출혈위험이 clopidogrel보다높은것으로나타났다 ( TIMI research: prasugrel vs clopidogrel = 2.4% vs 1.8%). Prasugrel을사용하는데관한 FDA금기는 transient ischemic attack(tia) 이나뇌졸증의병력이있는환자이거나병적으로출혈이있는환자에게는 prasugrel을사용할수없으며 (FDA contraindication) 75세이상의고령의환자에게는치명적인뇌경동맥출혈위험이증가할수있으므로주의가필요하고 (FDA warning) 당뇨병또는심근경색증병력이있는경우는 prasugrel의사용이효과적인것으로나타났다 (FDA indication). - Glycoprotein IIb/IIIa inhibitors Platelet integrin αⅡbβ3(glycoprotein IIb/IIIa) 이 soluble fibrinogen과결합하여 platelet aggregation을억제하는 antiplatelet agent이다. Aspirin이나 tienopyridine보다완전하게 platelet aggregation을억제하지만출혈위험이높다. PCI를실시할환자에게보조치료제로써사용되며경구용 dual antiplatelet 사용전에투약하며 PCI 를실시할계획이없는환자에게는 abciximab 사용은피하여야한다. Glycoprotein IIb/IIIa inhibitors를사용할수없는경우는 4-6 주내에급성출혈, 고혈압이심한경우 (SBP >180-200mmhg, DBP >110mmhg), 심혈관계출혈 (Intracranial neoplasm, AVM, Aneurysm), 4-6주 내의주수술또는외상, thrombocytopenia(platelet count <100,000/mm3), bleeding diathesis, warfarin 사용으로인하여 INR이상승한때이다. 사용중인 Glycoprotein IIb/IIIa inhibitors는아래와같다. Abciximab (Repro ) Murin-human chimeric antibodies로서비가역적으로 platelet aggregation을억제하며약물을단약할경우 24-48시간이내에 platelet 기능이정상으로돌아온다. PCI를시행하기전에 0.25mg/kg 을정맥투여하고유지용량으로 0.125mcg/kg/min (max. 10mcg/min) 을투여하며 12시간동안까지투여할수있다. 투약후첫 1시간동안매 15분마다 PCI 적용부위의출혈을검토하고다음 6시간동안은매시간마다출혈여부를확인하여야한다. 검토해야하는 laboratory data는 activated clotting time(act) 로서정상수치는 200-300 second이다. Eptifibatide (Integrilin ) Synthetic cyclic hepta peptide로서 glycoprotein receptor에서유사 amino acid sequence로작용하여 platelet aggregation을억제하며약물을단약하면 4시간후에 platelet 기능이정상으로돌아온다. PCI를시행하기전 180mcg/kg 을 1-2 분동안투여하고그다음 2mcg/kg/min을계속투여하여최대 72시간까지투여할수있다. 신장기능이저하된환자 (Scr 2-4mg/dl) 에게는용량을감소하여 135mcg/kg을초기용량으로투여하고그다음 0.5mcg/kg/min을계속하여투여한다. 신장기능 (Scr >4mg/dl) 이저하된환자에게는투여할수없다. 정상 ACT 수치는 300-350 second이다. Tirofiban (Aggrastat ) Synthetic non-peptide로서 glycoprotein receptor에서유사 amino acid sequence로작용하여 platelet aggregation을억제하며기전은 eptifibatide와유사하다. 초기용량은 0.4mcg/kg/min 을정맥투여하고그다음 0.1mcg/kg/min을계속투여하며최대 12-24 시간동안투여할수있다. 만일신장기능이저하된경우라면 (Clcr <30ml/min), 약용량은 50% 까지감소하여투여하여야한다. Tirofiban을 levothyroxin 함께, 또는 omeprazole - 339 -
JKSHP, VOL.27, NO.3 (2010) Table 2. Antiplatelet and anticoagulant therapy 과병용투여하면 tirofiban의청소율 (CL) 을증가시키므로주의하여야한다. (3) Anticoagulation agents UFH이나 LMWH은 thrombus에의하여혈관이다시막히는것을방지하는효과가있는 thrombin inhibitor로서 acute coronary syndrome 환자에게사용하는 heparin은 low molecular weight heparin(lmwh) 과 unfractioned heparin(ufh) 이있으며 low molecular weight heparin은 unfractioned heparin(ufh) 보다 NSTEMI 환자의사망률이나 MI 또는 ischemia 재발을보다효과적으로줄일수있는것으로나타났지만 (Braunwald, et al. 2002 p=0.032, p=0.029) 신장기능이상이나비만환자또는CABG를실시할환자에게는 UFH을사용할것을권장하고있다. Enoxaparin의초기용량 30mg을정맥투여하고 15 분후유지용량으로 1mg/kg 을 12시간마다피하로투여한다. 만일 Creatinine clearance(crcl) 30ml/min 이하인경우는 enoxaparin 1mg/kg 을피하로 24시간마다투여한다. LMWH은생체이용률을예측할수있으며모니터링이적고반감기가길 어서투여하기에편리하지만 UFH과비교할때가격이비싸고소출혈위험이많다. 