ACS Therapeutics Review Sheet PDF

Cassagnol ACS SHORT REVIEW Unstable Angina (UA): ● nonspecific ECG changes (ST segment depression, T wave inversion), no positive biomarkers for cardiac necrosis, no myocardial necrosis NSTEMI (non ST-segment elevated myocardial infarction): ● nonspecific ECG changes, positive biomarkers (TnT, CK-MB...

Cassagnol ACS SHORT REVIEW Unstable Angina (UA): ● nonspecific ECG changes (ST segment depression, T wave inversion), no positive biomarkers for cardiac necrosis, no myocardial necrosis NSTEMI (non ST-segment elevated myocardial infarction): ● nonspecific ECG changes, positive biomarkers (TnT, CK-MB) STEMI: ● ST-segment elevation and positive biomarkers ACS Symptoms: chest pain, arm/back/jaw pain, NV, SOB Clinical Suspicion of ACS 12-Lead ECG obtained within 10 minutes + look at labs for biomarkers (TnT, CK-MB) ● Drugs given within 120 minutes: o Give loading dose of chewable aspirin (162-325mg) – first antiplatelet o Give loading dose of P2Y12 inhibitor (Clopidogrel, Ticagrelor, or Prasugrel (last one is only if undergoing PCI)) – second antiplatelet o Give one anticoagulant (Heparin, Enoxaparin, Fondaparinux, or Bivalirudin (last one is only given if undergoing PCI)) before going to CATH lab o Give oxygen for patients with shortness of breath and <90% oxygen saturation o sublingual nitroglycerin to relieve anginal pain (if patient has anginal pain) ▪ nitroglycerin up to three max doses. If pain unresolved, give IV nitroglycerin ▪ if pain is not resolved, give morphine 1-5mg IV slow push (titrated to maximal tolerated dose) ● STEMI diagnosis: immediately give reperfusion therapy/revascularization with PCI (surgery) OR fibrinolysis (meds) o Preferred: PCI (not always available) intervention within 90 minutes of first contact in field -> hospital stay 4-5 days ▪ 30 minute door to needle time o Fibrinolytic: within 120 minutes ideally, but can be given up to 12 hours of symptoms ▪ Fibrinolytics utilized only in STEMI patients (fibrin-rich clots seen only in STEMI patients)– Alteplase & Tenecteplase (weight-based dosing), Reteplase ▪ Anticoagulant therapy used adjunct to fibrinolytics for at least 48h for up to 8 days or until revascularization is performed ▪ KNOW Absolute CIs: any prior hemorrhagic stroke, ischemic stroke within 3 mo, intracranial neoplasm or arteriovenous malformation, active internal bleeding, aortic dissection, considerable facial trauma/closed-head trauma within 3 mo, severe & unresponsive HTN ▪ Do not get streptokinase within 6 mo of previous streptokinase dose ▪ prefer to give Fibrinolytic with unfractionated heparin, NOT enoxaparin (due to risk of bleeding) ▪ only CLOPIDOGREL is given as second antiplatelet with fibrinolytic therapy 1 o GPIIa/IIIB inhibitors given adjuvant for anticoagulant therapy occasionally in high risk STEMI, NOT given as an antiplatelet (Eptifibatide or Tirofiban preferred) ● NSTEMI diagnosis: complete TIMI risk stratification score to determine invasive vs. conservative measures o High Risk TIMI 5-7 – INVASIVE - PCI or CABG (similar to STEMI tx) o Moderate Risk TIMI 3-4: can be invasive OR conservative (ischemia-guided) ▪ Intermediate/high risk features: invasive PCI or CABG ▪ Moderate: conservative -> stress test ((+) = invasive) vs. ((-)= noncardiac chest pain) o Low Risk TIMI 0-2 -> stress test ((+) = invasive) vs. ((-)= noncardiac chest pain) o Sometimes GPIIa/IIIb inhibitors are given for NSTEMI patients as the second antiplatelet agents with initial P2Y12 (given to those with high risks – elevated biomarkers, diabetes, undergoing revascularization) ▪ Eptifibatide or Tirofiban preferred, thrombocytopenia risk and renal adjustments necessary ● If PCI is given, you can now add on day 1 the high intensity statin (preferred Atorvastatin 80mg) and oral beta blocker (metoprolol succinate, carvedilol, or bisoprolol cardioprotective; continue for at least 3y in 40%+ ejection fraction) and low dose of anticoagulant for prevention of VTE o by day 2, continue statin, BB, anticoagulant. Add DAPT: maintenance dose of aspirin (81mg) and P2Y12 inhibitor (dual antiplatelet therapy). Add renin antagonist (ACEI/ARB) ▪ Note: DAPT premature d/c predicts stent thrombosis. DAPT used for 12 months for patients on conservative method, longer durations for patients with higher ischemic risk and lower bleeding risk (for patients with DAPT score 2+) ▪ reasoning for waiting until day 2 - wait to see if there’s contrast induced nephropathy after procedure before starting ACEI/ARB o Give ezetimibe or PCSK9 inhibitor to statin if LDL is >70mg/dL o Give aldosterone antagonist in 48 hours for patients with HEART FAILURE) ● Discharge meds: BB, ACEI/ARB, DAPT (duration varies), high intensity statin, (+/- AA) o Other: PPI, vaccines, avoid NSAIDs o If patient was on anticoagulant, but DO NOT GET PCI, continue heparin IV for 48 hours or enoxaparin IV for 8 days or the end of hospital course “THROMBINS2” – Treatment Overview for ACS ● Thienopyridines and other P2Y12 inhibitors – Prasugrel, Clopidogrel, Ticagrelor ● Heparin – anticoagulant can be UH, LMWH, or fondaparinux ● Renin-Angiotensin-Aldosterone System (RAS): ACEI/ARBs ● Oxygen (PRN) ● Morphine 1-5mg IV slow push every 5-30 min (if pain is still uncontrolled by sublingual then IV nitroglycerin) ● Beta Blockers (started within 24-48 hours of MI if there is no evidence of HF, shock, or heart block) – metoprolol succinate, carvedilol, or bisoprolol in stabilized HFrEF o No IV** 2 ● Invasive cardiac Interventions (PCI) ● Nitroglycerine 0.3-0.4 mg sublingual (PRN anginal pain) -> IV NTG 5-10mcg/min if still uncontrolled by three max doses of NTG sublingual ● Statin (high-intensity for <75y) ● Standard immediate ASA therapy (MUST BE CHEWED, NON-EC) 162-325mg SHORT REVIEW ENDS HERE… Comprehensive Review ACS: Abbreviations: ACS =acute coronary syndrome; ACEI=angiotensin converting enzyme inhibitor; ADP = adenosine diphosphate;ARB= angiotensin receptor blocker ACC=American College of Cardiology; AHA = American Heart Association; ASCVD= atherosclerotic cardiovascular disease; BB = beta=blocker; CABG=coronary artery bypass graft surgery; CAD = coronary artery disease; CCB = calcium channel blocker; CHD= coronary heart disease; CK =creatine kinase; CSA= chronic stable angina; CXr= chest xray; ECG = electrocardiograph; ECHO: echocardiograph; HF=heart failure; INR=internation normalized ratio; JVD= jugular venous distention; LV= left ventricle, LAD = left anterior descending artery; LCx = left circumflex artery; LCA = left coronary artery; MI myocardial infarction; MB=myocardial band; NTG = nitroglycerin; non-DHP CCB = non- dihydropyridine calcium channel blocker; NSTE=Non ST-segment elevation; PCI percutaneous coronary intervention; RCA = right coronary artery; RV = right ventricle STE= ST segment elevation; TXA2=thromboxane; TnT = troponin; SL = sublingual; UA= unstable angina Background ● Angina = clinical syndrome characterized by discomfort in chest, jaw, shoulder, back, or arm occurs dec. blood supply to myocardium ● ACS is classified by ECG changes: ● STE ACS = STEMI (formerly Qwave or transmural MI) ● 1/3 present as STE ● Injury that transects the thickness of the myocardial wall ● Pathologic Q-waves seen on ECG ● NSTE ACS = NSTEMI & UA (formerly non-Qwave or nontransmural MI) – unstable angina and NSTEMI