ACS

Approach Considerations Initial therapy for ACS should focus on stabilizing the patient's condition, relieving ischemic pain, and providing antithrombotic therapy to reduce myocardial damage and prevent further ischemia. Morphine (or fentanyl) for pain control, oxygen, sublingual or intravenous (IV) nitroglycerin, soluble aspirin 162-325 mg, and clopidogrel with a 300- to 600-mg loading dose are given as initial treatment. In complete vessel occlusion without collateralization of the infarct-related vessel, there is little utility in “pushing nitrates.” High-risk patients with non-ST-segment elevation myocardial infarction (NSTEMI ACS) should receive aggressive care, including aspirin, clopidogrel, unfractionated heparin or low–molecular-weight heparin (LMWH), IV platelet glycoprotein IIb/IIIa complex blockers (eg, tirofiban, eptifibatide), and a beta blocker. The goal is early revascularization. Intermediate-risk patients with NSTEMI ACS should rapidly undergo diagnostic evaluation and further assessment to determine their appropriate risk category. Low-risk patients with NSTEMI ACS should undergo further follow-up with biomarkers and clinical assessment. Optimal medical therapies include use of standard medical therapies, including beta blockers, aspirin, and unfractionated heparin or LMWH. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) study showed that clopidogrel would be beneficial even in low-risk patients. [53] If no further pain occurs, and follow-up studies are negative, a stress study should drive further management. Monitor and immediately treat arrhythmias in the first 48 hours. Pay attention to exacerbating factors, such as disturbances in electrolytes (especially potassium and magnesium), hypoxemia, drugs, or acidosis. Correct these factors accordingly. Humidified oxygen may reduce the risk of nosebleeds in patients with ACS who are receiving antiplatelet and antithrombin therapy. Do not administer nitrates if the patient is hypotensive (systolic BP < 90 mm Hg); if RV infarction, large pericardial effusion, or severe aortic stenosis is suspected; or if the patient recently received phosphodiesterase-5 inhibitors (eg, sildenafil). Patients with known hypersensitivity to antiplatelet agents, active internal bleeding, and bleeding disorders should not receive antiplatelet or antithrombotic therapy. Some patients with intractable chest pain or severe hypotension may require the insertion of an intra-aortic balloon pump. The EuroHeart survey showed a nearly 40% reduction in the risk of death in patients with ACS who received support with an intra-aortic balloon pump. This benefit was independent of the status of the ST segment. Congestive heart failure (CHF) can be due to systolic dysfunction or diastolic dysfunction in the setting of myocardial infarction. Aggressive treatment is indicated to prevent worsening of the situation. Patients presenting with cardiogenic shock should undergo percutaneous coronary intervention (PCI) as soon as possible. Cardiogenic shock is associated with a high mortality rate. Pressor agents, such as dopamine, and inotropic agents, such as dobutamine, may be needed. In a prospective, natural-history study of coronary atherosclerosis, patients underwent 3-vessel coronary angiography and gray-scale and radiofrequency intravascular ultrasonographic imaging after PCI. [54] Recurrent ischemia may be due to incomplete reperfusion. In the setting of PCI, consider stent thrombosis as a possible cause. Whether drug-eluting stents have an increased rate of thrombosis compared with bare metal stents is unclear. The clinical significance of incomplete coronary revascularization (ICR) following PCI in patients with ACS was examined in 2,954 patients from the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. At one year follow-up, ICR was strongly associated with ischemia-driven unplanned revascularization, myocardial infarction and major adverse cardiac events. [55] Drug-eluting stents are linked with fewer periprocedural risks bu 

