ACCP Updates in Therapeutics® 2023 Pharmacotherapy Preparatory Review PDF

Acute Care in Cardiology I. ACUTE CORONARY SYNDROME A. Definitions 1. Acute coronary syndrome (ACS) is a spectrum of conditions involving acute myocardial ischemia or infarction caused by an abrupt reduction in coronary blood flow (Figure 1). 2. This chapter will focus on the most common pre...

Acute Care in Cardiology I. ACUTE CORONARY SYNDROME A. Definitions 1. Acute coronary syndrome (ACS) is a spectrum of conditions involving acute myocardial ischemia or infarction caused by an abrupt reduction in coronary blood flow (Figure 1). 2. This chapter will focus on the most common presentation of ACS (type 1 MI), as defined by the Fourth Universal Definition of Myocardial Infarction, which is caused by coronary thrombosis. 3 Atherogenic plaque rupture is the underlying pathophysiology for ACS, causing several prothrombotic substances to be released, which results in platelet activation and aggregation and eventual thrombus formation leading to partial or total occlusion of the coronary artery. 4. ACS can be divided into ST-segment elevation myocardial infarction (STEMI) and non–ST-segment elevation acute coronary syndrome (NSTE-ACS). a. STEMI i. Defined by characteristic symptoms of myocardial ischemia in association with persistent ST-segment elevation on ECG with positive troponins ii. STEMI is an indication for immediate coronary angiography to determine whether reperfusion can be done (see section C in this section, “Decision for Invasive Management”). b. NSTE-ACS i. Suggested by the absence of persistent ST-segment elevation on ECG ii. NSTE-ACS can be divided into unstable angina (UA) and NSTEMI according to whether cardiac biomarkers of necrosis are present. UA and NSTEMI are closely related conditions whose pathogenesis and clinical presentation are similar but vary in risk and severity. iii. ECG abnormalities and elevated troponins in isolation are insufficient to make the diagnosis and must be interpreted in the appropriate clinical context (Table 1). 5. Optimal inhibition of thrombosis is paramount in ACS management. B. Clinical Assessment and Initial Evaluation 1. A 12-lead ECG should be done and interpreted within 10 minutes of presentation. a. Persistent ST-segment elevation should be treated according to the STEMI guidelines. b. Serial ECGs can be done if the initial ECG is nondiagnostic. 2. Serial cardiac troponins should be obtained at presentation every 1–3 hours for high sensitivity troponin and every 3–6 hours for conventional troponin. Troponin is typically trended to aid in diagnosis of ACS with concentrations more than the 99th percentile being indicative of myocardial injury. The duration for which to trend cardiac troponin is patient-specific and beyond the scope of this chapter. 3. At initial presentation, the clinical history, angina symptoms and equivalents, physical assessment, ECG, renal function, and cardiac troponin measurements can be integrated into an estimation of the risk of death and nonfatal cardiac ischemic events, which is useful for selecting the site of care, antithrombotic therapies, and invasive management. Risk calculators include the following: a. Thrombolysis in myocardial infarction (TIMI) risk score for UA/NSTEMI (available at www.timi. org) is useful in predicting 30-day and 1-year mortality in patients with NSTE-ACS. i. Composed of seven 1-point indicators rated on presentation; 1 point is given for each of the following: 65 or older, three or more risk factors for CAD, prior coronary stenosis 50% or greater, ST deviation on ECG, two or more anginal events in previous 24 hours, aspirin use in previous 7 days, and elevated cardiac biomarkers ii. Risk of mortality, new or recurrent MI, or severe recurrent ischemia through 14 days; 0–2 is low risk, 3 is intermediate risk, and 4 or more is high risk iii. Patients with higher risk scores (e.g., TIMI of 3 or more) have a greater benefit from therapies such as low-molecular-weight heparin, glycoprotein (GP) IIb/IIIa inhibitors, and invasive strategies. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-8 Acute Care in Cardiology b. The Global Registry of Acute Coronary Events (GRACE) risk model (https://www.outcomes-umassmed.org/grace/acs_risk2/index.html) predicts in-hospital and postdischarge mortality or MI. Patients with high GRACE risk model scores (i.e., GRACE score greater than 140) can be identified for early invasive strategies. 4. Angiographic features contributing to increasing complexity of coronary artery disease: Multivessel disease, left main or proximal LAD artery lesion, chronic total occlusion, trifurcation lesion, complex bifurcation lesion, heave calcification, severe tortuosity, aorto-ostial stenosis, diffuse disease, and narrow segments distal to lesion, thrombotic lesion, and lesion length greater than 20 mm (Circulation 2022;145:e18-114). Table 1. ACS Definition Subjective Findings Objective Findings NSTE-ACS Most commonly presents as a pressure- ST-segment depression, T-wave UA type chest pain that typically occurs at inversion, or transient or rest or with minimal exertion nonspecific ECG changes can occur Pain usually starts in the retrosternal area and can radiate to either or both arms, neck, or jaw Extent of Injury No myocardial injury; partial occlusion of coronary artery No positive biomarkers for cardiac necrosis Pain may also present with diaphoresis, dyspnea, nausea, abdominal pain, or syncope Unexplained new-onset or increased exertional dyspnea is the most common angina equivalent NSTEMI STEMI Nonclassic, commonly associated symptoms of ischemia such as epigastric pain, indigestion, nausea, vomiting, diaphoresis, unexplained fatigue, and syncope may be present.a ST-segment depression, T-wave inversion, or transient or nonspecific ECG changes can occur Myocardial injury; partial occlusion of coronary artery Positive biomarkers (conventional or high sensitivity troponin I or troponin T) Myocardial necrosis; Classic symptoms include worsening of ST-segment elevation > 1 mm pain or pressure in chest, characterized above baseline on ECG in two or total occlusion of as viselike, suffocating, squeezing, more contiguous leads coronary artery aching, gripping, and excruciating, that Positive biomarkers may be accompanied by radiation (conventional or high sensitivity troponin I or troponin T) a Up to one-half of all MIs are silent or unrecognized, and one-third present with symptoms other than chest discomfort. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-9 Acute Care in Cardiology Clinical suspicion of ACS Obtain and interpret 12 lead ECG within 10 minutes Aspirin within 10 minutes NSTE-ACS STEMI ST Depression ST Elevation NSTEMI UA Trop (+) Trop (-) Risk stratification Multi-lead continuous ECG monitoring Obtain serial troponin Begin adjunctive pharmacotherapy for NSTE-ACS based on risk stratification Includes anticoagulant and P2Y12 inhibitor once anatomy is verified STEMI Trop (+) Initiate immediate reperfusion (PCI vs. fibrinolysis) Primary PCI within 90 minutes Door to needle time of 30 minutes for fibrinolysis PCI not available within 120 minutes Begin adjunctive pharmacotherapy Anticoagulation with UFH or bivalirudin if primary PCI Low Risk “Ischemia-guided approach” Intermediate Risk “Ischemia-guided approach” High Risk Stress test to evaluate likelihood of CAD (may be done as outpatient) Stress testing or CCTA “Early invasive approach” Positive? No May rule out cardiac origin Yes Coronary angiography with revascularization (PCI vs. CABG) Figure 1. Acute coronary syndrome diagnosis and risk stratification. ACS = acute coronary syndrome; CABG = coronary artery bypass grafting; CAD = coronary artery disease; CCTA = coronary CT angiography; NSTE-ACS = non–ST-segment elevation acute coronary syndrome; NSTEMI = non–ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST-segment elevation myocardial infarction; UA = unstable angina; UFH = unfractionated heparin. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-10 Acute Care in Cardiology C. Decision for Invasive Management 1. STEMI a. The goal of therapy is to restore the patency of the infarct-related artery and minimize the infarct size. Secondary goals include preventing complications such as arrhythmias or death as well as controlling chest pain and associated symptoms. b. PCI, or CABG if PCI not feasible, is indicated in patients with STEMI and cardiogenic shock to improve survival irrespective of time delay from MI symptom onset (Circulation 2022;145:e18-114). c. Primary PCI is preferred to lytic therapy. Performance measure includes goal of primary PCI within 90 minutes of first medical contact. d. Fibrinolytic therapy is indicated for patients with a STEMI in whom PCI cannot be done (discussed later in chapter). If PCI cannot be done within 120 minutes, performance measure for lytic administration includes a door-to-needle time of 30 minutes. 2. NSTE-ACS a. The goal of therapy is to prevent total occlusion of the related artery and to control chest pain and associated symptoms. Patients with NSTE-ACS are treated on the basis of risk (TIMI, GRACE) with either an early invasive strategy (interventional approach) or an ischemia-guided strategy (a conservative management strategy using medications rather than an interventional approach). b. Early invasive strategy is a diagnostic angiography with intent to do revascularization, if appropriate, depending on coronary anatomy. i. Indicated in those with NSTE-ACS who have refractory angina or hemodynamic or electrical instability or those with high risk on the basis of clinical findings (a) In patients with NSTE-ACS who are initially stabilized, timing of PCI is dependent on risk for clinical events. (b) In patients who are initially stabilized but at high risk for clinical events, PCI may be preformed within 24 hours over a delayed invasive strategy to improve outcomes. ii. Routine invasive therapy is generally superior to an ischemia-guided strategy, resulting 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 deviation, HF, depressed resting left ventricle (LV) function (i.e., LVEF less than 40%), noninvasive stress findings, high TIMI or GRACE scores, markedly elevated troponins, and diabetes. iii. Not recommended for those with serious comorbidities or contraindications to such procedures (hepatic, renal, pulmonary failure, cancer), and for whom the risks for the procedure may outweigh the benefits of revascularization c. 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) or intermediate risk score (TIMI 3–4, GRACE 109–140). ii. Indicated for those with acute chest pain with a low likelihood of ACS who are troponin negative iii. Can be chosen according to clinician and patient preference 3. Patients should receive anti-ischemic and analgesic medications early in care: morphine, oxygen, nitroglycerin, and aspirin plus a β-blocker (Table 2). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-11 Acute Care in Cardiology Table 2. Initial Anti-ischemic and Analgesic Therapies for ACS Therapy Comments M = Morphine or other narcotic analgesic Provides analgesia and decreased pain-induced sympathetic/adrenergic tone Commonly used because it can also induce vasodilation and mediate some degree of preload and afterload reduction Morphine 1–5 mg IV every 5–30 min is reasonable if symptoms are not relieved despite maximally tolerated anti-ischemic medicationsa At least two large trials have identified an association between morphine administration and risk of deathb Slows the absorption of antiplatelet therapy, reduces time to peak antiplatelet activity, and may decrease area under the curve O = Oxygen Can help attenuate anginal pain secondary to tissue hypoxia Consider supplemental oxygen if Sao2 < 90%, respiratory distress, or high-risk features of hypoxemiac Excessive supplemental oxygen without depressed SaO2 can be associated with increased morbidity and mortality N = Nitroglycerin Facilitates coronary vasodilation and may also be helpful 