are indistinguishable for the most part, so treated as one and the same ● 2/3 present as NSTE ● Limited to subendocardial myocardium ● No Qwaves seen on ECG a. UA = No necrosis of tissue b. NSTE = ischemia causes necrosis of tissue leaking of enzymes (i.e. CK-MB, TnT Table 1. ACS Subclassifications and Clinical Findings NSTE-ACS UA (unstable angina) NSTEMI Subjective Findings Usually presents as a pressure-type chest pain that typically occurs at rest or with minimal exertion Pain usually starts in the retrosternal area and can radiate to either or both arms, neck, or jaw Pain may also present with diaphoresis, dyspnea, nausea, abdominal pain, or syncope Unexplained new-onset or increased Objective Findings ST-segment depression, T-wave inversion, or transient or nonspecific ECG changes may occur Extent of Injury No myocardial necrosis; partial occlusion of coronary artery No positive biomarkers for cardiac necrosis ST-segment depression, T-wave inversion, or transient or nonspecific Myocardial injury; partial occlusion of coronary artery 3 STEMI a exertional dyspnea is the most common angina equivalent Less common atypical symptomsa (without chest pain) include epigastric pain, indigestion, nausea, vomiting, diaphoresis, unexplained fatigue, and syncope ECG changes may occur Classic symptoms include worsening of pain or pressure in chest, characterized as viselike, suffocating, squeezing, aching, gripping, and excruciating, that may be accompanied by radiation Can present with less common atypical symptomsa as well; diagnosis cannot be made by symptoms alone without accompanying ECG and biomarker assessment ST-segment elevation Positive biomarkers (cTn elevation) – indicates tissue damage (CK-MB is specific for heart) > 1 mm above baseline on ECG in two or more contiguous leads Myocardial necrosis; total occlusion of coronary artery Positive biomarkers (cTn elevation) Up to one-half of all MIs are silent or unrecognized, and one-third present with symptoms other than chest discomfort. Women, older adults, and those with diabetes tend to present more often with atypical symptoms. ACS = acute coronary syndrome; cTn= Cardiac troponin; MI = myocardial infarction; NSTE-ACS = non–ST-segment elevation acute coronary syndrome; NSTEMI = non–ST-segment elevation myocardial infarction; STEMI = ST-segment elevation myocardial infarction; TnI = troponin I; TnT = troponin T; UA = unstable angina. Clinical Presentation and Diagnosis of ACS Symptoms ● ● ● ● Signs ● ● Laboratory ● ● ● ● ● ● Diagnosis ● ● ● ● Midline anterior chest discomfort; chest pain (typically at rest) Arm, back, or jaw pain (radiating pain – presents as this in women commonly) Accompanying nausea and vomiting, diaphoresis, or SOB (anginal equivalence) Patients less likely to present with classic symptoms include elderly, diabetic pts. women Acute heart failure (JVD, and S3 sound ) Arrythmias (heart block) Troponin I or T CKMB (creatinine specific for cardiac muscle) Blood chemistry (esp. K, Mg) SCr (for possible dose adjustments) Baseline CBC and coagulation tests (aPTT, INR) Fasting lipid (limited use) 12-lead ECG (Risk Stratification- STE vs. NSTE ACS) Chest radiography/echocardiograph (concomitant HF symptoms) Stress Testing (low risk patients) Cardiac Catheterization (vascular access to coronary arteries w/ radiocontrast dye) 12-Lead ECG: - look for ST elevation (STEMI) opposed to ST segment depression and T wave inversion (nonspecific; could be NSTEMI or UA or other) ● Obtain within 10 minutes of presentation ● Compare with prior ECG if possible ● Key findings on ECG STE, ST segment depression and Twave inversion ● Help to identify location occlusion 4 ● New left bundle branch block w/ chest discomfort Biochemical Markers /Cardiac Enzymes: ● TnT or TnI (stays in body for 10 days), CK-MB (only present for acute phase of heart attack and for 48h) ● Detection rise and/or fall of cardiac biomarkers ● At least 1 value >99th percentile upper limit + ECG change of new ischemia/Qwaves OR imaging of loss myocardium ● At presentation, 6-9 hours, 12-24h (in high risk + previous neg. ECG change) Risk Stratification: ( know scores for NSTEMI patients) STE ACS highest risk of death (Indicated by ST elevation) proceed without further evaluation ● Target times for reperfusion: o Treatment with fibrinolytics within 12 hours o Treatment with PCI within 120 minutes (preferred, not always available) o Length of stay in hospital 4-5 days NSTE ACS ST-segment depression elevated biomarkers at higher risk of death or recurrent infarction ● Use risk calculator to stratify risk (other tools GRACE useful in low TIMI risk score) o Stratified into high, moderate, low risk ▪ High risk (score 5-7) Early invasive Angiography with revascularization (PCI or CABG) ● Similar treatment to STEMI (“early invasive strategy”) ● PCI: singular lesions vs. CABG: requires bypass with multiple lesions ▪ Moderate risk (score 3-4) – can be INVASIVE or CONSERVATIVE ● Intermediate/High risk features (early invasive strategy) PCI or CABG ● Moderate (conservative strategy) stress test if (+), PCI or CABG if (-), non cardiac chest pain ▪ Low risk (conservative strategy) (score 0-2) stress test if (+), PCI or CABG if (-), non cardiac chest pain syndrome Table 2. TIMI Risk Score for Unstable Angina/NSTEMIa,b Historical Age > 65 Points 1 Three cardiac risk factors (HTN, diabetes, hyperlipidemia, smoking, family history) 1 Known CAD ≥ 50% stenosis 1 Presentation a Severe angina (≥ 2 episodes within 24 hr) ASA within 7 days 1 Elevated markers 1 ST-segment deviation ≥ 0.5 mm 1 1 Risk of mortality, new or recurrent MI, or severe recurrent ischemia through 14 days. Low is 0–2, intermediate is 3, and > 4 is high risk. TIMI score: score = 0–1, mortality 7%; score = 2, mortality 8%; score = 3, mortality 13%; score = 4, mortality 20%; score = 5, mortality 26%; and score = 6–7, mortality 41%. bRisk score = total points (0–7). ASA = aspirin; CAD = coronary artery disease; HTN = hypertension; TIMI = thrombolysis in myocardial infarction. Table 3. Selection of Initial Treatment Strategy: Invasive vs. Conservative/NSTE Early Invasive Strategy Recurrent angina/ischemia at rest with low-level activities despite intensive medical therapy Elevated cardiac biomarkers (cTn) New/presumably new ST-segment depression Signs/symptoms of HF or new/worsening mitral regurgitation 5 High-risk findings from noninvasive testing Hemodynamic instability Sustained VT PCI within 6 mo Prior CABG High-risk score (e.g., TIMI, GRACE) Reduced left ventricular function (LVEF < 40%) Ischemia-Guided Strategy/Conservative Low-risk score (e.g., TIMI, GRACE), high risk of catheterization-related complications, Not a good candidate for revascularization, or patient/physician presence in the absence of high-risk features CABG = coronary artery bypass grafting; GRACE = Global Registry of Acute Coronary Events; HF = heart failure; LVEF = left ventricular ejection fraction; PCI = percutaneous coronary intervention; VT = ventricular tachycardia. Goals: ● Early restoration of blood flow to the infarct-related artery to prevent infarct expansion (in the case of MI) or prevent complete occlusion and MI (in case UA) ● Prevent death and other complications ● Resolve ECG changes ● Prevent coronary artery re-occlusion ● Relief of ischemic chest discomfort