반면에 UFH은작용발현시간이빠른항응고제로 glycosaminoglycans 의 heterogenous mixture이다. Heparin은 antithrombin(at) 에결합하여 heparin-at complex를만들어서비가역적으로 factor IIa (thrombin) 과 factor Xa, IX, XI, XII를불활성화시키며, platelet기능을억제하고혈관의투과성을증가시켜출혈위험을증가시킬수있다. Doseresponse가다양하며생체이용률이낮으므로 heparin의효과를측정하기위하여투여후 3시간후에 activated partial thromboplastin time (aptt) 를측정하고투여후 6시간이내에 aptt 를검토하여환자에게투여하는 Heparin의용량을조절해야하는단점이있다 ( aptt수치 : 정상 aptt 수치의1.5-2.5배 ). 그리고드물지만 hepain의부작용으로 hepain-induced thrombocytopenia(hit) 와 hepain-associated-thrombocytopenia(hat) 가있으므로매일 platelet 수치를검토하여 platelet 수치가 50% 이하로감소하였거나 1,000,000/mm 3 이하로감소하였으면 heparin투여를중지하여야한다. Heparin의초기용량으로 60-70U/kg=(max. - 340 -
신혜연 : Non-ST segment elevation myocardial infarction 의치료 1,000units) 을정맥투여하고유지용량으로 12-15U/kg을투여하여 aspirin 또는 clopidogrel을복용하고있는모든 NSTEMI 환자에게첨가하도록권장하고있다. Acute coronary syndrome 환자에게 aspirin과 UFH의병용요법은 aspirin 단독투여와비교할때 aspirin보다사망률이나 MI의위험을더줄일수있는효과가있는것으로나타났다 (Theroux, RISC study, p=0.06). - Warfarin NSTEMI 환자에게효과에관한결정적인자료가없으므로사용을권장하지않는다. 그러나항응고제를사용하고있는환자중에서고위험군환자로과거나현재 atrial fibrillation(af), LV thrombus, cerebral, venous, pulmonary emboli 병력이있는경우 warfarin을첨가투여하고 INR수치는 2.0-2.5를그목표수치로하고있다. (4) Lipid lowering agents NSTEMI 환자를위하여입원후 24시간이내에환자의 lipid panel을확인하고입원후 24-96시간이내에 hydroxy methyl glutaryl-coenzyme A reductase inhibitors(statins) 를투여하기시작하여퇴원후에도고지질을관리하기위하여계속투여할것을권장하고있다. 만일환자의 low density lipoprotein cholesterol(ldl-c) 수치가 100mg/dl이상이면치료를시작할수있다. ACC/AHA, NCEPIII에안내지침에의하면심근경색이나당뇨병환자를위한 LDL-C목표수치는 100mg/dl 이하이며 L-TAP 연구에의하면관상동맥질환을갖고있는환자중에서 LDL-C수치가정상에도달한환자는 20% 미만인것으로나타났는데이것은환자가 lipid lowering agents 사용에대하여그순응도 (compliance) 가부족하였거나또는고지혈증을치료하기위한 lipid lowering agents가부적합하였거나운동과식이요법에관한환자교육이나환자자신의관리가부족하였음을나타낸다. 최근에변경된미국 AHA안내지침은만일 High density lipoprotein cholesterol 수치가 40mg/dl 이하일경우 niacin이나 fibrate를첨가하여치료할것을권유하고있다. (5) Others - Direct thrombin inhibitors NSTEMI 환자에게효과와안전성이입증되지않아서권장되지않고있다. - Thrombolysis 사망률과이환률이증가한연구결과 (TIMI IIB study) 과있으므로사용을권장하지않는다. Secondary prevention 1. Aspirin, ACEI, Beta-blocker를평생복용하며 aspirin으로인한위장관출혈이있는경우의료진에신속히연락할수있도록환자에게교육을제공한다. 2. Nitro sublingual은 MI로인한가슴의통증을소실할목적으로사용하는것이므로일반진통제가아님을반드시환자에게알려주어야하며 nitro sublingual을사용후 5분이지나도통증이소실되지않으면즉시응급의료서비스팀에연락하도록환자에게교육을실시한다. Nitro sublingual original bottle 을다른병으로바꾸지않도록환자에게설명하고유효기간을병위에기입하도록하여유효기간이지난약물을복용하지않도록한다. 3. 혈압은 SBP 140mmhg 이하, DBP 90mmhg 이하로조절하며만성신장기능이상이나당뇨병이있는경우는 SBP 130mmhg 이하, DBP 80mmhg 이하로혈압을조절하도록한다. 4. 당뇨병이있는경우 HbA1C 수치는 7% 이하로혈당을유지하여고혈당으로인한관상동맥합병증위험요소를감소하도록한다. 5. 흡연을금하고흡연환경에노출되지않도록금연교육을제공하며금연의의지를갖고있는환자에게는재활교육을안내함과동시에약물치료를제시하고금연하고있는환자를위하여지속적인격려와관찰 - 341 -