Drug-eluting stents are linked with fewer periprocedural risks but tend to have high incidence of postprocedural complications including myocardial infarction, repeat procedures, and 12-month major adverse cardiac and brain complications, compared with coronary bypass surgery. [56] One study by Ribichini et al suggests that prednisone treatment after bare metal stents or drug-eluting stent implantation results in a better event-free survival at 1 year. [57] In the final report of the HORIZONS-AMI trial, which assessed the 3 year outcomes of the effectiveness and safety of bivalirudin monotherapy and paclitaxel-eluting stenting, outcomes were sustained for patients with STEMI undergoing primary PCI. [58] In a study of 3031 patients, Mehta et al found that early intervention (coronary angiography < or = 24 h after randomization) in patients with ACS did not differ greatly from delayed intervention (coronary angiography > or = 36 h randomization) in the prevention of primary outcomes (ie, composite of death, myocardial infarction, or stroke at 6 mo). Early intervention did reduce the rate of secondary outcomes (ie, death, myocardial infarction, or refractory ischemia at 6 mo) and improved primary outcomes in patients who were at highest risk (ie, GRACE risk score >140). [59] In a Swedish registry of patients with STEMI from 1996-2007, reported an increase in the prevalence of evidence-based treatments. [60]The use of aspirin, clopidogrel, beta blockers, statins, and ACE inhibitors all increased. Clopidogrel increased from 0% to 82%, statins increased from 23% to 83%, and various ACE inhibitors increased by a large margin. A decrease was reported in 30-day and 1-year mortality that was sustained during long-term follow-up. By following the proper guidelines, patients who have experienced STEMI have higher survival rates. Pharmacologic Anti-ischemic Therapy Nitrates Nitrates do not improve mortality. [61]However, they provide symptomatic relief by means of several mechanisms, including coronary vasodilation, improved collateral blood flow, decrease in preload (venodilation and reduced venous return), and decrease in afterload (arterial vasodilation). Care should be taken to avoid hypotension, because this can potentially reduce coronary perfusion pressure (diastolic BP - LV diastolic pressure). Beta-blockers Beta-blockers are indicated in all patients unless they have the following contraindications: Systolic blood pressure less than 90 mm Hg Cardiogenic shock Severe bradycardia Second- or third-degree heart block Asthma or emphysema that is sensitive to beta agonists Peripheral vascular disease Uncompensated CHF Beta blockers reduce oxygen demand and ventricular wall tension. They also decrease mortality and adverse cardiovascular events. These drugs may prevent mechanical complications of myocardial infarction, including rupture of the papillary muscle, left ventricular free wall, and ventricular septum. Beta blockers meliorate dynamic obstruction of the left ventricular outflow tract in patients with apical infarct and hyperdynamic basal segments. The most frequently used regimen is IV metoprolol 2-5 mg given every 5 minutes (up to 15 mg total) followed by 25-100 mg given orally twice a day. Beta-blockers should not be used acutely in patients with cardiogenic shock or signs of heart failure on presentation. Pharmacologic Antithrombotic Therapy Aspirin Aspirin permanently impairs the cyclooxygenase pathway of thromboxane A2 production in platelets, in this way inhibiting platelet function. Aspirin reduces morbidity and mortality and is continued indefinitely. [62] Clopidogrel Clopidogrel (thienopyridine) inhibits adenosine 5'-diphosphate (ADP)–dependent activation of the glycoprotein IIb/IIIa complex, a necessary step for platelet aggregation. This process results in intense inhibition of platelet function, particularly in combination with aspirin. In the CURE trial, thienopyridine reduced the rate of myocardial infarction by 20%. [53] The optimal loading dose for clopidogrel is still being evaluat 