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 9-1-1); afterward, assess need for IV administrationc IV administration used in first 48 hr for 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) Contraindications: Sildenafil or vardenafil (use within 24 hr) or tadalafil (use within 48 hr); SBP < 90 mm Hg or ≥ 30 mm Hg below baseline, HR < 50 beats/min, HR > 100 beats/min in absence of symptomatic HF; right ventricular infarction A = Aspirin Inhibits platelet activation Mortality-reducing therapy Chew and swallow non–enteric coated aspirin 162–325 mg × 1 dosec Clopidogrel if aspirin allergy Performance measure β-Blocker Decrease myocardial ischemia, reinfarction, and frequency of dysrhythmias and increase long-term survival Oral β-blockerc should be initiated within 24 hr in patients who do not have signs of HF, evidence of low-output state, increased risk of cardiogenic shock, or other contraindications to β-blockade (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 functiona Use metoprolol succinate, carvedilol, or bisoprolol in concomitant stabilized HFrEFc; add cautiously in decompensated HF Avoid agents with intrinsic sympathomimetic activity (acebutolol, pindolol) IV β-blockerd is potentially harmful in patients with risk factors for shock (age > 70 yr, HR > 110 beats/min, SBP < 120 mm Hg, and late presentation) Class IIb may be considered. From: Montalescot G, van’t Hof AW, Lapostolle F, et al. Prehospital ticagrelor in ST-segment elevation myocardial infarction. N Engl J Med 2014;371:1016-27; and Meine TJ, Roe MT, Chen AY, et al. Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. Am Heart J 2005;149:1043-9. c Class I = should be performed or administered. d Class III = not to be administered or harmful. ACE = angiotensin-converting enzyme; ACS = acute coronary syndrome; HF = heart failure; HFrEF = heart failure with reduced ejection fraction; HR = heart rate; HTN = hypertension; LV = left ventricle; NTG = nitroglycerin; SBP = systolic blood pressure. a b ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-12 AL GRAWANY Acute Care in Cardiology 4. Patients with STEMI and NSTE-ACS should be treated with antiplatelet and anticoagulant therapy (Tables 3–9). a. Platelets are activated by several different mechanisms, only some of which can be inhibited by medications. b. 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. c. The roles and combinations of antiplatelet therapies continue to be refined through clinical trials in varying subsets of ACS presentation (Table 3). d. In general, all patients receive aspirin and P2Y12 receptor antagonists. e. A minority of patients may benefit from the use of GP IIb/IIIa inhibition as bailout or provisional therapy. Table 3. Antiplatelet Management Strategies According to ACS Presentation Antiplatelet Agent Aspirin P2Y12 receptor antagonist GP IIb/IIIa inhibitor NSTE-ACS Ischemia Guided NSTE-ACS Invasive STEMI Primary PCI STEMI + Fibrinolytic Aspirin Clopidogrel Ticagrelor Aspirin Aspirin Aspirin Clopidogrel Clopidogrel Clopidogrelb a Prasugrel Prasugrel Ticagrelora Ticagrelor Greatest benefit when given to patients with high-risk features (e.g., elevated troponin) not adequately pretreated with clopidogrel or TICc It may be reasonable to choose ticagrelor or prasugrel (in those who are not at high bleeding risk) over clopidogrel in patients treated with early invasive strategy for NSTE-ACS (class IIa, 2014 NSTE-ACS guideline). b Pre-PCI after fibrinolytic therapy: 300-mg LD if within 24 hr of event; clopidogrel 600-mg LD if > 24 hr after event. c Benefit 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 inhibitor. It is reasonable (class IIa, 2014 NSTE-ACS guideline) to give GP IIb/IIIa inhibitors to high-risk patients with NSTE-ACS treated with UFH and adequately pretreated with clopidogrel. PCI = percutaneous coronary intervention. a e. Antiplatelet recommendations i. Aspirin (a) An irreversible cyclooxygenase-1 inhibitor blocking the formation of thromboxane A 2– and thromboxane A2–mediated platelet activation (b) Given to all patients (class I) (c) Established first-line therapy in ACS; reduces the incidence of recurrent MI and death (d) LD is necessary for aspirin-naive patients; avoid enteric coated initially because of delayed and reduced absorption. (1) Dosing is 162–325 mg for patients at initial presentation of ACS (Table 4). (2) Dosing is 81–325 mg for those who are undergoing PCI, depending on chronic aspirin therapy regimen. (e) Aspirin is given indefinitely at a preferred dose of 81 mg after ACS with or without PCI (class I). (1) High dose (greater than 160 mg) is associated with more bleeding than lower dose (less than 160 mg). (2) High doses (greater than 160 mg) have not been shown to improve outcomes after ACS more effectively than lower doses (less than 160 mg). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-13 Acute Care in Cardiology (f) Dual antiplatelet therapy (DAPT) with aspirin plus a P2Y12 receptor inhibitor is indicated for all patients after ACS for at least 12 months (see D, “Long-term Management After ACS”). The optimal aspirin dose in patients treated with DAPT appears to be 75–100 mg daily. Table 4. Guideline Recommendations for Aspirin Therapy in ACS with or without PCIa Guideline Recommendation Initiate 162–325 mg of ASA before PCI; after PCI, give 81 mg ASA • 2013 ACCF/AHA guideline for STEMI • 2021 AHA/ACC/SCAI Guideline for Coronary Artery Revascularization Initiate 81–325 mg of non–enteric-coated ASA before PCI in patients already taking ASA; in patients not taking ASA, give 325 before PCI; after PCI, continue 81 mg ASA • 2014 NSTE-ACS guideline • 2021 AHA/ACC/SCAI Guideline for Cornonary Revascularization 81 mg of ASA preferred to higher maintenance doses • 2014 NSTE-ACS guideline • 2013 ACCF/AHA guideline for STEMI • 2021 AHA/ACC/SCAI Guideline for Coronary Revascularization Class/Grade I I IIa IIa I 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. ACCF = American College of Cardiology Foundation; AHA = American Heart Association; ASA = acetylsalicylic acid; SCAI = Society for Cardiovascular Angiography and Interventions. a ii. P2Y12 inhibitors (a) Inhibit the effect of adenosine diphosphate on the platelet, a key mediator resulting in amplification of platelet activation (b)  P2Y12 inhibitor therapy is given to all patients (class I). (c)  Choice of oral P2Y12 inhibitor depends on an ischemia-guided therapy or early invasive approach and pharmacokinetic differences (Tables 5–7). (1) Prasugrel should not be administered to patients with a history of stroke or transient ischemic attack (class III). (2) The efficacy of ticagrelor is decreased in patients treated with higher doses of aspirin (greater than 300 mg daily) compared with lower doses (less than 100 mg daily). (d) Clopidogrel and ticagrelor are preferred for a medical (i.e., ischemia-guided) strategy (Table 5). (1) Clopidogrel is the most studied P2Y12 inhibitor agent in patients immediately after the administration of fibrinolytic therapy. In the CLARITY trial, clopidogrel pretreatment in conjunction with fibrinolytic therapy resulted in a 46% reduction in the rate of cardiovascular death or recurrent MI or stroke at 30 days among patients referred for PCI. (e) Clopidogrel, ticagrelor, and prasugrel are options for an early invasive strategy (Table 5). (1) It is reasonable to choose ticagrelor over clopidogrel for P2Y12 inhibition in patients less than 75 years of age with NSTE-ACS or STEMI treated with an early invasive strategy or coronary stenting (class IIa). (2) It is reasonable to choose prasugrel over clopidogrel for P2Y12 inhibition in patients with NSTE-ACS or STEMI who undergo PCI and who are not at high risk of bleeding complications and have no history of transient ischemic attack or stroke (class IIa). (A) Prasurgel is not an appropriate agent to preload prior to PCI and should only be used once coronary anatomy is known and intent to perform PCI is confirmed. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-14 Acute Care in Cardiology (3) A  lthough not yet included in guidelines, results of the first head-to-head ISARREACT 5 open-label trial showed that prasugrel was superior to ticagrelor in reducing ischemic end points (6.9% vs. 9.3%, p=0.0006) without increasing bleeding risk in 4018 patients with ACS undergoing PCI; however, limitations to this study have been identified. (f) Limited data are available on the long-term safety or efficacy of “switching” patients treated for weeks or months with a P2Y12 inhibitor to a different P2Y12 inhibitor. Table 5. Guideline Recommendations for P2Y12 Inhibitor Therapy in ACS with or without PCI Guideline Recommendation An LD of P2Y12 receptor inhibitor should be given before PCI. Options include: a. Clopidogrelb 600 mg followed by 75 mg daily; b. PRA 60 mg followed by 10 mg daily; or c. TIC 180 mg followed by 90 mg BID • 2013 ACCF/AHA guideline for STEMI • 2014 NSTE-ACS guideline For patients with NSTE-ACS treated with an early invasive or ischemia-guided strategy: a. Clopidogrel 600 mg followed by 75 mg daily b. TIC 180 mg followed by 90 mg BID • 2014 NSTE-ACS guideline For patients with ACS undergoing PCI, it is reasonable to use ticagrelor or prasugrel in preference to clopidogrel in order to reduce ischemic events • 2021 ACC/AHA/SCAI Guideline for Coronary Revascularization • 2014 NSTE ACS guideline PRA should not be administered to patients with a history of TIA or stroke • 2014 NSTE-ACS guideline • 2013 ACCF/AHA guideline for STEMI Class/Gradea I LOE B LOE B LOE B I LOE B LOE B IIa LOE B Class III a 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. b Before PCI after fibrinolytic therapy: 300-mg LD if within 24 hr of event; clopidogrel 600-mg LD if > 24 hr after event. BID = twice daily; LOE = level of evidence; TIA = transient ischemic attack. Table 6. Comparison of Oral P2Y12 Receptor Inhibitors Parameter Clopidogrel (Plavix)a Prasugrel (Effient)b Ticagrelor (Brilinta)c Mechanism of action Thienopyridine; inhibits ADPmediated platelet activation at the P2Y12 receptor Thienopyridine; inhibits ADPmediated platelet activation at the P2Y12 receptor Inhibits ADP-mediated platelet activation at the P2Y12 receptor Onset of platelet inhibition 300-mg LD ~6 hr 600-mg LD ~2 hr 60-mg LD ~30 min 180 mg LD ~30 min % Platelet inhibition 30%–40% 60%–70% 60%–70% LD 300–600 mgd 60 mg 180 mg Maintenance dose 75 mg daily 10 mg daily; (5 mg if < 60 kg, BW ≥ 75 yr) 90 mg BIDe Metabolism Prodrug; converted by two-step process to active metabolite involving 2C19 in addition to other CYP enzymes Prodrug; converted by one step to active metabolite by several CYP pathways Not prodrug; reversible, noncompetitive binding; 3A4 (primary), 3A5, P-gp inhibitor Reversible platelet binding No No Yes ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-15 Acute Care in Cardiology Table 6. Comparison of Oral P2Y12 Receptor Inhibitors (Cont’d) Parameter Clopidogrel (Plavix)a Prasugrel (Effient)b Ticagrelor (Brilinta)c 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 interactions, drug-disease interactions, and common nonbleeding-related AEs 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 in pulmonary disease owing to dyspnea (up to 15%) and bradycardia (can cause ventricular pauses): More bleeding with NSAIDs, OACs Strong 3A4 inhibitors increase TIC concentrations; strong 3A4 inducers decrease TIC concentrations; do not exceed 40 mg of simvastatin or lovastatin Limit aspirin to < 100 mg; monitor digoxin concentrations Surgery hold timef 5 days 7 days 3–5 days Bleeding risk Less than PRA and TIC with standard dosing Risk of non-CABG, spontaneous, and fatal bleeds higher than with standard-dose clopidogrel Risk of non-CABG bleeds higher than with standarddose clopidogrel Box warning CYP2C19 polymorphisms Age-related bleeding; CVA/TIA Aspirin dosing > 100 mg Contraindications Active bleeding Active bleeding; TIA, CVA Active bleeding; ICH; severe hepatic disease Landmark trials CREDO, CURE, PCI-CURE, CLARITY, COMMIT TRITON-TIMI 38, TRILOGY, ISAR REACT 5 