JKSHP, VOL.27, NO.3 (2010) 이필요하다 ( 금연교육, 금연재활교육, 약물치료 ). 6. LDL-C수치는 100mg/dl 이하로감소하여심근경색의위험요소를감소하도록한다. 7. 주 7일간 30-60분 ( 최소주 5 일 ) 정도의규칙적인운동을하여심근경색의위험요소를감소하도록권장한다. 8. 체중조절을한다 [Body mass index(bmi) 18.5-24.9kg/m 2, waist circumference men: <40 in, women: <35 in] 9. 급성심근경색이왔을때약물사용및응급의료지원팀과의연락과약물사용순응도의중요성에관하여퇴원교육을실시한다 10. 매년독감예방접종을받도록한다. 참고문헌 1) ACC/AHA Guideline of ACS and NSTEMI.( 2009) 2) ACC/AHA Clinical performance measure for adults with ST-elvation and NON- ST-elevation myocardial infarction 3) Antman et al. JACC 44-689.(2004) 4) Stone et al. N Eng J Med. 358:2218-30.(2008) 5) ACC/AHA Guideline for the management of UA/NSTEMI. (2007) 6) Management of acute coronary syndrome: Larry S.Dean, FACC/FCSAI. NSTEMI 에사용되는약물 Classification Medication Dosage Comments: recommendation and contraindication Initiate loading dose 162~325mg/day,main- Consider discontinuation 1 week prior to surgery except CABG, PCI. Antiplatelet Aspirin tenace dose 75~162mg/day. Take aspirin CI: Allergic reaction, active bleeding, Hemophilia, acute peptic ulcer indefinitely. Abciximab 0.25mg/kg IV bolus over 10~60min before (Reopro ) PCI then, infuse IV 0.125mcg/kg/min(max. 10mcg/min) up to 12~18hr nitial bolus of 180 mcg/kg over 1-2 minutes CI: Active internal bleeding, GI/GU bleeding within 6 weks, history then,continuous infusion of 2 of cerebrovascular accident within 2 years, thrombocytopenia, major Antiplatelet : Glycoprotein IIb/IIIa inhibitors Eptifibatide (Integrilin ) mcg/kg/minute (maximum: 15 mg/hour) up to 72 hr. If Scr 2-4mg/dl, reduce first dose to 135mcg/kg and reduce the infusion rate to 0.5mcg/kg/min surgery or trauma within 6 weeks, uncontrolled hypertension, hypersensitivity. Eptifibatide: contraindication if Scr > 4mg/dl or dialysis. Monitor ACT level Initial IV infusion of 0.4mcg/kg/min for 30 Drug-drug interaction(ddi):combination use with levothyroxin Tirofiban min followed by continuous IV infusion of and/or omeprazole increases ticlopidine clearance (Aggrast ) 0.1mcg/kg/min up to 12-24 hr. Decrease bolus dose and infusion rate by 50% in patient with Clcr <30ml/min. Lamifiban On clinical trials - 342 -
신혜연 : Non-ST segment elevation myocardial infarction 의치료 Classification Medication Dosage Comments: recommendation and contraindication Clopidogrel (Plavix ) Initiate loading dose 300mg po > 6hours proir to procedure then, maintenance dose 75mg po daily Monitor CBC with platelet count Drug-drug interaction:atorvastatin increases clopidogrel clearance, may reduce the effect of clopidogrel, combination with aspirin may increase the bleeding time CI: active pathologic bleeding(peptic ulcer, ICH). Antiplatelet : Thienopyridines Ticlopidine (Ticlid ) Initiate dose 500mg daily,maintenance dose 250mg bid Monitor CBC with platelet count every 2 weeks for the first 3 months due to neutropenia, agranulocytopenia, and TTP, If suspected liver function, monitor LFT for the first 4 months. Prasugrel (Effient ) Initiate loading dose 60mg po then, continue maintenance dose 10mg po daily. Patient should take with Aspirin (75-325mg/day). CI: history if TIA, Stroke, and acute