General Approach to Treatment ● Modify CV risk factors and slow the progression of coronary atherosclerosis ● Stabilize existing atherosclerotic plaques ● Improve the balance between myocardial oxygen demand and supply 6 A. Decision for Invasive Management (Circulation 2014;130:e344-426; Circulation 2013;127:e362-425) 1. STEMI a. Goal of therapy is to restore the patency of the infarct-related artery and minimize infarct size. Secondary goals include preventing complications such as arrhythmias or death and controlling chest pain and associated symptoms. b. Requires urgent revascularization either by mechanical intervention (catheterization laboratory) or with drug therapy c. Primary PCI is preferred to fibrinolytic (drug) therapy. i. Greater than 90% achievement of good blood flow with primary PCI in STEMI ii. Only 50%–60% achievement of good blood flow with fibrinolytic therapy d. Performance measure includes goal of primary PCI within 90 minutes of first medical contact. e. Fibrinolytic therapy is indicated for patients with STEMI in whom PCI cannot be performed within 120 minutes (discussed later in chapter). f. Surgical revascularization may be indicated, depending on the severity of CAD, complexity of anatomy, or development of other complications. 2. NSTE-ACS a. Goals of therapy are to prevent total occlusion of the related artery and to control chest pain and associated symptoms. b. Patients with NSTE-ACS are treated according to risk (TIMI, GRACE) with either an early inva- sive strategy (interventional approach) or an ischemia-guided strategy (a conservative management strategy using medications rather than an interventional approach). c. Early invasive strategy is a diagnostic angiography with intent to perform revascularization if 7 d. e. appropriate depending on coronary anatomy. i. Indicated in those with NSTE-ACS who have refractory angina or hemodynamic or electrical instability or in those with a high risk according to clinical findings ii. Routine invasive therapy is usually superior to an ischemia-guided strategy (results in lower rates of recurrent UA, recurrent hospitalization, MI, and death) in patients with one or more of the following risk features: advanced age (older than 70), previous MI or revascularization, ST-segment deviation, heart failure, depressed resting left ventricular (LV) function (i.e., left ventricular ejection fraction [LVEF] less than 40%), noninvasive stress findings, high TIMI or GRACE scores, markedly elevated troponins, and diabetes. iii. Not for those with serious comorbidities or contraindications to such procedures (hepatic, renal, and pulmonary failure; cancer) for whom the risks of the procedure might outweigh the benefits of revascularization “Ischemia-guided” therapy seeks to avoid the routine early use of invasive procedures unless patients have refractory or recurrent ischemic symptoms or develop hemodynamic instability. i. Recommended for patients with a low risk score (TIMI 0 or 1, GRACE less than 109) ii. Indicated for those with acute chest pain with a low likelihood of ACS who are troponin negative (preferred for low-risk women) iii. May be chosen according to clinician and patient preference Surgical revascularization may be indicated, depending on the severity of CAD, complexity of anatomy, or development of other complications. Treatment Overview for ACS REMEMBER THROMBINS2 (https://acls.com/free-resources/knowledge-base/acute-coronarysyndrome/thrombins-is-new-mona) – not given in this order****** ● ● ● ● Thienopyridines (prasugrel and clopidogrel) & non-thienopyridine drugs that also inhibit the P2Y12 receptor (cangrelor and ticagrelor). o Platelet activation is inhibited differently than aspirin by all these drugs, which then provides a dualantiplatelet blockade. Anticoagulation, unfractionated Heparin (UFH) most common. o Heparin remains popular because of its low cost and reversibility o Low-molecular-weight heparins (LMWH), like enoxaparin, greater specificity for factor Xa than UFH, but their long duration of action puts them at odds for patients who may be undergoing percutaneous coronary intervention (PCI) or cardiac bypass surgery Renin-Angiotensin-Aldosterone System (RAS) using ACEI or ARBs o attenuate ventricular remodeling after acute MI, which provide benefits regarding mortality Oxygen o supplemental oxygen provides improved oxygen delivery to cardiac tissue, which then decreases the size of infarcted myocardium and ischemic injury. o Hyperoxygenation could lead to vasoconstriction through several mechanisms ▪ A prospective, randomized study in 2015 reported that supplemental oxygenation was associated with statistically significant elevations in creatinine kinase levels, recurrent MI, arrhythmias, and elevated infarct size by cardiac MRI compared to those without supplemental oxygen ▪ Burrell (2017) reported the DETO2X-AMI study showed the routine use of supplemental oxygen in patients with suspected MI who did not have hypoxemia was not found to reduce 8 one-year all-cause mortality, and that oxygen does not make any difference to outcomes in normoxic patients with suspected AMI Morphine used for pain control and relief of symptoms in patients with ACS. o Despite its ability to decrease oxygen demand on the myocardium through anxiolysis, venodilation, and decreased blood pressure and heart rate through increased vagal tone, no large randomized trials have shown an improvement in outcomes Beta-blockers (BB) reduce heart rate and myocardial oxygen consumption, improving outcomes in patients diagnosed with acute MI. o BB should be started within 24 hours of MI if there is no evidence of heart failure, shock, or heart block5. o Hauk (2014) also lists other contraindications as a PR interval greater than 0.24 seconds, second- or third-degree heart block in patients without a pacemaker, asthma, and reactive airway disease. Invasive cardiac interventions (PCI) o PCI is first line intervention o For providers practicing in facilities without this option, a clear and reliable referral system should be in place long before a patient is seen who is presenting with ACS symptoms. o Patients with non-ST elevation ACS who have refractory angina or hemodynamic or electrical instability may require immediate treatment via an invasive strategy4. o An early revascularization strategy relatively reduces the risk of mortality at two years by 25%1. Nitroglycerine acts as a venodilator to decrease venous return to the heart, which then decreases left ventricular workload and myocardial oxygen demand. At the same time, the coronary artery dilatory effects help deliver oxygen to ischemic areas in the myocardium. o Even with these pro-cardiac properties, nitrates have not shown to have a significant effect on mortality5. ● ● ● ● ● High-intensity statin for patients aged 75 and under, and moderate-intensity statin therapy for patients over 75 with coronary artery disease o The long-term benefit appears to happen after two years, with a 25% relative risk reduction in death after that point. o ACS diagnosed patients are considered the clinical ASCVD statin benefit group Aspirin immediate aspirin therapy is standard o The ISIS-2 trial showed that aspirin reduced death in STEMI by 23% at five weeks in comparison to placebo ● PHARMACOTHERAPY INTERVENTION