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 PRA in patients with active pathologic bleeding or a history of TIA or CVA and in patients > 75 yr unless the patient has diabetes mellitus or a history of MI. c Avoid TIC in patients with active pathologic bleeding or a history of ICH. Avoid aspirin doses > 100 mg daily (exception: first dose of 325 mg). d A 600-mg LD results in greater, more rapid, and more reliable platelet inhibition than a 300-mg LD. e Maintenance dosing of 60 mg BID is FDA approved for reducing thrombotic events after an initial 12 mo of therapy. f In emergency CABG, clopidogrel and TIC should be held for at least 24 hr to minimize the risk of CABG-related bleeding. ADP = adenosine diphosphate; AE = adverse event; BW = boxed warning; CABG = coronary artery bypass grafting; CVA = cerebrovascular accident; CYP = cytochrome P450; FDA = U.S. Food and Drug Administration; ICH = intracranial hemorrhage; NSAID = nonsteroidal antiinflammatory drug; O3FA = omega-3 fatty acid; OAC = oral anticoagulant; P-gp = P-glycoprotein; PPI = proton pump inhibitor; TIA = transient ischemic attack. a b ii. Intravenous P2Y12 inhibitor (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 4-mcg/kg/minute infusion) within 5 minutes and reaches steady state within 15–30 minutes of administration. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-16 Acute Care in Cardiology (b) 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) In patients undergoing PCI who are P2Y12 inhibitor naïve (or not candidates for oral therapy), intravenous cangrelor may be reasonable to reduce periprocedural ischemic events (Class IIb). (d) Pivotal trials comparing cangrelor with clopidogrel in ACS have not shown the superiority of cangrelor; however, both the CHAMPION PHOENIX PCI and the PLATFORM trials were discontinued prematurely. (e) Cangrelor had better efficacy than post-PCI clopidogrel with increases in minor bleeding (not major) (CHAMPION PHOENIX). (f) Cangrelor treatment is associated with a risk of dyspnea. (g) Cangrelor has not been studied in settings with preloaded clopidogrel or compared with prasugrel or ticagrelor. (h) Cangrelor has a potential use as a bridge therapy after discontinuation of oral P2Y12 inhibitors in high-risk patients undergoing coronary artery bypass grafting (CABG) (JAMA 2012;307:265-74). (i) The onset of action of both clopidogrel and prasugrel is delayed when coadministered with cangrelor, 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. (j) Expense and lack of evidence showing superiority to other P2Y12 inhibitors limit cangrelor’s use. iv. Intravenous GP IIb/IIIa inhibitors (a) Block the final common pathway of platelet aggregation; achieve 80% inhibition of ex vivo platelet aggregation (b) Double-bolus eptifibatide and high-dose bolus tirofiban are class I options for the invasive strategy (Table 7). (c) Most, but not all, data were gathered in the era before routine P2Y12 inhibitor use. (d) 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. (e) It is reasonable (class IIa, 2014 NSTE-ACS guideline) to give GP IIb/IIIa inhibitors to high-risk patients with NSTE-ACS treated with UFH and adequately pretreated with clopidogrel or ticagrelor. (f) Most studies combined GP IIb/IIIa inhibitors with UFH as the anticoagulant. (g) Upstream administration (given before PCI) has not been shown superior to delayed administration (given at time of PCI). (1) Upstream administration is noninferior to delayed timing for reducing ischemic events. (2) Significantly higher bleeding rates occur in those receiving upstream GP IIb/IIIa inhibitors than in those receiving delayed administration. (3) Bolus-only GP IIb/IIIa inhibitor administration has been adopted in clinical practice but not in the practice guidelines. (h) Common adverse events of GP IIb/IIIa inhibitors: (1) 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. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-17 Acute Care in Cardiology (2) N  ote that the smaller-molecule agents eptifibatide and tirofiban depend on renal clearance; adjustment of the infusion is recommended to decrease the risk of bleeding; monitor SCr (CrCl). (3) All GP IIb/IIIa inhibitors can cause thrombocytopenia; monitor hemoglobin (Hgb), hematocrit (Hct), and Plt. When administered with UFH, rates of thrombocytopenia with either tirofiban or eptifibatide are no greater than with UFH alone. (4) Secondary to their short half-life, eptifibatide and tirofiban can be reversed within a few hours by discontinuing the infusion and are preferred (class IIb) in the NSTEACS guideline. Table 7. GP IIb/IIIa Inhibitor Dosing in ACS with or without PCIa,b Agent Eptifibatide (Integrilin) Dosing PCI: 180 mcg/kg IVB × 2 (10 min apart); 2 mcg/kg/min initiated after first bolus for 18–24 hrc; ACS without PCI: Of uncertain benefit in patients adequately pretreated with a P2Y12 receptor inhibitor; bolus used as above Tirofiban (Aggrastat) PCI: 25 mcg/kg IVB over 3 min; then 0.15 mcg/kg/min for 18 hr Renal Adjustments If CrCl < 50 mL/min, reduce infusion by 50%; avoid in patients on hemodialysis; not studied in patients with SCr > 4 mg/dL If CrCl ≤ 60 mL/min, reduce infusion by 50% Adding GP IIb/IIIa inhibitors to aspirin therapy is most beneficial in patients with high-risk features (those with elevated biomarkers, those with diabetes, those undergoing revascularization) and in those not receiving adequate pretreatment with P2Y12 inhibitors. Administration of GP IIb/IIIa inhibitors to patients adequately treated with P2Y12 inhibitors is of uncertain clinical benefit. b GP IIb/IIIa inhibitors should be used in combination with heparin (either UFH or low-molecular-weight heparin) or used provisionally with bivalirudin. c Double bolus is recommended to support PCI in STEMI and NSTE-ACS. IVB = intravenous bolus. a v. Platelet function testing (a) Although platelet function can be evaluated by platelet function testing or genotyping, neither is routinely done in the clinical setting. (b) Although platelet function and genetic