pathologic bleeding. Not recommended in patient > 75yrs(excetpt DM, prior MI) Non- Cangrelor On clinical trials Tienopyridines Ticagrelor 180mg po load then 90mg po bid not yet available for clinical use Sublingual nitroglycerine (Nitrostst ) Administer 0.4mg one sublingual nitroglycerine every 5 min under tongue for ongoing ischemic discomfort up to 3 doses Call emergency medical service team if chest pain is not resolved after taking one sublingual nitroglycerine tablet. Unused tablet should be discarded 6 months after the original bottle is opened. Store in original bottle to maintain potency/stability Anti-Ischemic and analgesic Nitroglycerine(IV) (Tridil ) Start at IV 10 mcg/min, increase by 5 or 10 mcg/min every 5 to 10 min for the first 48 hr for persistent ischemia, heart failure, or hypertension CI: SBP < 90mmhg, Severe bradycardia < 50 bpm, Tarchycardia>100 bpm, suspected RV infarction If patient have received within 24 hours of sildenafil or 48 hours of tadalafil Nitroglycerine transdermal (Nitro-Dur ) apply 0.2-0.8mg/hour to a hairless area and rotate the site. Recommend 24 hours after clinical symptoms are resolved. Give nitrate free period of 10-14 hours each day to avoid nitrate tolerance Anti-ischemic and analgesic Morphine(IV) Initial infusion of IV 2~4mg every 5~15min as needed. Adjust the dose in renal insufficiency. CI: hypersensitivity, severe respiratory depressionmonitor repiratory rate, SBP/DBP over 90/50mmhg, hypersensitivity Adjust infusion to maintain aptt at 1.5-2.5 times control. SE: Unfractioned Heparin(UFH) Start with IV bolus of 60~70 U/kg(max. 5,000U) then infusion of 12~15U/kg(max. 1,000U) bleeding, thrombocytopenia, HIT, osteoporosis, hyperkalemia, elevation of liver enzymes. Monitor ApTT level, signs and symptoms of bleeding, aptt level. Do not use for >48hrs in patient without symp- Anticoagulant toms Start with IV bolus of 30mg then,injection Do not use in CABG Enoxaparin 1mg/kg SC every 12 hour for 2~8 days. if SE:osteoporosis, hypersensitivity, HIT,Caution :monitor antixa level, (Clexane ) CrCl < 30ml/min, reduce dose to 1mg/kg/day if use in patient with renal failure, elderly 75 years of age, and/or SC. obese - 343 -
JKSHP, VOL.27, NO.3 (2010) Classification Anticoagulant Direct thrombin inhibitor Beta-blockers Calcium channel blocker Medication Statins Aspirin Clopidogrel Medication Fondaparinux Dosage 2.5mg/day SC for up to 8 days (Arixtra ) IV bolus 0.75mg/kg prior to intervention, Bivalirudin followed by continuous infusion (Angiomax ) 1.75mg/kg/hr for the duration of procedure Start with IV dose of 2.5-5mg and repeat Metoprolol (Toprol XL ) every 5 min if needed(max. 10mg). At 15 min after last IV dose, start oral dose with 50mg every 6hrs for 48 hrs then, 100mg bid IV bolus 0.25mg/kg over 2min,continuous