The optimal loading dose for clopidogrel is still being evaluated. Reports show that a loading dose of 600 mg might be more beneficial than 300 mg. Withhold clopidogrel for at least 5 days before elective coronary artery bypass grafting (CABG). Since 12% of patients with non-ST elevation ACS have coronary anatomy that favors CABG, the use of clopidogrel is withheld until coronary angiography at some institutions. A meta-analysis of 34 studies analyzed the safety of CABG among patients with ACS continuing clopidogrel. The investigators found that although mortality is increased in those receiving clopidogrel, it is influenced by ACS status and case urgency in primarily nonrandomized studies. Among patients with ACS, no differences in mortality or postoperative myocardial infarction or stroke rates were found. This suggests that in patients with ACS who require urgent CABG, proceeding despite the continuation of clopidogrel is likely safe. [63] Clopidogrel can be considered an alternative to aspirin in patients with aspirin intolerance or who are allergic to aspirin. Patients with chronic kidney disease who have low platelet response to clopidogrel tend to have worse outcomes after PCI. [64] Evidence has shown that dexlansoprazole and lansoprazole do not significantly reduce the conversion of clopidogrel to its active metabolite (reduced by 9% and 14%, respectively), and no dose adjustment of clopidogrel is required. [65, 66] The group’s findings and recommendations are listed below. Clopidogrel reduces major CV events compared with placebo or aspirin. Dual antiplatelet therapy with clopidogrel and aspirin, compared with aspirin alone, reduces major CV events in patients with established ischemic heart disease, and it reduces coronary stent thrombosis but is not routinely recommended for patients with prior ischemic stroke because of the risk of bleeding. [67] Clopidogrel alone, aspirin alone, and their combination are all associated with increased risk of GI bleeding. Clopidogrel requires metabolic activation by cytochrome P450 2C19 (CYP2C19). PPIs that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of GI bleeding. A study by Simon et al showed that PPI use is not associated with an increased risk of cardiovascular events or mortality in patients who have been treated with clopidogrel for a recent MI, regardless of CYP2C19 genotype. [68] Patients with prior GI bleeding are at highest risk for recurrent bleeding on antiplatelet therapy; other risk factors include advanced age, concurrent use of anticoagulants, steroids, or NSAIDs including aspirin, and Helicobacter pyloriinfection; risk increases as the number of risk factors increases. Use of PPIs or histamine H2 receptor antagonists (H2RAs) reduces the risk of upper GI bleeding compared with no therapy; PPIs reduce upper GI bleeding to a greater degree than do H2Ras. PPIs are recommended to reduce GI bleeding among patients with a history of upper GI bleeding; PPIs are appropriate in patients with multiple risk factors for GI bleeding who require antiplatelet therapy. Routine use of either a PPI or an H2RA is not recommended for patients at lower risk of upper GI bleeding, who have much less potential to benefit from prophylactic therapy. Clinical decisions regarding concomitant use of PPIs and thienopyridines must balance overall risks and benefits, considering both CV and GI complications. Pharmacokinetic and pharmacodynamic studies, using platelet assays as surrogate endpoints, suggest that concomitant use of clopidogrel and a PPI reduces the antiplatelet effects of clopidogrel; the strongest evidence for an interaction is between omeprazole and clopidogrel; it is not established that changes in these surrogate endpoints translate into clinically meaningful differences. Observational studies and a single randomized clinical trial have shown inconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs; a clinically important interaction cannot be excluded, particularly in certain subgroups, such as  