I. ANTI-ISCHEMIC INTERVENTIONS KNOW THE RED Table 4. Initial Anti-ischemic Therapies in ACS Management Morphine, or other narcotic analgesic Oxygen • Provides analgesia and decreases pain-induced sympathetic/adrenergic tone • Commonly used because it may also induce vasodilation and mediate some degree of afterload reduction • Morphine 1–5 mg IV every 5–30 min is reasonable if symptoms are not relieved despite maximally tolerated anti-ischemic medicationsa • Carries a class IIb recommendation and may not be favored more than other narcotic analgesics, given that at least two large trials have identified an association between morphine administration and risk of death (N Engl J Med 2014;371:1016-27; Am Heart J 2005;149:10439) • Slows the absorption of antiplatelet therapy, reduces time to peak antiplatelet activity, and may decrease AUC • Can help attenuate anginal pain secondary to tissue hypoxia 9 • Consider supplemental oxygen if Sao2 < 90%, respiratory distress, or high-risk features of hypoxemiab Nitroglycerin Aspirin β-Blocker • Facilitates coronary vasodilation and may also help in severe cardiogenic pulmonary edema caused by venous capacitance • NTG spray or sublingual tablet (0.3–0.4 mg) every 5 min for up to three doses to relieve acute chest pain (if pain is unrelieved after one dose, call 911); afterward, assess need for IV • IV used in first 48 hr for treatment of persistent ischemic chest pain, HF, and HTN • IV NTG 5–10 mcg/min; titrate to chest pain relief or max 200 mcg/min • Use should not preclude other mortality-reducing therapies (β-blocker, ACE inhibitor) • CIs: Sildenafil or vardenafil (use within 24 hr) or tadalafil (use within 48 hr); SBP < 90 mm Hg or ≥ 30 mm Hg below baseline, heart rate < 50 beats/min, heart rate > 100 beats/min in absence of symptomatic HF or right ventricular infarction • Inhibits platelet activation • Chew and swallow non–enteric-coated 162–325 mg x 1 doseb • Clopidogrel if aspirin allergy • Performance measure • Decrease myocardial ischemia, reinfarction, and frequency of dysrhythmias, and increase longterm survival • Oral β-blockerb should be initiated within 24 hours in patients who do not have signs of HF, evidence of low-output state, increased risk of cardiogenic shock, or other CIs to βblockade (e.g., PR interval > 0.24 s, second- or third-degree heart block, active asthma, or reactive airway disease) • Reasonable to continue in patients with NSTE-ACS with normal LV functionb • Use metoprolol succinate, carvedilol, or bisoprolol in concomitant stabilized HFrEFb; add cautiously in decompensated HF • Avoid agents with intrinsic sympathomimetic activity (acebutolol, pindolol, penbutolol) • IV β-blockerc is potentially harmful in patients who have risk factors for shock (age > 70 yr, heart rate > 110 beats/min, SBP < 120 mm Hg, and late presentation) Class IIb, may be considered. bClass I, should be performed or administered; class IIa, reasonable to be performed or administered.cClass III, not to be administered or harmful.ACE = angiotensin-converting enzyme; AUC = area under the curve; CI = contraindication; HFrEF = heart failure with reduced ejection frac- tion; LV = left ventricular; SBP = systolic blood pressure. a II. ANTIPLATELET THERAPY A. Patients with STEMI and NSTE-ACS should be treated with antiplatelet therapy (Tables 5–8). 1. Platelets are activated by several different mechanisms, only some of which can be inhibited by medications. 2. Combination therapy with several antiplatelet agents plus a concomitant anticoagulant is the mainstay of acute ACS management, which targets the underlying pathophysiology of thrombus formation in ACS. 3. The roles and combinations of antiplatelet therapies continue to be refined through clinical trials in varying subsets of ACS presentation (Table 5). 4. In general, all patients receive aspirin and P2Y12 receptor antagonists, and some patients derive benefit from adding GP IIb/IIIa inhibition in the acute management of ACS. Table 5. Antiplatelet Management Strategies According to ACS Presentation Antiplatelet Aspirin P2Y12 receptor antagonist NSTE-ACS Ischemia Guided/Conservative Aspirin Clopidogrel600 Ticagrelor NSTE-ACS Invasive Aspirin Clopidogrel 600 Prasugrela STEMI PPCI Aspirin Clopidogrel 600 Prasugrel STEMI + Fibrinolytic Aspirin Clopidogrel – loading dose 300 only hereb 10 Ticagrelora Ticagrelor Greatest benefit when given to patients with high-risk features (e.g., elevated troponin) not adequately pretreated with clopidogrel or ticagrelorc GP IIb/IIIa inhibitor Ticagrelor or prasugrel may be preferred (in those who are not at high bleeding risk) to clopidogrel in patients treated with early invasive strategy for NSTE-ACS (class IIa, 2014 NSTE-ACS guideline).bPre-PCI after fibrinolytic therapy: 300-mg LD if within 24 hr of event; clopidogrel 600 mg LD if > 24 hr after event.cBenefit from adding GP IIb/IIIa inhibitors to aspirin therapy is greatest among those with highest-risk features (those with elevated biomarkers, those with diabetes, those undergoing revascularization) and in those not receiving adequate pretreatment with P2Y12. It is reasonable (class IIa, 2014 NSTE-ACS guideline) to give GP IIb/IIIa inhibitors to high-risk patients with NSTE-ACS treated with unfractionated heparin (UFH) and adequately pretreated with clopidogrel. PPCI = primary percutaneous coronary intervention.Information from: Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 ACC/AHA guideline for the management of patients with non– ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;130:e344-e426; O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78-140 a B. Antiplatelet Therapy Recommendations 1. Aspirin a. Given to all patients (class I) b. Established first-line therapy in ACS; reduces the incidence of recurrent MI and death c. Loading dose is necessary for aspirin-naive patients; avoid enteric-coated aspirin initially because of its delayed and reduced absorption. i. Dosing is 162–325 mg for patients at initial presentation of ACS (Table 6). ii. Dosing is 81–325 mg for those who are undergoing PCI, depending on chronic aspirin therapy regimen (Table 6). d. Aspirin is given indefinitely at a preferred dose of 81 mg post-ACS with or without PCI (class I). i. Higher doses (greater than 160 mg) are associated with more bleeding than lower doses (less than 160 mg). ii. Higher doses (greater than 160 mg) do not improve outcomes post-ACS more effectively than lower doses (less than 160 mg). e. Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 receptor inhibitor is indicated for all patients post-ACS for at least 12 months (discussed later in chapter). The optimal aspirin dose in patients treated with DAPT appears to be 75–100 mg daily. 