Ditiazem (Cardizem, Cardizem LA ) infusion of IV 5mg/hr and adjust as needed.then, Switch to PO(immediate release) medication then, switch to SR(sustained release) formular when discharge home Second prevention Dosage Rosuvastatin Atorvastatin Simvastatin Lovastatin Fluvastatin 5-80mg/day 10~80mg/day 5~40mg/day 10~80mg/day 20~40mg/day 75~325mg /day 75mg/day Metoprolol succinate extended release Start 12.5-25mg once (max. 200mg/day) (ToprolXL ) Comments: recommendation and contraindication Caution : If CrCl 30~50ml/min, use cautiously. Should not be used as the sole anticoagulant for PCI due to risk of catheter thrombosis CI: CrCl < 30ml/min due to increased bleeding risk Monitor renal function in all patients If Clcr > 30 ml/min, no adjustment needed. If Clcr 10-29 ml/min, decrease infusion rate to 1mg/kg/hr. Monitor ACT level CI: active major bleeding Efficacy and safety in UA/NSTEMI is not widely accepted CI: Sinus bradycardia, AV block (pr > 0.24 sec.), 2nd and 3rd degree heart block, SBP < 100mmhgcardiogenci shock and hypotension cocaine induced ischemia Caution: If with air way disease like asthma, COPD or diabetes, hyperlipidemia, use cautiously and monitor lipid profile and blood glucose level during the therapy CI: Left ventricular dysfunction/chf, pulmonary congestion, hypotension, 2nd or 3rd degree AV block. Do not use in patient with systolic dysdunction HF,DDI: increase digoxine level Comments: recommendation and contraindication Doses should be individualized according to the baseline LDL-C level. Recommended goal of LDL-C: less than100mg/dlif HDL-C is less than 40mg/dl, add niacin or fibrates. CI: active liver disease, elevation of serum transaminase,allergic reaction Administer indefinitely unless contraindication Alternative to Aspirin if allergic to aspirin Beta-blockers Carvedilol Bisoprolol Start 3.125 mg two times a day (max. 25mg two times a day. 50mg two times a day for patient >85kg) Start 1.25mg once a day (max. 10mg/day) Administer indefinitely unless contraindication - 344 -
신혜연 : Non-ST segment elevation myocardial infarction 의치료 Medication ACEinhibitors Warfarin (Coumadin ) Dosage Start 2,5-5mg/day (max. 20mg two Enalapril times a day Start 1.25-2.5mg/day (max.10mg two Ramipril times a day Lisinopril Start 2.5-5 mg/day (max. 40mg/day) Initial dose must be individualized. Consider patient's hepatic function, cardiac function, age, concurrent therapy, nutrition status and risk of bleeding. Start 5-10mg daily for 2 days and adjust dose to keep INR level between 2.0-3.0 for most indications, 2.5-3.5 for mechanical heart valve but INR value depends on the site and the type of vlave. Usual maintenance dose: 2-10mg/day. Note: Lower starting dose may be required for hepatic impairment, poor nutrition, CHF, elderly, higher risk of