Observational studies and a single randomized clinical trial have shown inconsistent effects on CV outcomes of concomitant use of thienopyridines and PPIs; a clinically important interaction cannot be excluded, particularly in certain subgroups, such as poor metabolizers of clopidogrel. The role of either pharmacogenomic testing or platelet function testing in managing therapy with thienopyridines and PPIs has not yet been established. Prasugrel Like clopidogrel, prasugrel is a thienopyridine ADP receptor inhibitor that inhibits platelet aggregation. It has been approved in the United States and has been shown to reduce new and recurrent myocardial infarctions. [69]The loading dose is 60 mg PO once and maintenance is 10 mg PO qd (given with aspirin 75-325 mg/d). Prasugrel is indicated for the reduction of thrombotic cardiovascular events (including stent thrombosis) with ACS that is managed with PCI. However, a 2014 report by Montalescot et al indicates that if angiography is to be performed in a patient with NSTEMI within 48 hours of admission, treatment with the P2Y12antagonist prasugrel should be postponed until a decision about revascularization has been reached owing to an increased bleeding risk without ischemia benefit from pre-PCI prasugrel therapy. [70, 71] The randomized, double-blind study included 2770 NSTEMI patients who underwent percutaneous coronary intervention (PCI), with 1394 patients receiving pretreatment with prasugrel and 1376 individuals receiving placebo. All patients received prasugrel at the time of PCI. The investigators found that the same percentage of patients (13.1%) in the pretreatment and placebo groups reached primary endpoint (defined as time to first occurrence of glycoprotein IIb/IIIa bailout, stroke, myocardial infarction [MI], urgent revascularization, or cardiovascular death, through 7 days after randomization). [70, 71] No reductions in ischemic events, including total mortality, were found in the patients who received prasugrel pretreatment. Moreover, pretreatment with prasugrel was associated with a six-fold increase in life-threatening bleeding unrelated to coronary artery bypass grafting (CABG), as well as a three-fold increase in all major bleeding associated with non-CABG thrombolysis in myocardial infarction (TIMI). An approximately three-fold increase in TIMI minor bleeding events was also seen. [70, 71] Earlier studies also found that significant, sometimes fatal, bleeding occurred more frequently with prasugrel than with clopidogrel, although the overall mortality rate did not differ significantly between a treatment group receiving prasugrel and another receiving clopidogrel. [69, 72] In a separate, earlier study of patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel, compared with clopidogrel, did not significantly reduce the frequency of the primary end point of death from cardiovascular causes, myocardial infarction, or stroke. Similar bleeding risks were observed. [73] 

Vorapaxar In May 2014, the FDA approved vorapaxar (Zontivity) to reduce the risk of MI, stroke, cardiovascular death, and need for revascularization procedures in patients with a previous MI or peripheral artery disease (PAD). It is a first-in-class antiplatelet medication that is a protease-activated receptor 1 (PAR-1) inhibitor. It is not indicated as monotherapy, but in addition to aspirin and/or clopidogrel. 

Approval was based on the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P TIMI-50) trial. Results of the trial (n = 26,499) showed that time to cardiovascular death, MI, stroke, or urgent coronary revascularization was decreased by 13% in patients taking vorapaxar. When coronary revascularization was excluded, the secondary endpoint of cardiovascular death, MI, or stroke was also significantly reduced. [74] Because of vorapaxar’s antiplatelet effects, moderate or severe bleeding occurred in 3.4% of patients compared with 2.1% in the placebo-treated patients. Intracranial hemorrhage occurred in 0.6% of those taking vorapaxar compared with 0.4% taking placebo. [74] Ticagrelor Ticagrelor (Brilinta) was approved by the US Food and Drug Administration in July 2011 and is the first reversible oral P2Y receptor antagonist. Results from the randomized PLATO (PLATelet inhibition and patient Outcomes) trial showed that ticagrelor provides faster, greater, and more consistent ADP-receptor inhibition than clopidogrel. [75] In the PLATO trial, the difference between treatments on the composite resulted from effects on CV death and MI; each was