2. Oral P2Y12 inhibitors a. P2Y12 inhibitor therapy is given to all patients (class I). i. Cangrelor only used as bridge therapy to CABG (very rarely used) – she won’t ask on this one b. Choice of oral P2Y12 inhibitor depends on approach and pharmacokinetic differences (Tables 6–8). i. Agents (a) Clopidogrel (1) An inactive thienopyridine prodrug that requires oxidation by isoenzymes of cytochrome 450 (CYP; mainly 2C19) by a two-step process to generate an active metabolite (A) Genetic polymorphisms of CYP2C19 (i.e., poor metabolizers) may form less active metabolite and have reduced antiplatelet activity. (B) Avoiding drug interactions with potent CYP2C19 inhibitors (omeprazole and esomeprazole) is cited in the package insert. (2) Given once daily (300- to 600-mg loading dose and 75-mg maintenance dose) (3) Risks include bleeding, pruritus (4) No routine monitoring recommended 11 ii. (b) Prasugrel (1) A thienopyridine prodrug that irreversibly blocks P2Y12 receptors with a faster onset and more profound inhibitory effect than clopidogrel (2) Given once daily (60-mg loading dose and 10-mg/day maintenance dose) (3) Risks include significant and fatal bleeding, rash (4) No routine monitoring required (c) Ticagrelor (drug of choice) (1) Given twice daily (180-mg loading and 90-mg twice-daily maintenance dose) (2) Risks include bleeding, dyspnea, and ventricular pauses (non-bleeding adverse effects because of inhibition of adenosine reuptake). (3) Monitor for drug interactions because ticagrelor is a substrate and a weak inhibitor of CYP3A4 and P-glycoprotein. (4) Ticagrelor is the only P2Y12 inhibitor that can be crushed and mixed with water and/ or given by nasogastric tube for patients with difficulty swallowing. Safety considerations: (a) Prasugrel should not be administered to patients with a history of stroke or TIA (class III). (b) In addition, there was no clinical benefit in patients older than 75 or those weighing less than 60 kg (c) Boxed warning: The efficacy of ticagrelor is decreased in patients treated with higher aspirin doses (greater than 300 mg daily) versus lower doses (less than 100 mg daily). In PLATO, patients treated with daily aspirin doses of greater than 300 mg had better clinical outcomes with clopidogrel and those treated with doses of 100 mg or less had better outcomes with ticagrelor. (d) Dyspnea with ticagrelor can occur in up to 15% of patients within the first week of therapy; rarely severe enough to cause treatment discontinuation (e) Clopidogrel and ticagrelor should be held for at least 5 days, and prasugrel should be held for 7 days before elective surgery. Table 6. Guideline Recommendations for Aspirin Therapy in ACS with or without PCI Guideline Recommendation Initiate 162–325 mg of ASA before PCI. Post-PCI, give ASA indefinitely • 2013 ACCF/AHA guideline for STEMI Initiate 81–325 mg of non–enteric-coated ASA before PCI in patients already taking ASA. In patients not taking ASA, give 325 mg before PCI. Post-PCI, continue ASA indefinitely 81 mg of ASA preferred to higher maintenance doses a Class/Gradea I I IIa Class I, should be performed or administered; class IIa, reasonable to be performed or administered; class IIb, may be considered; class III, not to be administered or harmful. Information from: Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 ACC/AHA guideline for the management of patients with non– ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;130:e344-e426; Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutane- ous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol 2011;58:e44-122; O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78-140. Table 7. Guideline Recommendations for P2Y12 Inhibitor Therapy in ACS with or without PCI Guideline Recommendation Class/Grade 12 An LD of P2Y12 receptor inhibitor should be given before PCI. Options include: a. Clopidogrelb 600 mg, followed by 75 mg daily b. Prasugrel 60 mg, followed by 10 mg daily; or c. Ticagrelor 180 mg, followed by 90 mg BID I For patients with NSTE-ACS treated with an early invasive or ischemia-guided strategy: a. Clopidogrel 600 mg, followed by 75 mg daily b. Ticagrelor 180 mg, followed by 90 mg BID I For patients with NSTE-ACS treated with an early invasive or ischemia-guided strategy: It is reasonable to use ticagrelor in preference to clopidogrel IIa For patients with NSTE-ACS treated with PCI who are not at risk of bleeding complications It is reasonable to choose prasugrel over clopidogrel IIa Prasugrel should not be administered to patients with a history of TIA or stroke Class III Parameter Clopidogrel (Plavix)a Thienopyridine; inhibits ADPmediated platelet activation at the P2Y12 receptor Prasugrel (Effient)b Thienopyridine; inhibits ADP-mediated platelet activation at the P2Y12 receptor Ticagrelor (Brilinta)c Inhibits ADP-mediated platelet activation at the P2Y12 receptor via a distinct site Mechanism of action Peak platelet inhibition 300 mg load ~6 hr 60 mg load ~30 mind 180 mg load ~30 mind 600 mg load ~2 hr % platelet inhibition 30%–40% 60%–70% 60%–70% LD 300–600 mge 60 mg 180 mg Maintenance dose 75 mg daily 90 mg BIDg Metabolism Prodrug; converted by two-step process to active metabolite involving 2C19 in addition to other CYP enzymes 10 mg daily; (5 mgf if < 60 kg, BW ≥ 75 yr) Prodrug; converted by 1 step to active metabolite by several CYP pathways Reversible platelet binding No No Yes Half-life 8 hr (metabolite) 3.7 hr (metabolite, range 2–15 hr) 7 hr (parent), 9 hr (active metabolite) Nonresponders Exposure to active drug affected by CYP2C19 genetic polymorphisms No known issues No known issues Drug-drug/drugdiesease interactions and common non– bleeding-related adverse events PPIs inhibit CYP2C19 (concomitant use with esomeprazole/omeprazole is discouraged on package labeling); increased bleeding with NSAIDs, OACs, O3FAs No clinically significant drug interactions; more bleeding with NSAIDs, OACs Careful with asthma, bradycardia; More bleeding with NSAIDs, OACs; strong 3A4 inducers ↓ ticagrelor concentrations; strong 3A4 inhibitors ↑ ticagrelor concentrations; do not exceed 40 mg of simvastatin or lovastatin Not prodrug; reversible, noncompetitive binding; 3A4 (primary), 3A5, P-gp inhibitor 13 Limit aspirin to < 100 mg. Monitor digoxin concentrations 5 days Surgery hold timeh 5 days 7 days Bleeding risk Less than prasugrel and ticagrelor with standard dosing Risk of non-CABG, spontaneous, and fatal bleeds higher than with standarddose clopidogrel Risk of non-CABG bleeds higher than with standarddose clopidogrel Box warning CYP2C19 polymorphisms Age-related bleeding CVA Aspirin dosing > 100 mg CIs TIA, CVA ICH, severe hepatic disease Supporting trials CREDO, CURE, PCI-CURE, CLARITY, COMMIT TRITON-TIMI 38, TRILOGY, ACCOAST PLATO, PEGASUS FDA indication ACS managed medically or with PCI ACS with PCI ACS managed medically or with PCI Administer clopidogrel indefinitely if aspirin allergy. Avoid LD if patient is ≥ 75 in STEMI when fibrinolysis is given.bAvoid prasugrel in patients with active pathologic bleeding or a history of TIA or CVA and in patients > 75 yr unless the patient has diabetes mellitus (DM) or a history of MI.cAvoid ticagrelor in patients with active pathologic bleeding or a history of ICH. Avoid aspirin doses > 100 mg daily (exception: first dose of 325mg) a Table 8. Comparison of Oral P2Y12 Receptor Inhibit (reference chart, don’t memorize) 14 1. Intravenous P2Y12 inhibitors – lol skip a. Cangrelor, a direct-acting, rapidly reversible, intravenous P2Y12 inhibitor, achieves a high level of platelet inhibition (greater than 90% with a 30-mcg/kg intravenous bolus, followed by a 4mcg/kg/ minute infusion) within 5 minutes and reaches steady state within 15–30 minutes of administration. b. Cangrelor’s rapid onset and offset (half-life less than 5 minutes) allows a quick, high degree of platelet inhibition with resolution of normal