testing are not routine and have not been endorsed by guidelines to date, several clinical trials have offered promise with utilizing genetic information in order to optimize antiplatelet choice and outcomes. f. Anticoagulant recommendations i. An anticoagulant should be administered to all patients with ACS in addition to antiplatelet therapy to reduce the risk of intracoronary and catheter thrombus formation (Tables 8 and 9), irrespective of initial treatment strategy. ii. Use of anticoagulants is typically concentrated in the procedural setting, though use may continue for a finite period after the procedure. iii. Selection and use among agents may depend on ACS presentation, timing or dose of preprocedural antiplatelet medication, clot burden during procedure, and estimated risk of bleeding during procedure. iv. Anticoagulants increase the risk of bleeding and will require some type of monitoring for agent-specific risks. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-18 Acute Care in Cardiology Table 8. Anticoagulant Management Strategies in ACS Management Strategy STEMI (PPCI) STEMI, with fibrinolyticb therapy NSTE-ACS, early invasive strategy NSTE-ACS, ischemia-guided strategy Class I Recommendationsa UFH, bivalirudin UFH, enoxaparin, fondaparinux Enoxaparin, bivalirudin,c UFH Enoxaparin, fondaparinux,d UFH Class IIa = reasonable to be performed or administered; class IIb = may be considered; class III = not to be administered or harmful. Fibrinolytics preferred when PCI cannot be done within 120 min of first medical contact (class I). Door-to-needle time goal < 30 min. Those who receive fibrinolytic therapy should receive anticoagulation after fibrinolysis for at least 48 hr with IV UFH or IV/SC enoxaparin during hospitalization, up to 8 days (preferred, selected patients), or IV/SC fondaparinux during hospitalization, up to 8 days. c If bleeding risk is high, it is reasonable to use bivalirudin monotherapy in preference to UFH plus GP IIb/IIIa inhibitor (class IIb). d Fondaparinux should not be used as the sole anticoagulant to support PCI. Give additional anticoagulant during revascularization if fondaparinux was initially chosen as the anticoagulant strategy. Fondaparinux is given a class I recommendation in the 2014 NSTE-ACS guidelines (for an ischemia-guided strategy) and a class III or harmful recommendation in the 2011 PCI and 2013 STEMI guidelines when PCI is indicated. PPCI = primary percutaneous coronary intervention; SC = subcutaneous(ly). a b g. Anticoagulant agents i. UFH (a) Exerts its effects as an indirect thrombin inhibitor on fibrin-bound clots (b) Given as an intravenous bolus with or without infusion to reduce ischemic events; adjusted according to activated partial thromboplastin time (aPTT), anti-Xa (Anti-Xa), or activated clotting time (ACT) to maintain therapeutic anticoagulation according to specific hospital protocol, usually continued for 48 hours or until PCI (1) Intravenous UFH: Initial bolus of 60 units/kg (maximum 4000 units) (2) Initial infusion of 12 units/kg/hour (maximum 1000 units/hour) (c) Risks include bleeding, thrombocytopenia, and HIT with or without thrombosis. (d) Monitoring includes aPTT or ACT, Hgb/Hct, and Plt. (e) Unlike other anticoagulants, UFH is not renally cleared and can be used safely in those with renal impairment. (f) Carries Class I recommendation to reduce ischemic events for those without a history of heparin-induced thrombocytopenia. ii. Enoxaparin: Molecular weight is one-third of UFH with balanced anti-factor Xa (anti-Xa) and anti-IIa activity. (a) Given as subcutaneous injection at least 2 inches on either side of the navel at a 90-degree angle into 1 inch of pinched skin (avoid injection into muscle); alternate dosing sites (1) Dosing varies depending on the reperfusion strategy and the time from the last dose to the procedure (Table 9). (2) 30-mg intravenous bolus given in STEMI (if age younger than 75) and in select patients with NSTE-ACS (3) Specific periprocedural dosing for PCI in relation to time of last subcutaneous dose (Table 9) (4) Decrease dosing interval to once daily when CrCl is less than 30 mL/minute. (b) Does not require routine anti-Xa monitoring; requires SCr to calculate CrCl for dosing; monitor Hgb, Hct, Plt (c) Risks include bleeding, injection site hematomas, spinal or epidural hematomas, retroperitoneal hematoma/bleeding, thrombocytopenia including HIT with or without thrombosis, mechanical prosthetic valve thrombosis (in pregnancy) ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-19 Acute Care in Cardiology iii. Fondaparinux (a) Selective inhibitor of activated factor X (b) Longest half-life of anticoagulants (17 hours) (c) Given as a subcutaneous injection into fatty tissue at a 90-degree angle into a pinched skinfold; alternate dosing sites between the left and right anterolateral and posterolateral abdominal wall (1) Dosing NSTE-ACS: 2.5 mg subcutaneously daily, continued for the duration of hospitalization or until PCI (2) Not to be used as the sole anticoagulant during PCI (class III) (3) Contraindicated if CrCl is less than 30 mL/minute (d) Does not require routine anti-Xa monitoring; requires SCr to calculate CrCl to assess for contraindication; monitor Hgb, Hct, Plt (e) Risks include bleeding, thrombocytopenia, and spinal or epidural hematomas. (f) No increased risk of HIT iv. Bivalirudin (a) A direct thrombin inhibitor; directly inhibits thrombin in both circulating and bound clots and inhibits thrombin-mediated platelet aggregation (b) Given as an intravenous bolus with fixed-rate infusion and usually continued until the end of PCI (with or without delay after infusion in some high-risk patients) (1) Early invasive strategy dosing: 0.1-mg/kg LD followed by 0.25 mg/kg per hour (only in patients with planned PCI), continued until diagnostic angiography or PCI (2) PCI dosing: 0.75-mg/kg intravenous bolus, 1.75 mg/kg/hour intravenously continued throughout the procedure (3) Adjust the infusion rate to 1 mg/kg/hour when the CrCl is less than 30 mL/minute or to 0.25 mg/kg/hour in patients receiving hemodialysis. (4) Can extend duration of infusion for up to 4 hours after procedure for prolonged antiplatelet protection (c) Does not require monitoring for adjustment during PCI; monitor SCr (adjustment required for infusion only in those with impaired CrCl), Hgb, Hct, Plt (d) Primarily reserved for patients with history of or suspected HIT undergoing PCI h. Guideline recommendations for specific anticoagulants i.  