bleeding. Comments: recommendation and contraindication Recommended goal of blood pressure: SBP/DBP= 140/90mmhg, If patient has diabetes and/or renal insufficiency, SBP/DBP=130/80mmhg. Take indefinitely unless contraindication Use warfarin for long term period for the patient with specific condition like AFib, LV thrombosis, cerebral, venous or pulmonay emboli at discharge. SE: hypercoagulability during first 24-36 hours of therapy, bleeding, hypersensitivity, teratogenicity, skin necrosis associated with malignancy - 345 -
JKSHP, VOL.27, NO.3 (2010) 1. Which of the following is true regarding the use of clopidogrel in patients with an acute coronary syndrome? A) A loading dose of at least 300mg should be used B) Clinical outcome in clopidogrel treated patients are significantly worse in the setting of concomitant treatment with atorvastatin C) Doubling the loading dose and maintenance dose of clopidogrel has been shown to be more effective than standard therapy D) A loading dose of clopidogrel is efficacious regardless of the time of dosing as long as it is prior to the percutaneous intervention 2mm in lateral leads) and initial cardiac enzymes within normal limits. However, a second and third set of cardiac enzymes are mildly elevated. The patient is scheduled for coronary angiography. The optimal antiplatelet regimen for this patient at this time of PCI in order to minimize PCI thrombotic events should include : A) Aspirin B) Aspirin + Clopidogrel 300mg at the time of PCI C) Aspirin + Clopidogrel 600mg at the time of PCI D) Aspirin + Clopidogrel loading dose administered prior to PCI + GPIIb/IIIa inhibitor 2. True statements about aspirin include all of the following, except for : A) The antiplatelet effects of aspirin can be prevented with concomitant nonsteroidal anti-inflammatory drug use B) Aspirin exerts its antiplatelet effects trough inhibition of the platelet thrombinreceptor for the life span of the platelet C) Aspirin is a relatively weak inhibitor of platelet aggregation in vitro D) When chewed or solubilized the full antiplatelet effects of aspirin can be achieved in ~15minutes. 3. A patient is admitted from the emergency room for a suspected acute coronary syndrome with EKG change( ST depression > 4. post intervention CK-MB leaks are : A) Of no concern B) Rarely occur C) Do not represent real myocardial injury D) Are related to late mortality and MI 5. what medications should a patient who is post MI with preserved LVEF receive as discharge therapy? A) Aspirin, plavix, cardizem, and simvastatin B) Aspirin, metoprolol, enalapril, atorvastatin, and SL NTG C) Plavix, metoprolol, enalapril, and simvastatin D) Morphine, aspirin, SL NTG, and Lovenox E) Morphine, IV NTG, aspirin, and oxygen 제 27 권 2 호정답 1. B) 2. C) 3. E) 4. E) 5. B) - 346 -