platelet function within 1 hour of ending treatment. c. Cangrelor has been primarily studied in the setting of PCI and may be considered in those under- going PCI who are not candidates for oral agents (i.e., significant nausea, altered mental status) d. Pivotal trials comparing cangrelor with clopidogrel in ACS have not shown the superiority of cangrelor; however, both the CHAMPION PCI and the PLATFORM trials were discontinued prematurely. e. Cangrelor has a potential use as a bridge therapy after discontinuation of oral P2Y12 inhibitors in high-risk patients undergoing CABG (JAMA 2012;307:265-74). f. The onset of action of both clopidogrel and prasugrel is delayed when coadministered with cangre- lor, suggesting that cangrelor preferentially binds to the P2Y12 and prevents irreversible inhibition with prasugrel and clopidogrel’s active metabolite. Therefore, clopidogrel and prasugrel should not be initiated until termination of the cangrelor infusion. No such drug interaction exists with ticagrelor. g. Expense and lack of evidence showing superiority to other P2Y12 agents limit the use of cangrelor. h. Cangrelor has not been included in the ACS guidelines to date because it was U.S. Food and Drug Administration (FDA) approved after guideline release. 2. Intravenous GP IIb/IIIa receptor inhibitors – remember, only give in NSTEMI patients a. Intravenous GP IIb/IIIa receptor inhibitors can be added to aspirin with or without an oral P2Y12 inhibitor for CV benefit in select high-risk patients in the acute management of ACS. b. Abciximab, double-bolus eptifibatide, and high-dose bolus tirofiban are class I options for invasive strategy (Table 9). Preferred options are eptifibatide and tirofiban (class IIb). c. GP IIb/IIIa inhibitors reduce the incidence of composite ischemic events, primarily through a decrease in documented MI, but they may increase the risk of bleeding. d. Most, but not all, data were gathered in the era before routine P2Y12 use; Most studies have combined GP IIb/IIIa inhibitors with unfractionated heparin as the anticoagulant. e. Benefit from adding GP IIb/IIIa inhibitors to aspirin therapy is greatest among those with highest-risk features (elevated biomarkers, diabetes, undergoing revascularization) and in those not receiving adequate pretreatment with clopidogrel or ticagrelor. f. It is reasonable (class IIa, 2014 NSTE-ACS guideline) to give GP IIb/IIIa inhibitors to high-risk patients with NSTE-ACS treated with unfractionated heparin and adequately pretreated with clopi- dogrel or ticagrelor. g. Common adverse events of GP IIb/IIIa inhibitors: iii. The most common adverse effect is bleeding, with rates as low as 1.4% and as high as 10.6%, depending on length of therapy and how bleeding rates were accrued in the individual studies. iv. Of note, the smaller molecule agents eptifibatide and tirofiban depend on renal 15 clearance; adjustment of the infusion is recommended to decrease the risk of bleeding; monitor SCr (CrCl) v. All GP IIb/IIIa inhibitors can cause thrombocytopenia; monitor hemoglobin (Hgb), hematocrit (Hct), and Plt. (a) Thrombocytopenia (Plt less than 50,000 cells/mm3) with abciximab in clinical trials occurs at 0.4%–1.4%. vi. The antiplatelet effects of abciximab can be reversed by platelet transfusion, whereas the anti- platelet effects of eptifibatide and tirofiban cannot. vii. Secondary to their short half-life, eptifibatide and tirofiban can be reversed within a few hours by discontinuing the infusion. viii. Eptifibatide and tirofiban are preferred options in ACS guideline (Class IIb) Table 9. GP IIb/IIIa Inhibitor Dosing in ACS with or without PCI Remember thrombocytopenia risk and renal adjustments Abciximab (ReoPro)b Eptifibatide (Integrilin) Pretreated with P2Y12 Of uncertain benefit Of uncertain benefit Not Pretreated with P2Y12 PCI: 0.25 mg/kg IV bolus; then 0.125 mcg/kg/min (max 10 mcg/kg) for 12 hr Renal Adjustments Not necessary ACS without PCI: Not recommended Not used often, very potent and causes a lot of bleeding PCI: 180 mcg/kg IV bolus × 2 (10 min If CrCl < 50 mL/min/1.73 m2, apart); 2 mcg/kg/min initiated after first reduce infusion 50%; avoid in bolus for 18–24 hrc patients on hemodialysis; not ACS without PCI: Of uncertain benefit studied in patients with SCr > 4 mg/dL in patients adequately pretreated with a P2Y12 receptor inhibitor; single bolus used as above Tirofiban (Aggrastat) Of uncertain benefit PCI: 25 mcg/kg IV bolus over 3 min; then 0.15 mcg/kg/min for 18 hr ACS without PCId: 0.4 mcg/kg/min for 30 min (LD infusion); then 0.1 mcg/kg/ min for 18–72 hr If CrCl < 60 mL/min/1.73 m2, reduce infusion 50% GP IIb/IIIa inhibitors should be used in combination with heparin (either UFH or low-molecular-weight heparin) or used provisionally with bivalirudin and aspirin.bNot recommended in those not undergoing PCI because of negative clinical trial results.cDouble bolus is recommended to support PCI in STEMI and NSTE-ACS.dLower dose used to treat NSTE-ACS when there is substantial delay to PCI (i.e. a III. ANTICOAGULANT THERAPY A. Patients with STEMI and NSTE-ACS should be treated with anticoagulant therapy (Tables 10 and 11). 1. Use of anticoagulants is mainly in the procedural setting, though use may continue for a finite period post-procedure. 2. Selection and use among agents may depend on ACS presentation, timing/dose of preprocedural anti- platelet medication, clot burden during procedure, and estimated risk of bleeding periprocedurally. 3. All anticoagulants increase the risk of bleeding and require some type of monitoring for agentspecific risks. B. Anticoagulant Therapy Guideline Recommendations 1. An anticoagulant should be administered to all patients with ACS in addition to antiplatelet 16 therapy to reduce the risk of intracoronary and catheter thrombus formation (Tables 8 and 9), irrespective of initial treatment strategy (early invasive vs. ischemia guided). a. Enoxaparin: 30-mg intravenous bolus; then 1 mg/kg subcutaneously every 12 hours (or 1 mg/kg subcutaneously once daily for CrCl less than 30 mL/minute/1.73 m2); continued for the duration of hospitalization or until PCI is performed i. b. c. d. 2. 3. 4. 5. Does not require routine anti-Xa monitoring; obtain SCr to calculate CrCl for dosing; monitor Hgb, Hct, Plt, SCr Bivalirudin: 0.1-mg/kg loading dose, followed by 0.25 mg/kg per hour (only in patients with early invasive strategy); continued until diagnostic angiography or PCI, with only provisional use of a GP IIb/IIIa inhibitor i. Given as an intravenous bolus with or without infusion fixed rate and usually continued until end of PCI (with or without delayed post-infusion in some high-risk patients) (a) Can extend duration of infusion for up to 4 hours after procedure for prolonged antiplatelet protection ii. Risks include bleeding. iii. Does not require monitoring for adjustment; monitor SCr (adjustment required for infusion in those impaired CrCl), Hgb, Hct, Plt iv. Can be given to a patient with a history of or suspected HIT undergoing PCI Fondaparinux: 2.5 mg subcutaneously daily; continued for the duration of hospitalization or until PCI is performed i. Dosing NSTE-ACS: 2.5 mg subcutaneously daily, continued for the duration of hospitalization or until PCI is performed ii. Not to be used as the sole anticoagulant during