In an ischemia-guided strategy, UFH, enoxaparin, and fondaparinux are class I recommended options. ii.  In an invasive strategy, UFH, enoxaparin, or bivalirudin are options. (a) Fondaparinux should not be used as the sole anticoagulant to support PCI (class III). An additional 85 units/kg of intravenous UFH is required immediately before PCI revascularization to reduce the risk of catheter thrombosis if fondaparinux was initially chosen as the anticoagulant strategy if no GP IIb/IIIa inhibitor is used and 60 units/kg intravenously if a GP IIb/IIIa inhibitor is used; re-bolus as needed according to target ACT. (b) Use of enoxaparin during PCI may be reasonable in patients treated with upstream subcutaneous enoxaparin with an ischemia-guided strategy. (1) Patients who have received enoxaparin within 8 hours of the last subcutaneous dose generally have adequate anticoagulation to undergo PCI without supplemental bolus. (2) An additional dose of 0.3 mg/kg of intravenous enoxaparin should be administered at the time of PCI to patients who have received fewer than two therapeutic subcutaneous doses or who received the last subcutaneous dose 8–12 hours before PCI. ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-20 Acute Care in Cardiology (3) Patients who undergo PCI more than 12 hours after the last subcutaneous dose are usually treated with full-dose de novo anticoagulation with an established regimen (e.g., full-dose UFH or bivalirudin). (c) In those at high risk of bleeding, it is reasonable to use bivalirudin monotherapy in preference to the combination of UFH and a GP IIb/IIIa receptor antagonist (class IIb). (1) For patients who have received UFH, wait 30 minutes and then give a 0.75-mg/kg intravenous LD, followed by a 1.75-mg/kg/hour intravenous infusion. (2) For patients already receiving a bivalirudin infusion, give an additional 0.5-mg/kg LD, and increase the infusion to 1.75 mg/kg/hour during PCI. (d) Anticoagulant therapy is generally discontinued after PCI unless there is a compelling reason to continue. iii.  In patients undergoing primary PCI, either UFH or bivalirudin for those with a history of heparin-induced thrombocytopenia is preferred. Table 9. Antithrombotic Dosing in ACS with or without PCI UFH Enoxaparin (Lovenox) Fondaparinux (Arixtra) Factor Xa inhibitor Bivalirudin (Angiomax) Classification — LMWH Direct thrombin inhibitor NSTE-ACS 60 units/kg IVB (max 4000 units), 12 units/ kg/hr IV (max 1000 units/hr) for 48 hr or until PCI; goal aPTT/ anti-Xa according to hospital-specific protocol 1 mg/kg SC every 12 2.5 mg SC daily hr for 24–48 hr or until PCI or throughout hospitalization (up to 8 days); 30 mg IVB 0.1 mg/kg IVB; then 0.25 mg/kg/hr IV (only for planned invasive strategy) 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 If last dose < 8 hr, nothing additional needed; if last dose > 8 hr, 0.3 mg/kg IVB if last dose 8–12 hr before or < 2 therapeutic doses received before PCI Fondaparinux should not be used as a sole anticoagulant for PCI 0.75 mg/kg IVB, 1.75mg/kg/hr IV d/c at end of PCI, or continue for up to 4 hr after procedure if needed; hold UFH 30 min before administration STEMI ± primary PCI Supplemental doses to target ACTa; if GP IIb/IIIa inhibitor, UFH 50–70 units/kg IVB; if no GP IIb/ IIIa inhibitor, UFH 70–100 units/kg IVB 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 2.5 mg IVB; then 2.5 mg SC dailyb 0.75 mg/kg IVB, 1.75 mg/kg/hr IV ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-21 Acute Care in Cardiology Table 9. Antithrombotic Dosing in ACS with or without PCI (Cont’d) Unfractionated Heparin Dose adjustments and contraindications Avoid if history of HIT Enoxaparin (Lovenox) If CrCl < 30 mL/min, 1 mg/kg SC daily; avoid if history of HIT Fondaparinux (Arixtra) Contraindicated if CrCl < 30 mL/min Bivalirudin (Angiomax) Adjust infusion dose in severe renal dysfunction If CrCl < 30 mL/min, 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 200–250 s in patients given concomitant GP IIb/IIIa inhibitors. b Fondaparinux should not be used as the sole anticoagulant in PCI. ACT = activated clotting time; HIT = heparin-induced thrombocytopenia; IVB = intravenous bolus; LMWH = low-molecular-weight heparin. a 5.  Fibrinolytic therapy is indicated for patients with a STEMI in whom PCI cannot be done (Table 10). a. In the absence of contraindications (Table 11), fibrinolytic therapy should be given to patients with a STEMI (class I when onset of ischemic symptoms is within the previous 12 hours) when it is expected that primary PCI cannot be done within 120 minutes of first medical contact, with an ideal door-to-needle time of less than 30 minutes. b.  