statistically significant when considered as a secondary endpoint, and there was no beneficial effect on strokes. [75, 76, 77] For all-cause mortality, the benefit was also statistically significant of 9.8% for ticagrelor and 11.7% for clopidogrel (p = 0.0003) with a hazard ratio of 0.78. Bleeding risk was assessed in the PLATO trial, and ticagrelor increased the overall risk of bleeding (major + minor) to a somewhat greater extent than did clopidogrel. [75] The increase was seen for non-CABG-related bleeding but not for CABG-related bleeding. Fatal and life-threatening bleeding rates were not increased. In September 2015, the indication for ticagrelor was expanded to include use in patients with a history of MI more than 1 year previously. [78] Approval is based on the PEGASUS TIMI-54 study, a large-scale outcomes trial involving over 21,000 patients.[79] PEGASUS TIMI-54 investigated ticagrelor 60 mg twice daily plus low-dose aspirin, compared to placebo plus low-dose aspirin, for the long-term prevention of CV death, heart attack, and stroke in patients who had experienced an MI 1-3 years prior to study enrollment. In patients with an MI more than 1 year previously, treatment with ticagrelor significantly reduced the risk of CV death, MI, or stroke compared with placebo. [79] 

Prevention of stent thrombosis A subgroup analysis of the PLATO trial indicated that treatment with ticagrelor resulted in a lower risk of stent thrombosis than treatment with clopidogrel in patients with ACS. [80, 81] This benefit was independent of patient characteristics at baseline, including type of ACS and stent type. Of the 18,624 ACS patients in the PLATO study, 11,289 (61%) had a previous stent implanted or received one during the trial. [81]Of these, 177 patients (1.6%) had a definite stent thrombosis (176 of them within 1 year), and 275 (2.5%) had definite or probable stent thrombosis. Definite stent thrombosis occurred in 1.37% of patients treated with ticagrelor and 1.93% of those treated with clopidogrel—a 33% reduction in risk with ticagrelor. [81] Definite or probable stent thrombosis occurred in 2.21% of ticagrelor-treated patients and 2.87% of those who received clopidogrel—a 25% reduction in risk with ticagrelor. Overall, the risk of definite, probable, or possible stent thrombosis was reduced by 23% with ticagrelor. Abciximab, eptifibatide, and tirofiban Glycoprotein IIb/IIIa receptor antagonists include abciximab, [82, 83] eptifibatide, [84] and tirofiban. [85] These drugs inhibit the glycoprotein IIb/IIIa receptor, which is involved in the final common pathway for platelet adhesion and aggregation. (See the image below.) Use of cardiac markers in the ED. Effect of time to treatment in patients with acute coronary syndrome (ACS) who are treated with the GIIb/IIIa inhibitor eptifibatide. View Media Gallery Use eptifibatide or tirofiban in patients with high-risk features in whom invasive treatment is not planned. The use of eptifibatide 12 hours or more before angiography was not superior to the provisional use of eptifibatide after angiography, according to results from the EARLY ACS trial. The study compared a strategy of early, routine administration of eptifibatide with delayed, provisional administration in patients who had ACS without ST-segment elevation and who were assigned to an invasive strategy. The study also found that early use of eptifibatide was associated with an increased risk of non–life-threatening bleeding and the need for transfusion. [86] Two trials with tirofiban and 1 trial with eptifibatide documented their efficacy in unstable angina/NSTEMI patients, only some of whom underwent interventions. These antagonists are a class I recommendation in patients in whom catheterization and PCI are planned. Intermediate- and high-risk patients appear to respond favorably to glycoprotein IIb/IIIa inhibitors. [87] They include patients with ST-segment depression, elevated risk scores, elevated serum troponin levels, [88]and/or diabetes mellitus. Currently, IIb/IIIb antagonists in combination with aspirin are considered standard antiplatelet therapy for patients at high risk for unstable angina.