PCI (Class III) iii. Contraindicated if CrCl <30 ml/min/1.73 m2 iv. Risks include bleeding and thrombocytopenia, spinal or epidural hematomas v. No increased risk of HIT vi. Does not require routine anti-Xa monitoring; requires SCr to calculate CrCl to assess for contraindications; monitor Hgb, Hct, Plt, SCr Intravenous unfractionated heparin: Initial bolus of 60 units/kg (maximum 4000 units) with initial infusion of 12 units/kg/hour (maximum 1000 units/hour) adjusted according to activated partial thromboplastin time to maintain therapeutic anticoagulation according to specific hospital protocol; continued for 48 hours or until PCI is performed In an ischemia-guided strategy, unfractionated heparin, enoxaparin, and fondaparinux are class I– recommended options. For an invasive strategy, unfractionated heparin, enoxaparin, and bivalirudin are class I–recommended options. a. Anticoagulant therapy is usually discontinued post-PCI unless there is a compelling reason to con- tinue it. In patients undergoing primary PCI, either unfractionated heparin or bivalirudin is preferred. a. Bivalirudin has been ftenefavored for its predictable pharmacokinetics, effects on thrombinmediated platelet inhibition, and favorable outcomes with respect to adverse bleeding profile, whereas unfractionated heparin is the gold standard anticoagulant during primary PCI. When a fibrinolytic agent is given as a reperfusion strategy, unfractionated heparin, enoxaparin, and fondaparinux are recommended. a. Those given fibrinolytic therapy should receive anticoagulation after fibrinolysis for at least 48 17 b. hours with intravenous unfractionated heparin or intravenous/subcutaneous enoxaparin during hos- pitalization, up to 8 days (preferred, selected patients), or intravenous/subcutaneous fondaparinux during hospitalization, up to 8 days. Bivalirudin is not recommended in this population. Table 11. Antithrombotic Dosing in ACS with or without PCI (dose reference chart, don’t memorize) UFH Enoxaparin (Lovenox) Fondaparinux (Arixtra) Bivalirudin (Angiomax) Classification Indirect thrombin inhibitor LMWH Factor Xa inhibitor Direct thrombin inhibitor NSTE-ACS 60 units/kg IVB 1 mg/kg SC every 12 hr for 24–48 hr or until PCI performed or throughout hospitalization (up to 8 days); 30 mg IVB 2.5 mg SC daily 0.1 mg/kg IVB; then 0.25 mg/kg/hr IV (only for planned invasive strategy) If last dose < 8 hr, nothing additional needed Fondaparinux should not be used as a sole anticoagulant for PCI 0.75 mg/kg IVB, 1.75 mg/kg/hr IV 2.5 mg IVB; then 2.5 mg SC daily 0.75 mg/kg IVB, 1.75 mg/kg/hr IV CI if CrCl < 30 mL/min/1.73 m2 Adjust infusion dose in severe renal dysfunction (max 4000 units), 12 units/kg/hr IV (max 1000 units/ hr) for 48 hr or until PCI performed; goal aPTT/anti-Xa according to hospital-specific protocol PCI Supplemental doses to target ACTa If GP IIb/IIIa inhibitors, UFH 50–70 units/kg IVB If no GP IIb/IIIa inhibitors, UFH 70–100 units/kg IVB STEMI ± PPCI Supplemental doses to target ACTa If GP IIb/IIIa, UFH 50–70 units/kg IVB If no GP IIb/IIIa, UFH 70–100 units/ kg IVB Dose adjustments Avoid if history of and CIs HIT If last dose > 8 hr, 0.3 mg/kg IVB if last dose 8–12 hr before or < 2 therapeutic doses received before PCI 30 mg IVB, followed immediately by 1 mg/ kg SC every 12 hr; do not exceed 100 mg on first two doses If > 75 yr, omit bolus; 0.75 mg/kg SC every 12 hr; do not exceed 75 mg on first two doses If CrCl < 30 mL/ min/1.73 m2, 1 mg/kg SC daily Avoid if history of HIT Discontinue at end of PCI, or continue for up to 4 hr after procedure if needed Hold UFH 30 min before administration If CrCl < 30 mL/ min/1.73 m2, reduce infusion to 1 mg/kg/ hr; if on hemodialysis, reduce infusion to 0.25 mg/kg/hr Target ACT is 250–300 s for HemoTec and 300–350 s for Hemochron without GP IIb/IIIa inhibitors and is 200–250 s in patients given concomitant GP IIb/IIIa inhibitors. a 18 ACT = activated clotting time; aPTT = activated partial thromboplastin time; HIT = heparin-induced thrombocytopenia; IVB = intravenous bolus; LMWH = low-molecular-weight heparin. IV. OTHER ANTITHROMBOTIC THERAPIES A. Fibrinolytic Therapy 1. Indicated for patients with STEMI in whom PCI cannot be performed (Table 12, 13) 2. In the absence of contraindications (Table 11), fibrinolytic therapy should be given to patients with STEMI (class I when onset of ischemic symptoms is within the previous 12 hours) when it is anticipated that primary PCI cannot be performed within 120 minutes of first medical contact, with an ideal door- to-needle time of less than 30 minutes. 3. Patients undergoing reperfusion with fibrinolytics should receive anticoagulant therapy (UFH, enoxa- parin, and fondaparinux are recommended) for at least 48 hours and preferably for the duration of the index hospitalization, for up to 8 days, or until revascularization is performed. 4. Recommended regimens include the following: a. Administer unfractionated heparin at a 60-unit/kg bolus (maximum 4000 units) and at 12 units/ kg/hour (maximum 1000 units/hour) to obtain an activated partial thromboplastin time of 1.5–2.0 times control (about 50–70 seconds). b. Enoxaparin 30 mg intravenously (if 75 or older, omit bolus), followed in 15 minutes by a 1mg/kg subcutaneous injection (if 75 or older, 0.75 mg/kg) every 12 hours for the duration of index hos- pitalization, for up to 8 days, or until revascularization. Maximum 100 mg for the first two doses. If 75 or older, maximum 75 mg for the first two doses. If CrCl is less than 30 mL/minute/1.73 m2, extend dosing interval to daily administration. c. Fondaparinux administered with initial 2.5-mg intravenous dose, followed in 24 hours by 2.5mg/ day subcutaneous injections (contraindicated if CrCl is less than 30 mL/minute/1.73 m2) for the duration of the index hospitalization, for up to 8 days, or until revascularization B. Fibrinolytic therapy is not recommended in patients with NSTE-ACS (class III: harm). Table 12. Fibrinolytic Therapy *know its weight based dosing for alteplase/tenecteplase Agent Alteplase (t-PA, Activase) Dosing ≤ 67 kg: 15 mg IVP over 1–2 min; then 0.75 mg/kg IV over 30 min (max 50 mg); then 0.5 mg/kg (max 35 mg) over 60 min > 67 kg: 15 mg IVP over 1–2 min; then 50 mg over 30 min; then 35 mg over 1 hr (max total dose 100 mg) Reteplase (r-PA, Retavase) 10 units IVP; repeat 10 units IV in 30 min Tenecteplase < 60 kg: 30 mg IVP; 60–69 kg: 35 mg IVP; 70–79 kg: 40 mg IVP; 80–89 kg: 45 mg (TNK-t-PA, TNKase) IVP; > 90 kg: 50 mg IVP (~0.5 mg/kg) IVP = intravenous push; r-PA = recombinant plasminogen activator; t-PA = tissue plasminogen activator. Table 13. CIs to Fibrinolytic Therapy ***** MEMORIZE ABSOLUTE CIs Relative CIs Absolute CIs BP > 180/110 mm Hg on presentation or history of Any prior hemorrhagic stroke chronic poorly controlled HTN Ischemic stroke within 3 mo (except in past 4½ hr) History of ischemic stroke > 3 mo before Intracranial neoplasm or arteriovenous malformation Recent major surgery (< 3 wk before) Active internal bleeding Traumatic or prolonged CPR (> 10 min) Aortic dissection 19 Recent internal bleeding (within 2–4 wk) Active peptic ulcer Considerable facial trauma or closed-head trauma in past 3 mo Noncompressible vascular punctures Intracranial or intraspinal surgery within 2 mo Pregnancy Severe uncontrolled HTN (unresponsive to emergency therapy) For streptokinase,a treatment within previous 6 mo (if considering streptokinase again) Known intracranial pathology (dementia) Oral anticoagulant therapy a Streptokinase is no longer marketed in the United States but is available in other countries. BP = blood pressure; CPR = cardiopulmonary resuscitation V. POST-PERCUTANEOUS INTERVENTION COMPLICATIONS A. Bleeding 1. Use of concomitant antiplatelet and anticoagulant agents increases the risk of bleeding, especially in those whose doses are not adjusted appropriately. a. Renal adjustments should be considered for GP IIb/IIIa receptor antagonists, bivalirudin, fondaparinux, and enoxaparin. b. SCr with estimated CrCl should be assessed in every patient. 