When a fibrinolytic agent is given as a reperfusion strategy, UFH, enoxaparin, and fondaparinux are recommended. c. Patients undergoing reperfusion with fibrinolytics should receive anticoagulant therapy after fibrinolysis for at least 48 hours with intravenous UFH or intravenous/subcutaneous enoxaparin during hospitalization, up to 8 days (preferred, selected patients), or intravenous/subcutaneous fondaparinux during hospitalization, up to 8 days. i. UFH administration of a 60-unit/kg bolus (maximum 4000 units) and 12 units/kg/hour (maximum 1000 units/hour), to obtain an aPTT of 1.5–2.0 times control (about 50–70 seconds) for at least 48 hours ii. Enoxaparin 30 mg intravenously (if 75 or older, omit bolus), followed in 15 minutes by a 1-mg/kg subcutaneous injection (if 75 or older, 0.75 mg/kg) every 12 hours for the duration of index hospitalization, 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, extend dosing interval to daily administration. iii. Fondaparinux administered with an initial 2.5-mg intravenous dose, followed in 24 hours by 2.5-mg/day subcutaneous injections (contraindicated if CrCl is less than 30 mL/minute) for the duration of the index hospitalization, for up to 8 days, or until revascularization ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-22 Acute Care in Cardiology Table 10. Fibrinolytic Therapy Dosing Alteplase (t-PA, Activase) ≤ 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 IVP in 30 min Tenecteplase < 60 kg: 30 mg IVP; 60–69 kg: 35 mg IVP; 70–79 kg: 40 mg IVP; 80–89 kg: (TNK-t-PA, TNKase) 45 mg IVP; ≥ 90 kg: 50 mg IVP (~0.5 mg/kg) IVP = intravenous push; r-PA = recombinant plasminogen activator; t-PA = tissue plasminogen activator. Table 11. Contraindications to Fibrinolytic Therapy Relative Contraindications BP > 180/110 mm Hg on presentation or history of chronic poorly controlled HTN Absolute Contraindications Any prior hemorrhagic stroke History of ischemic stroke > 3 mo before Intracranial neoplasm or arteriovenous malformation Recent major surgery (< 3 wk before) Traumatic or prolonged CPR (> 10 min) Recent internal bleeding (within 2–4 wk) Active peptic ulcer Noncompressible vascular punctures Pregnancy Known intracranial pathology (dementia) Ischemic stroke within 3 mo (except in past 4½ hr) Active internal bleeding Aortic dissection Considerable facial trauma or closed-head trauma in past 3 mo Intracranial or intraspinal surgery within 2 mo Severe uncontrolled HTN (unresponsive to emergency therapy) For streptokinase,a treatment within previous 6 mo (if considering streptokinase again) OAC therapy Streptokinase is no longer marketed in the United States but is available in other countries. BP = blood pressure; CPR = cardiopulmonary resuscitation. a D. Long-term Management After ACS 1. DAPT a. Given at least 12 months after ACS b. DAPT reduces mortality after ACS, regardless of whether the patient received stenting. i. Aspirin should be continued indefinitely at a maintenance dose of 81 mg daily in all patients after 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. After PCI (bare metal stent or drug-eluting stent), aspirin plus clopidogrel 75 mg daily, prasugrel 10 mg daily, or ticagrelor 90 mg twice daily should be continued for at least 12 months. c. Early discontinuation of DAPT i. Early discontinuation is reasonable when the risk of morbidity exceeds the expected benefit (class IIa). (a) DAPT should be continued after 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 disease who have undergone PCI with elective stent placement (class I, 6 months duration for elective PCI). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-23 Acute Care in Cardiology (c) It is reasonable to consider discontinuation of aspirin therapy after 1–3 months with continued P2Y12 monotherapy (class IIa). (1) In those who are at high risk of bleeding or in those with overt bleeding, discontinuation of P2Y12 after 6 months may be reasonable with continued aspirin (class IIb) 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. iii.  Trials comparing shorter DAPT durations have evaluated newer-generation stents in all patients undergoing PCI (including elective cases). (a) In aggregate, these data support a shorter course of DAPT followed by P2Y12 monotherapy, with a reduction in bleeding events (when compared with standard DAPT) and equivalent rates of ischemic events. (b) The trials evaluating short-term DAPT were not powered to assess differences in stent thrombosis and few included those with STEMI. (c) No trial has evaluated short-term DAPT followed by P2Y12 monotherapy compared with short-term DAPT followed by aspirin monotherapy. iv. Compared with first-generation stents, newer-generation stents have an improved safety profile and a lower risk of stent thrombosis. v. Proton pump inhibitors can reduce the risk of gastrointestinal (GI) bleeding from DAPT. d. Long-term DAPT i. In general, longer-duration DAPT may be reasonable for patients at a higher ischemic risk with a lower bleeding risk. ii. Trials evaluating the need for an extended DAPT duration (greater than 12 months) in patients with and without ACS undergoing PCI show a reduction in stent thrombosis and ischemia end points with increased bleeding for patients continued on DAPT beyond 12 months. iii. The risk of stent thrombosis is greater on DAPT cessation; however, continued DAPT beyond 1 year is not associated with reduced CV or total mortality. iv. A longer duration of P2Y12 inhibitor therapy is an individualized approach according to the patient’s risk of ischemia and bleeding. (a) DAPT may be reasonable beyond 12 months if the patient is at high risk and has no significant history of bleeding while receiving DAPT (class IIb). (b) A DAPT score derived from the DAPT study may help in deciding whether to prolong or extend DAPT in patients treated with coronary stent implantation (Table 12). (1) Derived from the DAPT study, which included 11,648 patients with mainly clopidogrel as the P2Y12 inhibitor (2) For those with a high DAPT score (2 or greater), prolonged DAPT reduces net (ischemic plus bleeding) events. (3) For those with a low DAPT score (less than 2), the benefit-risk ratio for prolonged DAPT is not favorable (increased bleeding without a reduction in ischemic events). (4) Duration of DAPT for more or less than 12 months should jointly be made by the clinician and the patient, balancing the risks of stent thrombosis and ischemic complications with the risks of bleeding. v. Ticagrelor has been shown to reduce CV end points of death, MI, and revascularization to a greater extent than placebo at a reduced dose of 60 mg twice daily (after at least 12 months of 90 mg twice daily) with less bleeding than extended use of 90 mg twice daily (N Engl J Med 2015;372:1791-800). ACCP Updates in Therapeutics® 2023: Pharmacotherapy Preparatory Review and Recertification Course 1-24