death in patients with unstable angina who were treated with aspirin plus heparin, compared with patients who were treated with aspirin alone. [89] The FUTURA/OASIS-8 randomized trial found that low-dose unfractionated heparin, 50 U/kg (regardless of use of glycoprotein IIb/IIIa inhibitors), compared with standard-dose unfractionated heparin, 85 U/kg (60 U/kg with Gp IIb/IIIa inhibitors), did not reduce major peri-PCI bleeding and vascular access-site complications. [90] Low–molecular-weight heparin LMWHs might be superior to unfractionated heparin in reducing cardiovascular outcomes, with a safety profile similar to that of heparin in patients receiving medical care. Conflicting results emerged from 9 randomized trials directly comparing LMWH with unfractionated heparin. Two trials evaluated dalteparin, another evaluated nadroparin, and 6 evaluated enoxaparin. [91,92] Trials with dalteparin and nadroparin reported similar rates of nonfatal myocardial infarction or death compared with heparin, whereas 5 of 6 trials of enoxaparin found point estimates for death or nonfatal myocardial infarction that favored enoxaparin over heparin. The benefit of enoxaparin appeared to be driven largely by a reduction in nonfatal myocardial infarction, especially in the cohort of patients who had not received any open-label anticoagulant therapy before randomization. In addition, a systematic review comparing LMWH with unfractionated heparin found no significant difference in benefits between the 2 drugs. Aside from the possible medical benefits of using LMWH in place of unfractionated heparin, advantages of LMWH include ease of administration, absence of need for anticoagulation monitoring, and potential for overall cost savings. Although 3 LMWHs are approved for use in the United States, only enoxaparin is currently approved for use in unstable angina. Lev et al found that the combination of eptifibatide with enoxaparin appears to have a more potent antithrombotic effect than that of eptifibatide and unfractionated heparin. [93] The role of LMWHs in patients for whom PCI is scheduled is relatively ill defined. However, it is likely to be at least equivalent to that of heparin. It appears reasonable to minimize the risk of excessive anticoagulation during PCI by avoiding crossover of anticoagulants (ie, maintain consistent anticoagulant therapy from the pre-PCI phase throughout the procedure itself). Additional experience with regard to the safety and efficacy of the concomitant administration of LMWHs with Gp IIb/IIIa antagonists and fibrinolytic agents is currently being acquired. Adding apixaban (5 mg twice daily) to antiplatelet therapy in high-risk patients after ACS may increase the number of major bleeding events without significantly reducing recurrent ischemic events. [94]

Factor Xa inhibitors Use of the oral Xa inhibitor rivaroxaban in patients with ACS was investigated in the ATLAS ACS 2-TIMI 51 trial. [95, 96] Cutting the rivaroxaban dosage from 5 mg twice daily to 2.5 mg twice daily reduced deaths and bleeding after ACS. Mortality from recurrent events was significantly lower with the 2.5-mg dose (30.6% vs 43.8%), as was the death rate from new MI (8.8% vs 17.2%). The risk of fatal bleeding was 61% lower with the 2.5-mg dose, and rates of TIMI bleeding requiring medical attention were significantly lower (12.9% vs 16.2%). Another factor Xda inhibitor, fondaparinux (Arixtra), has been studied for use in patients with STEMI who do not undergo PCI. [97] In the Fifth Organization to Assess Strategies in Ischemic Syndromes (OASIS-5) trial, fondaparinux reduced major bleeding and improved net clinical outcome compared with enoxaparin in patients receiving GP IIb/IIIa inhibitors or thienopyridines for ACS. [98]Fondaparinux is not currently FDA approved for use in ACS. Thrombolysis Prehospital thrombolysis allows eligible patients to receive thrombolysis 30-60 minutes sooner than if treatment were given in the ED; however, prehospital thrombolysis is still under investigation and has not become a trend, as a result of unproven benefit and an increase in the availability of PCI in many medical centers as an alternative to thrombolysis for STEMI. The Remodeling With Erythropoietin After Large Myocardial Infarction (REVEAL) trial evaluated the safety and efficacy of a single intravenous bolus of epoetin alfa in patients with STEMI who had successful reperfusion with primary or rescue PCI. [99] A single intravenous bolus of epoetin alfa within 4 hours of PCI did not reduce infarct size and was associated with higher rates of adverse cardiovascular events. Although PCI is the preferred treatment for STEMI, the distance to primary PCI centers and the inherent time delay in delivering primary PCI limits widespread use of this treatment. Prehospital electrocardiographic (ECG) diagnosis and direct referral for primary PCI enables patients with STEMI living far from a PCI center to achieve a system delay comparable to patients who are closer to a PCI center. [100]