2. Catheterization access site has been identified as a major contributor to post-PCI bleeding complica- tions. A radial approach has less bleeding risk than a femoral approach. B. Dissection/Rupture of Free Wall, Coronary Artery, or Aorta C. Stent Thrombosis 1. A catastrophic event, resulting in life-threatening complications 2. Premature discontinuation of DAPT is the most important predictor of stent thrombosis. a. When antiplatelet therapy is discontinued early, related thrombosis events increase exponentially (JAMA 2005;293:2126-30). b. 3. Almost 1 in 7 patients may discontinue P2Y12 inhibitors within 30 days post-PCI, thus increasing mortality risk (adjusted HR 9.0; 95% CI, 1.3–60.6) (JAMA 2013;310:189-98). c. Mortality rates associated with stent thrombosis can be as high as 45%. d. Counseling on therapy duration and avoiding premature discontinuation is of paramount importance. Duration of DAPT a. 12 months (from patients on conservative method) i. Aspirin should be continued indefinitely at a maintenance dose of 81 mg daily in all patients post-ACS (class I). ii. In patients who were treated with an ischemia-guided therapy, aspirin plus either clopidogrel 75 mg daily or ticagrelor 90 mg twice daily should be continued for up to 12 months. iii. Post-PCI (bare metal stent or DES), aspirin plus clopidogrel 75 mg daily, prasugrel 10 mg daily, or ticagrelor 90 mg twice daily should be continued for at least 12 months. b. Early discontinuation of DAPT i. Early discontinuation is reasonable when the risk of morbidity exceeds the anticipated benefit (class IIa). (a) DAPT should be continued post-ACS (with or without stent) for at least 12 months (class I). (b) Shorter-duration DAPT can be considered for patients with stable ischemic heart 20 c. disease who have undergone PCI with elective stent placement (class I, 6 months for elective PCI). ii. In general, shorter durations of DAPT are appropriate for those with a lower ischemic risk and a high bleeding risk, whereas longer-duration DAPT may be reasonable for patients with a higher ischemic risk and a lower bleeding risk. (a) Compared with first-generation stents, newer-generation stents have an improved safety profile and a lower risk of stent thrombosis. (b) Proton pump inhibitors can reduce the risk of bleeding from DAPT Long-term DAPT i. In general, longer-duration DAPT may be reasonable for patients at higher ischemic risk with a lower bleeding risk. ii. A longer duration of P2Y12 inhibitor therapy is an individualized approach, given the patient’s risk of ischemic events and bleeding. (a) It is reasonable to consider DAPT beyond 12 months if the patient is tolerating therapy and not at high risk of bleeding (class IIb). (b) Durations of DAPT may be reasonable beyond 12 months if the patient is at high risk for CV events and has no significant history of bleeding on DAPT (class IIb) (c) A DAPT score derived from the dual antiplatelet study may help the clinician decide whether to prolong or extend DAPT in patients treated with coronary stent implantation (Table 14). (1) For those with a high DAPT score (2 or higher), prolonged DAPT reduces net (isch- emic plus bleeding) events. (2) For those with a low DAPT score (less than 2), the benefit-risk for prolonged DAPT is unfavorable (increased bleeding without a reduction in ischemic events). (3) Derived from the DAPT study, which included 11,648 patients with mainly clopido- grel as the P2Y12 inhibitor Table 14. DAPT Score to Determine Favorability of Prolonged DAPT (to determine if DAPT needs to be longer than 12 months) Know how to interpret DAPT score (2+ score = continue) Factors Used to Calculate DAPT Score Age ≥ 75 Age 65–74 Current tobacco user DM NSTEMI or STEMI at presentation Prior MI or PCI Stent diameter < 3 mm Paclitaxel-eluting stent CHF or LVEF < 30% Saphenous vein graft PCI a Add Points for Total Score -2 -1 1 2 2 A score ≥ 2 favors prolonged DAPT; a score < 2 is of unfavorable risk- benefit. CHF = congestive heart failure; DAPT = dual antiplatelet therapy. A. Mechanical Complications (papillary muscle rupture and mitral regurgitation) B. Arrhythmias (particularly after reperfusion) C. Contrast-Induced Nephropathy 4. The PRESERVE trial (NEJM 2018;378:603-18) demonstrated no added benefit of bicarbonate or 21 5. acetyl- cysteine over isotonic saline in patients undergoing angiography with decreased eGFR +/diabetes Patients with ACS undergoing urgent procedures who may be at higher risk for contrast induced acute kidney injury were not included, however. VI. LIPID-LOWERING THERAPIES IN ACUTE CORONARY SYNDROME A. Statins 1. Post-MI, statins reduce total mortality, CV mortality, and stroke. 2. All patients should receive high-intensity statins post-ACS, preferably before revascularization (class I). a. Acute benefit includes reduced the frequency of periprocedural MI during PCI, and statins should be initiated as early as possible. b. Chronic benefit includes reduced secondary MI and other CV outcomes. 3. The amount of atherosclerotic CV disease risk reduction with statins is directly related to the amount of LDL reduction achieved as a percentage of baseline. a. Atorvastatin 40–80 mg and rosuvastatin 20–40 mg are considered high-intensity statins. 4. Patients should be considered for the addition of non-statin therapies with ezetimibe or proprotein con- vertase subtilisin/kexin type 9 enzyme (PSCK9) inhibitor if LDL-C is 70 mg/dL or greater to reduce the risk of major adverse cardiac events B. Ezetimibe 1. Ezetimibe added to a moderate-dose simvastatin in patients with a recent (within 10 days) ACS and an LDL concentration of 50–100 mg/dL modestly reduced the frequency of a composite end point of CV events or stroke over a median follow-up of 6 years compared with simvastatin alone in the IMPROVE-IT study. 2. Ezetimibe 10 mg daily is recommended by clinical guidelines as first-line add-on therapy when addi- tional LDL lowering is desired post-ACS for clinically modest reductions in outcome (lowers LDL by about 20% in addition to statin therapy). C. PCSK9 Inhibitors 1. New class of drugs that inhibit the PCSK9 enzyme, which plays a major role in the breakdown of hepatic LDL receptors; inhibition of this enzyme enables more efficient hepatic uptake of LDL, decreasing serum LDL concentrations by more than 50% in most cases 2. Both evolocumab (Repatha) and alirocumab (Praluent) are FDA approved for dyslipidemia and both have evidence in cardiovascular disease event reduction, although studied in slightly different populations. VII. SPECIAL POPULATIONS Older Patients (